Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:16](=[O:17])[C:6]2[CH:7]=[C:8]([C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)[S:9][C:5]=2[CH2:4][CH2:3]1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([Mg]Br)=[CH:22][CH:21]=1.CCOCC>O1CCCC1.[NH4+].[Cl-]>[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:16]2([OH:17])[C:6]3[CH:7]=[C:8]([C:10]4[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=4)[S:9][C:5]=3[CH2:4][CH2:3][C:2]2([CH3:18])[CH3:1])=[CH:22][CH:21]=1
Reactant: Clc1ccc([Mg]Br)cc1
Reactant: CC1(C)CCc2sc(-c3ccncc3)cc2C1=O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC1(C)CCc2sc(-c3ccncc3)cc2C1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 97 %

Procedure:
In a 100 mL round bottomed flask was placed 5,5-dimethyl-2-pyridin-4-yl-6,7-dihydro-1-benzothiophen-4(5H)-one (380 mg, 1.5 mmol) and then dissolved in tetrahydrofuran (30 mL). To the mixture was added 1 M of 4-chlorophenyl magnesiumbromide in ether (3.5 mL, 3.5 mmol) and then stirred for 3 h at rt. To the mixture was added 1 M of 4-chlorophenyl magnesiumbromide in ether (2.5 mL, 2.5 mmol) and then stirred for 16 h at rt. The mixture was stirred for 10 h at 70° C. The mixture was allowed to cool to rt and then 1 M of 4-chlorophenyl magnesiumbromide in ether (5 mL, 5 mmol) was added and the mixture was stirred for 16 h at rt. The mixture was diluted with saturated aqueous solution of NH4Cl (50 mL), which was extracted with EtOAc (50 mL×2). The combined organic phase was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residue was purified by pre-packed silica gel (24 g) column chromatography eluted with a 30% to 100% EtOAc/hexane to obtain title compound (530 mg; 97%) as a colorless foam. LCMS: (FA) ES+ 370, 372; 1H NMR (400 MHz, d6-DMSO) δ ppm 8.48 (dd, 2H), 7.45 (dd, 2H), 7.33 (d, 2H), 7.23-7.25 (m, 2H), 5.55 (s, 1H), 2.87-2.91 (m, 2H), 1.84-1.90 (m, 1H), 1.57-1.63 (m, 1H, 0.95 (s, 3H), 0.62 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[CH3:15][O:16][C:17]([C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[C:21]([N+:27]([O-:29])=[O:28])[CH:20]=1)=[O:18].[BH4-].[Na+]>CO>[C:9]1([CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([C:17]([O:16][CH3:15])=[O:18])=[CH:20][C:21]=3[N+:27]([O-:29])=[O:28])[CH2:3][CH2:4]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)c1ccc(C=O)c([N+](=O)[O-])c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(CNC2CCN(Cc3ccccc3)CC2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a solution of 41.0 g (0.215 mol) of 4-amino-1-(phenylmethyl)-piperidine and 45.0 g (0.215 mol) of 4-(methoxycarbonyl)-2-nitrobenzaldehyde in 1 l methanol were added in batches, at room temperature, 8.3 g (0.22 mol) of sodium borohydride and the mixture was then stirred for 30 minutes at the same temperature. The mixture was stirred into 1 l of ice water and thoroughly extracted with tert. butyl-methylether. The combined extracts were dried over sodium sulphate and evaporated down in vacuo, the residue was dissolved in as little methanol as possible and converted into the hydrochloride by treatment with methanolic hydrogen chloride solution. The crystalline salt was suction filtered, washed with methanol and diethylether, then taken up in water and made alkaline with saturated aqueous potassium carbonate solution. The mixture obtained was extracted thoroughly with ethyl acetate, the combined ethyl acetate extracts were dried over sodium sulphate and evaporated down. 58.2 g (70.6% of theory) of a brownish-yellow oil were obtained, which was further processed without any more purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH2:13][CH2:12][CH2:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.[CH3:14][C:15]1[O:20][C:18](=[O:19])[CH2:17][CH:16]=1>C1(C)C=CC=CC=1>[CH2:16]([C:17]1[C:18](=[O:19])[NH:10][CH2:11][CH2:12][CH2:13][C:9]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)[C:15]([CH3:14])=[O:20]
Reactant: COc1cccc(C2=NCCC2)c1
Reactant: CC1=CCC(=O)O1
Solvent: Cc1ccccc1
Product: COc1cccc(C2=C(CC(C)=O)C(=O)NCCC2)c1
Reaction time: 8 h

Procedure:
The starting material is prepared as follows: The solution of 70 g of 2-(3-methoxyphenyl)-1-pyrroline [J. Org. Chem. 23, 1278, 1281 (1958)] and 43.2 g of α-angelicalactone in 600 ml of toluene is refluxed overnight. A second portion of 43.2 g of α-angelicalactone is added, the mixture is again refluxed overnight, cooled and evaporated. The residue is crystallized from 50 ml of ethyl acetate, to yield the 3-acetonyl-4-(3-methoxyphenyl)-1,5,6,7-tetrahydro-2H-azepinone, melting at 140°-142°.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[O:15][CH2:14][CH2:13][O:12]1
Reactant: OCCO
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: O=C1Nc2ccc(Br)cc2C12OCCO2
Yield: 87.4 %

Procedure:
A magnetically stirred solution of 5-bromoindoline-2,3-dione (226 g, 1.0 mol, 1 eq.), ethylene glycol (186 g, 3.0 mol, 3 eq.), p-TSA (30 g, 0.16 mol, 16 mol %) and toluene (1500 mL) was refluxed overnight using a Dean-Stark apparatus. After total consumption of 5-bromoindoline-2,3-dione, EtOAc (1500 mL) and water (1000 mL) were added to remove excess of diol. The aqueous layer was extracted twice with EtOAc (500 mL). The collected organic layers were collected, dried over Na2SO4, filtered and concentrated under reduced pressure. The yellowish solid was washed with diethyl ether to give the desired compound as a pale yellow solid (236 g, 87%). 1H NMR (400 MHz, DMSO-d6): δH 10.56 (s, 1H), 7.31-7.33 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 4.27-4.35 (m, 4H), 2.35 (s, 3H), 2.18 (s, 3H). MS (ESI) m/e [M+1]+ 270, 272.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH2:23])=[CH:17][CH:16]=1.[BH4-].[Na+].Cl>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:24])[F:25])=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)c1ccc(CNCCc2ccc(C(F)(F)F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 75.4 %

Procedure:
0.67 ml of 4-tert-butylbenzaldehyde (3.99 mmol) and 600 mg 2-(4-trifluoromethyl-phenyl)-ethylamine (2.66 mmol) were dissolved in 9 ml methanol at rt, and after stirring for 30 min at rt, were refluxed for 2.5 h. After cooling down to rt, 151 mg (3.99 mmol) sodium borohydride were added and after stirring for 5 min at rt, the reaction mixture was then refluxed for 3 h. After cooling down to rt, the reaction mixture was treated with 1 ml 1 N HCl and concentrated in vacuo. The residue was diluted with water/EtOAc. After separation of the organic phase, the aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried with magnesium sulfate, filtered off and concentrated in vacuo. The residue was purified by column chromatography (40 g silica gel; EtOAc/heptane 2:1) to give 673 mg dark red oil (75%). MS (ISP) 336.2 (M+H)+.
Reaction SMILES: [CH2:1]([CH:4]1[CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:14])[CH:2]=[CH2:3].C(OC)(OC)OC.[CH:22](O)([OH:24])[CH3:23]>ClCCl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:22]1[O:24][C:5]2([CH:4]([CH2:1][CH:2]=[CH2:3])[CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[O:14][CH2:23]1
Reactant: C=CCC1Cc2ccccc2CC1=O
Reactant: CC(O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: COC(OC)OC
Solvent: ClCCl
Product: C=CCC1Cc2ccccc2CC12OCCO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 109 %

Procedure:
A mixture of 3-(2-propenyl)-2-tetralone (25.9 g, 139 mmol), trimethyl orthoformate (61.3 ml, 554 mmol), ethanediol (57.5 ml, 1.03 mol), p-toluenesulfonic acid monohydrate (0.27 mg, 1.4 mmol) in dichloromethane (650 ml) was stirred at room temperature, under argon for 2 h. Resulting mixture was partitioned between saturated aqueous sodium bicarbonate (1000 ml) and dichloromethane (3×500 ml). The combined organic extracts were washed with brine (500 ml), dried (Na2SO4) and evaporated in vacuo to give a brown oil (34.9 g). Chromatography on silica using 0-10% ether-hexane gradient elution gave the title compound as a yellow oil (20.1 g, 63%).
Reaction SMILES: [OH-].[K+].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]#[C:12][Si](C)(C)C>O.CO>[C:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[O:4][CH3:3])#[CH:12]
Reactant: COc1ccccc1C#C[Si](C)(C)C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: C#Cc1ccccc1OC
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 123 %

Procedure:
Add a solution of potassium hydroxide (3.66 g, 65.2 mmol) in water (30 mL) dropwise over 30 minutes to a stirred solution of (2-methoxy-phenylethynyl)-trimethylsilane (13.2 g, 64.6 mmol) in methanol (275 mL) and stir at room temperature for 1.5 hours. Concentrate, add brine to residue, and extract with EtOAc. Dry organic layer over MgSO4 and concentrate to get 10.5 grams of a black oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-5% EtOAc/hexanes to afford the title compound (7.6 g, 89%).
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH:12][NH2:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2)[N:3]=1.[CH:16](OCC)(OCC)OCC>>[Cl:1][C:2]1[C:11]2[N:10]([CH:16]=[N:13][N:12]=2)[C:9]2[C:4]([N:3]=1)=[CH:5][C:6]([F:15])=[C:7]([F:14])[CH:8]=2
Reactant: CCOC(OCC)OCC
Reactant: NNc1nc2cc(F)c(F)cc2nc1Cl
Product: Fc1cc2nc(Cl)c3nncn3c2cc1F
Temperature: 25 °C

Procedure:
A mixture consisting of 5.99 g. (0.026 mole) of 2-chloro-6,7-difluoro-3-hydrazinoquinoxaline and 30 ml. (0.18 mole) of triethyl orthoformate was heated at 100° C. for a period of 24 hours to give a red-brown solid. The resulting slurry was then cooled to room temperature and filtered, and the recovered product subsequently washed with diethyl ether to ultimately afford 5.15 g. (82%) of pure 4-chloro-7,8-difluoro-[1,2,4]triazolo[4,3-a]quinoxaline, m.p. >210° C. (decomp.). Mass Spectrum: m/e, 242/240 (P+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][C:5]2([CH3:12])[CH3:11].N1C=CC=CC=1.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:19](=[O:21])[CH3:20])[CH2:6][C:5]2([CH3:12])[CH3:11]
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)CNc2ccc(Br)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CC(C)(C)c2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.5 %

Procedure:
To a solution of 5-bromo-3,3-dimethyl-2,3-dihydro-1H-indole (1.6 g, 7.1 mmol) in DCM (40 mL) and pyridine (1.1 mL, 14.2 mmol) was added acetic anhydride (1 mL, 11 mmol). The reaction was stirred at room temperature overnight, then solvent was removed in vacuo and the residue partitioned between water and saturated aqueous NH4Cl. The organic phase was separated, dried (MgSO4), filtered and concentrated to give the title compound (1.8 g), used without further purification. Analytical data were consistent with those reported in Preparation 61.
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([OH:26])=O)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.Cl.[CH2:29]([NH2:31])[CH3:30]>>[CH2:29]([NH:31][C:24]([C:22]1[N:23]=[C:17]2[CH:16]=[C:15]([NH:14][C:12]([C:11]3[N:10]([CH3:27])[N:9]=[CH:8][C:7]=3[C:5]([N:1]3[CH2:4][CH2:3][CH2:2]3)=[O:6])=[O:13])[CH:20]=[CH:19][N:18]2[N:21]=1)=[O:26])[CH3:30]
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Reactant: CCN
Agent: Cl
Product: CCNC(=O)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Yield: 36.3 %

Procedure:
The product was prepared in the same manner as described in example 62 using 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (130 mg, 264 μmol) and ethanamine hydrochloride (215 mg, 2.64 mmol) as starting materials. The reactions affords 7-{[4-(azetidine-1-carbonyl)-2-methyl-2H-pyrazole-3-carbonyl]-amino}-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid ethylamide (38 mg, 36.3%) as a white solid. mp: 217-229° C., MS: m/z=397.1 (M+H+)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:19]=1[C:18]1[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:21])([CH3:20])[C:12](=[O:22])[NH:11]3)[C:8](=[O:23])[O:7]2.[C:24](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[CH3:24][O:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:19]=1[C:18]1[C:9](=[C:10]3[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([CH3:21])([CH3:20])[C:12](=[O:22])[NH:11]3)[C:8](=[O:23])[O:7]2
Reactant: CC1(C)Nc2ccc3c(c2NC1=O)c(=O)oc1cccc(O)c13
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COc1cccc2oc(=O)c3c4c(ccc3c12)NC(C)(C)C(=O)N4
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.3 %

Procedure:
To a solution of phenol viii (200 mg, 0.65 mmol) in DMF (10 mL) was added cesium carbonate (419 mg, 1.29 mmol) and methyl iodide (88 μL, 1.42 mmol). The mixture was stirred at room temperature for 1 h and then poured into cold water (50 mL). The mixture was then extracted with EtOAc (5×50 mL). The combined extracts were washed with brine and dried (MgSO4). The solvent was removed under reduced pressure to provide the crude tetracyclic lactone ether ix (163 mg) as a yellow solid that was used in the next step without further purification. A small portion of the crude ix was purified by reverse phase preparative HPLC for characterization. 1H NMR (acetone-d6) δ 10.90 (br s, 1H), 8.59 (d, J=8.4, 1H), 7.34 (t, J=8.4 Hz, 1H), 7.21 (d, J=8.4, 1H), 6.98 (d, J=8.4, 1H), 6.90 (d, J=8.4 Hz, 1H), 5.93 (br s, 1H), 4.01 (s, 3H), 1.34 (s, 6H). Anal. Calcd for C18H16N2O4: C, 66.66; H, 4.97; N, 8.64. Found: C, 66.66; H, 4.79; N, 8.96.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([O:35][CH3:36])[C:24]([NH:27]C(=O)OC(C)(C)C)=[N:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:37])=[N:7]1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:38]=[C:39]([F:41])[CH:40]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:22]=[C:23]([O:35][CH3:36])[C:24]([NH2:27])=[N:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[C:8]([CH3:37])=[N:7]1
Reactant: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)cnc1NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc3[nH]cc(-c4c(C)nn(Cc5cc(F)cc(F)c5)c4C)c3c2)cnc1N
Yield: 12.2 %

Procedure:
Using similar reaction conditions as described in step-ii of example-7, tert-butyl (5-(3-(1-(3,5-difluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-3-methoxypyridin-2-yl)carbamate (100 mg, 0.178 mmol) was deprotected in TFA/DCM (2/5 ml) to afford 10 mg (9.8% yield) of the titled compound. 1H NMR (CD3OD, 400 MHz): δ 8.56 (s, 1H), 8.14-8.13 (d, 1H), 7.70-7.69 (d, 2H), 7.53 (s, 1H), 6.91-6.86 (td, 1H), 6.79-6.76 (d, 2H), 5.36 (s, 2H), 4.07 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H). MS: m/z=461.3 (M+1), HPLC: 95.61% in method B.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]([C@H:7]1[C@@H:12]2[O:13]S(=O)O[C@@H:11]2[CH:10]=[C:9]([C:17]([O:19][CH3:20])=[O:18])[CH2:8]1)=[CH2:6]>CN(C=O)C.CCOC(C)=O>[N:1]([C@@H:11]1[C@@H:12]([OH:13])[C@H:7]([CH:5]=[CH2:6])[CH2:8][C:9]([C:17]([O:19][CH3:20])=[O:18])=[CH:10]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: C=C[C@@H]1CC(C(=O)OC)=C[C@H]2OS(=O)O[C@@H]12
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=C[C@@H]1CC(C(=O)OC)=C[C@H](N=[N+]=[N-])[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium azide can be added to a solution of Example 17G in DMF. The reaction mixture can be stirred overnight at room temperature, diluted with EtOAc, washed with brine, dried (MgSO4), filtered and concentrated. The concentrate can be purified by flash column chromatography to afford the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:56]=[CH:55][C:6]([CH2:7][N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16]([O:17][C:18]4[CH:23]=[CH:22][C:21]([NH:24][C:25]([C:27]5[C:32](=[O:33])[N:31]([C:34]6[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=6)[N:30]=[CH:29][CH:28]=5)=[O:26])=[CH:20][C:19]=4[F:41])=[C:11]3[C:10]([CH:42]3[CH2:47][CH2:46][N:45](C(OC(C)(C)C)=O)[CH2:44][CH2:43]3)=[N:9]2)=[CH:5][CH:4]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:41][C:19]1[CH:20]=[C:21]([NH:24][C:25]([C:27]2[C:32](=[O:33])[N:31]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[N:30]=[CH:29][CH:28]=2)=[O:26])[CH:22]=[CH:23][C:18]=1[O:17][C:16]1[CH:15]=[CH:14][N:13]=[C:12]2[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:56][CH:55]=3)[N:9]=[C:10]([CH:42]3[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]3)[C:11]=12
Reactant: COc1ccc(Cn2nc(C3CCN(C(=O)OC(C)(C)C)CC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Cn2nc(C3CCNCC3)c3c(Oc4ccc(NC(=O)c5ccnn(-c6ccc(F)cc6)c5=O)cc4F)ccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.1 %

Procedure:
A round-bottomed flask was charged with tert-butyl 4-(1-(4-methoxybenzyl)-4-(2-fluoro-4-(1-(4-fluorophenyl)-6-oxo-1,6-dihydropyridazine-5-carboxamido)phenoxy)-1H-pyrazolo[3,4-b]pyridin-3-yl)piperidine-1-carboxylate (74.3 mg, 0.0973 mmol), 2,2,2-trifluoroacetic acid (111 mg, 0.973 mmol) and CH2Cl2 (10 mL). The reaction mixture was stirred at ambient temperature 1 hour. The solvent was removed and the residue was purified by silica gel chromatography (DCM/7 M NH3 in MeOH from 50/1 to 10/1, v/v) to afford product (58.8 mg, 91.1%). LRMS (APCI pos): >99% purity, 254 nm, m/e 664 (M+1).
Reaction SMILES: [CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23]([OH:25])=O)[CH2:2][CH:3]([CH3:5])[CH3:4].CN1CCOCC1.[N:33]1([CH2:39][CH2:40][NH2:41])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[OH-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([C:6]1[S:10][C:9]([NH:11][C:12]([C:14]2[N:15]([CH3:22])[CH:16]=[C:17]([N+:19]([O-:21])=[O:20])[CH:18]=2)=[O:13])=[N:8][C:7]=1[C:23]([NH:41][CH2:40][CH2:39][N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)=[O:25])[CH2:2][CH:3]([CH3:5])[CH3:4]
Reactant: NCCN1CCOCC1
Reactant: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)CCc1sc(NC(=O)c2cc([N+](=O)[O-])cn2C)nc1C(=O)NCCN1CCOCC1
Reaction time: 24 h

Procedure:
5-Isopentyl-2-{[(1-methyl-4-nitro-1H-pyrrol-2-yl)carbonyl]amino}-1,3-thiazole-4-carboxylic acid (330 mg, 0.90 mmol; see Preparation 3(iv) above) was dissolved in DMF (2.5 mL, dry), to which was added NMM (0.1 mL, dry), 2-(4-morpholinyl)ethanamine (117 mg, 0.90 mmol), and HBTU (682 mg, 1.80 mmol) at room temperature with stirring. The stirring was continued at room temperature for 24 h and then the reaction mixture was extracted with sodium hydroxide solution (381 mg, 9.52 mmol in water 10 mL) and ethyl acetate (3×50 mL). The organic layers were collected, dried (MgSO4) and the solvent removed under reduced pressure. The crude product was purified by column chromatography using ethyl acetate/methanol containing 1% TEA as eluent (RF=0.15). The sub-title compound was obtained as pale yellow solid (400 mg, 93%).
Reaction SMILES: [NH2:1][CH:2]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:9][CH:8]=[CH:7][CH2:6]1)[CH2:3][CH3:4].B.[OH:18]O.[OH-].[Na+]>C1COCC1.O>[NH2:1][CH:2]([C:5]1([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH2:6][CH2:7][CH:8]([OH:18])[CH2:9]1)[CH2:3][CH3:4]
Reactant: CCC(N)C1(c2ccc(F)cc2)CC=CC1
Reactant: OO
Agent: B
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCC(N)C1(c2ccc(F)cc2)CCC(O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(1-aminopropyl)-1-(4-fluorophenyl)cyclopent-3-ene (118, 348 mg, 1.6 mmol) was dissolved in THF at 0° C. under argon. Borane (1.75 mL, 1.75 mmol, 1M in THF) was added dropwise over 10 minutes. The reaction mixture was allowed to warm to room temperature before stirring overnight. After cooling to 0° C., water was added (4 mL), followed by hydrogen peroxide (0.61 mL, 30% solution in water) and sodium hydroxide solution (1.75 mL, 1M aqueous solution). After stirring for 5 minutes the mixture was extracted with ethyl acetate, dried over sodium sulphate and evaporated to give 458 mg of desired product, which was stirred for 15 minutes with dilute hydrochloric acid (10 mL, 2M aqueous solution). Evaporation, followed by freeze drying gave 514 mg of the desired product as mixture of four stereoisomers as a colourless hydrochloride salt. Rt=1.83, 1.99, 2.36, 2.86 min (Method 2). Detected mass: 203.1 (M—NH3—H2O+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[O:19])=[N:9]1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=1)=[O:35].O>O1CCCC1>[O:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[C:10]([NH:17][C:18]([N:20]2[CH2:25][CH2:24][N:23]([C:34]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[CH:39]=3)=[O:35])[CH2:22][CH2:21]2)=[O:19])=[N:9]1
Reactant: O=C(Cl)OCc1cccc(F)c1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1noc2ccccc12)N1CCN(C(=O)OCc2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.7 %

Procedure:
To a solution of N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) and triethylamine (0.309 ml, 2.22 mmol) in tetrahydrofuran (4 ml) was added 3-fluorobenzyl chloroformate (157 mg, 0.833 mmol) under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured to water and extracted with ethyl acetate. The extract was washed with water, and the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 132 mg (59.7%) of the desired product as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[CH3:2].[CH3:13][CH:14](O)[CH:15]=[CH2:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: C=CC(C)O
Reactant: CCc1ccc2c(c1)C(=O)CC2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(CC)cc2C1=O
Yield: 50 %

Procedure:
A solution of 11.8 g of 6-ethyl-1-indanone, 15.4 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 46 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). 7.92 g (50%) of (RS)-2-(2-buten-1-yl)-6-ethyl-1-indanone were obtained as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][NH2:6].Cl[C:12]1[C:13]2[CH:26]=[C:25]([Cl:27])[S:24][C:14]=2[N:15]=[C:16]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[N:17]=1>>[N:20]1[CH:21]=[CH:22][CH:23]=[C:18]([C:16]2[N:17]=[C:12]([NH:6][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([Cl:10])=[C:2]([Cl:1])[CH:3]=3)[C:13]3[CH:26]=[C:25]([Cl:27])[S:24][C:14]=3[N:15]=2)[CH:19]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Clc1cc2c(Cl)nc(-c3cccnc3)nc2s1
Product: Clc1cc2c(NCc3ccc(Cl)c(Cl)c3)nc(-c3cccnc3)nc2s1

Procedure:
With the procedure of Example 1, the reaction of 3,4-dichlorobenzylamine with 4-chloro-2-(pyridin-3-yl)-6-chloro-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-dichlorobenzylamino)-6-chloro-thieno-[2,3-d]-pyrimidine.