Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24][NH2:25])[S:21][N:20]=1.C(=O)(O)[O-:27].[Na+]>COCCOC>[OH2:6].[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24]([NH2:25])=[O:27])[S:21][N:20]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:19]1[N:23]=[C:22]([S:24]([NH2:25])=[O:6])[S:21][N:20]=1
Reactant: Cc1ccccc1-c1nsc(SN)n1
Reactant: O=C([O-])O
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: COCCOC
Product: Cc1ccccc1-c1nsc(S(N)=O)n1
Product: O
Reaction time: 2 h

Procedure:
A solution of 3.86 g of 85% m-chloroperoxybenzoic acid (MCPBA) in 100 ml of 1,2-dimethoxyethane (DME) was added to a solution of 4 g of 3-(2-methylphenyl)-1,2,4-thiadiazole-5-sulfenamide in 150 ml of DME at -70° C. over an hour. The resulting solution was stirred for 2 hours at -70° and thereafter at room temperature overnight. Concentration gave a solid which was stirred with 100 ml of sodium bicarbonate solution for 2 hours, collected, washed with water and dried. Recrystallization from cyclohexane/toluene (2:1) gave 2.2 g of solid, m.p. 110°-112°.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([OH:15])=[CH:9][CH:10]=3)[CH2:5][C:4]=2[CH:3]=1.[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18].[CH2:37](Cl)[CH2:38]Cl.ClCCl>CN(C1C=CN=CC=1)C.O>[C:16]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:27][C:38]1[CH:37]=[CH:35][C:31]([C:32]([O:1][C:2]2[CH:14]=[CH:13][C:12]3[C:11]4[C:6](=[CH:7][C:8]([O:15][C:32](=[O:33])[C:31]5[CH:35]=[CH:36][C:28]([O:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][O:20][C:16](=[O:19])[CH:17]=[CH2:18])=[CH:29][CH:30]=5)=[CH:9][CH:10]=4)[CH2:5][C:4]=3[CH:3]=2)=[O:33])=[CH:30][CH:29]=1)(=[O:19])[CH:17]=[CH2:18]
Reactant: Oc1ccc2c(c1)Cc1cc(O)ccc1-2
Reactant: ClCCCl
Reactant: C=CC(=O)OCCCCCCOc1ccc(C(=O)O)cc1
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: C=CC(=O)OCCCCCCOc1ccc(C(=O)Oc2ccc3c(c2)Cc2cc(OC(=O)c4ccc(OCCCCCCOC(=O)C=C)cc4)ccc2-3)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.3 %

Procedure:
A mixture of 2,7-dihydroxyfluorene (0.5 g), 4-(6-acryloyloxyhexyloxy)benzoic acid (1.62 g), EDC (1.06 g), DMAP (6.16 mg) and dichloromethane (30 mL) was stirred at a room temperature for 12 hours. Water was added to the reaction mixture to separate an organic layer, and the resulting organic layer was washed with water and dried on anhydrous magnesium sulfate. The solvent was distilled off from this organic layer under reduced pressure, and the resulting residue was purified by means of column chromatography (silica gel, eluting solvent: toluene/ethyl acetate [95/5]) and recrystallization (ethanol/ethyl acetate/toluene) to obtain 2,7-bis(4-(6-acryloyloxyhexyl)oxybenzoyloxy)fluorene (0.42 g) of colorless crystal.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1)[CH:6]=O.[C:17]([NH2:23])(=[O:22])[CH2:18][C:19]([CH3:21])=O.[NH2:24][C:25]([NH2:27])=[O:26].B(F)(F)F.CCOCC>[Cu](Cl)Cl.C1COCC1.CC(O)=O>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([CH:6]2[C:18]([C:17]([NH2:23])=[O:22])=[C:19]([CH3:21])[NH:27][C:25](=[O:26])[NH:24]2)[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: NC(N)=O
Reactant: CC(=O)CC(N)=O
Agent: Cl[Cu]Cl
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOCC
Product: CC1=C(C(N)=O)C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)NC(=O)N1
Temperature: 65 °C
Yield: 36.2 %

Procedure:
A mixture of 3,5-bis(trifluoromethyl)benzaldehyde (2.42 g, 10.0 mmol), acetoacetamide (1.01 g, 10.0 mmol), urea (0.90 g, 15.0 mmol), copper chloride (0.1 g, 1.0 mmol), boron trifluoride etherate (0.09 mL), AcOH (0.04 mL), and THF (20 mL) was heated at 65° C. for 18 h and cooled to room temperature. The resulting precipitates were collected by vacuum filtration, washed with THF, and air dried to give the title compound as an off-white solid(1.33 g, 36%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7]([C:12]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[N:6]=[C:5]2[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[CH:32]=1.C(=[NH:51])(C1C=CC=CC=1)C1C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[F:37][C:33]1[CH:32]=[C:31]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([NH2:51])[CH:3]=3)[N:7]([C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:6]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: Cc1cc(Br)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1cc(N)cc2c(-c3cccc(F)c3)nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c12
Reaction time: 0.5 h
Yield: 48.7 %

Procedure:
To a solution of 2.0 g of 5-bromo-3-(3-fluorophenyl)-7-methyl-1-trityl-1H-indazole obtained in Production Example II-9-c in 20 ml toluene at room temperature were added 0.73 g of benzophenoneimine, 95 mg of tris(dibenzylideneacetone)(chloroform)dipalladium(0), 0.17 g of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl and 0.53 g of sodium tert-butyrate, and the mixture was heated under reflux for one day. The mixture was diluted with water and ethyl acetate, and the organic layer was sequentially washed with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was dissolved in 30 ml of tetrahydrofuran, 10 ml of 5 N hydrochloric acid was added at room temperature, and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was neutralized with 5 N aqueous sodium hydroxide solution and was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated. The crude product was purified and separated by silica gel column chromatography (ethyl acetate:n-hexane=1:10 to 1:3), and the resulting obtained crystals were washed with diethyl ether, to give 0.86 g of the title compound as colorless crystals.
Reaction SMILES: C(OC([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:10]([OH:12])=[O:11])=O)(C)(C)C.S(Cl)(Cl)=O.[CH2:25](O)[CH3:26]>>[ClH:19].[NH2:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[C:10]([O:12][CH2:25][CH3:26])=[O:11]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)C(N)c1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 25 °C
Yield: 35 %

Procedure:
tert-Butoxycarbonylamino-(3,4-dichlorophenyl)-acetic acid (900 g) was dissolved in ethanol (4.5 L). Thionyl chloride (417 mL) was added to the resultant solution, followed by refluxing for one hour. The reaction mixture was left to cool to room temperature. The solvent was evaporated under reduced pressure. Ethyl acetate was added to the residue, followed by filtration and drying, to thereby give the title compound (286 g, 35%, 3 steps).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:7]=1[C:8]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:18]([N:20]2[C:26]3[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]=3[CH:24]([OH:32])[CH2:23][CH2:22][CH2:21]2)=[O:19])=[C:15]([CH3:17])[CH:16]=1)=[O:9].N1C=CC=CC=1.[Cl:39][CH2:40][CH2:41][CH2:42][C:43](Cl)=[O:44].O>ClCCl>[Cl:39][CH2:40][CH2:41][CH2:42][C:43]([O:32][CH:24]1[CH2:23][CH2:22][CH2:21][N:20]([C:18](=[O:19])[C:14]2[CH:13]=[CH:12][C:11]([NH:10][C:8](=[O:9])[C:7]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[CH3:1])=[CH:16][C:15]=2[CH3:17])[C:26]2[CH:27]=[CH:28][C:29]([Cl:31])=[CH:30][C:25]1=2)=[O:44]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(O)c3cc(Cl)ccc32)c(C)c1
Reactant: O=C(Cl)CCCCl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(OC(=O)CCCCl)c3cc(Cl)ccc32)c(C)c1

Procedure:
Tolvaptan (10.0 g, 22.3 mmol) was dispersed in dichloromethane (100 ml). Pyridine (2.7 ml) was added thereto, and the mixture was stirred. 4-Chlorobutyric acid chloride (3.74 ml) was gradually added to the obtained mixture, and the mixture was stirred at room temperature over night. The reactant was then poured into water, and the mixture was extracted with dichloromethane, washed with a sodium hydrogen sulfate aqueous solution, dried over magnesium sulfate. After filtration and concentration under reduced pressure, the resulted residue was crystallized with diethyl ether. The resulted crystals were collected by filtration, and dried to obtain 10.7 g of 7-chloro-1-[2-methyl-4-(2-methylbenzamido)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl 4-chlorobutyrate as white powder.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17][C:16]=1[S:25](Cl)(=[O:27])=[O:26].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([S:25]([C:16]2[CH:17]=[CH:18][C:19]3[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=2)(=[O:27])=[O:26])[CH2:13][CH2:14]1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc(N2CCN(S(=O)(=O)c3ccc4ccccc4c3)CC2)c(C)c1
Yield: 92 %

Procedure:
Sulfonylation of 1-(2,4-dimethylphenyl)piperazine (293 mg, 1.54 mmol) with naphthalene-2-sulfonyl chloride (350 mg, 1.54 mmol) was carried out according to a similar procedure described for example 3A using anhydrous dichloromethane (5 mL) as solvent and diisopropylethylamine (0.670 mL, 3.85 mmol) as base. 1-(2,4-dimethylphenyl)-4-(2-naphthylsulfonyl)piperazine was obtained in 92% yield (539 mg) as white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([OH:13])=[N:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:16][O:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32]Cl)[C:20]1[O:25][CH2:24][CH2:23][O:22][N:21]=1.O>CN(C)C=O>[CH3:16][O:17][N:18]=[C:19]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:13][C:10]1[CH:11]=[CH:12][N:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:9]=1)[C:20]1[O:25][CH2:24][CH2:23][O:22][N:21]=1
Reactant: CON=C(C1=NOCCO1)c1ccccc1CCl
Reactant: Oc1ccn(-c2ccc(Cl)cc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CON=C(C1=NOCCO1)c1ccccc1COc1ccn(-c2ccc(Cl)cc2)n1
Temperature: 22.5 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A solution of 0.97 g of 1-(para-chlorophenyl)-3-hydroxypyrazole in 20 ml of anhydrous dimethylformamide (DMF) was admixed with 0.13 g of sodium hydride and then stirred at 20-25 ° C. for approximately one hour. 1.34 g of the oxime from Example 2 were then added and the mixture was stirred at 60° C. for approximately three hours and then at 20-25° C. for approximately 14 hours. 300 ml of water were added and the mixture was then extracted with methyl tert-butyl ether (MTBE). The combined organic phases were washed with water and dried, and the solvent was then removed. The residue was chromatographed over silica gel (cyclohexane/ethyl acetate mixture [1:1]), giving 1.15 g of the title compound as a light-beige amorphous powder of m.p. 56-59° C.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([O:22]C(C)(C)C)=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1>ClCCl>[Cl:8][C:9]1[C:14]([N:15]2[CH2:19][CH:18]([C:20]([OH:22])=[O:21])[N:17]([CH3:27])[C:16]2=[O:28])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1C(=O)N(c2cccnc2Cl)CC1C(=O)O
Temperature: 25 °C
Reaction time: 36 h
Yield: 113.1 %

Procedure:
Trifluoroacetic acid (2.5 ml) was added to a solution of 1,1-dimethylethyl 1-(2-chloro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylate (579 mg, 1.857 mmol) in dichloromethane (10 ml) and the solution was stirred at room temperature for 36 hours. The solvent was evaporated under vacuum azeotroping with toluene and the residue dried under heated vacuum overnight 1-(2-chloro-3-pyridinyl)-3-methyl-2-oxo-4-imidazolidinecarboxylic acid (537 mg, 70.4% yield) which was used crude in the next step. LC/MS MH+=256.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]([CH3:11])=[C:6]([CH:10]=1)[C:7]([O-:9])=[O:8].[C:15](=O)([O-])[O-].[Cs+].[Cs+].I[CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1.C(OCC)(=O)C>C(#N)C.O>[CH3:15][O:8][C:7]([C:6]1[CH:10]=[C:2]([CH:3]=[C:4]([N+:12]([O-:14])=[O:13])[C:5]=1[CH3:11])[O:1][CH:22]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:23]1)=[O:9]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: Cc1c(C(=O)[O-])cc(O)cc1[N+](=O)[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cc(OC2CN(C(=O)OC(C)(C)C)C2)cc([N+](=O)[O-])c1C
Temperature: 80 °C
Yield: 46.1 %

Procedure:
To stirred solution of 5-hydroxy-2-methyl-3-nitrobenzoate (1.5 g, 7.1 mmol) in ACN (15 mL) were added cesium carbonate (4.64 g, 14.2 mmol) and tert-butyl 3-iodoazetidine-1-carboxylate (3.0 g, 11 mmol). The resulting mixture was heated at 80° C. overnight. On completion, the reaction mixture was diluted with water and extraction was carried out using ethyl acetate. The combined organic layers were washed with water, dried and concentrated under reduced pressure. The crude material was purified by column chromatography to afford the title compound (1.2 g, 46%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[N:17]=2)=O)=[CH:5][CH:4]=1)#[N:2].O>O1CCCC1>[CH3:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([C:16]2[N:17]=[C:13]([NH:12][CH2:10][CH2:9][C:6]3[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=3)[S:14][CH:15]=2)=[CH:23][CH:22]=1
Reactant: COc1ccc(-c2csc(NC(=O)Cc3ccc(C#N)cc3)n2)cc1
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2csc(NCCc3ccc(C#N)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.5 %

Procedure:
610 mg 2-(4-Cyano-phenyl)-N-[4-(4-methoxy-phenyl)-thiazol-2-yl]-acetamide were suspended in 20 ml tetrahydrofuran. 2.1 ml of a one molar solution of borane tetrahydrofuran complex were added at room temperature. The reaction mixture was stirred at room temperature for two hours and then at 50° C. for two hours. The cooled reaction mixture was poured on 50 ml water and extracted five times with portions of 50 ml ethyl acetate. The combined organic layers were dried over MgSO4. Then the solvents were removed in vacuo to obtain 600 mg 4-{2-[4-(4-Methoxy-phenyl)-thiazol-2-ylamino]-ethyl}-benzonitrile.
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C@H:6]([CH:25]([CH3:27])[CH3:26])[C:7]([N:9]1[CH2:14][CH2:13][C@@:12]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)([OH:15])[C:11]([CH3:24])([CH3:23])[CH2:10]1)=[O:8])=[O:4].C(=O)([O-])[O-].[K+].[K+].[OH:34][C:35]1[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=1[C:37]([O:39][CH3:40])=[O:38].CS(C)=O>CCOC(C)=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C@@:12]2([OH:15])[CH2:13][CH2:14][N:9]([C:7](=[O:8])[C@H:6]([NH:5][C:3](=[O:4])[CH2:2][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[CH:41][C:36]=3[C:37]([O:39][CH3:40])=[O:38])[CH:25]([CH3:27])[CH3:26])[CH2:10][C:11]2([CH3:23])[CH3:24])=[CH:17][CH:18]=1
Reactant: COC(=O)c1ccccc1O
Reactant: CC(C)[C@@H](NC(=O)CCl)C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccccc1OCC(=O)N[C@@H](C(=O)N1CC[C@](O)(c2ccc(Cl)cc2)C(C)(C)C1)C(C)C
Temperature: 25 °C
Yield: 40.5 %

Procedure:
2-Chloro-N—((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-yl)acetamide (35 mg, 0.084 mmol), potassium carbonate (35 mg, 0.253 mmol), methyl 2-hydroxybenzoate (13 mg, 0.084 mmol) and DMSO (3 mL) were mixed with stirring at 25° C. The reaction was stirred for 20 hours, diluted with EtOAc, and then rinsed 4 times with water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give an amber oil which was purified over silica gel in (3:1 to 1:1 hexanes/EtOAc to 100% EtOAc) to obtain methyl 2-(2-((R)-1-((S)-4-(4-chlorophenyl)-4-hydroxy-3,3-dimethylpiperidin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-2-oxoethoxy)benzoate (18 mg, 0.034 mmol, 40% yield) as a white glass. MS found: (M+H)+=531.21.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1(OP(Cl)(OC2C=CC=CC=2)=O)C=CC=CC=1.[NH2:35][C@@H:36]1[CH:41]2[CH2:42][CH2:43][N:38]([CH2:39][CH2:40]2)[CH2:37]1.CO>C(Cl)Cl>[N:38]12[CH2:43][CH2:42][CH:41]([CH2:40][CH2:39]1)[C@@H:36]([NH:35][C:11](=[O:13])[C:10]1[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=3)=[CH:15][CH:14]=1)[CH2:37]2
Reactant: O=C(O)c1ccc(Oc2ccc(F)cc2)cc1
Reactant: N[C@H]1CN2CCC1CC2
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Solvent: CO
Solvent: ClCCl
Product: O=C(N[C@H]1CN2CCC1CC2)c1ccc(Oc2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
TEA (50 μL, 0.35 mmol) is added to a suspension of the acid from Step F (81 mg, 0.35 mmol) in CH2Cl2 (1 mL). Diphenylchlorophosphate (62 μL, 0.3 mmol) is added and the resulting solution is stirred at room temperature for 30 minutes. A solution of (R)-3-aminoquinuclidine (1.0M in CH3CN, 0.2 mL, 0.2 mmol) is added and the resulting solution is shaken overnight at room temperature. MeOH is added and the mixture is poured through a column of AG50W×2 ion exchange resin (H+ form). The resin is washed with MeOH and then the product is eluted with 5% TEA in MeOH. The eluent is evaporated to dryness to yield the desired product (58 mg, 85%). MS for C20H21FN2O2 (ESI) (M+H)+ m/z 341.
Reaction SMILES: O[CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH2:13]O)[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:15].N1C=CC=CC=1.P(Cl)(Cl)[Cl:23]>C1COCC1>[Cl:23][CH2:2][C-:3]1[CH:7]=[CH:6][CH:5]=[CH:4]1.[C-:8]1([CH2:13][Cl:23])[CH:12]=[CH:11][CH:10]=[CH:9]1.[Fe+2:15]
Reactant: ClP(Cl)Cl
Reactant: OC[c-]1cccc1
Agent: [Fe+2]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: ClC[c-]1cccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a flask containing 1,1′-bis(hydroxymethyl)ferrocene (0.5 g, 2.0 mmol) under an atmosphere of nitrogen, was added THF (30 mL) and pyridine (0.33 mL, 4.1 mmol). PCl3 (0.35 mL, 4.1 mmol) was added dropwise to this solution and a yellow precipitate immediately formed. The mixture was stirred at room temperature for 3 hours. The yellow solution was decanted from the solid using a syringe and the remaining solid was washed with THF (2×15 mL). The washings and original solution were combined and evaporated to dryness. The resulting residue was used immediately in subsequent reactions.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:21]=[CH:20][C:8]([C:9](=[O:19])[CH2:10][CH:11]([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[H-].[Na+].[CH3:24]I.O>O1CCCC1>[CH3:24][C:11]([CH2:10][C:9]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:21][CH:20]=1)=[O:19])([C:16]([CH3:18])=[O:17])[C:12]([O:14][CH3:15])=[O:13]
Reactant: COC(=O)C(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(C)(CC(=O)c1ccc(S(C)(=O)=O)cc1)C(C)=O
Reaction time: 0.17 h
Yield: 78.8 %

Procedure:
0.65 g (2.1 mmol) of methyl 2-(4-methylsulfonylphenacyl)acetoacetate [prepared as described in Example 43(ii)] was dissolved in 20 ml of anhydrous tetrahydrofuran, and 92 mg (2.3 mmol) of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to the resulting solution, whilst ice-cooling and under a nitrogen atmosphere. The mixture was stirred for 10 minutes, after which 1.1 ml (2.5 mmol) of methyl iodide were added, whilst ice-cooling, and the mixture was stirred for 2 hours. At the end of this time, water was added to the mixture, which was then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride, after which it was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure. The residue was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of ethyl acetate and hexane, to give 0.54 g (yield 80%) of the title compound as a slightly yellow powder.
Reaction SMILES: Cl.[C:2](=[NH:12])(OCC)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH2:17]>CO.[OH-].[Na+]>[CH3:13][O:14][CH:15]([O:18][CH3:19])[CH2:16][NH:17][C:2](=[NH:12])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: COC(CN)OC
Reactant: CCOC(=N)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(CNC(=N)c1ccccc1)OC
Reaction time: 72 h
Yield: 104.5 %

Procedure:
(EX-1A) A solution of ethyl benzimidate hydrochloride (92.25 g, 496.9 mmol) in 300.0 mL dry methanol (1.68 M) was cooled to ca 0° C. and added a solution of aminoacetaldehyde dimethyl acetal (73.10 mL, 670.9 mmol) in dry methanol (75.0 mL, 9.0 M) drop wise at such a rate the temperature was kept below 5° C. The resulting solution was allowed to stir for 3 days with the temperature being maintained below 5° C. The reaction mixture was then concentrated under reduced pressure to give a yellow oil. The residue was dissolved in 1 N NaOH (750 mL) and extracted with dichloromethane (4×250 mL). The organic solutions were combined, dried (MgSO4), and concentrated to give 108.13 g crude N-(2,2-dimethoxyethyl)benzamidine as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:12][CH2:11][CH:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH:3]=1.[H-].[Na+].Cl[C:24]1[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=1>>[NH2:13][CH:10]1[CH2:11][CH2:12][N:8]([C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:24]3[S:25][C:26]([C:29]#[N:30])=[CH:27][N:28]=3)[CH:3]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(N)ncn2)C1
Reactant: N#Cc1cnc(Cl)s1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3CCC(N)C3)ncn2)s1

Procedure:
Tert-butyl 1-(6-aminopyrimidin-4-yl)pyrrolidin-3-ylcarbamate 14-2 (0.483 g, 1.73 mmol), sodium hydride (0.277 g, 6.92 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.25 g, 1.73 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column after treating the crude product with trifluoroacetic acid and then isolated via lyophilization. Hi-Res MS: calc: 288.1026 found: 288.1046. 1NMR (CD3OD): 8.43 ppm (s, 1H); 8.0 ppm (s, 1H); 6.02 ppm (s, 1H); 4.05 ppm (m, 1H); 3.87 ppm (m, 1H); 3.69 ppm (m, 3H); 2.51 ppm (m, 1H); 2.22 ppm (m, 1H).