Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:8]([N:10]2[CH:14]([C:15]([OH:17])=O)[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:19])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O.[NH2:61][C:62]1[C:67]([CH3:68])=[CH:66][CH:65]=[CH:64][N:63]=1>C1(C[C@H](CN(C=O)OCC2C=CC=CC=2)C(N2[C@H](C(O)=O)CCN2C(OCC2C=CC=CC=2)=O)=O)CCCC1.O1CCCC1.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:6][C@H:7]([CH2:28][N:29]([CH:38]=[O:39])[O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:8]([N:10]2[C@H:14]([C:15]([NH:61][C:62]3[C:67]([CH3:68])=[CH:66][CH:65]=[CH:64][N:63]=3)=[O:17])[CH2:13][CH2:12][N:11]2[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[O:19])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)N1C(C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: Cc1cccnc1N
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Agent: O=CN(C[C@@H](CC1CCCC1)C(=O)N1[C@H](C(=O)O)CCN1C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1NC(=O)[C@@H]1CCN(C(=O)OCc2ccccc2)N1C(=O)[C@H](CC1CCCC1)CN(C=O)OCc1ccccc1
Reaction time: 2 h
Yield: 61 %

Procedure:
To a solution of 2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidine carboxylic acid (as a mixture of diastereomers enriched in (3S)-2-[(2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoyl]-1-{[(phenylmethyl)oxy]carbonyl}-3-pyrazolidinecarboxylic acid) (250 mg, 0.465 mmol) in tetrahydrofuran (3 ml) was added N,N-diisopropylethylamine (405 μl, 2.325 mmol) and 2,4,6-trichlorobenzoyl chloride (0.087 mL, 0.558 mmol). The mixture was stirred for 2 h and then the solvent was evaporated. The residue was then diluted with toluene (3 mL). The resulting suspension was treated with 2-amino-3-methylpyridine (61 mg, 0.56 mmol) followed by DMAP (11.3 mg, 0.093 mmol). After 2 h, 15 minutes, the solvent mixture was removed. The residue was diluted with MeOH and purified by reverse-phase HPLC to afford 179 mg (61%) of the title compound as a white solid. LC/MS: (M+H)+: 628.5.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16]O)[C:11]=2[CH3:18])[O:4][CH2:3]1.C(N(CC)CC)C.CS(Cl)(=O)=O.[SH:32][C:33]1[NH:34][C:35]2[CH:41]=[CH:40][CH:39]=[CH:38][C:36]=2[N:37]=1>CO.O1CCCC1>[CH3:1][C:2]1([CH3:19])[CH2:7][O:6][CH:5]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([CH2:16][S:32][C:33]3[NH:37][C:36]4[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=4[N:34]=3)[C:11]=2[CH3:18])[O:4][CH2:3]1
Reactant: Sc1nc2ccccc2[nH]1
Reactant: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CO
Agent: CS(=O)(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1c(OCC2OCC(C)(C)CO2)ccnc1CSc1nc2ccccc2[nH]1
Temperature: -19 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
The (4-((5,5-dimethyl-1,3-dioxan-2-yl)methoxy)-3-methylpyridin-2-yl)methanol (500 mg, 1.87 mmol) obtained by the step (1d) was mixed with triethylamine (1.04 ml, 7.48 mmol) and tetrahydrofuran (15 ml). This mixture was cooled to −19° C. and methanesulfonyl chloride (217 μl, 2.81 mmol) was added thereto and then stirred at −19° C. for 30 minutes. Under the same conditions, 2-mercaptobenzimidazole (309 mg, 2.06 mmol) was added to the reaction mixture. After the reaction mixture was stirred overnight at room temperature, methanol and NH silica gel were added to the mixture, and then, the solvent was distilled off. The mixture of the reaction mixture and NH silica gel was purified by silica gel column chromatography (silica gel: 80 g, elution solvent: ethyl acetate/heptane=1/1 to 4/1→methanol/ethyl acetate=1/9) to obtain the title compound (599 mg, yield: 80.2%) as a light red foam.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5].C(N(CC)CC)C.[C:18]([O:21][CH2:22][C:23](Cl)=[O:24])(=[O:20])[CH3:19].O>C(Cl)(Cl)Cl>[C:18]([O:21][CH2:22][C:23]([NH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[C:4]#[N:5])=[O:24])(=[O:20])[CH3:19]
Reactant: CC(=O)OCC(=O)Cl
Reactant: N#Cc1c(N)cccc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClC(Cl)Cl
Product: CC(=O)OCC(=O)Nc1cccc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-amino-6-chlorobenzonitrile (4.6 g) in chloroform (100 ml) is added triethylamine (4.8 ml), and thereto is added dropwise acetoxyacetyl chloride (3.8 ml). The mixture is stirred at room temperature for 1 hour, and thereafter, water is added thereto, and the mixture is extracted with chloroform. The organic layer is washed with saturated aqueous sodium chloride and then dried over anhydrous sodium sulfate, and the solvent is distilled off under reduced pressure. The resulting crude crystals are recrystallized from ethanol-water to give the title compound (3.8 g) having the following physical properties.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]([NH:13][C:14]1[C:15](=[O:21])[NH:16][C:17]([CH3:20])=[CH:18][CH:19]=1)=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[C:22]([O:26][C:27](=[O:30])[CH2:28]Br)([CH3:25])([CH3:24])[CH3:23]>C1COCC1>[C:22]([O:26][C:27](=[O:30])[CH2:28][N:16]1[C:17]([CH3:20])=[CH:18][CH:19]=[C:14]([NH:13][C:11]([O:10][CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[O:12])[C:15]1=[O:21])([CH3:25])([CH3:24])[CH3:23]
Reactant: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)[nH]1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)OCc2ccccc2)c(=O)n1CC(=O)OC(C)(C)C
Temperature: 25 °C

Procedure:
##STR51## Sodium hydride (5.3 g, 0.22 mol) was added to a stirred slurry of 3-benzyloxycarbonylamino-6-methyl-2-pyridinone (16-2; 53.2 g, 0.20 mol) in THF at 0° C. t-Butylbromoacetate (45 ml, 0.27 mol) was added to the resulting solution and a precipitate rapidly forms. The reaction was warmed to rt over 1 h and after 2 h the solvent was evaporated in vacuo and the residue was partitioned between 1:1 water/brine (200 ml) and 6:1 THF/methylene chloride (700 ml). The organic layer was dried (Na2SO4) and evaporated in vacuo to a solid which was triturated with hexane to give the title compound 16-3 as a crystalline solid:
Reaction SMILES: OC[CH:3]1[CH2:8][CH2:7][CH:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.[H-].[Na+].[N+:17]([C:20]1[CH:27]=[CH:26][CH:25]=[C:24]([N+]([O-])=O)[C:21]=1[C:22]#[N:23])([O-:19])=[O:18].C1C[O:34][CH2:33]C1>>[C:22]([C:21]1[C:20]([N+:17]([O-:19])=[O:18])=[CH:27][CH:26]=[CH:25][C:24]=1[O:34][CH2:33][C:6]1([C:9]([NH:11][CH:12]([CH3:13])[CH3:14])=[O:10])[CH2:5][CH2:4][CH2:3][CH2:8][CH2:7]1)#[N:23]
Reactant: CC(C)NC(=O)C1CCC(CO)CC1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: C1CCOC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)NC(=O)C1(COc2cccc([N+](=O)[O-])c2C#N)CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
To a solution of 4-(hydroxymethyl)-N-isopropylcyclohexanecarboxamide (Example 126d, 480 mg, 2.41 mmol) in dry THF (10 mL) was added NaH (60% in mineral oil, 116 mg, 4.82 mmol) in small portions at 0° C. under N2. The reaction mixture was stirred at 0° C. under N2 for 2 h. To this solution was added 2,6-dinitrobenzonitrile (465 mg, 2.41 mmol), and the reaction mixture was stirred at 0° C.—RT for another 2 h, and then at 60° C. overnight under N2 and cooled down to room temperature. The reaction was quenched with brine, and extracted with EtOAc (3×). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 50% EtOAc in hexanes) to give the title compound as yellow solid (594 mg, 71%). 1H NMR (400 MHz, DMSO-d6) δ 1.00 (d, J=7.6 Hz, 6H), 1.22-2.08 (m, 9H), 2.19 (m, 1H), 3.79 (m, 1H), 4.15 (d, J=7.6 Hz, 2H), 7.45 (brs, 1H), 7.78 (d, J=7.2 Hz, 1H), 7.88 (m, 2H). MS 346 (H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.O=[C:22]1[CH2:26][CH2:25][CH2:24][CH:23]1[C:27]#[N:28].[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH:22]3[CH2:26][CH2:25][CH2:24][CH:23]3[C:27]#[N:28])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Reactant: N#CC1CCCC1=O
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NC3CCCC3C#N)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and rac-2-oxo-cyclopentanecarbonitrile using decaborane yielded a mixture of epimers of the title compound as a white solid. MS (ESI): m/z=372.3 [M+H]+.
Reaction SMILES: [CH:1]1([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][NH:17][CH:18]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]3)[CH:11]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1>CCCCCC>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:34])[N:17]([CH2:16][C:12]2[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][N:8]([CH:1]3[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[C:33]([NH:32][C:29]3[CH:30]=[CH:31][C:26]([Cl:25])=[CH:27][CH:28]=3)=[O:34])[CH:11]=2)[CH:18]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:28][CH:27]=1
Reactant: c1cc(CNC2CCCCCC2)cc(CNC2CCCCCC2)c1
Reactant: O=C=Nc1ccc(Cl)cc1
Solvent: CCCCCC
Product: O=C(Nc1ccc(Cl)cc1)N(Cc1cccc(CN(C(=O)Nc2ccc(Cl)cc2)C2CCCCCC2)c1)C1CCCCCC1
Reaction time: 2 h
Yield: 173.9 %

Procedure:
To a solution of 0.5 g N,N'-dicycloheptyl-m-xylylenediamine in 50 ml n-hexane, was added dropwise with stirring 5 ml of a n-hexane solution containing 0.25 g 4-chlorophenyl isocyanate under ice cooling, and stirring was continued at room temperature for two hours. After distilling off the solvent under reduced pressure, the residue was purified by silica gel column chromatography, giving 0.9 g of 1,3-bis[[3-(p-chlorophenyl)-1-cycloheptylureido]methyl]benzene as amorphous solid.
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[C:8]1([N:14]2[C:18]([NH2:19])=[C:17]([C:20]#[N:21])[CH:16]=[N:15]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C.[CH:29]1([NH:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl.O>[C:8]1([N:14]2[C:18]([NH:19][C:6]([NH:5][S:2]([N:35]([CH:36]3[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]3)[CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]3)(=[O:4])=[O:3])=[O:7])=[C:17]([C:20]#[N:21])[CH:16]=[N:15]2)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1CCC(NC2CCCCC2)CC1
Reactant: O=C=NS(=O)(=O)Cl
Reactant: N#Cc1cnn(-c2ccccc2)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: N#Cc1cnn(-c2ccccc2)c1NC(=O)NS(=O)(=O)N(C1CCCCC1)C1CCCCC1
Reaction time: 0.5 h
Yield: 87 %

Procedure:
4.4 ml (50 mmol) of chlorosulfonyl isocyanate were added to a solution of 9.2 g (50 mmol) of 1-phenyl-4-cyano-5-aminopyrazole in 100 ml of methylene chloride. Stirring was carried out for 30 minutes at about 20° C., after which a solution of 7.5 ml (60 mmol) of triethylamine and 10 ml (50 mmol) of dicyclohexylamine in 50 ml of methylene chloride was slowly added dropwise. After the end of the addition, stirring was continued for a further hour and hydrolysis was then carried out with 200 ml of water. The organic phase was separated off and was worked up in a conventional manner to give the product. Yield: 87%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[OH:9].C(P(CCCC)CCCC)CCC.[CH:23]1([C:26]2[CH:27]=[CH:28][C:29]([CH:42]([C:44]3[CH:49]=[CH:48][C:47]([S:50]([CH:53]4[CH2:55][CH2:54]4)(=[O:52])=[O:51])=[CH:46][CH:45]=3)O)=[N:30][C:31]=2[O:32][CH2:33][C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)[CH2:25][CH2:24]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH:23]1([C:26]2[C:31]([O:32][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=3)=[N:30][C:29]([CH:42]([C:44]3[CH:45]=[CH:46][C:47]([S:50]([CH:53]4[CH2:54][CH2:55]4)(=[O:52])=[O:51])=[CH:48][CH:49]=3)[O:9][C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[CH:28][CH:27]=2)[CH2:25][CH2:24]1
Reactant: COc1ccc(COc2nc(C(O)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Reactant: Oc1ccc(F)cc1F
Agent: CCCCP(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(COc2nc(C(Oc3ccc(F)cc3F)c3ccc(S(=O)(=O)C4CC4)cc3)ccc2C2CC2)cc1
Temperature: 86 °C
Yield: 77.1 %

Procedure:
2,4-Difluorophenol (219 mg), tributylphosphine (340 mg) and N,N,N′,N′-tetramethylazodicarboxyamide (289 mg) were sequentially added to a solution of {5-cyclopropyl-6-[(4-methoxybenzyl)oxy]pyridin-2-yl}[4-(cyclopropylsulfonyl)phenyl]methanol (390 mg) in tetrahydrofuran (12 mL). After replacement with nitrogen, the mixture was stirred under reflux at an external temperature of 86° C. for six hours, returned to room temperature and stirred overnight. The reaction solution was poured into water and a potassium carbonate solution was added, followed by extraction with chloroform. The organic layer was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=92:8→34:66) to give 3-cyclopropyl-6-{[4-(cyclopropylsulfonyl)phenyl](2,4-difluorophenoxy)methyl}-2-[(4-methoxybenzyl)oxy]pyridine as a yellow gum (373 mg, 77%).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[NH:45]1[CH2:50][CH2:49][CH:48]([C:51]2[C:52](=[O:57])[NH:53][CH:54]=[CH:55][CH:56]=2)[CH2:47][CH2:46]1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:45]2[CH2:50][CH2:49][CH:48]([C:51]3[C:52](=[O:57])[NH:53][CH:54]=[CH:55][CH:56]=3)[CH2:47][CH2:46]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=c1[nH]cccc1C1CCNCC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21)N1CCC(c2ccc[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.3 %

Procedure:
Triethylamine (40 μL, 0.285 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (33 mg, 0.095 mmol) and 4-nitrophenyl chloroformate (19 mg, 0.095 mmol) in dichloromethane (2 mL) at 0° C. After 15 min, a solution of the hydrochloride salt of 3-piperidin-4-ylpyridin-2(1H)-one (23 mg, 0.105 mmol) in dichloromethane (1 mL) and triethylamine (26 μL, 0.19 mmol) were added and the mixture was allowed to warm to ambient temperature. After 3 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (8.5 mg). MS 650.2244 (M+1).
Reaction SMILES: [S:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.[ClH:17]>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:3]2[C:4](=[O:7])[C:5](=[CH:13][C:12]3[CH:15]=[CH:16][C:9]([Cl:17])=[CH:10][CH:11]=3)[CH2:6][S:1][CH2:2]2)=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cl
Reactant: O=C1CCSCC1
Solvent: CCO
Product: O=C1C(=Cc2ccc(Cl)cc2)CSCC1=Cc1ccc(Cl)cc1

Procedure:
A solution of tetrahydro-4H-thiopyran-4-one (10.0 g, 0.086 mole) and 4-chlorobenzaldehyde (24.0 g, 0.172 mole) in 60 ml ethanol is treated with 6 ml of concentrated HCl and heated at reflux temperature for 2 hours. Upon cooling, 10 g of product is collected. Concentration of the mother liquor and washings to the original volume and adding additional concentrated HCl (4 ml) gives another 12 g of product. The combined crude material, recrystallized from CHCl3 /EtOH gives 15 g of product, m.p. 163°-165°.
Reaction SMILES: Cl.[CH3:2][C:3]1[N+:4]([O-])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].P(Cl)(Cl)([Cl:22])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:22][CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8]
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)[n+]([O-])c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 28.1 %

Procedure:
In to a 5° C. solution of 4,5-dimethyl-2-(4-trifluoromethyl-phenyl)-oxazole N-oxide hydrochloride (113.71 g, 387.5 mmol) in CHCl3 (560 ml), was added phosphorus oxychloride (39.4 ml, 422.4 mmol) in CHCl3, dropwise over 15 min. The reaction was refluxed for 2.5 h, then cooled to 5° C., poured into ice water, and basified with NaOH (1N). The organic layer was dried over MgSO4. Evaporation and recrystallization from ether/hexane, gave a yellow solid (30.0 g, 28% yield, mp 84°-85° C.).
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[H-].[Na+].[CH3:14]N(C=O)C.IC>O>[I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH3:14])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: CN(C)C=O
Reactant: Nc1ccc(I)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CNc1ccc(I)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 4-iodo-2-nitro-phenyl amine (2.0 g), 60% sodium hydride (oil) (330 mg), and DMF (20 ml) was added dropwise iodomethane (470 μL) while ice-cooling. The reaction mixture was heated to room temperature, and then stirred for 2 hours. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give (4-iodo-2-nitro-phenyl)-methyl-amine (2.0 g).
Reaction SMILES: C(OC([N:8]1[CH:17]([C:18](=[O:50])[NH:19][CH:20]([CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[C:21]([N:23]2[CH2:28][CH2:27][N:26]([CH:29]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[F:41])[CH2:30][NH:31][C:32](=[O:34])[CH3:33])[CH2:25][CH2:24]2)=[O:22])[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=O)(C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[ClH:49].[C:32]([NH:31][CH2:30][CH:29]([N:26]1[CH2:27][CH2:28][N:23]([C:21](=[O:22])[CH:20]([NH:19][C:18]([CH:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][NH:8]2)=[O:50])[CH2:42][C:43]2[CH:48]=[CH:47][C:46]([Cl:49])=[CH:45][CH:44]=2)[CH2:24][CH2:25]1)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[F:41])(=[O:34])[CH3:33]
Reactant: CC(=O)NCC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2C(=O)OC(C)(C)C)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)NCC(c1ccccc1F)N1CCN(C(=O)C(Cc2ccc(Cl)cc2)NC(=O)C2Cc3ccccc3CN2)CC1
Product: Cl
Reaction time: 3 h
Yield: 52 %

Procedure:
3-[2-{4-[2-Acetylamino-1-(2-fluoro-phenyl)-ethyl]-piperazin-1-yl}-1-(4-chloro-benzyl)-2-oxo-ethylcarbamoyl]-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester: To a mixture of 0.28 g (0.62 mmol) of product from Preparation SM3, 0.15 g (0.57 mmol) of material from part B and 0.24 g (0.62 mmol) of O-(7-azabenzotriazole-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate in 2 ml of dichlorormethane is added 0.11 mL (0.62 mmol) of N,N-diisopropylethylamine. The mixture is stirred for three hr and washed with 10% aqueous sodium bisulfate. After the organic portion is separated, the aqueous portion is saturated with sodium chloride and extracted three times with dichloromethane. The combined organics are dried (Na2SO4), filtered and concentrated in vacuo. Chromatography (Biotage, 5% ethanol, ethyl acetate) afforded 0.23 g (52%) of the title compound.
Reaction SMILES: [OH:1][CH:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]([NH:11][C:12]([NH2:14])=[O:13])[CH2:4][CH2:3]1.[OH-].[Na+].[CH2:17]=O.[C:19](=[O:21])=O>O.CO>[CH3:17][O:21][CH2:19][NH:14][C:12]([NH:11][CH:5]1[C:6]2[CH:10]=[CH:9][S:8][C:7]=2[CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:13]
Reactant: NC(=O)NC1CCC(O)c2sccc21
Reactant: C=O
Reactant: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COCNC(=O)NC1CCC(O)c2sccc21
Yield: 65 %

Procedure:
A mixture of 4,5,6,7-tetrahydro-7-hydroxybenzo[b]thien-4-yl urea (4 g., 18.87 mmole), sodium hydroxide (0.969 g., 24.22 mmole), paraformaldehyde (1.038 g., 34.6 mmole) and methanol (94 ml.) is stirred and heated at reflux under a nitrogen atmosphere for 23 hours. The mixture is allowed to cool and excess solid carbon dioxide is added. Evaporation in vacuo affords a solid which is stirred with water (50 ml.) for 2 hours, filtered and air dried to furnish 3.16 g. of the title compound (65% yield) m.p. 157°-159° C. dec. Recrystallization from hot acetone gives the analytical specimen 160°-161° C. dec.
Reaction SMILES: [C:1]1([C:7]2[S:11][N:10]=[C:9](OCCCCl)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O>ClCCl>[C:1]1([C:7]2[S:11][N:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCCOc1nsc(-c2ccccc2)n1
Solvent: ClCCl
Solvent: O
Product: c1ccc(-c2ncns2)cc1
Temperature: 65 °C
Reaction time: 10.5 h

Procedure:
0.85 g of the product obtained above were reacted with 0.7 g of 3-(5-phenyl-1,2,4-thiadiazole-3-yloxy)-propyl chloride [for preparation, see Example 54B)] and the reaction mixture was stirred for 10.5 hours at 65° C. Then the reaction mixture was dissolved in dichloromethane and the solution shaken with water. The dichloromethane phase was separated, dried, and concentrated. The crude product obtained was purified by medium-pressure chromatography on fine-grained silica gel (Lichroprep Si 60®) using 9:1 ethyl acetate/methanol as the eluent. 0.5 g of 3-{3-[N-[2-(4-(2-trimethylsilyl)-ethoxymethoxy)-3-methoxyphenyl)-ethyl]-N-methylamino]-propyloxy}-5-phenyl-1,2,4-thiadiazole were obtained as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:21])[NH:10][C:11](=S)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.O.[NH2:23][NH2:24]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=[O:21])[NH:10][C:11]([NH:23][NH2:24])=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(=S)[nH]c(-c2ccncc2)c1-c1ccc(F)cc1
Reactant: NN
Solvent: O
Product: NNc1nc(-c2ccncc2)c(-c2ccc(F)cc2)c(=O)[nH]1
Temperature: 120 °C

Procedure:
A mixture of 5-(4-fluorophenyl)-6-(4-pyridyl)-2-thiouracil (500 mg, 1.66 mmol) and hydrazine hydrate (800 ml, ˜14 mmol) was heated at 120° C. for 60 min. It was evaporated and the reaction product was recrystallized from hot methanol to provide the title compound. MS (m/z): 298.0 (M+H)+; C15H12FN5O requir. 297.3. 1H-NMR (DMSO-d6): d 8.41, 7.12 (2 m, each 2H, Pyrid.), 7.05, 7.00 (2 m, each 2H, PhF).