Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][C:11](O)=[O:12].CO>C1COCC1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][OH:12]
Reactant: COc1ccccc1CCC(=O)O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1CCCO
Reaction time: 4 h
Yield: 102.5 %

Procedure:
3-(2-methoxyphenyl)propanoic acid (1.0 g, 5.55 mmol) was dissolved in THF (27.7 ml). A solution of borane tetrahydrofuran complex (12.21 ml, 12.21 mmol) was added slowly. The reaction was stirred for about 4 h. Methanol was added and the solvents removed. This process was repeated twice. The solution was passed through a short pad of silica gel with 1:1 ethyl acetate/heptane And then rotovapped to give 3-(2-methoxyphenyl)propan-1-ol (0.946 g, 5.69 mmol, 103% yield) as a colorless oil. 1H NMR (400 MHz, CDCl3) δ ppm 7.19 (dt, 1H), 7.15 (dd, 1H), 6.90 (dt, 1H), 6.86 (d, 1H), 3.84 (s, 3H), 3.60 (t, 2H), 2.73 (t, 2H), −1.92-1.79 (m, 2H), 1.76 (s, 1H),
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[NH:16][CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1.[CH:18](OC)=[O:19]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]2[N:16]([CH:18]=[O:19])[CH2:15][CH2:14][NH:13][C:12]2=[O:17])=[CH:3]1
Reactant: COC=O
Reactant: Cn1cc(C2NCCNC2=O)c2ccccc21
Product: Cn1cc(C2C(=O)NCCN2C=O)c2ccccc21

Procedure:
22.9 g (0.1 mol) of 3-(1-methylindol-3-yl)-piperazin-2-one, prepared in accordance with Example 34, are reacted with methyl formate, as described in Example 5.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:24])([O-:20])=[O:19]
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)c4ccccc4[N+](=O)[O-])nc23)CC1
Yield: 89.9 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.007 mL (0.048 mMol) 2-nitrobenzoyl chloride, 0.015 gm (92%) of the title compound was prepared essentially by the procedure described in Example 7.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:13][CH2:12][NH:11][C:10]2=[O:14])=[CH:5][CH:4]=1.CN(C=O)C.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]>O>[O:14]=[C:10]1[N:9]([C:6]2[CH:5]=[CH:4][N:3]=[CH:8][CH:7]=2)[CH2:13][CH2:12][N:11]1[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C1NCCN1c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCN(c2ccncc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
Sodium hydride (60% in oil, 0.40 g, 10.1 mmol) was added to a mixture of 1-(4-pyridyl)-2-imidazolidinone (1.5 g, 9.2 mmol) and DMF (20 ml) at 0° C., and the mixture was stirred at room temperature for 30 minutes. Successively, tert-butyl bromoacetate (2.2 g, 11.2 mmol) was added to the mixture, and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was combined with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with ethyl acetate-methanol (5:1, v/v) were collected, concentrated and recrystallized from tetrahydrofuran-hexane to give the titled compound (1.7 g, 68%) as white crystals.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>C(O)(CC)C>[Br:1][C:2]1[C:3]([N:24]2[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:25]2)=[C:4]2[C:10]([NH:11][C:12]([C@@H:14]3[CH2:16][C@H:15]3[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCNC1
Reactant: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Solvent: CCC(C)O
Product: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)[C@@H]4C[C@H]4c4ccccc4)c23)C1
Yield: 48.3 %

Procedure:
trans-N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (500 mg, 1.34 mmol) and (R)-tert-butyl piperidin-3-ylcarbamate (1338 mg, 6.68 mmol) in s-BuOH (5 mL) were heated to 135° C. in a sealed tube for 24 hours. After cooling down, the residue was concentrated and purified by reverse phase chromatography (SP4, 25M, water/ACN 80/20→0/100, 30 CV) to yield tert-butyl (R)-1-(5-bromo-3-(trans-2-phenyl cyclopropanecarboxamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (359 mg, 48.5% yield) as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[NH:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(#N)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:30]([CH2:34][CH2:35][OH:36])[CH2:31][CH2:32][OH:33])=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: OCCNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN(CCO)CCO)ccc21
Yield: 63.3 %

Procedure:
In a similar manner to Step 2 of Example 6, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (37.6 mg, 0.0922 mmol) was dissolved in acetonitrile (2 mL), and the solution was treated with diethanolamine (0.035 mL, 0.37 mmol), acetic acid (0.106 mL, 1.85 mmol) and sodium triacetoxyborohydride (98 mg, 0.46 mmol), followed by purification by preparative thin-layer chromatography (hexane/ethyl acetate=1/2) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[di(2-hydroxyethyl)aminomethyl]indol-2-yl)isoindolinone (29.2 mg, yield 64%).
Reaction SMILES: [CH:1]1([N:6]2[C:10]([C:11]3[CH:16]=[CH:15][NH:14][C:13](=S(=O)=O)[N:12]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH:27]1([N:33]2C(C3C=CNC(=S(=O)=O)N=3)=C(C3C=CC(F)=CC=3)N=C2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1>>[CH:1]1([N:6]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:33][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[N:12]=3)=[C:9]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:8]=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)=c1nc(-c2c(-c3ccc(F)cc3)ncn2C2CCCCC2)cc[nH]1
Reactant: O=S(=O)=c1nc(-c2c(-c3ccc(F)cc3)ncn2C2CCCC2)cc[nH]1
Product: Fc1ccc(-c2ncn(C3CCCC3)c2-c2ccnc(Nc3ccccc3)n2)cc1

Procedure:
The reaction was conducted in a manner analogous to Example 2d except substituting polymer-bound 1-cyclopentyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole for polymer-bound 1-cyclohexyl-4-(4-fluorophenyl)-5-[(2-sulfonyl)pyrimidin-4-yl]imidazole: ESMS m/z=400 (MH)+
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C1COCC1.[Cl:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=O)[O:34][CH2:33]2.Cl>C(COC)OC>[Cl:26][CH2:27][CH2:28][N:29]([CH3:40])[C:30]1[CH:31]=[C:32]2[C:36](=[CH:37][CH:38]=1)[C:35](=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])[O:34][CH2:33]2
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(CCCl)c1ccc2c(c1)COC2=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COCCOC
Product: CN(CCCl)c1ccc2c(c1)COC2=C1C(=O)Nc2ccccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 80 %

Procedure:
To a stirred solution of oxindole (0.739 g, 5.55 mmol) in anhydrous dimethoxyethane (10 ml) under nitrogen was added 1.0M LiHMDS/THF solution (14.0 ml, 14.0 mmol). The mixture was stirred at room temperature for 10 minutes, and 5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-one (1.0 g, 4.4 mmol) was added. The mixture was stirred at room temperature for 3 hours and was then poured into 1M HCl aqueous solution (300 ml) with stirring. The resulting mixture was heated at 40° C. for 30 minutes. The solid was filtered, washed with water and dried under vacuum to afford 3-{5-[(2-chloro-ethyl)-methyl-amino]-3H-isobenzofuran-1-ylidene}-1,3-dihydro-indol-2-one as a yellow solid (1.20 g, 79%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]([CH2:29][CH2:30][C:31]3[CH:36]=[C:35]([O:37][CH3:38])[C:34]([NH2:39])=[CH:33][C:32]=3[Cl:40])[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:41]([C:43]1[N:44]=[CH:45][C:46]([NH:49][C:50](=O)[O:51]C2C=CC=CC=2)=[N:47][CH:48]=1)#[N:42]>CN(C=O)C.O>[C:25]([O:24][C:22]([N:21]([CH2:20][C:17]1[CH:18]=[CH:19][C:14]([N:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH2:10]2)=[CH:15][CH:16]=1)[CH2:29][CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([NH:39][C:50]([NH:49][C:46]2[CH:45]=[N:44][C:43]([C:41]#[N:42])=[CH:48][N:47]=2)=[O:51])=[CH:33][C:32]=1[Cl:40])=[O:23])([CH3:26])([CH3:28])[CH3:27]
Reactant: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1N
Reactant: N#Cc1cnc(NC(=O)Oc2ccccc2)cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(CCN(Cc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 25 °C
Yield: 54.2 %

Procedure:
A stirred solution of tert-butyl-4-(4-(((4-amino-2-chloro-5-methoxyphenethyl)(tert-butoxycarbonyl)amino)methyl)phenyl)piperazine-1-carboxylate (0.46 g, 0.800 mmol) and phenyl 5-cyanopyrazin-2-ylcarbamate (0.153 g, 0.64 mmol) in DMF (18 mL) was heated to 100° C. for 1.5 hours. The mixture was allowed to cool to room temperature, diluted with water (40 mL) and extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water (3×15 mL), brine (10 mL), dried (Na2SO4) and concentrated under reduced pressure. The residue was purified with column chromatography on neutral silica gel using 1.5% methanol in DCM to give the title compound (0.25 g, 43%).
Reaction SMILES: CN(C)C(N(C)C)=N.[CH3:9][O:10][C:11](=[O:40])[CH:12](P(OC)(OC)=O)[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32].[CH2:41]([C:43]1[S:44][C:45]([CH:51]=O)=[C:46]([CH:48]([CH3:50])[CH3:49])[N:47]=1)[CH3:42].O>ClCCl>[CH3:9][O:10][C:11](=[O:40])/[C:12](/[NH:13][C:14](=[O:33])[C:15]1[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=2)=[O:22])=[CH:17][C:16]=1[Cl:32])=[CH:51]/[C:45]1[S:44][C:43]([CH2:41][CH3:42])=[N:47][C:46]=1[CH:48]([CH3:49])[CH3:50]
Reactant: CCc1nc(C(C)C)c(C=O)s1
Reactant: COC(=O)C(NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: ClCCl
Product: CCc1nc(C(C)C)c(/C=C(\NC(=O)c2ccc(C(=O)NCc3cccc(O)c3)cc2Cl)C(=O)OC)s1
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
1,1,3,3-Tetramethylguanidine (107 mg, 0.93 mmol) was added to a solution of rac.-N-[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (Example 141; 300 mg, 0.62 mmol) in dichloromethane (10 mL) at ˜5° C. The solution was stirred at ˜5° C. for 30 min and then 2-ethyl-4-(1-methylethyl)thiazole-5-carboxaldehyde (Example 61; 224 mg, 1.24 mmol) was added. The solution was stirred over a weekend at room temperature, then water was added and the layers were separated. The aqueous layer was extracted with two portions of dichloromethane then the combined organic layers were washed in turn with brine, 0.5N hydrochloric acid solution, water and brine. The dried (MgSO4) organic extracts were evaporated and the resulting oil was purified by chromatography over silica gel. Evaporation of the appropriate fractions afforded (Z)-2-[[2-chloro-4-[[(3-hydroxybenzyl)amino]carbonyl]benzoyl]amino]3-[2-ethyl-4-(1-methylethyl)thiazole-5-yl]propenoic acid methyl ester (220 mg, 65% yield).
Reaction SMILES: CN([CH:4]=[C:5]1[C:10](=O)[CH2:9][CH2:8][N:7]([C:12]2[C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=3)=[N:14][CH:15]=[CH:16][C:17]=2[CH3:18])[CH2:6]1)C.C(=O)(O)O.[NH2:33][C:34]([NH2:36])=[NH:35].O.O.O.C([O-])(=O)C.[Na+]>CO>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][O:19][C:13]2[C:12]([N:7]3[CH2:8][CH2:9][C:10]4[N:35]=[C:34]([NH2:36])[N:33]=[CH:4][C:5]=4[CH2:6]3)=[C:17]([CH3:18])[CH:16]=[CH:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(=O)C(=CN(C)C)C2)cc1
Reactant: N=C(N)N
Agent: CC(=O)[O-]
Agent: O=C(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1ccc(COc2nccc(C)c2N2CCc3nc(N)ncc3C2)cc1
Reaction time: 8 h
Yield: 37 %

Procedure:
A solution of 3-dimethylaminomethylene-2′-(4-methoxybenzyloxy)-4′-methyl-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (5.21 g, 13.66 mmol) in methanol (340 ml) was treated with guanidine carbonate (9.84 g, 54.63 mmol), followed by addition of sodium acetate trihydrate (14.87 g, 109.28 mmol) and the reaction mixture was refluxed for 3 hours. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The separated organic layer was dried (MgSO4), filtered, and concentrated to a red oil. The oil was taken up in a minimal volume of EtOAc and allowed to stand overnight at room temperature. The resulting yellow, crystalline solid was collected, washed with EtOAc, and dried to give the title compound (1.91 g). The mother liquor was concentrated and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, EtOAc) to obtain an additional lot of the title compound (1.05 g) The total amount 2.96 g, 57%). HPLC analysis showed the compound has a purity of 98%.
Reaction SMILES: [CH3:1][C:2]1[O:13][C:5]2[CH2:6][N:7]([CH3:12])[CH2:8][CH2:9][CH:10]([OH:11])[C:4]=2[CH:3]=1.[Br:14][C:15]1[CH:16]=[C:17](F)[CH:18]=[CH:19][C:20]=1[Br:21]>>[Br:14][C:15]1[CH:16]=[C:17]([O:11][CH:10]2[CH2:9][CH2:8][N:7]([CH3:12])[CH2:6][C:5]3[O:13][C:2]([CH3:1])=[CH:3][C:4]2=3)[CH:18]=[CH:19][C:20]=1[Br:21]
Reactant: Cc1cc2c(o1)CN(C)CCC2O
Reactant: Fc1ccc(Br)c(Br)c1
Product: Cc1cc2c(o1)CN(C)CCC2Oc1ccc(Br)c(Br)c1

Procedure:
The same method as in Example 1 was conducted using 2,7-dimethyl-5,6,7,8-tetrahydro-4H-furo[2,3-c]azepin-4-ol (Reference Example 20) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 3,4-dibromo-1-fluorobenzene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8](=[O:13])[CH2:7]2)([OH:3])=O.C(N(CC)CC)C.ClC(OCC(C)C)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C=O)C>[CH2:29]([N:36]1[CH2:41][CH2:40][N:39]([C:1]([C:4]2[CH:5]=[C:6]3[C:10](=[CH:11][CH:12]=2)[NH:9][C:8](=[O:13])[CH2:7]3)=[O:3])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: O=C1Cc2cc(C(=O)O)ccc2N1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C1Cc2cc(C(=O)N3CCN(Cc4ccccc4)CC3)ccc2N1
Reaction time: 1 h
Yield: 42 %

Procedure:
To a solution of 0.88 g of 5-carboxyoxindol in 10 ml of DMF was added under ice-cooling 0.82 ml of triethylamine, and 0.77 ml of isobutyl chloroformate was added thereto subsequently. The mixture was stirred at the same temperature for 1 hour. Then, 1.1 g of 1-benzylpiperazine was added thereto, and the mixture was stirred at room temperature overnight. After the reaction was completed, DMF was removed under reduced pressure, and to the residue was added an aqueous sodium hydrogencarbonate solution and extracted with chloroform. After washing with water and drying over magnesium sulfate, chloroform was distilled off under reduced pressure. The resultant residue was purified by silica-gel column chromatography (eluent: methylene chloride:methanol=50:1) and recrystallized from isopropyl alcohol to give 0.7 g of 5-(4-benzyl-1-piperazinylcarbonyl)oxindol.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[C:22]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[OH:13][CH2:12][CH2:11][NH:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([N:31]2[CH2:32][CH2:33][CH:28]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:29][CH2:30]2)[N:3]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:5]=1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Reactant: c1ccc(C2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccccc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with 4-phenyl-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-(2-hydroxy-ethylamino)-6-(4-phenyl-piperidin-1-yl)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, brownish powder; MS: [M+H]+=430.
Reaction SMILES: [F:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:21][CH2:22][NH:23][CH2:24][CH2:25]Cl>ClC1C=CC=CC=1Cl>[F:1][C:2]1[C:3]([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)=[C:4]([N:8]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)[CH:5]=[CH:6][CH:7]=1
Reactant: ClCCNCCCl
Reactant: CC1(C)C=C(c2c(N)cccc2F)CC(C)(C)C1
Agent: Cl
Solvent: Clc1ccccc1Cl
Product: CC1(C)C=C(c2c(F)cccc2N2CCNCC2)CC(C)(C)C1
Temperature: 200 °C
Yield: 26.8 %

Procedure:
To a solution of 3-fluoro-2-(3,3,5,5-tetramethylcyclohex-1-enyl)phenylamine (623 mg, 2.52 mmol) produced in Example (97c) in 1,2-dichlorobenzene (7 mL) was added bis(2-chloroethyl)amine hydrochloride (560 mg, 3.14 mmol), followed by reflux for 5 hours at an external temperature of 200° C. under a nitrogen atmosphere. During the reaction, a nitrogen stream was circulated into the reactor several times to remove the hydrogen chloride gas. After cooling the reaction mixture to room temperature, ethyl acetate, tetrahydrofuran, methanol, saturated aqueous solution of sodium carbonate and water were added for partition between oil and water. The aqueous layer was further extracted with ethyl acetate, and the combined organic layer was dried over anhydrous sodium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 214 mg of the title compound as a light brown oil.
Reaction SMILES: Cl[C:2]1[CH:6]=[C:5]([Cl:7])[S:4][C:3]=1[CH:8]=[O:9].[Na+].[N:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([O-:19])=[O:18]>>[Cl:7][C:5]1[S:4][C:3]([CH:8]=[O:9])=[C:2]([S:17]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][N:11]=2)(=[O:19])=[O:18])[CH:6]=1
Reactant: O=S([O-])c1ccccn1
Reactant: O=Cc1sc(Cl)cc1Cl
Agent: [Na+]
Product: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccn1

Procedure:
The title compound was prepared by the method of Preparation 42a using 3,5-dichlorothiophene-2-carbaldehyde and pyridine-2-sulfinate sodium salt.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[CH2:11]([O:13][CH2:14][C:15](Cl)=[O:16])[CH3:12]>N1C=CC=CC=1>[CH2:11]([O:13][CH2:14][C:15]([NH:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1)=[O:16])[CH3:12]
Reactant: CCOCC(=O)Cl
Reactant: Nc1nc2ccccc2s1
Solvent: c1ccncc1
Product: CCOCC(=O)Nc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2-Aminobenzothiazole (4.5 g) is dissolved in pyridine (100 ml) and thereto is added dropwise ethoxyacetyl chloride (3.0 ml) at room temperature. After the mixture is stirred at room temperature for 2 hours, the solvent is distilled off. The resulting solids are washed with water, dried and recrystallized from a mixed solvent of diethyl ether/n-hexane to give the title compound (4.5 g) having the following physical properties.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:7])[CH2:4][CH:5]=[CH2:6].[CH2:8](Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C=O)C>[CH2:3]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:4][CH:5]=[CH2:6]
Reactant: C=CCCO
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCCOCc1ccccc1
Reaction time: 0.5 h

Procedure:
NaH (0.24 g) was slowly added to a solution of 3-buten-1-ol (0.72 g) in DMF (15 ml) at 0° C., and the reaction stirred for 30 minutes. Benzyl bromide (1.9 g) was added and the reaction was stirred at 25° C. for 18 hours. The mixture was filtered and concentrated. The residue was dissolved in hexane, washed with water (3×), dried over MgSO4, and concentrated. Purification by chromatography over silica gel (5% ethyl ether in hexane) afforded the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:21][CH2:20]1)[N:13]=2)[CH:5]=O.FC(F)(F)C(O)=O.[NH:35]1[CH2:38][CH:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:36]1>>[F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[C:10]1[S:11][C:12]2[C:17]([N:18]=1)=[CH:16][CH:15]=[C:14]([C:19]1([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:21]1)[N:13]=2)[CH2:5][N:35]1[CH2:38][CH:37]([CH2:39][C:40]([OH:42])=[O:41])[CH2:36]1
Reactant: O=C(O)CC1CNC1
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CC1CN(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)C1

Procedure:
Reaction of 3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (100.0 mg, 0.267 mmol) and 2-(azetidin-3-yl)acetic acid trifluoroacetic acid (88.1 mg, 0.384 mmol) according to Reference R and the general procedure for reductive amination to give 2-(1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)azetidin-3-yl)acetic acid as a tan solid. MS (ESI) m/z: Calculated: 473.2; Observed: 474.1 (M++1).
Reaction SMILES: [N+](C1C=C([N+]([O-])=O)C=[CH:6][C:5]=1[S:13]([O-:16])(=[O:15])=O)([O-])=O.[Na+].[N+](C1C=C(C=[C:28]([N+]([O-])=O)[CH:29]=1)C(O)=O)([O-])=O>>[CH:29]([S:13]([CH2:5][S:13]([CH:5]=[CH2:6])(=[O:15])=[O:16])(=[O:16])=[O:15])=[CH2:28]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)[O-])c([N+](=O)[O-])c1
Agent: [Na+]
Product: C=CS(=O)(=O)CS(=O)(=O)C=C
Yield: 85 %

Procedure:
By the procedure used in A, except that sodium 2,4-dinitrobenzenesulfonate was substituted for 3,5-dinitrobenzoic acid, a 16.5 g (85 percent yield) sample (m.p. 59°-61° C.) of bis(vinylsulfonyl)methane was obtained. A 2 percent by weight aqueous solution was made up (no insoluble material) and let stand for more than 10 months at room temperature. Analysis of the still clear solution by high pressure liquid chromatography (HPLC) showed a 1.6 percent concentration of bis(vinylsulfonyl)methane remaining. A sample of the dry compound was also kept at room temperature for more than 10 months. A fresh 2 percent by weight solution made from this sample was found to contain 1.8 percent bis(vinylsulfonyl)methane by HPLC analysis.