Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20]OS(C)(=O)=O)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.[ClH:39].CO>CC(C)=O>[ClH:39].[ClH:39].[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC(C)=O
Product: CN1CCN(Cc2ccc3c(c2)CN(C(=O)OCc2ccccc2)C3)CC1
Temperature: 15 °C
Reaction time: 3 h
Yield: 65 %

Procedure:
The solid from Step 8 (assume 0.232 mol) was dissolved in acetone (700 mL) and this solution was added over 45 mins to a cooled (internal temp 15-17° C.) suspension of K2CO3 (48 g) and N-methylpiperazine (50 mL, 0.45 mol) in acetone (330 mL). The suspension was stirred at 15° C. for 3 h (complete removal of starting material by tlc) when the solution was evaporated to a small volume and the residue partition between EtOAc (1000 mL) and a mixture of water (500 mL) and saturated brine (50 mL). The organic phase was washed with a mixture of water (500 mL) and saturated brine (150 mL) and finally washed with saturated brine (300 mL). The solution was dried (MgSO4) and filtered and to this solution was added 1M-HCl in MeOH (430 mL, 0.43 mol). The suspension was cooled (0° C. for 30 mins) and the solid removed by filtration which was washed with EtOAc and then heptane on the sinter and the solid dried (oil-pump, RT 72 h) to give crop 1 of the title compound 66.34 g (65%) as a colourless solid. 1H NMR (400 MHz, Me-d3-OD): 7.64-7.51 (m, 2H), 7.51-7.29 (m, 6H), 5.23 (s, 2H), 4.79 (dd, J=16.2, 6.1 Hz, 4H), 4.49 (s, 2H), 3.66 (s, 8H), 3.03 (s, 3H).
Reaction SMILES: [O:1]=[O+][O-].[CH2:4]([CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=2)[C:9]1=[O:22])[CH:5]=CC>ClCCl.CO>[O:1]=[CH:5][CH2:4][CH:8]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:13][CH:14]=2)[C:9]1=[O:22]
Reactant: CC=CCC1Cc2ccc(OS(C)(=O)=O)cc2C1=O
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)Oc1ccc2c(c1)C(=O)C(CC=O)C2
Reaction time: 0.92 h
Yield: 85 %

Procedure:
An ozone stream (2 g ozone/hour) was conducted for 55 minutes while stirring through a solution, cooled to -70°, of 11.3 g of (RS)-2-(2-buten-1-yl)-6-mesyloxy-1-indanone in 300 ml of anhydrous dichloromethane and 60 ml of anhydrous methanol. Subsequently, the solution was flushed with oxygen for 5 minutes and with argon for 10 minutes. After the addition of 4.51 ml of dimethyl sulfide, the mixture was stirred at room temperature for 15 hours. The reaction mixture was evaporated in a vacuum. The residue was treated with 250 ml of dichoromethane and, after the addition of 25 ml of water and 25 ml of trifluoroacetic acid, stirred at room temperature for 4 hours. The mixture was subsequently poured into 200 ml of water and neutralized by the spatula-wise addition of sodium hydrogen carbonate while stirring. An additional 50 ml of water were added. The phases were separated and the aqueous phase was extracted twice with 200 ml of dichloromethane each time. The combined organic phases were dried over magnesium sulfate and concentrated in a vacuum. 9.38 g (85%) of (RS)-2-(2-oxoethyl)-6-mesyloxy-1-indanone were obtained as a light brown solid with m.p. 85°-87°.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=[C:11]2[C:31]2[CH:32]=[N:33][C:34]([C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:35][C:36]=2[O:37][CH2:38][CH3:39])=[O:9])[CH2:4][CH2:3]1.[CH:44]1([N:49]=[C:50]=[O:51])[CH2:48][CH2:47][CH2:46][CH2:45]1>>[C:40]([C:34]1[N:33]=[CH:32][C:31]([C:11]2[N:10]([C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][C:50]([NH:49][CH:44]4[CH2:48][CH2:47][CH2:46][CH2:45]4)=[O:51])[CH2:7][CH2:6]3)=[O:9])[C@@:14]([C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=3)([CH3:15])[C@@:13]([C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=3)([CH3:23])[N:12]=2)=[C:36]([O:37][CH2:38][CH3:39])[CH:35]=1)([CH3:42])([CH3:41])[CH3:43]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(N)CC1
Reactant: O=C=NC1CCCC1
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(NC(=O)NC2CCCC2)CC1

Procedure:
In a manner similar to the method described in example 160, (4-amino-piperidin-1-yl)-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazol-1-yl]-methanone (example 204) was reacted with cyclopentyl isocyanate (Aldrich) to give the title compound. LC-MS (ES+) 733 [(M+H)+].
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[C:17]([O:19][CH3:20])[C:16]([O:21][CH3:22])=[C:15]([O:23][CH3:24])[CH:14]=2)[S:11][CH:12]=1)(=O)=O.[NH:25]1[CH2:31][CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>>[CH3:24][O:23][C:15]1[CH:14]=[C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][CH2:6][N:25]3[CH2:31][CH2:30][CH2:29][N:28]([CH2:6][CH2:7][C:8]4[N:9]=[C:10]([C:13]5[CH:14]=[C:15]([O:23][CH3:24])[C:16]([O:21][CH3:22])=[C:17]([O:19][CH3:20])[CH:18]=5)[S:11][CH:12]=4)[CH2:27][CH2:26]3)[N:9]=2)[CH:18]=[C:17]([O:19][CH3:20])[C:16]=1[O:21][CH3:22]
Reactant: C1CNCCNC1
Reactant: COc1cc(-c2nc(CCOS(C)(=O)=O)cs2)cc(OC)c1OC
Product: COc1cc(-c2nc(CCN3CCCN(CCc4csc(-c5cc(OC)c(OC)c(OC)c5)n4)CC3)cs2)cc(OC)c1OC

Procedure:
4-(2-Methanesulfonyloxyethyl)-2-(3,4,5-trimethoxy-phenyl)thiazole (250mg) and homopiperazine (30mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15](Cl)(=[O:18])[CH2:16][CH3:17]>C(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH2:3][CH:2]1[NH:14][C:15](=[O:18])[CH2:16][CH3:17]
Reactant: CCC(=O)Cl
Reactant: NC1CCc2c([nH]c3ccccc23)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCC(=O)NC1CCc2c([nH]c3ccccc23)C1
Reaction time: 5 h

Procedure:
A solution of 0.05 mol of 2,3,4,9-tetrahydro-1H-carbazol-2-amine in 450 ml of CHCl3 and 185 ml of saturated aqueous NaHCO3 was stirred vigorously at room temperature and treated dropwise during 30 min with a solution of 0.15 mol of propanoyl chloride in an equal volume of CHCl3. After stirring vigorously for 5 hr, the CHCl3 layer was separated, washed in succession with 10% aqueous K2CO3, H2O, 0.1 N hydrochloric acid, H2O, and dried over anhydrous Na2SO4. The residue remaining after evaporation of the CHCl3 was recrystallized from ethyl acetate to give the title compound, mp 169°-170°.
Reaction SMILES: [C:1]1([C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[S:8][CH2:9][CH2:10][C:11](ON2C(=O)CCC2=O)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:33][CH2:34][CH2:35][O:36][CH2:37][CH2:38][O:39][CH2:40][CH2:41][O:42][CH2:43][CH2:44][OH:45].[OH-].[NH4+]>ClCCl>[OH:45][CH2:44][CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38][CH2:37][O:36][CH2:35][CH2:34][NH:33][C:11](=[O:12])[CH2:10][CH2:9][S:8][C:7]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCCOCCOCCOCCO
Reactant: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)ON1C(=O)CCC1=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)NCCOCCOCCOCCO
Temperature: 25 °C
Reaction time: 48 h
Yield: 82.7 %

Procedure:
Succinimido 3-(triphenylmethylthio)propanoate (4.06 mg, 9.12 mmol) was added to a 0° C. solution of 2-{2-[2-(2-aminoethoxy)ethoxy]ethoxy}ethanol (C. Bertozzi and M. Bednarski, J. Org. Chem. 1991, 56, 4326-4329) (9.12 mmol) in dichloromethane (20 mL). The solution was stirred at room temperature for 2 days and concentrated ammonium hydroxide (1 mL) was added. After 20 minutes, the mixture was filtered and the filtrate was subjected to an extractive workup. The organic layer were dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by HPFC on silica gel (gradient elution with 2-19% CMA in chloroform) to provide 3.95 g of N-(2-{2-[2-(2-hydroxyethoxy)ethoxy]ethoxy}ethyl)-3-(tritylthio)propanamide as a colorless oil.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:24].[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([CH3:33])=[C:30]([OH:32])[CH:31]=1>C1COCC1>[OH:32][C:30]1[CH:31]=[C:26]([NH:25][CH:2]=[C:3]2[C:11]3[C:6](=[CH:7][C:8]([C:12]([C:14]4[CH:15]=[C:16]([NH:20][C:21](=[O:23])[CH3:22])[CH:17]=[CH:18][CH:19]=4)=[O:13])=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:24])[CH:27]=[CH:28][C:29]=1[CH3:33]
Reactant: Cc1ccc(N)cc1O
Reactant: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(C)c(O)c2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 72.6 %

Procedure:
A small screw cap test tube was charged with N-[3-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-acetamide (as prepared in Example 40, 100 mg, 0.310 mmol) and THF (2 mL). To the resulting solution was added 5-amino-2-methylphenol (42.03 mg, 0.341 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature. Hexanes were added to the reaction mixture. The solid precipitate that formed was washed with ˜1 mL of i-prOH yielding 73% (100 mg, 0.225 mmol) of the title compound.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.Cl.[CH3:27][C@H:28]1[C:36]2[C:35]([N:37]3[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]3)=[N:34][CH:33]=[N:32][C:31]=2[C@H:30]([OH:43])[CH2:29]1.C(OC([N:51]1[CH2:55][CH2:54][C:53]([C:59]2[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=2)([C:56](O)=[O:57])[CH2:52]1)=O)(C)(C)C>C(Cl)Cl>[Cl:65][C:62]1[CH:63]=[CH:64][C:59]([C:53]2([C:56]([N:40]3[CH2:39][CH2:38][N:37]([C:35]4[C:36]5[C@H:28]([CH3:27])[CH2:29][C@@H:30]([OH:43])[C:31]=5[N:32]=[CH:33][N:34]=4)[CH2:42][CH2:41]3)=[O:57])[CH2:54][CH2:55][NH:51][CH2:52]2)=[CH:60][CH:61]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CCNCC3)c21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccc(Cl)cc2)C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1C[C@@H](O)c2ncnc(N3CCN(C(=O)C4(c5ccc(Cl)cc5)CCNC4)CC3)c21
Temperature: 25 °C
Reaction time: 10 h
Yield: 80.8 %

Procedure:
HBTU (37 mg, 0.098 mmol) was added to a solution of (5R,7R)-5-methyl-4-(piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride (30 mg, 0.098 mmol) and 1-(tert-butoxycarbonyl)-3-(4-chlorophenyl)pyrrolidine-3-carboxylic acid (32 mg, 0.098 mmol) in DCM (5 mL) and TEA (1 mL). The mixture was stirred at room temperature for 10 hours. The solvent was removed, and the residue was subjected to column chromatography, eluted by ethyl acetate-DCM/MeOH (20:1). The product was treated with HCl (4M, 2 mL) in DCM (5 mL) to afford (3-(4-chlorophenyl)pyrrolidin-3-yl)(4-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazin-1-yl)methanone as the HCl salt (35 mg, 81%).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5].CO.[H][H]>C(Cl)Cl.[Ru]>[OH:1][C@H:2]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:3][C:4]([O:6][CH3:7])=[O:5]
Reactant: [H][H]
Reactant: CCCCCC(=O)CC(=O)OC
Agent: [Ru]
Solvent: CO
Solvent: ClCCl
Product: CCCCC[C@@H](O)CC(=O)OC
Yield: 94.9 %

Procedure:
Into a 100-ml autoclave (made of Hastelloy) were introduced 20 g of methyl 3-oxooctanoate (manufactured by Inoue Perfumery Mfg. Co., Ltd., Japan) and 40 ml of methanol. The atmosphere in the autoclave was replaced with nitrogen gas. Thereto was added a solution prepared by dissolving 150 mg of Ru2Cl4 ((+)-(T)BINAP)2Et3N as a ruthenium-optically active phosphine complex in 1.2 ml of methylene chloride. Asymmetric hydrogenation was conducted at a reaction temperature of 65° C. and a hydrogen pressure of 30 atm. After the reaction mixture was thus reacted for 6 hours, it was taken out of the autoclave. The methanol was distilled off, and the residue was subjected to vacuum distillation to obtain 19.2 g of methyl (R)-3-hydroxyoctanoate. Yield, 95%.
Reaction SMILES: [C:1]([NH:20][C@@H:21]1[CH2:26][CH2:25][CH2:24][CH2:23][C@H:22]1[OH:27])(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40](O)=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1>>[CH3:28][C:29]1([CH3:45])[O:34][CH:33]([C:35]([NH:37][CH2:38][CH2:39][C:40]([O:27][C@@H:22]2[CH2:23][CH2:24][CH2:25][CH2:26][C@H:21]2[NH:20][C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:41])=[O:36])[C:32]([CH3:44])([CH3:43])[CH2:31][O:30]1
Reactant: CCCCCCCCCCCCCCCCCC(=O)N[C@@H]1CCCC[C@H]1O
Reactant: CC1(C)OCC(C)(C)C(C(=O)NCCC(=O)O)O1
Product: CCCCCCCCCCCCCCCCCC(=O)N[C@@H]1CCCC[C@H]1OC(=O)CCNC(=O)C1OC(C)(C)OCC1(C)C
Yield: 45.3 %

Procedure:
(1R,2R)-2-(N-Stearoylamino)cyclohexanol (3.81 g) and 2.59 g of 3-[N-(2,2,5,5-tetramethyl-1,3-dioxane-4-carbonyl)amino]propionic acid were reacted in the same manner as in Example 15 to obtain 2.82 g of the title compound (yield: 45%)
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3]1=[O:25].Cl[CH2:27][CH:28]1[CH2:30][CH2:29]1>>[CH:28]1([CH2:27][N:7]2[C:6]3[C:5](=[O:11])[N:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][P:17](=[O:24])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20])[C:3](=[O:25])[N:2]([CH3:1])[C:10]=3[N:9]=[CH:8]2)[CH2:30][CH2:29]1
Reactant: CCOP(=O)(CCCCCn1c(=O)c2[nH]cnc2n(C)c1=O)OCC
Reactant: ClCC1CC1
Product: CCOP(=O)(CCCCCn1c(=O)c2c(ncn2CC2CC2)n(C)c1=O)OCC

Procedure:
The title substance was prepared from 0.011 mol of diethyl [5-(3-methyl-xanthin-1-yl)pentyl]phosphonate and 0.013 mol of chloromethylcyclo-propane analogously to Example 46.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26](=[O:30])[N:27]([CH3:29])[CH3:28])[NH2:20]>>[Cl:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[O:24][CH2:25][C:26](=[O:30])[N:27]([CH3:28])[CH3:29])[NH:20][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(Nc2cc(Cl)ncn2)c1
Reactant: CN(C)C(=O)COc1ccc(N)cc1Cl
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(=O)N(C)C)c(Cl)c3)ncn2)c1
Yield: 46 %

Procedure:
Using an analogous procedure to that described in Example 18, 4-chloro-6-(3'-methylanilino)pyrimidine (0.33 g) was reacted with 3-chloro-4-(N,N-dimethylcarbamoylmethoxy)aniline to give 4-[3'-chloro-4'-(N,N-dimethylcarbamoylmethoxy)anilino]6-(3'-methylanilino)pyrimidine is 46% yield, m.p. 190°-193° C.;
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:13]=[N:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[Cl:14][C:15]1[CH:20]=[C:19](Cl)[N:18]=[CH:17][N:16]=1>CN(C=O)C>[Cl:14][C:15]1[N:16]=[CH:17][N:18]=[C:19]([O:3][C:4]2[CH:13]=[N:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:20]=1
Reactant: Oc1cnc2ccccc2n1
Reactant: Clc1cc(Cl)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1cc(Oc2cnc3ccccc3n2)ncn1
Reaction time: 0.25 h

Procedure:
40 mg (0.92 mmol) sodium hydride (55%, suspension in mineral oil) were added to 0.10 g (0.68 mmol) 2-hydroxyquinoxaline in 1.5 mL DMF and the mixture was stirred for 15 min. Then 0.11 g (0.69 mmol) 4,6-dichloropyrimidine were added and the mixture was stirred overnight at RT. The reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined, the acetonitrile was eliminated i.vac., and the precipitated product was suction filtered and dried.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=1.Cl.[CH:16]12[NH:23][CH:20]([CH2:21][CH2:22]1)[CH2:19][O:18][CH2:17]2.CCN(CC)CC>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:3]=[C:2]([N:23]2[CH:16]3[CH2:22][CH2:21][CH:20]2[CH2:19][O:18][CH2:17]3)[N:7]=1
Reactant: C1CC2COCC1N2
Reactant: Clc1nc(Cl)nc(N2CCOCC2)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Clc1nc(N2CCOCC2)nc(N2C3CCC2COC3)n1
Temperature: 25 °C
Yield: 96.2 %

Procedure:
To a solution of 4-(4,6-dichloro-1,3,5-triazin-2-yl)morpholine (2.34 g, 10 mmol) in CH2Cl2 (100 mL) were added 3-oxa-8-azabicyclo[3,2,1]octane hydrochloride (1.645 g, 11 mmol) and Et3N (4.2 mL, 30 mmol). The mixture was stirred at room temperature over night. The reaction mixture was washed with water and brine, and dried over MgSO4. The solvent was removed in vacuum to give the title compound as white solid (3.0 g, 96% yield). MS (ESI) m/z 312.1.
Reaction SMILES: [Cl:1][C:2]1(Cl)[CH2:8][CH2:7][C:6]([CH3:10])([CH3:9])[CH2:5][NH:4][C:3]1=[O:11].[H][H]>C(O)(=O)C.[Pd]>[Cl:1][CH:2]1[CH2:8][CH2:7][C:6]([CH3:9])([CH3:10])[CH2:5][NH:4][C:3]1=[O:11]
Reactant: CC1(C)CCC(Cl)(Cl)C(=O)NC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC1(C)CCC(Cl)C(=O)NC1
Yield: 99.5 %

Procedure:
3.0 g (14.3 mmoles) of 3,3-dichloro-6,6-dimethyl-2-oxoperhydroazepine were dissolved in 300 ml of glacial acetic acid and shaked at 40 psi of hydrogen with 1.9 g of 10% Pd/C. When the theoretical amount of hydrogen was consumed the catalyst was filtered off and the filtrate evaporated in vacuo to yield 2.5 g of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][N:9]=2)[CH:4]=1.Cl.[NH2:13][C:14]1[CH:15]=[C:16]([NH:21][C:22](=[O:34])[C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([C:32]#[N:33])([CH3:31])[CH3:30])[CH:24]=2)[CH:17]=[CH:18][C:19]=1[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[C:32]([C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[C:22]([NH:21][C:16]1[CH:17]=[CH:18][C:19]([CH3:20])=[C:14]([NH:13][CH2:2][C:3]2[S:11][C:10]3=[N:9][CH:8]=[CH:7][N:6]=[C:5]3[CH:4]=2)[CH:15]=1)=[O:34])([CH3:30])[CH3:31])#[N:33]
Reactant: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1N
Reactant: BrCc1cc2nccnc2s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1NCc1cc2nccnc2s1
Yield: 6.2 %

Procedure:
A solution of 6-(bromomethyl)thieno[3,2-b]pyrazine 47 (50 mg, 0.218 mmol), N-(3-amino-4-methylphenyl)-3-(2-cyanopropan-2-yl)benzamide hydrochloride 6 (72 mg, 0.218 mmol) and potassium carbonate (90 mg, 0.655 mmol) in acetonitrile (2 mL) was stirred overnight at 50° C. Water was added and extracted with EtOAc. Organic layer was washed with brine, dried and evaporated. Purification by HPLC gave the title compound 3-(2-cyanopropan-2-yl)-N-(4-methyl-3-(thieno[2,3-b]pyrazin-6-ylmethylamino)phenyl)benzamide 48 (6 mg, 6.23%). NMR (400 MHz, DMSO-d6) 1.71 (s, 6H), 2.16 (s, 3H), 4.72 (d, J=5.5 Hz, 2H), 6.02 (t, J=6.2 Hz, 1H), 6.98 (s, 2H), 7.08 (s, 1H), 7.54 (m, 2H), 7.70 (d, J=7.8 Hz, 1H), 7.83 (d, J=7.8 Hz, 1H), 7.92 (t, J=1.6 Hz, 1H), 8.50 (d, J=2.3 Hz, 1H), 8.66 (d, J=2.3 Hz, 1H), 10.00 (s, 1H). (m/z)=442 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:6]=1.[S:15](Cl)([CH3:18])(=[O:17])=[O:16]>N1C=CC=CC=1>[CH3:18][S:15]([NH:1][C:2]1[S:3][C:4]([S:7][CH2:8][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][N:6]=1)(=[O:17])=[O:16]
Reactant: Nc1ncc(SCc2ccccc2)s1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ncc(SCc2ccccc2)s1
Temperature: 60 °C
Yield: 85.1 %

Procedure:
To a mixture of 2-amino-5-benzylthiothiazole (6.7 g.) and pyridine (50 ml.) was dropwise added mesyl chloride (10.3 g.) over 15 minutes under ice-cooling and stirring, and the mixture was stirred for 3.5 hours at room temperature. After the reaction, the reaction mixture was poured into ice-water (300 ml.), and the precipitates were collected by filtration and then washed with water. The precipitates were added to 1 N sodium hydroxide aqueous solution (50 ml.), and the mixture was heated at 60° C. to produce a solution. The solution was treated with activated carbon and then neutralized. The precipitates were collected by filtration, washed with water and then dried to give powder of 2-methanesulfonamido-5-benzylthiothiazole (7.7 g.), mp 159° to 162° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([S:22][CH2:23][CH2:24][C:25](OC)=O)[CH:12]=[N:13][C:14]=1[NH:15][C:16]1[S:17][CH:18]=[C:19]([CH3:21])[N:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Cl:35][C:36]1[CH:41]=CC(CCl)=[CH:38][CH:37]=1.Cl>>[ClH:35].[Cl:35][C:36]1[CH:41]=[CH:25][C:24]([CH2:23][S:22][C:11]2[CH:10]=[C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:14]([NH:15][C:16]3[S:17][CH:18]=[C:19]([CH3:21])[N:20]=3)=[N:13][CH:12]=2)=[CH:38][CH:37]=1
Reactant: COC(=O)CCSc1cnc(Nc2nc(C)cs2)c(OCc2ccccc2)c1
Reactant: ClCc1ccc(Cl)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Product: Cc1csc(Nc2ncc(SCc3ccc(Cl)cc3)cc2OCc2ccccc2)n1
Yield: 137.2 %

Procedure:
Methyl 3-(5-(benzyloxy)-6-(4-methylthiazol-2-ylamino)pyridin-3-ylthio)propanoate (prepared according to Example 42; 70 mg, 0.17 mmol), KOtBu (0.59 mL, 0.59 mmol) and 1-chloro-4-(chloromethyl)benzene (27 mg, 0.17 mmol) were reacted according to the method of Example 43 to afford 5-(4-chlorobenzylthio)-3-(benzyloxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine hydrochloride (57.2 mg, 69.2% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 10.85 (bs, 1H), 7.79 (d, 1H), 7.57 (m, 2H), 7.53 (d, 1H), 7.45-7.34 (m, 3H), 7.30 (m, 2H), 7.18 (m, 2H), 6.78 (s, 1H), 5.29 (s, 2H), 4.17 (s, 2H), 2.29 (d, 3H); Mass spectrum (apci) m/z=238.0 (100), 454.0 (75), 362.9 (60).
Reaction SMILES: [CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=O)=[CH:6][CH:5]=1)[CH3:2].[C:22]1([CH:28](P(=O)(OCC)OCC)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(C)([O-])C.[K+]>CN(C=O)C>[CH2:1]([N:3]([CH2:20][CH3:21])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=[C:28]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc(C(=CC=O)c2ccccc2)cc1
Reactant: CCOP(=O)(OCC)C(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCN(CC)c1ccc(C(=CC=C(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Temperature: 31 °C
Reaction time: 4 h
Yield: 68 %

Procedure:
2.79 g of 3-(p-diethylaminophenyl)-3-phenylacrolein and 3.34 g of diethyl diphenylmethylphosphonate were dissolved in 100 ml of DMF, and 1.23 g of potassium t-butoxide was added thereto at room temperature. The temperature of the reaction mixture was increased to 31° C. by a heat generated and, thereafter, the reaction was conducted at room temperature for 4 hours. The reaction mixture was poured into 100 cc of ice water and stirred. Deposited crystals were collected by filtration, dissolved in benzene, and separated and purified on silica gel column chromatography. After distilling off benzene from the eluate, the purified product was recrystallized from ethyl acetate to obtain 2.9 g (yield: 68% (theory)) of a pale-yellow crystal. m.p.: 124°-5° C.