Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C@@H:6]([NH:11][C:12]3[CH:13]=[CH:14][C:15]([F:29])=[C:16]([C@:18]4([CH3:28])[C:24]([F:26])([F:25])[CH2:23][O:22][CH2:21][C:20](=S)[NH:19]4)[CH:17]=3)[CH2:7][CH2:8][C:9]=2[CH:10]=1.CO.C(OO)(C)(C)C.C([O-])([O-])=O.[Na+].[Na+].[NH3:44]>>[NH2:44][C:20]1[CH2:21][O:22][CH2:23][C:24]([F:26])([F:25])[C@:18]([C:16]2[CH:17]=[C:12]([NH:11][C@@H:6]3[C:5]4[N:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:9]=4[CH2:8][CH2:7]3)[CH:13]=[CH:14][C:15]=2[F:29])([CH3:28])[N:19]=1
Reactant: N
Reactant: C[C@]1(c2cc(N[C@H]3CCc4cc(Cl)cnc43)ccc2F)NC(=S)COCC1(F)F
Agent: CC(C)(C)OO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: C[C@]1(c2cc(N[C@H]3CCc4cc(Cl)cnc43)ccc2F)N=C(N)COCC1(F)F
Temperature: 23 °C
Reaction time: 22 h
Yield: 45 %

Procedure:
To a solution of (R)-5-[5-((S)-3-chloro-6,7-dihydro-5H-[1]pyrindin-7-ylamino)-2-fluoro-phenyl]-6,6-difluoro-5-methyl-[1,4]oxazepane-3-thione (intermediate A20Ab) (16 mg, 36.2 μmol) in 7 M ammonia in methanol (0.4 mL, 2.8 mmol) at 23° C. was added tert-butyl hydroperoxide (70% in water, 16.3 mg, 17.4 μL, 181 μmol) and the mixture stirred at 23° C. for 22 hours. Poured into aqueous 2 M Na2CO3 solution, extracted with ethyl acetate, the organic layer was dried over Na2SO4. Removal of the solvent in vacuum left a light brown solid, which was purified by flash chromatography (silica gel (amine)) with n-heptane/ethyl acetate to give the title compound as a yellow solid (7 mg, 45%). MS (ISP): m/z=425.1 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[CH:5][N:6]=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16]Cl)=[C:12]([C:18]([Cl:21])([Cl:20])[Cl:19])[CH:11]=1)([O-:9])=[O:8].O>O1CCCC1>[S:3]1[CH:4]=[CH:5][N:6]=[C:2]1[NH:1][S:16][C:13]1[CH:14]=[CH:15][C:10]([N+:7]([O-:9])=[O:8])=[CH:11][C:12]=1[C:18]([Cl:19])([Cl:20])[Cl:21]
Reactant: Nc1nccs1
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])c1ccc(SNc2nccs2)c(C(Cl)(Cl)Cl)c1
Temperature: 10 °C
Yield: 67.4 %

Procedure:
40 g of 2-aminothiazole is dissolved in 500 ml of tetrahydrofuran; while stirring and at 10° C., 61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride is added. The addition of water precipitates the sulfenamide, which is filtered and recrystallized from ethyl acetate. There is obtained 50 g (70% of theory) of N-(1,3-thiazol-2-yl)-4-nitro-2-trichloromethylphenylsulfenamide; m.p.: 165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[NH2:8].C(N(C(C)C)C(C)C)C.[C:19](Cl)(Cl)=[S:20]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:9])[C:7]=1[N:8]=[C:19]=[S:20]
Reactant: S=C(Cl)Cl
Reactant: Nc1c(Cl)cncc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: S=C=Nc1c(Cl)cncc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 20.3 %

Procedure:
To a solution of 3,5-dichloropyridin-4-amine (4.0 g, 24.53 mmol) in DCM (20 mL), was added N-ethyl di-isopropyl amine (6.3 g, 48.83 mmol). The reaction mixture was stirred at RT for 30 minutes. The reaction mixture was cooled at 0° C. and thiophosgene (2.76 g, 24.00 mmol) was added drop wise. The reaction mixture was stirred at 0° C. to RT for 3-4 h. The reaction mixture was diluted with DCM and the obtained crude was purified by column chromatography to afford 1.0 g of the desired product. 1HNMR (DMSO-d6): δ 8.77 (s, 2H); MS [M+H]+: 205.20.
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:21][CH3:22])[N:12]2[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Cl)=[C:8]([NH2:23])[N:7]=1)[CH2:2][CH2:3][CH3:4].[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[N:24]1([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]2[C:11]([O:21][CH3:22])=[N:10][C:9]3[C:13]2=[N:14][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[N:7][C:8]=3[NH2:23])[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCCCCl)c2n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCCOc1nc(N)c2nc(OC)n(CCCCCN3CCC3)c2n1
Temperature: 50 °C
Yield: 6.4 %

Procedure:
2-(Butyloxy)-9-(5-chloropentyl)-8-(methyloxy)-9H-purin-6-amine (100 mg, 0.293 mmol), azetidine (0.020 ml, 0.293 mmol) and N,N-diisopropylethylamine (0.102 ml, 0.585 mmol) were dissolved in DMF (2 ml) and heated at 50° C. for 72 hours. The solvent was removed in vacuo and the residue partitioned between DCM (5 ml) and water (5 ml) and the layers separated using a hydrophobic frit. The aqueous phase was re-extracted with DCM (5 ml) and the combined organic extracts concentrated and the residue dissolved in 1:1 MeOH:DMSO (1 ml) and purified by MDAP (Method A). The product-containing fractions were evaporated under a stream of nitrogen to give the title compound as a clear gum (6.8 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12](O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[NH2:36])[C:31]#[N:32]>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[NH:36][C:35]3[CH:34]=[CH:33][C:30]([C:31]#[N:32])=[CH:29][C:28]=3[N:27]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: N#Cc1ccc(N)c(N)c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CC(c2nc3cc(C#N)ccc3[nH]2)C1
Temperature: 100 °C
Reaction time: 2 h
Yield: 40.6 %

Procedure:
To the mixture of azetidine-1,3-dicarboxylic acid mono-tert-butyl ester (1.5 g, 6.6 mmol) in DMF (50 mL) and pyridine (50 mL) was added CDI (1.06 g, 6.8 mmol) at 45° C. and the mixture was stirred for another 2 h at this temperature. Then 3,4-diamino-benzonitrile (0.87 g, 6.6 mmol) was added and the mixture was stirred at RT overnight. Solvents were removed in vacuo and the residue was dissolved in HOAc (20 mL) and heated for 1 h at 100° C. Then the reaction mixture was concentrated and the residue was partitioned between DCM and aqueous of Na2CO3. The organic layer was dried over Na2SO4 and concentrated to give the crude product which was purified by column chromatography (ethyl acetate:petroleum ether=1:2) to give the compound 3-(5-cyano-1H-benzoimidazol-2-yl)-azetidine-1-carboxylic acid tert-butyl ester (0.8 g, 65%) as pale solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7](Cl)=[N:6][CH:5]=1.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][CH:26]([NH2:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([NH:29][CH:26]2[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:22])[CH2:28][CH2:27]2)=[N:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COC(=O)c1cnc(Cl)cc1C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COC(=O)c1cnc(NC2CCN(C(=O)OC(C)(C)C)CC2)cc1C(F)(F)F
Yield: 49 %

Procedure:
A solution of 6-chloro-4-trifluoromethyl-nicotinic acid methyl ester (2.00 g, 8.35 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.01 g, 10.02 mmol, 1.2 equiv; commercially available) in anhydrous DMF (10 mL) was heated by microwave irradiation to 110° C. for 4 h. A solution of 1 M NaOH (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO4, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (5:1→3:1) to yield 1.65 g (49%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.36-1.41 (m, 2H), 1.40 (s, 9H), 1.95-1.97 (m, 2H), 2.85-2.93 (m, 2H), 3.81 (s, 3H), 3.92-3.98 (m, 1H), 3.98-4.05 (m, 2H), 5.12 (d, J=8.1 Hz, 1H), 6.59 (s, 1H), 8.68 (s, 1H). 19F NMR (282 MHz, CDCl3): δ-62.38. MS (ISP): 404.5 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([O:10][CH3:11])[C:3]=1[S:12][CH3:13].N1C=CC=NC=1.[CH3:20][SH:21].[Na]>O1CCCC1>[CH3:9][O:8][C:6]1[N:5]=[C:4]([O:10][CH3:11])[C:3]([S:12][CH3:13])=[C:2]([S:21][CH3:20])[N:7]=1
Reactant: CS
Reactant: COc1nc(Cl)c(SC)c(OC)n1
Agent: [Na]
Solvent: C1CCOC1
Solvent: c1cncnc1
Product: COc1nc(OC)c(SC)c(SC)n1

Procedure:
Into a 100-milliliter, 4-necked flask equipped with a reflux condenser, thermometer and stirrer, were charged 5.51 g of 6-chloro-2,4-dimethoxy-5-methylthiopyrimidine and 50 ml of tetrahydrofuran. After causing the pyrimidine derivative to dissolve completely in the solvent, a 15% aqueous solution of sodium methyl mercaptan (commercially available; product of Tokyo Kasei Kogyo K.K.) was added dropwise and the resultant mixture was refluxed for 5 hours.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:7][CH2:8][C:9]#[CH:10].[CH2:18]([Sn:22](Cl)([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:23][CH2:24][CH2:25][CH3:26])[CH2:19][CH2:20][CH3:21].[OH-].[Na+]>C1COCC1>[CH2:27]([Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:23][CH2:24][CH2:25][CH3:26])[C:10]#[C:9][CH2:8][CH2:7][CH2:6][O:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[CH2:28][CH2:29][CH3:30]
Reactant: C#CCCCOC1CCCCO1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCC[Sn](C#CCCCOC1CCCCO1)(CCCC)CCCC
Temperature: 15 °C
Yield: 26 %

Procedure:
A solution of n-butyllithium (2.5M in hexanes, 22 mL) was added dropwise to a solution of 2-(pent-4-ynyloxy)tetrahydropyran (Intermediate 25, 7.70 g) in THF (60 mL), at −60° C. The mixture was stirred and allowed to warm to 15° C. over 1 hour. It was then re-cooled to −60° C. and a solution of tributyl tin chloride (16.4 g) in THF (50 mL) was added dropwise over 30 minutes. The mixture was stirred and allowed to warm to 20° C. over 1 hour. 1M aqueous sodium hydroxide (4 mL) was cautiously added and the resultant mixture was filtered through Celite, and washed with ethyl acetate. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give tributyl-[5-(tetrahydropyran-2-yloxy)-pent-1-ynyl]-stannane (5.44 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([O:18][CH:19]3[CH2:24][CH2:23][N:22](CC4C=CC=CC=4)[CH2:21][CH2:20]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1.[H][H]>[Pd].[Ni].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:17]([O:18][CH:19]3[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]3)=[N:16][C:15]3[C:10]2=[N:11][CH:12]=[N:13][CH:14]=3)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(OC3CCN(Cc4ccccc4)CC3)nc3cncnc32)cc1
Reactant: [H][H]
Agent: [Ni]
Agent: [Pd]
Solvent: CO
Product: Fc1ccc(Cn2c(OC3CCNCC3)nc3cncnc32)cc1
Yield: 82.2 %

Procedure:
A mixture of 16.25 parts of 9-[(4-fluorophenyl)methyl]-8-[[1-(phenylmethyl)-4-piperidinyl]oxy]-9H-purine and 200 parts of methanol was hydrogenated at normal pressure and at 50° C. with b 3 parts of palladium-on-charcoal catalyst 10% and 6 parts of Raney-nickel catalyst. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was taken up in trichloromethane and water was added. The product was extracted with trichloromethane. The extract was washed with water, dried, filtered and evaporated. The residue was stirred in 1,1'-oxybisethane. The precipitated product was filtered off and dried, yielding 10.5 parts (82.2%) of 9-[(4-fluorophenyl)methyl]-8-(4-piperidinyloxy)-9H-purine; mp. 79.3° C. (compound 56).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:27])[CH2:10][N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Br:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[C:5]([CH3:28])[CH:4]=1.[CH3:29][NH:30][CH3:31]>CN(C)C(=O)C>[Br:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([CH2:10][C:9]([C:6]3[CH:7]=[CH:8][C:3]([CH2:2][N:30]([CH3:31])[CH3:29])=[CH:4][C:5]=3[CH3:28])=[O:27])[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Reactant: CNC
Solvent: CC(=O)N(C)C
Product: Cc1cc(CN(C)C)ccc1C(=O)Cn1ccc(OCc2ccc(Br)cn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-[2-(4-bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-bromo-pyridin-2-ylmethoxy)-1H-pyridin-2-one (preparation 4b, 1000 mg, 1.98 mmol) in N,N-dimethylacetamide (5 mL) is added dimethylamine (3.0 mL of 2M solution in THF, 6.0 mmol). The reaction mixture is stirred 2 h at room temperature. The mixture is purified via reverse phase HPLC chromatography (Gilson Xbridge C18 5 μm, gradient 5%→90% acetonitrile in water+0.3% NH4OH, 120 mL/min).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10](Br)[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2].[CH3:23][Si:24]([C:27]#[CH:28])([CH3:26])[CH3:25].C(N(CC)CC)C>O1CCCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH2:1]([O:3][C:4]([C:6]1[N:11]=[C:10]([C:28]#[C:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]2[N:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:15][C:8]=2[C:7]=1[OH:22])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nc(Br)c2nc(-c3ccccc3)sc2c1O
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#C[Si](C)(C)C)c2nc(-c3ccccc3)sc2c1O
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 67.2 %

Procedure:
A mixture of 4-bromo-7-hydroxy-2-phenyl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (636 mg, 1.68 mmole), trimethylsilylacetylene (309 μl, 2.19 mmole), bis(triphenylphosphine)palladium chloride (35 mg, 0.05 mmole), copper(I) iodide (19 mg, 0.10 mmole) and triethylamine (352 μl, 2.52 mmole) in tetrahydrofuran (3.4 ml) was stirred at room temperature for 3.5 h before it was partitioned between ethyl acetate and water, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel with a gradient of dichloromethane and hexanes to give the title compound as a yellow solid (448 mg). MS: (+) m/z 397.28 (M+1), MS: (−) m/z 395.18 (M−1).
Reaction SMILES: [Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10](Cl)[C:5]=2[S:4][CH:3]=1.C(O)(C)C.[NH3:17]>>[Br:1][C:2]1[C:6]2[N:7]=[C:8]([Cl:12])[N:9]=[C:10]([NH2:17])[C:5]=2[S:4][CH:3]=1
Reactant: N
Reactant: Clc1nc(Cl)c2scc(Br)c2n1
Solvent: CC(C)O
Product: Nc1nc(Cl)nc2c(Br)csc12
Temperature: 80 °C
Reaction time: 5 h
Yield: 74.6 %

Procedure:
7-Bromo-2,4-dichlorothieno[3,2-d]pyrimidine (3.0 g, 10.64 mmol) was added to a sealed reactor and 2.0 N ammonia isopropanol (26.6 mL, 53.2 mmol) was added thereto. The reaction mixture was stirred at 80° C. for 5 hours and then cooled to room temperature. The reaction mixture was added to ice water (100 mL). Thus prepared solid was filtered and dried by blowing nitrogen gas. The resultant target compound (2.1 g, 75% yield) was used in the following reaction without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[S:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1.C([C:28]1[C:29]([N:34]=[CH:35][N:36]([CH3:38])C)=[N:30][CH:31]=[CH:32][CH:33]=1)#N.NC1C=C(OCC2C=CC=C(F)C=2)C=CC=1SC1C=CC(O)=CC=1>>[CH3:17][O:16][C:13]1[CH:12]=[CH:11][C:10]([CH2:9][O:8][C:6]2[CH:5]=[CH:4][C:3]([S:18][C:19]3[CH:20]=[CH:21][C:22]([OH:25])=[CH:23][CH:24]=3)=[C:2]([NH:1][C:38]3[C:28]4[CH:33]=[CH:32][CH:31]=[N:30][C:29]=4[N:34]=[CH:35][N:36]=3)[CH:7]=2)=[CH:15][CH:14]=1
Reactant: CN(C)C=Nc1ncccc1C#N
Reactant: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(N)c2)cc1
Agent: Nc1cc(OCc2cccc(F)c2)ccc1Sc1ccc(O)cc1
Product: COc1ccc(COc2ccc(Sc3ccc(O)cc3)c(Nc3ncnc4ncccc34)c2)cc1
Yield: 55 %

Procedure:
The product from Example 10E and the product from Example 57A were reacted according to the procedure in Example 57E substituting the product of Example 10E for the product of Example 57D to provide a solid which was triturated with methanol to provide the title compound (49 mg, 55%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 10.07 (s, 1H), 9.63 (s, 1H), 9.05 (s, 1H), 8.83 (s, 1H), 8.58 (s, 1H), 7.64 (s, 1H), 7.38 (d, J=8.46 Hz, 2H), 7.20-7.29 (m, 1H), 7.12-7.18 (m, 1H), 7.06-7.12 (m, 2H), 6.90-6.99 (m, 3H), 6.62-6.69 (m, 2H), 5.02 (s, 2H), 3.75 (s, 3H); MS (ESI+) m/z 483.2 (M+H)+, (ESI−) m/z 481.2 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[CH3:11][N:12]([CH2:14][CH2:15]Cl)[CH3:13].Cl>CS(C)=O.O>[Br:8][C:6]1[CH:5]=[CH:4][N:3]([CH2:15][CH2:14][N:12]([CH3:13])[CH3:11])[C:2](=[O:1])[CH:7]=1
Reactant: CN(C)CCCl
Reactant: Oc1cc(Br)ccn1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CN(C)CCn1ccc(Br)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of 2-hydroxy-4-bromopyridine (0.10 g, 0.57 mmol) in DMSO (1.0 mL) was added KOH (0.13 g, 2.29 mmol) and the resulting reaction mixture was stirred for 10 min at room temperature followed by addition of N,N-dimethylaminoethylchloride.HCl (0.098 g, 0.68 mmol). The reaction mixture was then stirred at 40° C. for 1 h. After the completion of reaction (TLC monitoring), water was added to the reaction and extracted with EtOAc (3×25 mL). The combined organics was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was triturated with ether to obtain the desired product (0.10 g, 72%). MS: 245.10 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1.[CH3:14]N(CCN(C)C)C.[Li]CCCC.IC>C1COCC1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9]2)=[CH:5][CH:4]=1
Reactant: CN(C)CCN(C)C
Reactant: COc1ccc2c(c1)NC(=O)C2C
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: COc1ccc2c(c1)NC(=O)C2(C)C
Temperature: -25 °C
Reaction time: 0.25 h

Procedure:
To a cooled solution (−78° C.) of 6-methoxy-3-methyl-1,3-dihydro-indol-2-one (679 mg, 3.83 mmol, example 77) in THF (13 mL) is added TMEDA (1.16 mL, 7.66 mmol) followed by dropwise addition of 2.5M n-BuLi (3.06 mL, 7.66 mmol). The mixture is stirred 15 min then warmed to −25° C. Iodomethane (275 μL, 4.40 mmol) is added dropwise and stirred for 30 min. Reaction is quenched with sat NH4Cl soln, warmed to room temp and diluted with EtOAc. Washed organic layer with sat NH4Cl soln, brine, dried over MgSO4 and concentrated. The residue is purified by flash chromatography (silica, 35% ethyl acetate in hexanes) to give the title compound as a white crystalline solid. MS (ESI) 192 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[O-:10][CH2:11][CH3:12].[Na+]>C(O)C.O>[Br:1][C:2]1[C:3]([O:10][CH2:11][CH3:12])=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cnc(Cl)c(Br)c1
Reactant: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOc1ncc(C)cc1Br
Temperature: 100 °C
Reaction time: 48 h
Yield: 71.7 %

Procedure:
To a solution of 3-bromo-2-chloro-5-methylpyridine (4.00 g, 19.37 mmol) in ethanol (100 mL) was added sodium ethoxide (6.59 g, 96.9 mmol) in three portions. The mixture was stirred under nitrogen at 100° C. for 2 days. The reaction was cooled to room temperature, diluted with water and extracted with DCM. The combined organic layers were dried (Na2SO4), and the solvent was removed under reduced pressure. Purification (FCC, SiO2, 20%, EtOAc/hexanes) afforded the title compound (3.00 g, 72%). 1H NMR (400 MHz, DMSO-d6) δ 7.94 (dd, J=0.8, 2.3 Hz, 1H), 7.89-7.82 (m, 1H), 4.31 (q, J=7.0 Hz, 2H), 2.18 (t, J=0.8 Hz, 3H), 1.30 (t, J=7.0 Hz, 3H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].[OH-].[Na+].[C:9]1([C:14](Cl)=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1.C([O-])(O)=O.[Na+]>C(OCC)C.O>[C:9]1([C:14]([S:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5])=[O:15])[S:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)c1cccs1
Reactant: O=C(O)CCS
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: O=C(O)CCSC(=O)c1cccs1

Procedure:
A mixture of 26.5 g (0.25 mol) of 3-mercaptopropionic acid, 150 mls of ethyl ether and 250 mls of 1-normal NaOH has been treated dropwise, the temperature being maintained between 0° C. and 5° C., with vigorous stirring, with 40.3 g of 2-thenoyl chloride (0.275 mol) in 80 mls of ethyl ether, while concurrently adding, so as to keep the pH of the reaction environment constantly alkaline, 31.5 g (0.36 mol) of NaHCO3 in 800 mls of water. On completion of dripping, stirring has been continued for 16 additional hours at room temperature. Upon separation of the organic phase, the waters have been extracted with ethyl ether again, and then made acidic with 4-normal hydrochloric acid. The as-formed precipitate has been recrystallized from 70% ethanol.
Reaction SMILES: [H-].[Na+].[S:3]1(=[O:10])(=[O:9])[N:8]=[CH:7][CH:6]=[CH:5][NH:4]1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32]Br)[CH2:27][CH2:26]1>CN(C)C=O>[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[N:25]1[CH2:30][CH2:29][CH:28]([CH2:31][CH2:32][N:8]2[CH:7]=[CH:6][CH:5]=[N:4][S:3]2(=[O:10])=[O:9])[CH2:27][CH2:26]1
Reactant: COc1cc2ncnc(N3CCC(CCBr)CC3)c2cc1OC
Reactant: O=S1(=O)N=CC=CN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(CCN4C=CC=NS4(=O)=O)CC3)c2cc1OC

Procedure:
Sodium hydride (0.19 g. of a 50% dispersion in oil) was added to a stirred solution of 2H-1,2,6-thiadiazine-1,1-dioxide (0.52 g) in dimethylformamide (4 cm3). After 0.5 hours 1-(6.7-dimethoxyquinazolin-4-yl)-4-(2-bromoethyl)piperidine (0.60 g) was added and the mixture was warmed at 70° for 10 hours. The solvent was removed in vacuo, water was added and the mixture was extracted with chloroform (4×20 cm3). The dried (MgSO4) extracts were evaporated and the residue was chromatographed on silica (Merck 60. 9385) eluting with methanol:ethyl acetate, 1:19, to give an oil which was crystallised from ethyl acetate to afford 1-(6,7-dimethoxyquinazolin-4-yl)-4-[2-(1,1-dioxo-1,2,6-thiadiazin-2-yl)ethyl]piperidine as microcrystals, m.p. 176°-8°, (0.18 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1.[Cl:14][CH:15]=[CH:16][CH2:17]Cl.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CS(C)=O>[Cl:14]/[CH:15]=[CH:16]/[CH2:17][N:2]([CH3:1])[CH2:3][C:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1cccc2ccccc12
Reactant: ClC=CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CN(C/C=C/Cl)Cc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 77 %

Procedure:
To a solution of 9.84 g (57.5 mmol) of N-methyl-1-naphthalenemethanamine in 60 ml of dimethyl sulfoxide were added 5.5 ml (60 mmol) of 1,3-dichloropropene (E/Z=9/1) and 8.28 g (60 mmol) of potassium carbonate under ice cooling. The mixture was stirred for 6 hours at room temperature, poured into 250 ml of ethyl acetate, washed with 150 ml×3 of water and 150 ml of saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel chromatography (n-hexane→n-hexane/ethyl acetate=9/1). The desired fractions were put together and concentrated under reduced pressure to obtain 10.86 g (yield: 77%) of the above identified compound as an oil.