Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2)(=O)=O.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCOCC1.C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[C:7]1[C:8]([C:17]([N:19]([O:21][CH3:22])[CH3:20])=[O:18])=[CH:9][CH:10]=[C:11]2[C:16]=1[N:15]=[CH:14][CH:13]=[CH:12]2
Reactant: OB(O)c1ccccc1F
Reactant: CON(C)C(=O)c1ccc2cccnc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CON(C)C(=O)c1ccc2cccnc2c1-c1ccccc1F
Temperature: 100 °C
Yield: 78.6 %

Procedure:
To a mixture of 7-{[methoxy(methyl)amino]carbonyl}quinolin-8-yl trifluoromethanesulfonate (0.15 g, 0.41 mmol) and (2-fluorophenyl)boronic acid (0.069 g, 0.49 mmol) in 1,4-dioxane (2 mL) was added 1 N solution of sodium carbonate (0.065 g, 0.62 mmol) in water (0.62 mL, 34 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.024 g, 0.020 mmol). The mixture was heated at 100° C. overnight. After cooling, the mixture was diluted with ethyl acetate, washed with water, dried over MgSO4, and concentrated and purified on silica gel (0-100% EtOAc in Hexane) to give the desired product (100 mg, 78%). LCMS calculated for C18H16FN2O2(M+H)+: m/z=311.1; found: 311.0.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([O:20]C)[CH:17]=[CH:16][C:15]=2[CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].[B]>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:15]=2[CH3:22])=[O:12])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: COc1ccc(C)c(NC(=O)CNc2ccc(F)c(Cl)c2)c1
Agent: [B]
Solvent: ClCCl
Product: Cc1ccc(O)cc1NC(=O)CNc1ccc(F)c(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.5 %

Procedure:
To a solution of 2-(3-chloro-4-fluorophenylamino)-N-(5-methoxy-2-methylphenyl)-acetamide (3.93 g) in anhydrous dichloromethane (450 ml) was stirred under nitrogen at −78° C. was added a solution of boron tribrouide (1M in dichloromethane, 95 ml) dropwise. The mixture was then allowed to warm to room temperature and stirred under nitrogen for 20 hours before being poured into ice/water (1 l), stirred vigorously for 1 hour and extracted into ethyl acetate (3×500 ml), dried (MgSO4) and concentrated. Purification of the residue by silica gel chromatography (eluting with 3% methanol in dichloromethane) gave the sub-title compound (2.65 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])[CH2:7][CH2:6]1)=[O:4].[Cl:21][S:22](O)(=[O:24])=[O:23]>ClCCl>[CH3:18][O:17][C:12]1[CH:13]=[CH:14][C:15]([S:22]([Cl:21])(=[O:24])=[O:23])=[CH:16][C:11]=1[N:8]1[CH2:7][CH2:6][N:5]([C:3](=[O:4])[C:2]([F:1])([F:19])[F:20])[CH2:10][CH2:9]1
Reactant: COc1ccccc1N1CCN(C(=O)C(F)(F)F)CC1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)Cl)cc1N1CCN(C(=O)C(F)(F)F)CC1
Reaction time: 0.17 h

Procedure:
A solution of 2,2,2-trifluoro-1-[4-(2-methoxy-phenyl)-piperazin-1-yl]-ethanone (14 g; 0.48 mol) in dichloromethane (20 mL) was added to chlorosulfonic acid (75 mL) in such a rate that the inner temperature did not exceed −5° C. After 10 min at this temperature, the solution was poured slowly onto ice-water (500 g), the precipitate was filtered and washed with cold water (2×200 mL) and cold diethyl ether (200 mL). The resulting solid was recrystallized from diethyl ether to give 4-methoxy-3-[4-(2,2,2-trifluoro-acetyl)-piperazin-1-yl]-benzenesulfonyl chloride as white powder (7.7 g; 41%), MS, MH+ 387, m. p. 125-127.3° C.
Reaction SMILES: [C:1]([N:8]([C:25]([O:27]C(C)(C)C)=O)[C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:32](OC(=O)NC(=O)CC)(C)(C)[CH3:33]>>[C:4]([O:3][C:1](=[O:2])[N:8]([C@H:9]1[CH2:13][C@@H:12]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([Cl:24])=[N:18][C:19]=3[Cl:23])[CH:11]=[CH:10]1)[C:25](=[O:27])[CH2:32][CH3:33])([CH3:5])([CH3:7])[CH3:6]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1
Reactant: CCC(=O)NC(=O)OC(C)(C)C
Product: CCC(=O)N(C(=O)OC(C)(C)C)[C@@H]1C=C[C@H](n2cnc3c(Cl)nc(Cl)nc32)C1

Procedure:
The title compound is prepared analogously to di-Boc-[(1S,4R)-4-(2,6-dichloro-purin-9-yl)-cyclopent-2-enyl]-amine (by replacing di-t-butyliminodicarboxylate with propionyl-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH:9]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].[F:26][C:27]([F:38])([F:37])[C:28]1([CH2:31]OS(C)(=O)=O)[CH2:30][CH2:29]1>>[CH3:1][S:2]([N:5]1[CH2:6][CH:7]=[C:8]([C:11]2[CH:12]=[C:13]3[CH2:19][CH:18]([CH:20]4[CH2:25][CH2:24][N:23]([CH2:31][C:28]5([C:27]([F:38])([F:37])[F:26])[CH2:30][CH2:29]5)[CH2:22][CH2:21]4)[O:17][C:14]3=[CH:15][N:16]=2)[CH2:9][CH2:10]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCNCC2)C3)CC1
Product: CS(=O)(=O)N1CC=C(c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)CC1

Procedure:
The title compound is prepared from 5-(1-methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 3): tR=0.67 min; Mass spectrum (ESI+): m/z=486 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=2[CH3:18])=[O:9])[CH:3]=1.[CH:19]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([NH:26][C:2]2[N:7]=[CH:6][N:5]=[C:4]([C:8]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][C:12]=3[CH3:18])=[O:9])[CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Cc1cc(O)ccc1NC(=O)c1cc(Cl)ncn1
Reactant: NC1CCCCCC1
Product: Cc1cc(O)ccc1NC(=O)c1cc(NC2CCCCCC2)ncn1

Procedure:
Following the general method as outlined in Example 20, starting from 6-chloro-N-(4-hydroxy-2-methylphenyl)pyrimidine-4-carboxamide (Intermediate 8) and cycloheptylamine (Aldrich), the title compound was obtained as a beige solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[O:9]2)=[CH:4][C:3]=1[C:47]([C:49]1[N:50]=[N:51][C:52]([O:55][CH2:56][CH3:57])=[CH:53][CH:54]=1)=[O:48].[BH4-].[Na+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[C@H:13]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C@@H:12]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@H:11]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@@H:10]([CH2:38][O:39][CH2:40][C:41]3[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=3)[O:9]2)=[CH:4][C:3]=1[CH:47]([C:49]1[N:50]=[N:51][C:52]([O:55][CH2:56][CH3:57])=[CH:53][CH:54]=1)[OH:48]
Reactant: CCOc1ccc(C(=O)c2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCOc1ccc(C(O)c2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)ccc2Cl)nn1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-chloro-5-((2S,3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)phenyl)(6-ethoxypyridazin-3-yl)methanone (970 mg; 1.24 mmol) in MeOH (20 mL) was added NaBH4 (93.5 mg; 2.47 mmol) at 0° C., then stirred for 3 h at room temperature. The reaction was quenched with 2N HCl, extracted with ethyl acetate (3×50 mL) and washed with brine. The organic layer was dried over MgSO4 and the solvents were evaporated under a vacuum. The crude mixture was further purified by flash column chromatography (Biotage SP1™) (eluent: hexane/EtOAc mixture (40/60; v/v)) to obtain 907 mg (1.15 mmol; 93%) of the title compound as colorless oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N:12]=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:30])C=1.[OH-].[Na+].O>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH3:19])[CH:17]=2)[N+:12]([O-:30])=[C:11]([CH3:20])[C:10]=1[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2nc(C)c(C)c(OCc3ccccc3)c2c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)c(OCc1ccccc1)c(C)c(C)[n+]2[O-]
Temperature: 0 °C
Reaction time: 4.5 h
Yield: 83.4 %

Procedure:
To an ice-cold solution of 4-(benzyloxy)-2,3,6-trimethylquinoline (1.36 g) in chloroform (25 mL) was added m-chloroperbenzoic acid (75%, 1.35 g), and the mixture was stirred for 4.5 hours. A 1M aqueous sodium hydroxide solution (10 mL) and water (10 mL) were added to the reaction mixture, followed by extraction with chloroform (20 mL). The organic layer was washed sequentially with water and saturated brine, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=95/5) to obtain 4-(benzyloxy)-2,3,6-trimethylquinoline-1-oxide (1.20 g).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1.Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>>[CH2:35]([O:34][C:32]([N:1]1[CH2:4][CH:3]([NH:5][C:6]([C:8]2[C:12]3[N:13]=[CH:14][N:15]=[C:16]([C:17]4[C:25]5[O:24][CH2:23][O:22][C:21]=5[CH:20]=[CH:19][C:18]=4[O:26][CH2:27][CH:28]4[CH2:30][CH2:29]4)[C:11]=3[NH:10][CH:9]=2)=[O:7])[CH2:2]1)=[O:33])[CH3:36]
Reactant: O=C(NC1CNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Reactant: CCOC(=O)Cl
Product: CCOC(=O)N1CC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid azetidin-3-ylamide (example A172) and ethyl chloroformate the title compound is obtained as colorless solid.
Reaction SMILES: [OH:1][CH:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=2[C:4](=[O:13])[O:3]1.[C:14](=O)([O-])[O-].[K+].[K+].IC>CN(C)C=O>[CH:2]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]([CH:11]=[O:12])[C:5]=1[C:4]([O:3][CH3:14])=[O:13])=[O:1]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1cccc2c1C(=O)OC2O
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c(C=O)cccc1C=O
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a solution of 1-hydroxy-3-oxo-1,3-dihydro-2-benzofuran-4-carbaldehyde (720 mg) in anhydrous dimethylformamide (4 ml) was added potassium carbonate (613 mg). It was stirred for 30 minutes to give a thick white suspension. Iodomethane (0.4 ml) was added and stirred for 3 days. More methyl iodide (0.4 ml) was added and stirring continued for 24 hours. Most of the dimethylformamide was evaporated in vacuo. The pale yellow residue was partitioned between ethyl acetate (25 ml) and water (25 ml) and the organic phase was washed with aqueous lithium chloride (50 ml) and saturated brine (25 ml), dried over sodium sulphate and evaporated to give a pale yellow solid (645 mg).
Reaction SMILES: C([O:8][C:9]([N:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]([CH2:23][CH3:24])[C:14](=[O:25])[CH2:13][O:12]1)=O)C1C=CC=CC=1.[C:26](OC(=O)C)(=O)C>[Pd]>[C:9]([N:11]1[CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:15]([CH2:23][CH3:24])[C:14](=[O:25])[CH2:13][O:12]1)(=[O:8])[CH3:26]
Reactant: CCN1C(=O)CON(C(=O)OCc2ccccc2)C1c1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: [Pd]
Product: CCN1C(=O)CON(C(C)=O)C1c1ccccc1
Yield: 82 %

Procedure:
0.69 g. (2 mmoles) of 2-benzyloxycarbonyl-3-phenyl-4-ethyl-tetrahydro-1,2,4-oxadiazin-5-one are dissolved in 7 ml. of acetic anhydride, 0.1 g. of a 5%, palladium-on-activated carbon catalyst are added and hydrogen gas is bubbled through the mixture at room temperature under vigorous stirring. The progress of hydrogenation is monitored by thin layer chromatography. As soon as the reaction is complete, the catalyst is filtered off, the filtrate is evaporated to dryness under reduced pressure and the residue is recrystallized from 1 ml. of ethanol. 0.41 g. (82%) of 2-acetyl-3-phenyl-4-ethyl-tetrahydro-1,2,4-oxadiazin-5-one are obtained, melting at 130° C. to 132° C. RfA =0.6.
Reaction SMILES: NC1C(O)=NC(N2C=CC=N2)=NC=1.[CH2:14]([O:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][N:25]=[C:24]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[N:23]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)(=O)C(Cl)=O.CCN(CC)CC.[N-:49]=[N+:50]=[N-:51].[Na+]>ClCCl.CN(C=O)C.O>[CH2:14]([O:21][C:22]1[C:27]([C:28]([OH:30])=[O:29])=[CH:26][N:25]=[C:24]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[N:23]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1.[N:49]([C:28]([C:27]1[C:22]([O:21][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:23][C:24]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[N:25][CH:26]=1)=[O:29])=[N+:50]=[N-:51]
Reactant: [N-]=[N+]=[N-]
Agent: Nc1cnc(-n2cccn2)nc1O
Agent: O=C(Cl)C(=O)Cl
Agent: O=C(O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: [N-]=[N+]=NC(=O)c1cnc(-n2cccn2)nc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid (3-c) was synthesized in a manner outlined in Steps A through Step C of the synthesis of Intermediate 3-e. To a solution of 4-(benzyloxy)-2-(1H-pyrazol-1-yl)pyrimidine-5-carboxylic acid, 3-c, (500 mg, 1.69 mmol) in dry dichloromethane (10 ml) was added dropwise oxalyl chloride (0.29 ml, 3.38 mmol) at 0° C. and a catalytic amount of DMF (3-5 drops). The mixture was stirred at room temperature for 3 hours. Then the mixture was concentrated under vacuum and the residue was dissolved in acetone (10 ml). Et3N (205 mg, 2.03 mmol) was added at 0° C. and the mixture was stirred for 5 mins before sodium azide (988 mg, 15.2 mmol) in water (1 ml) was added. The resulting mixture was stirred at room temperature for 1 h. Subsequently, the mixture was diluted with water and filtered. The solid was washed with water (5-10 ml) and then taken into approximately 20-30 mL of dichloromethane. The organic layer was dried over sodium sulfate and concentrated under vacuum to provide compound 5-a as a solid (130 mg) which was used in Step B without any further purification. (M+H)+=322.
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15](O)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.N1C=CN=C1.[H-].[Na+].[NH2:42][C:43]1[S:44][S:45][C:46](=[S:48])[N:47]=1.O.[Cl-].[NH4+]>O1CCCC1>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([CH:14]([CH:18]([CH3:20])[CH3:19])[C:15]([NH:42][C:43]3[S:44][S:45][C:46](=[S:48])[N:47]=3)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Nc1nc(=S)ss1
Reactant: CC(C)C(C(=O)O)c1ccc(OCc2ccc(F)cc2)cc1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)C(C(=O)Nc1nc(=S)ss1)c1ccc(OCc2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 13.1 %

Procedure:
2-{4-[(4-Fluorobenzyl)oxy]phenyl}-3-methylbutanoic acid(1.00 g, 3.31 mmol) was dissolved in tetrahydrofuran (11 ml), and 1,1′-carbonyldiimidazole (0.644 g, 3.97 mmol) was added thereto. The imidazole mixture was stirred for 1 hour at room temperature. Sodium hydride (60% oil suspension 0.132 g, 3.31 mmol) was suspended in tetrahydrofuran (11 ml), and 3-amino-1,2,4-dithiazole-5-thione (0.497 g, 3.31 mmol) was added thereto. After being stirred for 30 minutes at 0° C., the reaction mixture, with the imidazole mixture added thereto, was stirred for 21 hours at room temperature. The reaction mixture, with saturated ammonium chloride water added thereto, was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and saturated brine successively, dried over MgSO4, and then concentrated. The obtained residue was purified by silica gel column chromatography (chloroform), to give 2-{4-[(4-fluorobenzyl)oxy]phenyl}-3-methyl-N-(3-thioxo-3H-1,2,4-dithiazol-5-yl)butanamide (Compound 12) (0.188 g, 13%).
Reaction SMILES: C(O[C:4]([C:6]1([CH2:19][CH2:20][NH:21][C:22]2[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=2[CH3:29])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)=[O:5])C.CC(C)([O-])C.[K+].O.CO>C1COCC1.C(Cl)Cl>[C:15]([O:14][C:12]([N:9]1[CH2:10][CH2:11][C:6]2([C:4](=[O:5])[N:21]([C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:23]=3[CH3:29])[CH2:20][CH2:19]2)[CH2:7][CH2:8]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1(CCNc2ccc(Br)cc2C)CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1N1CCC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a clear solution of 4-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (3.42 mmol) in THF (40 mL) was added a solution of potassium t-butoxide (1M in THF) 1 mL (1 mmol, 0.3 equiv.) at r.t. (water bath at rt). The clear solution turned a little bit cloudy. After 30 min, TLC (5% MeOH in DCM) showed the reaction is complete (spot to spot), LC/MS detected the product peak of 423/425 (t 3.267 min). The reaction was cooled in an ice-water bath, diluted with 100 mL of DCM, quenched with 20 mL of water. The two layers were separated. The aqueous layer was extracted with DCM (2×20 mL). The combined DCM extracts were washed with brine, and concentrated on rotavap to yield 0.90 g (63% yield) of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8].[C:10]([O:13][CH:14]1[CH:19]([O:20][C:21](=[O:23])[CH3:22])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH:17]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[O:16][CH:15]1Br)(=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].O>ClCCl.[Cl-].C([N+](CCCC)(CCCC)CCCC)C1C=CC=CC=1>[C:10]([O:13][CH:14]1[CH:19]([O:20][C:21](=[O:23])[CH3:22])[CH:18]([O:24][C:25](=[O:27])[CH3:26])[CH:17]([CH2:28][O:29][C:30](=[O:32])[CH3:31])[O:16][CH:15]1[O:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](=[O:9])[CH3:8])(=[O:12])[CH3:11]
Reactant: CC(=O)c1sccc1O
Reactant: CC(=O)OCC1OC(Br)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O
Agent: CCCC[N+](CCCC)(CCCC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)OCC1OC(Oc2ccsc2C(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC(C)=O

Procedure:
2 g of 1-(3-hydroxy-thiophen-2-yl)-ethanone were dissolved in 120 ml of dichloromethane and stirred with 6.4 g of 4,5-diacetoxy-6-acetoxymethyl-2-bromotetrahydropyran-3-yl acetate, 1.4 g of benzyltributylammonium chloride, 6.4 g of potassium carbonate and 1.2 ml of water at 22° C. for 20 h. Insoluble constituents were removed by filtration, the filtrate was concentrated and the crude product mixture was purified by column chromatograph (SiO2, ethyl acetate/n-heptane=1:1). The product with the molecular weight of 472.5 (C20H24O11S), MS (Cl): 473 (M+H+) was obtained
Reaction SMILES: CO[C:3](=[O:17])/[CH:4]=[CH:5]/[CH:6]=[CH:7]/[CH2:8][CH2:9][C:10]([O:12][C:13](C)(C)C)=[O:11].C(O)(C(F)(F)F)=O.[NH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)CCl>C(Cl)Cl.CN(C1C=CN=CC=1)C.CCOC(C)=O>[CH3:13][O:12][C:10](=[O:11])/[CH:9]=[CH:8]/[CH:7]=[CH:6]/[CH2:5][CH2:4][C:3](=[O:17])[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1ccccc1
Reactant: COC(=O)/C=C/C=C/CCC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: COC(=O)/C=C/C=C/CCC(=O)Nc1ccccc1
Reaction time: 1.5 h
Yield: 52.3 %

Procedure:
To a stirred solution of diester 43 (1.00 g, 4.61 mmol) in CH2Cl2 (40 mL) was added TFA (4.0 mL) and let react for 6 h. The mixture was concentrated under reduced pressure to remove volatiles. A white solid consisting of the crude acid (710 mg, 3.85 mmol) remained. This acid (400 mg, 2.17 mmol) was dissolved in CH2Cl2 (20 mL) and to this stirred solution were added DMAP (13 mg), aniline (218 μL, 2.39 mmol), and EDC (500 mg, 2.61 mmol). After 1.5 h, the mixture was diluted with EtOAc and washed with H2O. The layers were separated, and the aqueous extracted with EtOAc (3×15 mL). The organic portions were combined and washed with HCl (1 N, 1×5 mL) and brine, dried over MgSO4, and filtered. Concentration under reduced pressure left a brown solid. This was dissolved in a minimum of CH2Cl2, then passed through a plug of silica gel (20–30% EtOAc/hexanes, 200 mL) to remove baseline impurities. The eluent was concentrated to a light brown oil which was taken up in a small amount of CH2Cl2 and from which crystals were precipitated upon the addition of hexanes/diethyl ether. The mother liquor was drawn off, the crystals rinsed with ether, and the liquid fraction concentrated and this procedure repeated several times to ultimately give 44 as off-white crystals (324 mg, 1.25 mmol, 58%). TLC Rf 0.44 (50% EtOAc/hexanes); 1H-NMR (400 MHz, CDCl3) δ 7.47 (d, 1H), 7.30 (t, 2H), 7.24 (m, 1H), 7.09 (t, 1H), 6.24 (dd, 1H), 6.14 (m, 1H), 5.81 (d, 1H), 3.72 (s, 3H), 2.60 (m, 2H), 2.47 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([NH2:6])=[C:4]([F:12])[CH:3]=1.[C:13](Cl)(Cl)=[S:14].C(N(CC)CC)C>C(Cl)Cl.C(OCC)(=O)C.CCCCCCC>[Cl:1][C:2]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][C:5]([N:6]=[C:13]=[S:14])=[C:4]([F:12])[CH:3]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc([N+](=O)[O-])c(Cl)cc1F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(N=C=S)c(F)cc1Cl
Temperature: 0 °C
Yield: 95.5 %

Procedure:
To a cold (0° C.), stirring mixture of 12.0 g (0.0630 mole) of 4-chloro-2-fluoro-5-nitroaniline in 100 mL of methylene chloride was added dropwise 7.3 g (0.063 mole) of thiophosgene. While maintaining a temperature of 0° C., 13.2 g (0.130 mole) of triethylamine was added dropwise to the mixture. After complete addition, the mixture was allowed to warm to room temperature and stir for approximately 18 hours. The solvent was evaporated under reduced pressure leaving a residue. This residue was stirred in a mixture of ethyl acetate and n-heptane (30:70). The insoluble amine hydrochloride salts were removed by filtration. The filtrate was evaporated under reduced pressure to yield 14.0 g of 4-chloro-2-fluoro-5-nitrophenylisothiocyanate.