Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8]([CH3:10])=O.C(S)[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[S:8][CH2:10][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: SCCc1ccccc1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(SCCc2ccccc2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-ylamine, phenethylmercaptan and DBU in THF. ES-MS m/e (%): 378 (M{81Br}+H+, 100), 376 (M {79Br}+H+, 99).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:32]=[CH:33][N:34]=3)[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][CH2:21][CH:20]([NH:24]C(=O)OC(C)(C)C)[CH2:19]3)[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>ClCCl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[NH2:24][CH:20]1[CH2:21][CH2:22][CH2:23][N:18]([C:16]2[CH:17]=[C:12]([NH:11][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[C:8]([O:9][CH3:10])[N:7]=3)[C:13]3[N:14]([CH:32]=[CH:33][N:34]=3)[N:15]=2)[CH2:19]1
Reactant: COc1ccc(Nc2cc(N3CCCC(NC(=O)OC(C)(C)C)C3)nn3ccnc23)nc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(Nc2cc(N3CCCC(N)C3)nn3ccnc23)nc1OC
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of tert-butyl 1-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)piperidin-3-ylcarbamate (300 mg, 0.64 mmol) and TFA (5 mL) in dichloromethane (5 mL) was stirred at 25° C. for 6 h. The residue was concentrated to give the crude 6-(3-aminopiperidin-1-yl)-N-(5,6-dimethoxypyridin-2-yl)imidazo[1,2-b]pyridazin-8-amine trifluoroacetate salt (350 mg, crude) as a brown liquid that was used directly without further purification. LC-MS: 370 [M+1]+, tR=1.09 min
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[N:15]1([CH2:21][CH2:22][OH:23])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>O1CCCC1>[OH:23][CH2:22][CH2:21][N:15]1[CH2:20][CH2:19][N:18]([C:2]2[CH:11]=[C:10]([CH2:12][CH2:13][CH3:14])[C:5]([C:6]([NH:8][CH3:9])=[O:7])=[CH:4][N:3]=2)[CH2:17][CH2:16]1
Reactant: OCCN1CCNCC1
Reactant: CCCc1cc(Cl)ncc1C(=O)NC
Solvent: C1CCOC1
Product: CCCc1cc(N2CCN(CCO)CC2)ncc1C(=O)NC
Temperature: 100 °C
Reaction time: 18 h
Yield: 0.1 %

Procedure:
6-Chloro-N-methyl-4-propylnicotinamide (123 mg, 0.578 mol) was dissolved in tetrahydrofuran (2 mL), added 1-piperazineethanol (355 μL, 2.89 mol) at room temperature, and stirred at 100° C. for 18 hours. The reaction solution was purified by silica-gel column chromatography (chloroform/methanol). The title compound (177 mg (yield >99%)) was obtained as a yellow crystal.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Br[C:9]1[CH:14]=[C:13]([Cl:15])[C:12]([N:16]2[CH:26]=[C:19]3[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]3=[N:17]2)=[C:11]([Cl:27])[CH:10]=1.C(Cl)(Cl)Cl>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:15][C:13]1[CH:14]=[C:9]([CH:1]=[CH2:2])[CH:10]=[C:11]([Cl:27])[C:12]=1[N:16]1[CH:26]=[C:19]2[CH:20]=[N+:21]([O-:25])[CH:22]=[C:23]([F:24])[C:18]2=[N:17]1
Reactant: CCN(CC)CC
Reactant: [O-][n+]1cc(F)c2nn(-c3c(Cl)cc(Br)cc3Cl)cc2c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: CCCO
Product: C=Cc1cc(Cl)c(-n2cc3c[n+]([O-])cc(F)c3n2)c(Cl)c1
Temperature: 25 °C
Yield: 61.7 %

Procedure:
Triethylamine (3.5 mL, 25 mmol) was added to a mixture of 2-(4-bromo-2,6-dichlorophenyl)-7-fluoro-2H-pyrazolo[4,3-c]pyridine 5 oxide (1.88 g, 5.0 mmol), potassium vinyl trifluoroborate (1.0 g, 7.5 mmol) and Pd(dppf)Cl2.CHCl3 (408 mg, 0.5 mmol) in propan-1-ol (50 mL) and the reaction mixture was heated at 100° C. for 1.5 hours. The resultant mixture was allowed to cool to room temperature before being partitioned between ethyl acetate and saturated aqueous sodium hydrogen carbonate solution. The layers were separated and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (4-5% methanol in DCM) to afford the title compound as a beige solid (1.0 g, 62% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.00 (d, J=2.6 Hz, 1H), 8.89 (d, J=1.4 Hz, 1H), 8.35 (dd, J=6.3, 1.5 Hz, 1H), 7.97 (s, 2H), 6.85 (dd, J=17.6, 11.0 Hz, 1H), 6.24 (d, J=17.6 Hz, 1H), 5.60 (d, J=11.0 Hz, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:3][CH2:2]1.Cl[CH2:17][C:18]([CH3:30])([CH3:29])[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].ClCC(C)(C)C(Cl)=O.C(O)C1C=CC=CC=1.C(N(C(C)C)C(C)C)C.[I-].[Na+]>CN(C)C=O>[C:11]([O:10][C:9](=[O:15])[NH:8][CH2:7][CH:4]1[CH2:5][CH2:6][N:1]([CH2:30][C:18]([C:19]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])([CH3:17])[CH3:29])[CH2:2][CH2:3]1)([CH3:12])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: CC(C)(CCl)C(=O)OCc1ccccc1
Agent: CC(C)(CCl)C(=O)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: OCc1ccccc1
Product: CC(C)(C)OC(=O)NCC1CCN(CC(C)(C)C(=O)OCc2ccccc2)CC1
Temperature: 120 °C
Reaction time: 14 h
Yield: 1 %

Procedure:
To a stirred solution of tert-butyl (piperidin-4-ylmethyl)carbamate (38.8 g, 181 mmol) in N,N-dimethylformamide (100 mL) was added benzyl 3-chloropivalate (14.2 g, 124 mmol, prepared from 3-chloropivaloyl chloride (25.6 g, 165 mmol) and benzyl alcohol (19.6 g, 181 mmol), ethyldiisopropylamine (64.0 g, 495 mmol) and sodium iodide (27.1 g, 181 mmol) at ambient temperature. The resulting mixture was stirred at 120° C. for 14 h. The volatile components were removed by evaporation and the resulting residue was chromatographed on a column of silica gel eluting with hexane/ethyl acetate (1:1) to give 640 mg (1%) of the title compound as a pale yellow oil.
Reaction SMILES: [N+:1]([C:4]([N+]([O-])=O)([N+:9]([O-:11])=[O:10])[CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2]>CO>[N+:1]([CH:4]([N+:9]([O-:11])=[O:10])[CH2:5][CH2:6][CH2:7][OH:8])([O-:3])=[O:2]
Reactant: O=[N+]([O-])C(CCCO)([N+](=O)[O-])[N+](=O)[O-]
Solvent: CO
Product: O=[N+]([O-])C(CCCO)[N+](=O)[O-]

Procedure:
This alcohol was prepared by stirring 4,4,4-trinitro-1-butanol (554 g, 2.65 mol) in methanol (6 l) with KI (1426 g, 8.6 mol) for 6 days at room temperature. The precipitated potassium salt was filtered, suspended in water (4 L), acidified with concentrated HCl (250 ml), and extracted into CH2Cl2 (6×500 ml). The extracts were washed with 10% NaHSO3 (1000 ml). The solution was dried over anhydrous MgSO4 and concentrated to give the product (220 g, 51%) as a yellow oil. The infrared spectrum had peaks at 3450, 2950, 1575, 1340, and 1070 cm-1.
Reaction SMILES: C([O:5][C:6](=[O:60])[CH2:7][N:8](C(OC(C)(C)C)=O)[CH2:9][CH2:10][NH:11][C:12](=[O:52])[CH2:13][CH:14]([C:22](=[O:51])[NH:23][C@H:24]([C:31](=[O:50])[NH:32][C@@H:33]([CH2:43][CH:44]1[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]1)[C@@H:34]([OH:42])[CH2:35][C@@H:36]([CH:39]([CH3:41])[CH3:40])[CH:37]=[CH2:38])[CH2:25][C:26]1[N:27]=[CH:28][NH:29][CH:30]=1)[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(C)(C)C.[ClH:61].C(O)(=O)C>C(O)(=O)C>[ClH:61].[ClH:61].[CH:44]1([CH2:43][C@H:33]([NH:32][C:31]([C@@H:24]([NH:23][C:22]([CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:13][C:12]([NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]([OH:60])=[O:5])=[O:52])=[O:51])[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[O:50])[C@@H:34]([OH:42])[CH2:35][C@@H:36]([CH:39]([CH3:40])[CH3:41])[CH:37]=[CH2:38])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCN(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)Cc1ccccc1)C(C)C
Agent: Cl
Solvent: CC(=O)O
Product: C=C[C@@H](C[C@H](O)[C@H](CC1CCCCC1)NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)C(CC(=O)NCCNCC(=O)O)Cc1ccccc1)C(C)C

Procedure:
100 mg (0.13 mmol) of t-butoxycarbonyl [2-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]- 2 imidazol-4-ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]glycine t-butyl ester were dissolved in 2 ml of acetic acid and stirred at room temperature for 3 hours with 4 ml of 1N hydrochloric acid/acetic acid. Thereafter, the reaction mixture was evaporated under reduced pressure and the residue was digested with ether and filtered off, to give N-[2-[(RS)-3-[[(S)-1-[[(1S,2S,4S)-1-(cyclohexylmethyl)-2-hydroxy-4-isopropyl-5-hexenyl]carbamoyl]-2-imidazol 4-ylethyl]carbamoyl]-4-phenylbutyramido]ethyl]glycine dihydro chloride as a powder, MS: 681 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8](=O)[CH2:9][C@H:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH:25]=3)=[CH:20][CH:19]=2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[CH:5]=[CH:4][N:3]=1.Cl.[NH2:33][OH:34].C(=O)([O-])O.[Na+]>>[OH:34]/[N:33]=[C:8](/[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=1)\[CH2:9][C@H:10]([C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH2:29][CH2:28][NH:27][C:26](=[O:30])[CH:25]=2)=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH3:17]
Reactant: Cc1cc(C(=O)C[C@H](c2ccc(C3=CC(=O)NCC3)cc2)c2ccccc2C)ccn1
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cc(/C(C[C@H](c2ccc(C3=CC(=O)NCC3)cc2)c2ccccc2C)=N/O)ccn1

Procedure:
In analogy to example 132, step 6, from (R)-4-(4-(3-(2-methylpyridin-4-yl)-3-oxo-1-o-tolylpropyl)phenyl)-5,6-dihydropyridin-2(1H)-one and hydroxylamine hydrochloride in the presence of sodium hydrogencarbonate was prepared the title compound as a light yellow foam, MS (ESI+): m/z=426.1 ([M+H]+).
Reaction SMILES: [C:1]([O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:17])=[O:16])(=[O:8])=[O:7])(=[O:3])[CH3:2].C(N(CC)CC)C.Cl[C:27]([O:29][CH2:30][CH3:31])=[O:28]>ClCCl>[C:1]([O:4][N:5]([S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:16])=[O:17])(=[O:8])=[O:7])[C:27](=[O:28])[O:29][CH2:30][CH3:31])(=[O:3])[CH3:2].[C:1]([O:4][NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([CH3:18])(=[O:16])=[O:17])(=[O:8])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)Cl
Agent: CC(=O)ONS(=O)(=O)c1ccccc1S(C)(=O)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N(OC(C)=O)S(=O)(=O)c1ccccc1S(C)(=O)=O
Reaction time: 3 h

Procedure:
Ethyl (acetyloxy){[2-(methylsulfonyl)phenyl]sulfonyl}-carbamate (48) is prepared according to Scheme 3. To a stirred solution of N-(acetyloxy)-2-(methylsulfonyl)benzene-sulfonamide (0.085 g, 0.29 mmol) in dichloromethane (5 ml) is added triethylamine (50 μl, 0.35 mmol) and ethyl chloroformate (30 μl, 0.32 mmol). The reaction mixture is stirred for 3 hours before quenching with water (1 ml). The organics are separated and dried over sodium sulfate, filtered and concentrated in vacuo to yield the title compound which is purified by silica column chromatography, eluting with 40% ethyl acetate: heptane. (60 mg, 57%), 1H NMR (250 MHz, CHLOROFORM-d) δ ppm 8.47-8.58 (1H, m), 8.34-8.45 (1H, m), 7.82-7.94 (2H, m), 4.25 (2H, q, 7.2 Hz), 3.42 (3H, s), 2.31 (3H, s), 1.25 (3H, t, 7.2 Hz).
Reaction SMILES: [CH3:1][C:2]([N:5]1[C:10](=O)[CH2:9][O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)([CH3:4])[CH3:3].B.CSC>>[CH3:4][C:2]([N:5]1[CH2:10][CH2:9][O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6]1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)N1CC(c2ccccc2)OCC1=O
Agent: B
Solvent: CSC
Product: CC(C)(C)N1CCOC(c2ccccc2)C1

Procedure:
4-[1,1-Dimethylethyl]-2-phenylmorpholine was prepared from 4-[1,1-dimethylethyl]-5-oxo-2-phenylmorpholine and borane-methyl sulphide by an analogous procedure to that described in Example 1. After purification by column chromatography on silica using 0->8% methanol in dichloromethane as eluant, the resultant oil was converted to its hydrochloride salt, m.p. 208°-210° C., (ethyl acetate).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:20][CH:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1.O.NN>C(O)C>[NH2:3][CH2:12][CH2:13][CH2:14][C:15]#[C:16][C:17]1[CH:18]=[C:19]([CH:34]=[C:35]([O:37][CH3:38])[CH:36]=1)[O:20][CH:21]1[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:32])([CH3:33])[CH3:31])=[O:28])[CH2:25][CH2:26]1
Reactant: COc1cc(C#CCCCN2C(=O)c3ccccc3C2=O)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: COc1cc(C#CCCCN)cc(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Temperature: 80 °C
Reaction time: 2.5 h

Procedure:
tert-Butyl 4-(3-(5-(1,3-dioxoisoindolin-2-yl)pent-1-ynyl)-5-methoxyphenoxy)piperidine-1-carboxylate (0.500 g, 0.97 mmol) and hydrazine monohydrate (0.094 mL, 1.94 mmol) were taken up into ethanol (5 mL) and the resulting mixture was stirred at 80° C. for 2.5 hours. The resulting mixture was filtered and the solvent was removed in vacuo to yield tert-butyl 4-(3-(5-aminopent-1-ynyl)-5-methoxyphenoxy)piperidine-1-carboxylate. MH+ 388.2
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([O:17]CC)=[O:16])=[O:8])=[O:4].O.[OH-].[Li+]>C(O)C>[CH3:1][O:2][C:3]([NH:5][C@@H:6]([CH:20]([CH3:22])[CH3:21])[C:7]([N:9]1[C@@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]1[C:15]([OH:17])=[O:16])=[O:8])=[O:4]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(=O)N[C@H](C(=O)N1[C@@H](C)CC[C@H]1C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 98.1 %

Procedure:
To an ice-cold stirred solution of ethyl (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylate (5.6 g, 17.8 mmol) in ethanol (18 ml) is added a solution of lithium hydroxide monohydrate (17.8 mL of 1.7 M, 30.3 mmol). The reaction mixture is stirred for 5 hours at rt. The reaction mixture is concentrated, diluted with water, washed with ether. The aqueous solution is acidified with aq. 1N HCl, extracted with CH2Cl2. The combined extracts are washed with brine, dried (Na2SO4), concentrated to afford (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylic acid (5 g, 94%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:26])=[O:25])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16](O)=[O:17].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[F:13][C:14]1[C:22]([NH:23][S:24]([CH2:27][CH2:28][CH3:29])(=[O:25])=[O:26])=[CH:21][CH:20]=[C:19]([F:30])[C:15]=1[C:16]([NH:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][OH:12])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1)=[O:17]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1F
Reactant: Nc1cnc2[nH]nc(CO)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(CO)c3c2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
(5-Amino-1H-pyrazolo[3,4-b]pyridin-3-yl)methanol (0.040 g, 0.675 mmol), 2,6-difluoro-3-(propylsulfonamido)benzoic acid (0.071 g, 0.256 mmol), EDCI (0.049 g, 0.256 mmol) and HOBt (0.033 g, 0.244 mmol) were dissolved in DMF (0.53 mL) and stirred at room temperature for 16 hours. The reaction mixture was directly purified by reverse phase HPLC to give 2,6-difluoro-N-(3-(hydroxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide (0.051 g, 49%) as a solid. 1H NMR (400 MHz, d6-DMSO) δ 13.37 (s, 1H), 11.05 (s, 1H), 9.93 (br s, 1H), 8.74 (d, 1H), 8.58 (d, 1H), 7.58-7.52 (m, 1H), 7.26 (t, 1H), 5.36 (t, 1H), 4.78 (d, 2H), 3.12 (m, 2H), 1.77 (m, 2H), 1.00 (t, 3H); m/z (ES-MS) 426.1 (98.0%) [M+1].
Reaction SMILES: [CH2:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH2:3][CH2:2]1.C(NC(C)C)(C)C.[Br:18]N1C(=O)CCC1=O.S(=O)(=O)(O)O>ClCCl>[Br:18][C:6]1[CH:7]=[CH:8][C:9]2[CH2:1][CH2:2][CH2:3][C:4]=2[C:5]=1[OH:10]
Reactant: Oc1cccc2c1CCC2
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: Oc1c(Br)ccc2c1CCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
To a solution of indan-4-ol (24.2 g) in dichloromethane (200 mL) was added diisopropylamine (2.55 mL). To the solution was added N-bromosuccinimide (32.07 g) in small portions under ice-cooling, and the mixture was stirred at room temperature overnight. Diluted sulphuric acid (pH1, 200 mL) was added to the reaction mixture, and the mixture was separated. The organic layer was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=3/1−1/1) to give the title compound (31.1 g).
Reaction SMILES: [O:1]([CH2:8][C:9]1[NH:10][CH:11]=[C:12]([C:14]2[CH:27]=[CH:26][C:17]([O:18][C:19]3[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=3)=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:32]=[C:33]=[O:34])[CH2:29][CH2:30][CH3:31].C(#N)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>O1CCCC1>[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41].[CH2:28]([NH:32][C:33]([NH:23][C:22]1[CH:21]=[CH:20][C:19]([O:18][C:17]2[CH:26]=[CH:27][C:14]([C:12]3[N:13]=[C:9]([CH2:8][O:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[NH:10][CH:11]=3)=[CH:15][CH:16]=2)=[CH:25][CH:24]=1)=[O:34])[CH2:29][CH2:30][CH3:31]
Reactant: CCCCN=C=O
Reactant: Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CCCCNC(=O)Nc1ccc(Oc2ccc(-c3c[nH]c(COc4ccccc4)n3)cc2)cc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A mixture containing 4-{4-[2-(phenoxymethyl)-1H-imidazol-4-yl]phenoxy}aniline (0.2 g, 0.56 mmol) and butylisocyanate (0.094 g, 0.84 mmol) in 3 ml of tetrahydrofuran is stirred for a day at ambient temperature. Aminomethylpolystyrene resin EHL (Novabiochem, 200-400 mesh, 2% DVB) (200 mg, approximately 1 mmol) is added and stirring is maintained for three hours. After filtration on frit then concentration of the filtrate in a rotavapor, the residue obtained is passed through an RP18 silica column (eluent: acetonitrile-trifluoroacetic acid 0.1N: 5-5); a beige-coloured powder is obtained with a yield of 43%.
Reaction SMILES: [CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19](I)=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29](B1OC(C)(C)C(C)(C)O1)([CH3:31])=[CH2:30].C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.O>[CH:1]1([NH:7][C:8]([NH:10][C:11]2[N:12]=[C:13]3[C:19]([C:29]([CH3:31])=[CH2:30])=[CH:18][N:17]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:14]3=[N:15][CH:16]=2)=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1cc(I)c2nc(NC(=O)NC3CCCCC3)cnc21
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)c1cn(COCC[Si](C)(C)C)c2ncc(NC(=O)NC3CCCCC3)nc12
Temperature: 25 °C
Yield: 52.4 %

Procedure:
1-Cyclohexyl-3-[7-iodo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea (300 mg, 0.582 mmol), 2-isopropenyl-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane (0.33 mL, 1.75 mmol), Cs2CO3 (948 mg, 2.91 mmol), and Pd(dppf)Cl2 DCM complex (47 mg, 0.058 mmol) were dissolved in THF (2.3 mL) and H2O (0.7 mL). The mixture was irradiated at 100° C. using microwave for 1 hr, cooled to RT, partitioned between EtOAc and brine. The organic layer was dried (MgSO4), filtered, concentrated, and purified by SiO2 chromatography (24 g SiO2, DCM/MeOH 0 to 5% MeOH) to give 131 mg of impure 1-cyclohexyl-3-[7-isopropenyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as an off-white solid (52% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C@H:18]1[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20][CH2:19]1.[Cl:33][C:34]1[CH:39]=[C:38](B2OC(C)(C)C(C)(C)O2)[CH:37]=[C:36]([Cl:49])[C:35]=1[OH:50]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C@H:18]2[CH2:23][CH2:22][C@H:21]([N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:20][CH2:19]2)=[CH:3][C:2]([C:38]2[CH:39]=[C:34]([Cl:33])[C:35]([OH:50])=[C:36]([Cl:49])[CH:37]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(Br)cc23)CC1
Product: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](Nc2c(C(=O)C3CC3)cnc3ccc(-c4cc(Cl)c(O)c(Cl)c4)cc23)CC1

Procedure:
Following general procedure F, tert-butyl {trans-4-[6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino]cyclohexyl}(methyl)carbamate (61 mg, 0.120 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (52 mg, 0.180 mmol) to afford the crude product (65 mg) as a brown oil: ESI MS m/z 584 [C31H35Cl2N3O4+H]+.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:11]1([CH3:21])[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[N:1]1([CH2:7][CH2:8][CH2:9][O:10][S:17]([C:14]2[CH:15]=[CH:16][C:11]([CH3:21])=[CH:12][CH:13]=2)(=[O:19])=[O:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCCCN1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCN2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.6 %

Procedure:
To a mixture of 0.286 g (2 mmole) of 3-piperidin-1-yl-propan-1-ol, and 2 mL of pyridine was added 0.001 g of 4-dimethylaminopyridine and 0.381 g (2 mmole) of p-toluenesulphonyl chloride. The mixture was stirred at ambient temperature overnight and then concentrated under reduced pressure. The residue was taken up in 20 mL of dichloromethane and washed once with 10 mL of saturated sodium bicarbonate, twice with 10 mL of water, and then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give 0.384 g of toluene-4-sulfonic acid 3-piperidin-1-yl-propyl ester as a pink solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:9])=[N:4][CH:5]=[CH:6][C:7]=1[Cl:8].Cl[CH2:11][C:12](Cl)=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:8][C:7]1[C:2]2[NH:1][C:12](=[O:13])[CH2:11][O:9][C:3]=2[N:4]=[CH:5][CH:6]=1
Reactant: O=C(Cl)CCl
Reactant: Nc1c(Cl)ccnc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1COc2nccc(Cl)c2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
3-amino-4-chloro-pyridin-2-ol (650 mg, 4.49 mmol) was dissolved in anhydrous N,N-dimethyl formamide (22 ml) under nitrogen atmosphere, and chloroacetyl chloride solution (0.394 ml, 4.94 mmol) was added thereto dropwise at room temperature and stirred for 30 minutes. Potassium carbonate (1.55 g, 11.24 mmol) was added thereto dropwise at room temperature, and the reaction mixture was heated to 1000 and stirred for 18 hours. The reaction mixture was cooled to room temperature and water was added to quench the reaction, and the organic layer was extracted with ethyl acetate. The combined organic layer was washed with water and saturated saline solution, dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was recrystallized from dichloromethane and diisopropyl ether to obtain white solid (608 mg, 73%).
Reaction SMILES: [C:1]([CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:12]([O-])=O)[CH:9]=2)[CH2:4]1)#[N:2]>CO.ClCCl.[Pd]>[NH2:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[CH2:4][CH:3]([C:1]#[N:2])[CH2:11]2
Reactant: N#CC1Cc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: N#CC1Cc2ccc(N)cc2C1
Yield: 103.9 %

Procedure:
A solution of 2-cyano-5-nitroindane (11.90 g, 63.3 mmol) in methanol/dichloromethane=1:1 (200 ml) was hydrogenated over 10% palladium on charcoal (1.2 g) at 30 p.s.i and 20° C. for 5 hours. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give 5-amino-2-cyanoindane (10.4 g) which was used directly for the next reaction. A portion, recrystallised from ethanol, formed pinkish needles, m.p. 73°-76° C.