Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:9][C:10]1[CH2:15][CH2:14][CH2:13][C:12]([CH3:17])([CH3:16])[C:11]=1/[CH:18]=[CH:19]/[C:20](/[CH3:29])=[CH:21]/[CH:22]=[CH:23]/[C:24](/[CH3:28])=[CH:25]/[CH2:26][OH:27].C(N(CC)CC)C>ClCCl>[CH3:28]/[C:24](/[CH:23]=[CH:22]/[CH:21]=[C:20](\[CH3:29])/[CH:19]=[CH:18]/[C:11]1[C:12]([CH3:17])([CH3:16])[CH2:13][CH2:14][CH2:15][C:10]=1[CH3:9])=[CH:25]\[CH2:26][O:27][C:5](=[O:6])[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCC(=O)O1
Reactant: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/CO)C(C)(C)CCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(/C=C/C(C)=C/C=C/C(C)=C/COC(=O)CCCC(=O)O)C(C)(C)CCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
Glutaric anhydride (220 mg, 1.93 mmol) and retinol (500 mg, 1.75 mmol) were dissolved in dichloromethane (5 mL) in an amber-colored vial. Triethylamine (513 ul, 3.68 mmol) was added and the vial was flushed with argon. Reaction mixture was allowed to stir at room temperature for 4 hours. The material was concentrated and purified by silica gel chromatography with a dichloromethane/methanol gradient. Fractions were pooled and concentrated to yield yellowish oil (700 mg). The product was verified by NMR.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.O[N:14]=[C:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[N:18][CH:17]=1.N>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3[O:12][N:22]=[C:15]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:14]=3)=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Reactant: NC(=NO)c1cccnc1
Agent: N
Product: c1cncc(-c2noc(-c3ccc4[nH]cnc4c3)n2)c1

Procedure:
The title compound was prepared according to Method C using 1H-benzo[d]imidazole-5-carboxylic acid (Aldrich) and N′-hydroxynicotinimidamide (Tyger). 1H NMR (300 MHz, DMSO-d6) δ 7.66 (ddd, J=8.1, 4.8, 1.0 Hz, 1H), 7.75-7.98 (m, 1H), 7.99-8.17 (m, 1H), 8.34-8.56 (m, 3H), 8.82 (dd, J=5.1, 1.7 Hz, 1H), 9.28 (dd, J=2.2, 0.8 Hz, 1H) ppm; MS (DCI/NH3) m/z 264 (M+H)+.
Reaction SMILES: [CH:1]1([CH2:4][OH:5])[CH2:3][CH2:2]1.[H-].[Na+].[NH2:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](Cl)[N:10]=1.[Na+].[Cl-]>CN(C=O)C.O>[CH:1]1([CH2:4][O:5][C:11]2[N:10]=[C:9]([NH2:8])[CH:14]=[CH:13][N:12]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccnc(Cl)n1
Reactant: OCC1CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ccnc(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Cyclopropylmethanol (724 mg) was dissolved in DMF (4 mL) and treated with sodium hydride (401 mg, 60% in mineral oil) at 0° C. for 30 minutes. Then, a solution of 4-amino-2-chloro-pyrimidine (260 mg, CAS 7461-50-9 or made according to J. Am. Chem. Soc. 1930, 52, 1152-1157) in DMF (4 mL) was added drop by drop. The mixture was stirred at room temperature for 1 hour and then allowed to stir at 50° C. over night. The mixture was poured into water and the mixture was saturated with NaCl. The aqueous solution was then extracted with ethyl acetate and the organic layer was washed with brine, dried over Na2SO4 and evaporated to dryness. The residue was purified by flash chromatography on silica gel using a gradient of ethyl acetate in heptane as an eluant. The desired product was obtained as a light yellow oil (169 mg). MS (EI): 166.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11](F)=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:21])[F:20])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1.[CH3:27][N:28]([CH3:33])[CH2:29][CH2:30][CH2:31][OH:32].[H-].[Na+].O>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[C:13]([F:14])=[CH:12][C:11]([O:32][CH2:31][CH2:30][CH2:29][N:28]([CH3:33])[CH3:27])=[CH:10][C:9]=2[F:16])=[C:6]([NH:17][C@@H:18]([CH3:23])[C:19]([F:22])([F:20])[F:21])[N:5]2[N:24]=[CH:25][N:26]=[C:4]2[N:3]=1
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Reactant: CN(C)CCCO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](Nc1c(-c2c(F)cc(OCCCN(C)C)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Temperature: 50 °C
Yield: 67.7 %

Procedure:
To a solution of 5-chloro-6-(2,4,6-trifluorophenyl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine (600 mg, 1.5 mmol) and 3-dimethylamino-1-propanol (1.03 g, 10 mmol) in 5 mL of dimethylsulfoxide at room temperature is added sodium hydride (60% in mineral oil, 400 mg, 10 mmol). The mixture is heated at 50° C. for 30 min, and cooled to room temperature. Water is added to quench the reaction, and the product is extracted with ethyl acetate (x2). The combined organic extracts are washed with saturated sodium chloride (x4), dried over magnesium sulfate, and concentrated to a residue. The residue is chromatographed over silica gel, eluting with a gradient of ethyl acetate to 20% methyl alcohol in ethyl acetate. Concentration provides 5-chloro-6-{4-[3-(dimethylamino)propoxy]-2,6-difluorophenyl}-N-[(1S)-2,2,2-trifluoro-1-methylethyl][1,2,4]triazolo[1,5-a]pyrimidin-7-amine as a colorless oil (486 mg). MS: m/z 479.2 (M+H).
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[NH2:5][C:6]1[CH:34]=[CH:33][C:9]([O:10][C:11]2[CH:12]=[C:13]([NH:18][C:19](=[O:32])[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[C:21]=3[Cl:31])[CH:14]=[CH:15][C:16]=2[F:17])=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[NH2:3][C:2]1[S:1][C:7]2[CH:8]=[C:9]([O:10][C:11]3[CH:12]=[C:13]([NH:18][C:19](=[O:32])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:27])[CH3:28])[C:21]=4[Cl:31])[CH:14]=[CH:15][C:16]=3[F:17])[CH:33]=[CH:34][C:6]=2[N:5]=1
Reactant: N#C[S-]
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc(N)cc3)c2)c1Cl
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: CC(C)(C#N)c1cccc(C(=O)Nc2ccc(F)c(Oc3ccc4nc(N)sc4c3)c2)c1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 43 %

Procedure:
To a solution of potassium thiocyanate (1.65 g, 17.0 mmol) in acetic acid (15 mL) was added a solution of N-[3-(4-aminophenoxy)-4-fluorophenyl]-2-chloro-3-(1-cyano-1-methylethyl)benzamide (1.75 g, 4.13 mmol) in acetic acid (5 mL), and the mixture was stirred at room temperature for 15 min. To the obtained solution was added dropwise a solution of bromine (726 mg, 4.54 mmol) in acetic acid (15 mL) at room temperature over 30 min or longer. After the completion of the dropwise addition, the mixture was stirred at room temperature for 4 hr. The resulting yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in tetrahydrofuran (100 mL) and ethyl acetate (200 mL), and basified with 2N aqueous sodium hydroxide solution. The aqueous layer was separated, and the organic layer was washed with saturated aqueous ammonium chloride solution (200 mL) and dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (854 mg, 43%) as a yellow amorphous substance. The obtained compound was used in the next reaction without a further purification.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[C:6]([N:8]1[CH2:25][CH2:24][C:11]2([C:15](=[O:16])[NH:14][C:13](=[O:17])[CH:12]2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7].[CH3:35]I>>[F:32][C:29]([F:30])([F:31])[C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([C:2]([F:1])([F:33])[F:34])[CH:28]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([C:15](=[O:16])[N:14]([CH3:35])[C:13](=[O:17])[CH:12]2[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:24][CH2:25]1)=[O:7]
Reactant: O=C1NC(=O)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1c1ccccc1
Reactant: CI
Product: CN1C(=O)C(c2ccccc2)C2(CCN(C(=O)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)C1=O

Procedure:
The title compound, MS: m/e=499.2 (M+H+), was prepared in accordance with the general method of example 121 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-4-phenyl-2,8-diaza-spiro[4.5]decane-1,3-dione and methyl iodide.
Reaction SMILES: [CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[C:17](=[CH:18][C:19]4[O:20][CH2:21][O:22][C:23]=4[CH:24]=3)[C:16](=[O:26])[CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5].[N-:28]=[N+]=[N-].[Na+].FC(F)(F)C(O)=O>O>[CH2:1]([N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]2([C:25]3[CH:24]=[C:23]4[O:22][CH2:21][O:20][C:19]4=[CH:18][C:17]=3[C:16](=[O:26])[NH:28][CH2:15]2)[C:7]1=[O:27])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCN1C(=O)C2(CC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CCCCCN1C(=O)C2(CNC(=O)c3cc4c(cc32)OCO4)c2ccccc21
Temperature: 50 °C
Reaction time: 8 h
Yield: 75.5 %

Procedure:
A mixture of 1′-pentylspiro[indeno[5,6-d][1,3]dioxole-5,3′-indole]-2′,7(1′H,6H)-dione (0.10 g, 0.28 mmol), sodium azide (0.09 g, 1.40 mmol) and trifluoroacetic acid (2.00 mL) was stirred at 50° C. overnight. The mixture was poured into water (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The residue was subjected to flash column chromatography to afford the title compound (0.08 g, 74%) as a white solid: 1H NMR (300 MHz, CDCl3) δ 7.60 (s, 1H), 7.30 (td, 1H), 7.20 (dd, 1H), 6.98 (td, 1H), 6.93 (d, 1H), 6.32 (br, 1H), 6.21 (s, 1H), 5.97-5.92 (m, 2H), 4.02 (dd, 1H), 3.87-3.70 (m, 2H), 3.47 (dd, 1H), 1.80-1.66 (m, 2H), 1.42-4.30 (m, 4H), 0.90 (t, 3H); 13C NMR (75 MHz, CDCl3) δ 175.8, 165.2, 151.6, 147.9, 141.7, 134.3, 130.9, 129.0, 124.5, 123.2, 122.9, 109.0, 108.5, 105.4, 101.9, 51.9, 48.2, 40.4, 29.1, 27.1, 22.3, 14.0; MS (ES+) m/z 379.3 (M+1).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:13]=[CH:12][C:11](=[O:14])[CH:10]=[CH:9]2)[CH2:4][CH2:3]1.[NH:15]1[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[O:21])[CH2:16]1>>[O:14]=[C:11]1[CH:12]=[CH:13][N:8]([CH:5]2[CH2:6][CH2:7][CH:2]([N:15]3[CH2:18][CH:17]([NH:19][C:20]([CH2:22][NH:23][C:24](=[O:35])[C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:32])[F:33])[CH:26]=4)=[O:21])[CH2:16]3)[CH2:3][CH2:4]2)[CH:9]=[CH:10]1
Reactant: O=C1CCC(n2ccc(=O)cc2)CC1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Product: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(n3ccc(=O)cc3)CC2)C1

Procedure:
The title compounds were prepared as white solids from the reductive amination of 1-(4-oxo-cyclohexyl)-1H-pyridin-4-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in Example 2 Step C) using the procedure described in Step D of Example 1.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.[Cl:10][CH2:11][CH2:12][N:13]=[C:14]=[O:15]>C1COCC1>[Cl:10][CH2:11][CH2:12][NH:13][C:14]([NH:8][C:6]1[CH:5]=[C:4]([CH3:9])[N:3]=[C:2]([CH3:1])[CH:7]=1)=[O:15]
Reactant: Cc1cc(N)cc(C)n1
Reactant: O=C=NCCCl
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCCl)cc(C)n1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
2,6-Dimethyl-pyridin-4-ylamine (Example C1.2., 1.22 g, 10 mmol) is dissolved in dry THF (30 mL) and 1-chloro-2-isocyanato-ethane (1.06 g, 10 mmol) is added. The mixture is stirred at r.t. for 15 h. The mixture is evaporated and the residue purified by MPLC to provide the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@H:14](OS(C)(=O)=O)[CH2:13]1)[CH:6]=[CH:5]2.[CH2:32]([CH2:34][NH2:35])[OH:33]>>[Cl:1][C:2]1[C:3]([NH:22][C:23](=[O:31])[CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]1[CH2:16][CH2:15][C@@H:14]([NH:35][CH2:34][CH2:32][OH:33])[CH2:13]1)[CH:6]=[CH:5]2
Reactant: CS(=O)(=O)O[C@H]1CCN(c2ccc3c(NC(=O)CC4CCCCC4)c(Cl)ccc3n2)C1
Reactant: NCCO
Product: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(N3CC[C@@H](NCCO)C3)ccc12

Procedure:
Prepared according to the method of example 33(b), using N-[6-Chloro-2-[(3S)-3-[(methylsulfonyl)oxy]-1-pyrrolidinyl]-5-quinolinyl]-cyclohexaneacetamide (Example 33(a)) (0.225 g) and ethanolamine (2 mL) to afford the title compound (0.052 g).
Reaction SMILES: [OH:1][C:2]1[CH:28]=[CH:27][C:5]([C:6]([C:8]2[CH:26]=[CH:25][C:11]([CH2:12][S:13][C:14]3[N:15]([CH3:24])[C:16](=[O:23])[C:17]4[S:22][CH:21]=[CH:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl.Cl[CH2:31][CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:24][N:15]1[C:16](=[O:23])[C:17]2[S:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:14]1[S:13][CH2:12][C:11]1[CH:25]=[CH:26][C:8]([C:6](=[O:7])[C:5]2[CH:27]=[CH:28][C:2]([O:1][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: ClCCN1CCCCC1
Reactant: Cn1c(SCc2ccc(C(=O)c3ccc(O)cc3)cc2)nc2ccsc2c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(SCc2ccc(C(=O)c3ccc(OCCN4CCCCC4)cc3)cc2)nc2ccsc2c1=O
Yield: 90.7 %

Procedure:
A solution of 2-[4-(4-hydroxybenzoyl)benzylthio]-3-methylthieno[3,2-d]pyrimidin-4(3H)-one (408 mg), 1-(2-chloroethyl) piperidine hydrochloride (202 mg) and potassium carbonate (414 mg) in DMF (10 ml) was stirred at 60° C. for 15 hours. This reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water, and dried. Then, hydrogen chloride/ethyl acetate was added and the precipitated hydrochloride was collected by filtration and dried to provide the title compound as colorless solid (471 mg).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH2:10][C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH3:12][Si](C)(C)[N-][Si](C)(C)C.[Li+].CI>C1COCC1>[Cl:1][C:2]1[C:3]2[CH:10]([CH3:12])[C:9](=[O:11])[NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: O=C1Cc2c(Cl)ncnc2N1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1C(=O)Nc2ncnc(Cl)c21
Temperature: -78 °C
Yield: 56.8 %

Procedure:
Add 4-chloro-5,7-dihydro-pyrrolo[2,3-d]pyrimidin-6-one (0.4 g; 0.0023 mol; 1.0 equiv) in THF (15 mL) and cool to −78° C. under an argon atmosphere. Add drop-wise lithium hexamethyldisilazide (4.7 mL; 0.0047 mol; 2.0 equiv; 1 M in THF). Stir the reaction at −78° C. for 30 min. Add drop-wise methyl iodide (0.29 mL; 0.0047 mol; 2.0 equiv), allow the reaction temperature to come to −20° C. slowly and stir at −20° C. for 2 h. Quench the reaction with saturated ammonium chloride aqueous and extract with EA. Evaporate the organic layer to give the title compound (0.24 g; 41.38%).
Reaction SMILES: Br[C:2]1[CH:36]=[CH:35][C:5]([CH2:6][C:7]2[N:8]([C:20]3[CH:25]=[CH:24][C:23]([N:26]4[S:30](=[O:32])(=[O:31])[NH:29][C:28](=[O:33])[CH:27]4[CH3:34])=[CH:22][CH:21]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[C:37]([C:41]1[CH:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]>>[C:37]([C:41]1[CH:46]=[CH:45][C:44]([C:2]2[CH:3]=[CH:4][C:5]([CH2:6][C:7]3[N:8]([C:20]4[CH:21]=[CH:22][C:23]([N:26]5[S:30](=[O:31])(=[O:32])[NH:29][C:28](=[O:33])[CH:27]5[CH3:34])=[CH:24][CH:25]=4)[CH:9]=[C:10]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[N:11]=3)=[CH:35][CH:36]=2)=[CH:43][CH:42]=1)([CH3:40])([CH3:39])[CH3:38]
Reactant: CC1C(=O)NS(=O)(=O)N1c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: CC1C(=O)NS(=O)(=O)N1c1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(C(C)(C)C)cc3)cc2)cc1

Procedure:
5-{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-methyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide (61 mg, 0.1 mmol) was treated as described in general procedure G using 4-tert-butylphenylboronic acid (36 mg, 0.2 mmol) to give 5-{4-[2-(4′-tert-butyl-biphenyl-4-ylmethyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenyl}-4-methyl-1,2,5-thiadiazolidine-3-one-1,1-dioxide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH2:7]([N:9]([CH2:13][CH3:14])[CH2:10][CH2:11][NH2:12])[CH3:8].Cl.[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([S:34](Cl)(=[O:36])=[O:35])=[CH:30][CH:29]=3)=[CH:22][N:23]=[N:24]2)=[CH:19][CH:18]=1>C(Cl)(Cl)Cl>[Cl:16][C:17]1[CH:26]=[C:25]2[C:20]([C:21]([NH:27][C:28]3[CH:29]=[CH:30][C:31]([S:34]([NH:12][CH2:11][CH2:10][N:9]([CH2:13][CH3:14])[CH2:7][CH3:8])(=[O:35])=[O:36])=[CH:32][CH:33]=3)=[CH:22][N:23]=[N:24]2)=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Reactant: CCN(CC)CCN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCN(CC)CCNS(=O)(=O)c1ccc(Nc2cnnc3cc(Cl)ccc23)cc1
Temperature: 5 °C

Procedure:
A mixture of anhydrous sodium carbonate (3.08 g) and N,N-diethylethylenediamine (0.43 ml) in chloroform (30 ml) was vigorously stirred at 5° C. and treated with 4-(7-Chloro-4-cinnolinylamino)benzenesulphonyl chloride hydrochloride (1.0 g). The mixture was stirred at room temperature for 11/2 hours and then filtered. The filtrate was evaporated to give a residue that crystallised from ethanol to give the title compound (0.456 g), m.p. 175°-76° C.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38](Cl)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26].C(N(C(C)C)C(C)C)C>CN1CCCC1=O>[CH2:25]([O:27][C:28](=[O:43])[CH2:29][NH:30][C:31]([C:33]1[N:34]=[C:35]2[CH:40]=[CH:39][C:38]([NH:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][CH:9]([O:8][CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[CH2:10][CH2:11]3)=[N:37][N:36]2[CH:42]=1)=[O:32])[CH3:26]
Reactant: CCOC(=O)CNC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Temperature: 95 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
1.90 g of 4-(diphenylmethoxy)-1-piperidinepropanamine and 1.38 g of N-(6-chloroimidazo-[1,2-b]pyridazine-2-carbonyl)glycine ethyl ester were dissolved in 15 ml of 1-methyl-2-pyrrolidone; 0.841 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (90-100° C.) for 24 hours. After cooling, ice water and saline were added, followed by extraction with ethyl acetate; the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (95:5:1). The desired fraction was collected and recrystallized from ethyl acetate to yield 1.28 g of the title compound.
Reaction SMILES: [OH:1][N:2]1[C:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)=[CH:5][C:4]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)=[N:3]1.[CH3:23][N:24]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](Cl)=[O:26]>>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([C:4]2[CH:5]=[C:6]([C:7]3[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[CH:11][CH:12]=3)[N:2]([O:1][C:25](=[O:26])[N:24]([CH3:23])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:3]=2)=[CH:16][CH:17]=1
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(O)n2)cc1
Product: COc1ccc(-c2cc(-c3ccc(OC)cc3)n(OC(=O)N(C)c3ccccc3)n2)cc1

Procedure:
The title compound was prepared from 1-hydroxy-3,5-bis-(4-methoxyphenyl)pyrazole and N-methyl-N-phenylcarbamoyl chloride applying the general procedure 8. The crude product was purified by flash chromatography (Quad flash 12,.EtOAc-heptane) (29%, beige crystals).
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:10]=[C:11]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]3[N:26]=[C:25]([CH3:27])[CH:24]=[C:23]([C:28]4[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=4)[N:22]=3)[CH:16]=2)[CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[CH3:27][C:25]1[CH:24]=[C:23]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:30][CH:29]=2)[N:22]=[C:21]([C:17]2[CH:16]=[C:15]([C:11]3[CH:12]=[CH:13][CH:14]=[C:9]([S:6]([NH2:5])(=[O:8])=[O:7])[CH:10]=3)[CH:20]=[CH:19][CH:18]=2)[N:26]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3cccc(S(N)(=O)=O)c3)c2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 89.7 %

Procedure:
To a cooled and stirred solution of 3′-[4-methyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-sulfonic acid tert-butylamide (example 165) (0.3 g, 0.57 mmol) in dichloromethane (5 mL) was added TFA (5 mL) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness and saturated NaHCO3 solution (5 mL), diethyl ether and heptane were added. The mixture was stirred at room temperature for 1 h, the precipitate was collected by filtration, washed with water and heptane and dried to yield the title compound as a white solid (0.24 g, 90%). MS (ISP) 570.3 [(M+H)+]; mp 224.5° C.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[N:24]=[CH:25][C:26]4[CH:31]=[CH:30][NH:29][C:27]=4[N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH:15]2[CH2:17]C2)[CH2:12][CH2:11][CH2:10][CH2:9]1.[H][H]>CO.[Pd]>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:8]1([CH:13]([N:18]2[CH:22]=[C:21]([C:23]3[C:31]4[CH:26]=[CH:25][NH:24][C:30]=4[N:29]=[CH:27][N:28]=3)[CH:20]=[N:19]2)[CH2:14][CH2:15][CH3:17])[CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: c1cc2cnc(-c3cnn(C(CC4CC4)C4CCCC4)c3)nc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CCCC(C1CCCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-[1-(1-Cyclopentylbut-3-yn-1-yl)-1H-pyrazol-4-yl]-7H-pyrrolo[2,3-d]pyrimidine trifluoro-acetate salt (prepared in Example 729) (20 mg, 0.048 mmol) was dissolved in methanol (2 mL) and a catalytic amount of 5% Pd—C was added. The mixture was stirred under 1 atmosphere of hydrogen via an affixed balloon. After 2 hours, the mixture was filtered and purified via preparative-HPLC/MS (C18 eluting with a gradient of H2O and ACN containing 0.1% TFA) to afford the product (14 mg, 69%).
Reaction SMILES: [ClH:1].C(OC(=O)[NH:8][C@H:9]([CH3:17])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[CH3:17][C@@H:9]([NH2:8])[CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: C[C@H](CN1CCOCC1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](N)CN1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
Add 1.6 M hydrogen chloride in dioxane (120 mL) to a solution of (R)-(1-methyl-2-morpholin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.05 mol, 12 g) in dry dichloromethane (75 mL) at 0° C. Warm the reaction mixture to room temperature and stir for 2 h. Filter the precipitate and dry under vacuum to obtain the title compound (9.2 g, 86%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, 3H), 3.10 (br s, 2H), 3.38 (br s, 4H), 3.79 (br s, 5H).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5]([O:12][CH2:13][C@@H:14]([OH:16])[CH3:15])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[Se](=O)=[O:18]>O1CCOCC1.O>[OH:16][C@@H:14]([CH3:15])[CH2:13][O:12][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([CH:1]=[O:18])[CH:11]=[CH:10]2
Reactant: Cc1ccc2cccc(OC[C@H](C)O)c2n1
Reactant: O=[Se]=O
Solvent: C1COCCO1
Solvent: O
Product: C[C@H](O)COc1cccc2ccc(C=O)nc12
Yield: 57 %

Procedure:
To a solution of (S)-1-(2-methylquinolin-8-yloxy)propan-2-ol (0.15 g, 0.69 mmol) in dioxane (10 mL) and water (0.1 mL) was added selenium dioxide (0.092 g, 0.83 mmol) and the resultant mixture heated at reflux for 2.5 hours. The cooled reaction mixture was filtered through a plug of Celite® to remove solids, rinsing with dichloromethane, and the filtrate was concentrated under reduced pressure. The residue was purified by normal phase chromatography on silica gel (20-40% ethyl acetate/hexanes) providing the title compound (0.091 g, 57%).