Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:22]=[CH:21][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=2)=[O:10])=[CH:5][CH:4]=1)=[O:2].Br[CH2:24][C:25]([O:27][CH3:28])=[O:26].S(=O)(=O)(O)O>C1C=CC=CC=1.[Zn]>[OH:2][CH:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]([O:11][CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:19][CH3:20])=[CH:17][CH:18]=2)=[O:10])=[CH:21][CH:22]=1)[CH2:24][C:25]([O:27][CH3:28])=[O:26]
Reactant: COC(=O)CBr
Reactant: COc1ccc(COC(=O)C=Cc2ccc(C=O)cc2)cc1
Agent: O=S(=O)(O)O
Agent: [Zn]
Solvent: c1ccccc1
Product: COC(=O)CC(O)c1ccc(C=CC(=O)OCc2ccc(OC)cc2)cc1

Procedure:
Next, 296 mg of p-anisyl 4-formylcinnamate and 0.14 ml of methyl bromoacetate were dissolved in 4 ml benzene, and mixed with 95 mg of zinc powder to form a suspension, followed by heating under a stream of argon for 5 hours. The reaction mixture was allowed to cool, mixed with 10% sulfuric acid, extracted with ether and then washed with 5% sulfuric acid. The organic layer was washed with 10% aqueous sodium carbonate, and dried over magnesium sulfate. The drying agent was filtered off and the filtrate was evaporated under reduced pressure and dried to give p-anisyl 4-[1-hydroxy-2-(methoxycarbonyl)ethyl]-cinnamate of interest (51 mg, 14%) as a pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][C@@H:9]1[C:21](O)=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].B.C1COCC1.CO>C1COCC1>[OH:22][CH2:21][C@H:9]1[CH2:10][N:11]([C:14]([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](C(=O)O)C1
Agent: B
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OC(C)(C)C)[C@@H](CO)C1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 99.4 %

Procedure:
A 250-mL round bottom flask was charged with (2R)-1,4-bis(tert-butoxycarbonyl)-2-piperazinecarboxylic acid (10.5 g, 31.8 mmol, ASW Medchem, New Brunswick, N.J.) under nitrogen. THF (20 mL) was added and the mixture was cooled in an ice bath. A solution of BH3.THF (1M in THF, 65 mL, 65.0 mmol, Sigma-Aldrich) was added over 10 min. The ice bath was removed and after 15 min, the flask was equipped with a reflux condenser and was the reaction was heated at 60° C. After 1.5 h, the mixture was cooled in an ice bath and was then quenched with MeOH (10 mL, 247 mmol) over 20 min. The mixture was concentrated, treated with MeOH (20 mL), and concentrated a second time to give di-tert-butyl (2R)-2-(hydroxymethyl)-1,4-piperazinedicarboxylate as a white solid (10 g).
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:21][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=1)=[O:5].[N:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[O:36]1[CH2:37][CH2:38][N:33]([C:39]([O:1][C:2]2[CH:24]=[CH:23][C:22]([CH:25]=[CH:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)=[CH:21][C:3]=2[C:4]([NH:6][C:7]2[CH:8]=[C:9]([C:17]([F:18])([F:19])[F:20])[CH:10]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:12]=2)=[O:5])=[O:40])[CH2:34][CH2:35]1
Reactant: O=C(Cl)N1CCOCC1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C=Cc2ccccc2)ccc1O
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C=Cc2ccccc2)ccc1OC(=O)N1CCOCC1
Yield: 99.5 %

Procedure:
Using 2-hydroxy-5-phenylethenyl-N-[3,5-bis(trifluoromethyl)-phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.C1CCC(N=C=NC2CCCCC2)CC1.[C:28](=S)=[S:29]>C(OCC)C>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][N:8]=[C:28]=[S:29])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: S=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Product: FC(F)(F)c1ccc(CN=C=S)cc1
Reaction time: 12 h

Procedure:
10 g of 4-trifluoromethylbenzylamine was added dropwise at -10° C. with stirring to a mixture of 11.78 g of DCC, 25 ml of carbon disulfide and 50 ml of diethyl ether. The temperature of the mixture was returned to room temperature, and it was left to stand for 12 hours. The reaction solution was filtered, and the residue was washed with diethyl ether. The filtrate and the washing were combined, and the solvent was evaporated under reduced pressure. The resulting oily product was purified by column chromatography silica gel; developing solvent hexane/ethyl acetate (10:1)]to give 11.15 g of the desired 4-trifluoromethylbenzyl isothiocyanate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17]I)[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23.[C-:19]#[N:20].[Na+].O.Cl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH2:16][CH2:15][CH:14]([CH2:17][C:19]#[N:20])[N:6]3[C:7](=[O:13])[C:8](=[O:12])[NH:9][C:10]([CH:11]=1)=[C:5]23
Reactant: O=c1[nH]c2cc(Br)cc3c2n(c1=O)C(CI)CC3
Reactant: [C-]#N
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCC1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Temperature: 40 °C
Yield: 24.4 %

Procedure:
A mixture of 9-bromo-5-iodomethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (Example 36) (632 mg, 1.5 mmol) and sodium cyanide (147 mg, 3 mmol) in DMF (5 mL) was heated at 40° C. for 14.5 h. The mixture was poured into water, acidified by addition of 1N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography with ethyl acetate to 1% acetic acid/ethyl acetate to give 117 mg of the title compound (24%): mp>280° C.; 1H NMR (270 MHz, DMSO-d6) δ12.10 (bs, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 4.97~5.07 (m, 1H), 2.74~3.10 (m, 4H), 2.20 (dm, 1H, J=13.5 Hz), 1.87~2.03 (m, 1H).
Reaction SMILES: [C:1]1([CH3:29])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:17]1)=[O:15]>C1COCC1>[C:1]1([CH3:29])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C@:14]([C@@H:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][C:25]([CH3:26])([CH3:28])[CH3:27])=[O:23])[CH2:17]1)([OH:15])[CH2:5][CH2:6][CH2:1][CH2:2][O:7][CH3:8]
Reactant: Cc1ccccc1Oc1ccccc1C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1ccccc1C)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 165.4 %

Procedure:
A 1000-mL, three-necked flask was charged with the (2-(o-tolyloxy)phenyl)((R)-1-(tert-butoxycarbonyl)piperidin-3-yl)methanone (20 g, 0.05 mol) and THF (250 mL). The flask was evacuated and refilled with N2, the mixture was cooled with a dry ice-acetone bath and the Grignard reagent was added dropwise. The mixture was allowed to warm slowly to rt and stirred overnight. After quenching with sat'd aq NH4Cl (500 mL), the mixture was extracted with EtOAc (3×150 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed and the crude product was purified by flash column chromatography to afford the (R)-tert-butyl 3-((S)-1-(2-(o-tolyloxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (20 g, 83%).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8]([O:12][C:13]2[N:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][N:14]=2)=[CH:7][C:6]=1[CH3:21])=O.[NH2:22][C:23]([NH2:25])=[S:24]>CCO>[CH3:20][O:19][C:16]1[CH:15]=[N:14][C:13]([O:12][C:8]2[CH:9]=[C:10]([CH3:11])[C:5]([C:3]3[N:22]=[C:23]([NH2:25])[S:24][CH:2]=3)=[C:6]([CH3:21])[CH:7]=2)=[N:18][CH:17]=1
Reactant: COc1cnc(Oc2cc(C)c(C(=O)CBr)c(C)c2)nc1
Reactant: NC(N)=S
Solvent: CCO
Product: COc1cnc(Oc2cc(C)c(-c3csc(N)n3)c(C)c2)nc1
Yield: 83.2 %

Procedure:
A mixture of 2-bromo-1-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}ethanone (8-3, 0.51 g, 1.5 mmol) and thiourea (0.13 g, 1.6 mmol) in 95% EtOH (10.0 mL) was heated at reflux for 60 min. The solution was concentrated and added with water (10 mL) and saturated aqueous Na2CO3 (1.0 mL). The resultant precipitate was filtered and washed with hot water. The solids were filtered and dried under vacuum to give 4-{4-((5-methoxypyrimidin-2-yl)oxy)-2,6-dimethylphenyl}thiazol-2-amine (8-4, 0.41 g) as yellow solids in 86% yield: 1H NMR (500 MHz, DMSO-d) 9.00 (s, 2 H), 8.41 (s, 2 H), 6.99 (s, 2 H), 6.88 (s, 1 H), 3.87 (s, 3 H), 2.17 (s, 6 H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH3:9])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1.Br[CH2:30][CH2:31][O:32][CH3:33]>>[CH3:9][O:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:1][CH2:30][CH2:31][O:32][CH3:33])[C:3]=1[CH:10]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:25])[F:26])=[CH:19][CH:18]=2)[C:14](=[O:28])[CH2:13][CH2:12][CH2:11]1
Reactant: COCCBr
Reactant: COc1cccc(O)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1
Product: COCCOc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc(OC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 7 (GP7) by O-alkylation of 6-(2-hydroxy-6-methoxyphenyl)-1-(4-(trifluoromethoxy)benzyl)piperidin-2-one with commercially available 1-bromo-2-methoxyethane. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions E): tR=0.80 min.; [M+H]+: 454.25 g/mol.
Reaction SMILES: [Cl:1][C:2](Cl)([CH:5]=[C:6]([Cl:8])[Cl:7])[CH:3]=[O:4].[P:10]([O:15]C)([O:13][CH3:14])[O:11][CH3:12]>C1C=CC=CC=1>[P:10]([O:13][CH3:14])([O:11][CH3:12])([O:4][CH:3]=[C:2]([Cl:1])[CH:5]=[C:6]([Cl:8])[Cl:7])=[O:15]
Reactant: O=CC(Cl)(Cl)C=C(Cl)Cl
Reactant: COP(OC)OC
Solvent: c1ccccc1
Product: COP(=O)(OC)OC=C(Cl)C=C(Cl)Cl
Reaction time: 0.25 h
Yield: 80 %

Procedure:
60 g of this 2,2,4,4-tetrachloro-but-3-enal in 100 ml of benzene were reacted with 45 g of trimethyl phosphite in 100 ml of benzene, while stirring, and at a temperature of 60 to 65° C over a period of 15 minutes, and subsequently heated under reflux for 1.5 hours. After the solvent had been removed, 81 g of crude product remained. This was distilled at 0.1 to 0.2 torr and yielded 65 g of product at 110 to 112° C. NMR-spectrum: δ(CH3O--) : 3.9 ppm, J = 12 Hz; δ(C=CH-C) : 6.68 ppm; δ(CH-O-P) : 7.4 ppm, J = 6 Hz.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].Cl[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[N:11][CH:12]=1
Reactant: Oc1ccccc1O
Reactant: Clc1ccc(Cl)nc1
Solvent: ClCCl
Product: Oc1ccccc1Oc1ccc(Cl)cn1

Procedure:
Under nitrogen, a mixture of 15.0 grams (0.136 mole) of catechol, and 22.0 grams of 2,5-dichloropyridine was heated as a melt at 140°-150° for 12 hours. The resulting black residue was dissolved in a minimum amount of methylene chloride, i.e., about 50 ml, chromatographed through a silica gel column using methylene chloride as the eluent. The 2-(5-chloropyridin-2-yloxy)phenol was isolated in the latter fraction, whereas starting material 2,5-dichloropyridine eluted with the solvent front. Yield 8.0 grams, m.p. 97°-100°; NMR (CDCl3): δ6.70-7.70 (m's, ArH and OH), 8.0 (d, ArH); ir (Nujol): 3.20-2.80 (OH), 6.30 (C=N), 13.30 microns.
Reaction SMILES: BrC1C=CC([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)=CC=1.[Br:22][C:23]1[CH:24]=[C:25](I)[CH:26]=[CH:27][CH:28]=1>>[Br:22][C:23]1[CH:28]=[C:27]([C:8]2[CH:21]=[CH:20][C:19]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=4)[CH:12]=[CH:11][C:10]=3[CH:9]=2)[CH:26]=[CH:25][CH:24]=1
Reactant: Brc1cccc(I)c1
Reactant: Brc1ccc(-c2ccc3c(ccc4ccccc43)c2)cc1
Product: Brc1cccc(-c2ccc3c(ccc4ccccc43)c2)c1

Procedure:
Synthesis was performed in the same manner as in the synthesis of 2-(4-bromophenyl)phenanthrene except that 3-bromoiodobenzene was used instead of 4-bromoiodobenzene.
Reaction SMILES: [CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH2:3]1)=[C:11]1[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][S:15][C:10]1=[CH:9][CH:8]=3.[H-].[Na+].[CH2:26](Br)[CH2:27][CH3:28]>>[CH3:1][N:2]1[CH2:23][CH2:22][C:5]2[N:6]([CH2:26][CH2:27][CH3:28])[C:7]3[C:12]([C:4]=2[CH2:3]1)=[C:11]1[C:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:14][S:15][C:10]1=[CH:9][CH:8]=3
Reactant: CN1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1
Reactant: CCCBr
Agent: [H-]
Agent: [Na+]
Product: CCCn1c2c(c3c4c(-c5ccccc5)csc4ccc31)CN(C)CC2

Procedure:
The compound is formed analogously to that described in Example 28, from 4.8 g of 9-methyl-1-phenyl-7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole, NaH and 1.5 ml of propyl bromide. Melting point: 156° C.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.CC(C)=O.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>O>[CH3:22][S:23]([O:4][C@@H:3]1[C@@H:5]([CH2:6][O:7][S:23]([CH3:22])(=[O:25])=[O:24])[O:8][C@@H:1]([N:9]2[CH:17]=[C:15]([CH3:16])[C:13](=[O:14])[NH:12][C:10]2=[O:11])[CH2:2]1)(=[O:25])=[O:24]
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CC(C)=O
Product: Cc1cn([C@H]2C[C@H](OS(C)(=O)=O)[C@@H](COS(C)(=O)=O)O2)c(=O)[nH]c1=O
Reaction time: 0.75 h
Yield: 98.1 %

Procedure:
To a dry, round-bottom flask purged with nitrogen was added thymidine (10.0 g, 0.0412 mole) and acetone (30 mL). The slurry was stirred and 3, 5-lutidine (17.7 g, 0.165 mole) was added. Then, methanesulfonyl chloride (13.8 g, 0.124 mole) was added over ten minutes with the temperature rising to 40° C. After 45 minutes, the reaction was complete and the thick slurry was diluted with 150 mL of water. The slurry was stirred for 25° C. for 30 minutes, and then cooled at 0°-5° C. for 30 minutes. The solids were collected, washed with water (80 mL) and isopropanol (40 mL), then dried to give 16.1 g (98.2%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:9](=[O:11])[NH:8][CH:7]=[N:6][C:5]=2[S:4][C:3]=1[S:12](Cl)(=[O:14])=[O:13].CCN(C(C)C)C(C)C.[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH2:30].Cl>C(Cl)Cl>[CH3:25][N:26]([CH3:31])[CH2:27][CH2:28][CH2:29][NH:30][S:12]([C:3]1[S:4][C:5]2[N:6]=[CH:7][NH:8][C:9](=[O:11])[C:10]=2[C:2]=1[CH3:1])(=[O:14])=[O:13]
Reactant: Cc1c(S(=O)(=O)Cl)sc2nc[nH]c(=O)c12
Reactant: CN(C)CCCN
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(S(=O)(=O)NCCCN(C)C)sc2nc[nH]c(=O)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.7 %

Procedure:
To a stirred suspension of 5-methyl-4-oxo-3,4-dihydrothieno[2,3-d]pyrimidine-6-sulfonyl chloride (1.0 g, 12 mmol) in DCM (10 mL) at 0° C. was added Hünig's base (0.79 mL, 4.5 mmol) followed by N1,N1-dimethylpropane-1,3-diamine (0.52 mL, 4.2 mmol) and the solution stirred at ambient temperature for 2 hours. The suspension was adjusted to pH 8 with 2N hydrochloric acid, the precipitate collected by filtration, washed with water, diethyl ether and dried under vacuum to give the product as off-white solid (1.12 g, 89%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[N:16][C:17]([NH:20][C:21]3[N:22]=[CH:23][C:24]4[C:30]([CH3:31])=[C:29]([C:32]([O:34]CC)=[CH2:33])[C:28](=[O:37])[N:27]([CH:38]5[CH2:42][CH2:41][CH2:40][CH2:39]5)[C:25]=4[N:26]=3)=[CH:18][CH:19]=2)[CH2:10][C:9]1([CH3:44])C)=O)(C)(C)C.[Cl:45][CH2:46]Cl>Cl.C(OCC)C>[ClH:45].[C:32]([C:29]1[C:28](=[O:37])[N:27]([CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)[C:25]2[N:26]=[C:21]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([N:11]4[CH2:10][CH:9]([CH3:44])[NH:8][CH:13]([CH3:46])[CH2:12]4)=[CH:15][N:16]=3)[N:22]=[CH:23][C:24]=2[C:30]=1[CH3:31])(=[O:34])[CH3:33]
Reactant: C=C(OCC)c1c(C)c2cnc(Nc3ccc(N4CCN(C(=O)OC(C)(C)C)C(C)(C)C4)cn3)nc2n(C2CCCC2)c1=O
Reactant: ClCCl
Agent: Cl
Solvent: CCOCC
Product: CC(=O)c1c(C)c2cnc(Nc3ccc(N4CC(C)NC(C)C4)cn3)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.1 %

Procedure:
4-{6-[8-Cyclopentyl-6-(1-ethoxy-vinyl)-5-methyl-7-oxo-7,8-dihydro-pyrido[2,3-d]pyrimidin-2-ylamino]-pyridin-3-yl}-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (0.250 g, 0.414 mmol) was dissolved in dichloromethane (3 mL) to which 2 N HCl in diethyl ether (3 mL) was added and the mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the solid was dried in a vacuum oven for 24 hours at 50° C. to give 6-acetyl-8-cyclopentyl-2-[5-(3,5-dimethyl-piperazin-1-yl)-pyridin-2-ylamino]-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one hydrochloride salt as a yellow solid (0.120 g, 38.1%). 1H NMR δ(400 MHz, DMSO-d6) 9.51 (m, 2H), 9.0 (m, 1H), 8.97 (s, 1H), 8.08 (d, J=2.7 Hz, 1H), 7.84 (d, J=9.3 Hz, 1H), 7.78 (m, 1H), 5.80 (m, 1H), 3.35 (d, J=11.5 Hz, 2H), 3.35 (m, 2H), 2.75 (dd, J=12.2, 2H), 2.40 (s, 3H), 2.30 (s, 3H), 2.19 (m, 2H), 1.88 (m, 2H), 1.76 (m, 2H), 1.57 (m, 2H), 1.29 (d, J=6.6 Hz, 6H). MS (APCI); M++1: Calc'd, 476.3. Found 476.1. Anal. Calc'd for C26H33N7O22.70HCl, 0.10H2O: C, 54.23, H, 6.28, N, 17.03. Found: C, 54.60; H, 6.68; N, 16.57.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([O:22]C(=O)C)=[C:17]([CH:21]=2)[C:18]([OH:20])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].C(=O)([O-])O.[Na+]>CO.O>[CH3:1][O:2][C:3]1[C:4](=[O:27])[C:5]([CH3:26])=[C:6]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([OH:22])=[C:17]([CH:21]=2)[C:18]([OH:20])=[O:19])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC1=C(OC)C(=O)C(Cc2ccc(O)c(C(=O)O)c2)=C(C)C1=O
Yield: 41.4 %

Procedure:
5-(5,6-Dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.150 g, 0.401 mmol) was dissolved in methanol (2 ml) and after adding thereto an aqueous saturated sodium hydrogencarbonate solution (3 ml), the solution was stirred at room temperature for 3 hours. After the completion of reaction, the reaction solution was diluted with water and then extracted with ethyl acetate. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.055 g, 0.166 mmol, 42%).
Reaction SMILES: [NH:1]([CH2:5][CH2:6][OH:7])[CH2:2][CH2:3][OH:4].[O:8]([CH2:15][CH2:16][CH2:17]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[OH:4][CH2:3][CH2:2][N:1]([CH2:17][CH2:16][CH2:15][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][CH2:6][OH:7]
Reactant: BrCCCOc1ccccc1
Reactant: OCCNCCO
Product: OCCN(CCO)CCCOc1ccccc1

Procedure:
2-[(2-Hydroxy-ethyl)-(3-phenoxy-propyl)-amino]-ethanol was prepared according to the general method as outlined in example 83. Starting from diethanolamine (15.8 g, 151 mmol). and 3-Phenoxypropyl bromide (21.5 g, 100 mmol). Yield 21.31 g, (95%); yellow oil; MS: 238.1 (M+H)+.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[OH-].[K+].[C:13](=S)=[S:14]>>[SH:14][C:13]1[NH:10][C:1](=[O:9])[C:2]2[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:4]=1
Reactant: S=C=S
Reactant: NC(=O)c1ccccc1N
Agent: [K+]
Agent: [OH-]
Product: O=c1[nH]c(S)nc2ccccc12
Yield: 91 %

Procedure:
Aminoalcohol VIII was then allowed to react with 2,4-dimethylthioquinazoline (IX) in acetonitrile at reflux to give 4-[(3-(4-methoxyphenyl)piperazine-1-yl)propan-2-ol-1-yl]amino-2-methylthioquinazoline (XI). But the results were variable in the yields ranging from 24 to 56% and the reaction released notorious methylthiol. The possibility of synthesizing compound XI by using 4-chloro-2-methylthioquinazoline (X) was also investigated. Compound X was obtained in good yield (90-93%) starting from anthranilamide by heating with carbon disulfide in water-alcohol solution of potassium hydroxide to afford 2-mercaptoquinazolin-4-one (XII) in 91% yield. (Zakerinia, M. et. al. Helv. Chim. Acta. 1990, 73, 912-915) Compound XII was then methylated with methyl iodide to give 2-methylthioquinazolin-2-one (XIII) which was subsequently converted to 4-chloro-2-methylthioquinazoline (X) in high yield (90-93%) by treating with POCl3, followed by precipitation with water from acetone solution. Compound X was reacted smoothly with amino alcohol VIII in the presence of triethylamine to give compound XI in 72% yield. The cyclization of XI to compound I was achieved by methanesulphonylchloride (MsCl) and triethylamine. The cyclization reaction proceeded in 12-17 hours to give compound I with 47-69% chemical yield after chromatographical purification. The addition of potassium carbonate to the reaction mixture to trap hydrogen chloride formed allowed to obtain a chromatographically pure compound I in 77% yield without column chromatography. ##STR7##
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2.[N-:17]=[N+:18]=[N-:19].[Na+]>CN(C)C=O>[N:17]([CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:16])[CH:10]=[CH:9]2)=[N+:18]=[N-:19]
Reactant: O=c1ccc2cc(OCCCCl)ccc2[nH]1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1ccc2[nH]c(=O)ccc2c1
Temperature: 80 °C
Yield: 97.3 %

Procedure:
A suspension of 6-(3-chloropropoxy)carbostyril (100 g) and sodium azide (33 g) in dimethylformamide is refluxed at 80° C. for 4 hours. After the mixture is allowed to cool, to the mixture is added ice-water, and the precipitated crystals are collected by filtration, washed with diethyl ether, and dried to give 6-(3-azidopropoxy)carbostyril (100 g) as a white powder.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36](Cl)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([N:20]2[CH2:21][CH2:22][CH:17]([N:15]3[C:14](=[O:23])[C:13]([CH3:25])([CH3:24])[C:12]([C:6]4[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH3:2])[CH:5]=4)=[N:16]3)[CH2:18][CH2:19]2)(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C(C)(C)C)cc4)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 4-tert-butylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from methanol to yield the title compound.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][NH:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[N:23][CH:24]=[N:25][CH:26]=3)=[CH:17][CH:16]=2)[CH:7]=1.Cl.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:30]=1>C(N(CC)CC)C>[N:29]1[CH:34]=[CH:33][CH:32]=[C:31]([S:35]([N:13]([CH2:12][C:8]2[CH:7]=[C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:27])[CH:11]=[CH:10][CH:9]=2)[CH2:14][C:15]2[CH:16]=[CH:17][C:18]([C:21]3[CH:26]=[N:25][CH:24]=[N:23][CH:22]=3)=[CH:19][CH:20]=2)(=[O:37])=[O:36])[CH:30]=1
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: COC(=O)CCc1cccc(CNCc2ccc(-c3cncnc3)cc2)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: O=C(O)CCc1cccc(CN(Cc2ccc(-c3cncnc3)cc2)S(=O)(=O)c2cccnc2)c1

Procedure:
The title compound of Step A was prepared from 3-{3-[(4-pyrimidin-5-yl-benzylamino)-methyl]-phenyl}-propionic acid methyl ester, of Step A of Example 11t, and pyridine-3-sulfonyl chloride hydrochloride, of Preparation 2, following the method described in Example 1, Step B using triethylamine in place of N,N-diisopropylethylamine. 1H NMR (400 MHz, CDCl3) δ 9.20 (s, 1H), 9.06 (s, 1H), 8.92 (s, 2H), 8.81 (s, 1H), 8.08 (m, 1H), 7.46 (m, 3H), 7.26 (m, 2H), 7.15 (m, 1H), 7.06 (d, 1H), 6.91 (d, 1H), 6.86 (s, 1H), 4.42 (s, 2H), 4.37 (s, 2H), 3.65 (s, 3H), 2.82 (t, 2H), 2.50 (t, 2H).