Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:6])[O:4][CH3:5].[CH2:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1O)[CH2:8][CH2:9]C.P(Br)(Br)Br>ClC(Cl)C>[CH3:1][NH:2][C:3](=[O:6])[O:4][C:5]1[CH:9]=[CH:8][CH:7]=[CH:11][C:12]=1[CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCc1ccccc1O
Reactant: CNC(=O)OC
Agent: BrP(Br)Br
Solvent: CC(Cl)Cl
Product: CCCCc1ccccc1OC(=O)NC

Procedure:
To a mixture of methyl N-methylcarbamate (0.89 g, 0.01 mole) and 2-sec butylphenol (1.5 g, 0.01 mole) in dichloroethane (10 ml), a solution of phosphorus tribromide (2.7 g, 0.01 mole) in dichloro-ethane (6 ml) was added and the mixture was refluxed for eight hours. It was then worked up and purified as described earlier to give 2-sec butylphenyl N-methylcarbamate of the formula (III).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:8]2[CH2:14][C:13](=[O:15])[NH:12][C:11]3[CH:16]=[C:17]([C:20]#[C:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH:18]=[CH:19][C:10]=3[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:28][Si:29]([C:32]#[CH:33])([CH3:31])[CH3:30]>>[C:22]1([C:21]#[C:20][C:17]2[CH:18]=[CH:19][C:10]3[N:9]=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([C:33]#[C:32][Si:29]([CH3:31])([CH3:30])[CH3:28])[CH:3]=4)[CH2:14][C:13](=[O:15])[NH:12][C:11]=3[CH:16]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C1CC(c2cccc(I)c2)=Nc2ccc(C#Cc3ccccc3)cc2N1
Reactant: C#C[Si](C)(C)C
Product: C[Si](C)(C)C#Cc1cccc(C2=Nc3ccc(C#Cc4ccccc4)cc3NC(=O)C2)c1
Yield: 47.2 %

Procedure:
Prepared from 4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo [b][1,4]diazepin-2-one (Example 11) (231 mg, 0.5 mmol) and trimethylsilylacetylene (0.4 mL, 1.0 mmol) according to the general procedure F. Obtained as a light brown solid (102 mg).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH2:13])=[CH:6][CH:5]=1.[CH3:14][S:15][C:16](SC)=[CH:17][N+:18]([O-:20])=[O:19].[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25]>CN(C)C=O>[C:23]([OH:28])(=[O:27])[C:24]([OH:26])=[O:25].[CH3:1][NH:2][CH2:3][C:4]1[O:8][C:7]([CH2:9][S:10][CH2:11][CH2:12][NH:13][C:16]([S:15][CH3:14])=[CH:17][N+:18]([O-:20])=[O:19])=[CH:6][CH:5]=1
Reactant: CNCc1ccc(CSCCN)o1
Reactant: CSC(=C[N+](=O)[O-])SC
Agent: O=C(O)C(=O)O
Solvent: CN(C)C=O
Product: CNCc1ccc(CSCCNC(=C[N+](=O)[O-])SC)o1
Yield: 26.6 %

Procedure:
A solution of 2-[[5-[(methylamino)methyl]-2-furanylmethyl]thio]ethanamine (6.0 g) and 1,1-bis-(methylthio)-2-nitroethene (19.8 g) in dry dimethylformamide (150 ml) was stirred for 1 hour at 0° and for 5 hours at room temperature. A solution of oxalic acid (4.0 g) in dry dimethylformamide (16 ml) was added and the solid which formed during 18 hours was filtered, washed with dimethylformamide, ethanol and ether and dried. The solid was suspended in water (200 ml) at 55° and on cooling was filtered, washed with water and dried to give the title compound (3.25 g) m.p. 158°-160° dec.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.C(N(CC)CC)C.[CH2:38]([N:45]=[C:46]=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>ClCCl>[CH2:38]([NH:45][C:46]([N:26]1[C:24]2[C:23](=[CH:22][CH:21]=[C:20]([O:19][CH2:18][CH2:17][CH2:16][CH2:15][N:12]3[CH2:13][CH2:14][N:9]([C:3]4[CH:2]=[CH:1][CH:6]=[C:5]([Cl:7])[C:4]=4[Cl:8])[CH2:10][CH2:11]3)[CH:25]=2)[CH2:30][CH2:29][C:27]1=[O:28])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of aripiprazole (1.5 g, 3.35 mmol) in dichloromethane (33 mL) was added triethylamine (0.56 mL, 4.01 mmol) and benzyl isocyanate (0.82 mL, 6.69 mmol). The reaction was stirred at room temperature for 48 hours. The reaction was quenched with water and extracted with dichloromethane (3×20 mL). The organics were combined, washed with brine (20 mL), dried over MgSO4 and concentrated. The residue was purified by column chromatography on silica eluting with 0-10% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-79 (0.575 g) as a colorless solid.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:15]([C:16]([O:18]C)=[O:17])=[C:14]([O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH:28][C:29](=[O:41])[CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=5)[CH:22]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1.CO.O.[OH-].[Li+].Cl>O1CCCC1.O>[CH:1]1([C:4]([NH:6][C:7]2[S:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[C:14]([O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[C:23]([NH:28][C:29](=[O:41])[CH2:30][C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=5)[CH:22]=4)[CH:13]=[CH:12][C:10]=3[N:11]=2)=[O:5])[CH2:3][CH2:2]1
Reactant: COC(=O)c1c(Oc2ccc(F)c(NC(=O)Cc3cccc(C(F)(F)F)c3)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cc1cccc(C(F)(F)F)c1)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)sc3c2C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 82.6 %

Procedure:
To a solution of methyl 2-[(cyclopropylcarbonyl)amino]-6-[4-fluoro-3-({[3-(trifluoromethyl)phenyl]acetyl}amino)phenoxy]-1,3-benzothiazole-7-carboxylate (1.50 g, 2.68 mmol) produced in Example 54(iv) in tetrahydrofuran (24 mL)/methanol (8 mL) was added a solution of lithium hydroxide monohydrate (1.05 g, 25.7 mmol) in water (8 mL), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and the organic solvent was evaporated under reduced pressure. The obtained residue was collected by filtration, repeatedly washed with water to give the title compound (1.27 g, 83%) as a white powder.
Reaction SMILES: O=[C:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1.[ClH:29].Cl.[NH2:31][CH2:32][CH2:33][O:34][NH2:35].N1C=CC=CC=1>C(O)C>[ClH:28].[ClH:29].[NH2:31][CH2:32][CH2:33][O:34][N:35]=[C:2]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH2:3][CH2:4][CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[NH:14][C:13]2=[O:21])[CH2:8][CH2:7]1
Reactant: O=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(Cl)cc1
Reactant: NCCON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: NCCON=C(CCCN1CCC(n2c(=O)[nH]c3ccccc32)CC1)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 105.3 %

Procedure:
A mixture of 1-{1-[4-oxo-4-(4-chlorophenyl)butyl]-4-piperidinyl}-1,3-dihydro-2-benzimidazolone (3.00 g), O-(2-aminoethyl)hydroxylamine dihydrochloride (1.35 g), 3 equivalents of pyridine, and absolute ethanol (75 ml) was heated under reflux, under nitrogen, with stirring, for three hrs. The reaction mixture was partitioned between 10% sodium hydroxide solution and ethyl acetate. The layers were separated and the aqueous phase extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated. The residue was taken up in toluene and evaporated. The residue was purified by flash chromatography (180:19:1 dichloromethane/methanol/ammonium hydroxide). The appropriate fractions were collected and evaporated. The residue was dissolved in absolute ethanol and treated with ethereal hydrogen chloride. The solvent was evaporated, and the residue was taken up in hot 2-propanol and chilled. The precipitate was collected and recrystallized twice from absolute ethanol/ether to give 2.1 g (53%) of product, mp 140°-145° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][N:3]=1.CN.[CH3:13][NH:14]N1C=CC=C([N+]([O-])=O)C1>O1CCCC1>[ClH:1].[NH2:8][C:7]1[C:2]([NH:14][CH3:13])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: CNN1C=CC=C([N+](=O)[O-])C1
Agent: CN
Solvent: C1CCOC1
Product: CNc1ncccc1N
Product: Cl

Procedure:
2-chloro-3-nitro-pyridine (16g) was dissolved in dry tetrahydrofuran (200ml). The solution was exposed to gaseous methylamine untill the reaction to N-methylamino-3-nitropyridine was completed. The mixture was filtered and the filtrate was evaporated. The yellow residue was dissolved in 96% EtOH (250ml) and was charged with 5% Pd/C (1 g) and hydrogenated under standard conditions. After completion of the hydrogenation an aqueous solution of hydrochloric acid was added (5Oml,4N), the Pd catalyst was filtered of and the filtrate was evaporated to give the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([CH2:23][O:24][S:25]([C:28]2[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=2)(=[O:27])=[O:26])[CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CCOCC>[C:31]1([CH3:34])[CH:30]=[CH:29][C:28]([S:25]([OH:27])(=[O:24])=[O:26])=[CH:33][CH:32]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][O:20][CH:19]([CH2:23][NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:18]1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CN(Cc3ccccc3)CCO2)cc1
Reactant: COc1cccc(N)c1
Solvent: CCOCC
Product: COc1cccc(NCC2CN(Cc3ccccc3)CCO2)c1
Product: Cc1ccc(S(=O)(=O)O)cc1
Temperature: 95 °C

Procedure:
A mixture of 3-methoxyaniline (12.5 g.) and 4-benzyl-2-toluene-p-sulphonyloxymethylmorpholine (18.6 g.) is stirred and heated on the steam bath (95°C.) under nitrogen for 24 hours. The mixture is cooled and ether added. The solid thus obtained is collected and crystallised from ethyl acetate to give 4-benzyl-2-(3-methoxyanilino)methylmorpholine toluene-p-sulphonate, m.p. 102-103°C. The toluene-p-sulphonate salt is converted into the corresponding dihydrochloride by basifying it with dilute sodium hydroxide solution, extracting the base into ether (3 × 200 ml.), washing the ethereal extract with water and then drying it over anhydrous magnesium sulphate followed by filtration and treatment of the ethereal solution of base with ethereal hydrochloric acid solution. The 4-benzyl-2-(3-methoxyanilino)methylmorpholine dihydrochloride monohydrate melts at 116-118°C. after crystallisation from methanol/ethyl acetate.
Reaction SMILES: C([O:8][C:9]1[CH:13]([CH2:14][CH:15]2[CH2:20][CH2:19][S:18](=[O:22])(=[O:21])[CH2:17][CH2:16]2)[NH:12][C:11](=[O:23])[C:10]=1[C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[CH:26][C:25]=1[CH3:31])C1C=CC=CC=1>CO.[Pd]>[CH3:31][C:25]1[CH:26]=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=1[C:10]1[C:11](=[O:23])[NH:12][CH:13]([CH2:14][CH:15]2[CH2:16][CH2:17][S:18](=[O:22])(=[O:21])[CH2:19][CH2:20]2)[C:9]=1[OH:8]
Reactant: Cc1ccc(C)c(C2=C(OCc3ccccc3)C(CC3CCS(=O)(=O)CC3)NC2=O)c1
Agent: [Pd]
Solvent: CO
Product: Cc1ccc(C)c(C2=C(O)C(CC3CCS(=O)(=O)CC3)NC2=O)c1
Reaction time: 2 h

Procedure:
10% Pd/C (50 mg) was added to a solution of 4-benzyloxy-3-(2,5-dimethyl-phenyl)-5-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-ylmethyl)-1,5-dihydro-pyrrol-2-one (280 mg, 0.64 mmol) in 20 ml of methanol and the mixture was hydrogenated for 2 h. Then, the resulting mixture was filtered and the filtrate was evaporated in vacuo. The residue was purified by flash chromatography on silica gel. Yield: 200 mg of 3-(2,5-dimethyl-phenyl)-5-(1,1-dioxo-hexahydro-1λ6-thiopyran-4-ylmethyl)-4-hydroxy-1,5-dihydro-pyrrol-2-one (title compound P2.6) as a solid, mp 244-246° C.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([OH:10])(=[S:9])[CH3:8].[CH2:11]([O:14][C:15]([N:17]1[CH2:21][C@H:20](OS(C)(=O)=O)[CH2:19][C@H:18]1[CH2:27][CH2:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=1)=[O:16])[CH:12]=[CH2:13]>CN(C)C=O>[C:7]([S:9][C@@H:20]1[CH2:21][N:17]([C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[O:16])[C@H:18]([CH2:27][CH2:28][C:29]2[CH:30]=[N:31][CH:32]=[CH:33][CH:34]=2)[CH2:19]1)(=[O:10])[CH3:8]
Reactant: C=CCOC(=O)N1C[C@H](OS(C)(=O)=O)C[C@H]1CCc1cccnc1
Reactant: CC(O)=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CCc1cccnc1
Temperature: 0 °C

Procedure:
To a solution of potassium t-butoxide (1.50 g) in N,N-dimethylformamide (20 ml) was added dropwise thioacetic acid (0.96 ml) with stirring at -10°~-5° C. The mixture was stirred at the same temperature for 10 minutes. A solution of (2R,4R)-1-allyloxycarbonyl-4-methanesulfonyloxy-2-[2-(pyridin-3-yl)ethyl]pyrrolidine (3.39 g) in N,N-dimethylformamide (20 ml) was added to the mixture obtained above with stirring at the same temperature. The mixture was stirred at 80°-90° C. for 3 hours. The reaction mixture was poured into ice-water (120 ml) and extracted three times with ethyl acetate (80 ml). The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (150 g) eluting with a mixture of chloroform and methanol (19:1, V/V). The fractions containing the desired compound were collected and evaporated in vacuo to give (2R,4S)-4-acetylthio-1-allyloxycarbonyl-2-[2-(pyridin-3-yl)ethyl]pyrrolidine (3.12 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([O:26][CH2:27][C:28](O)=[O:29])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2].S(Cl)(Cl)=O.C[N:38](C=O)C>C1(C)C=CC=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:32])[N:14]([CH3:31])[N:15]=[C:16]([O:26][CH2:27][C:28](=[O:29])[NH2:38])[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH3:2]
Reactant: CN(C)C=O
Reactant: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OCC(=O)O)nn(C)c1=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: CCc1cc(C)cc(CC)c1-c1c(OCc2ccccc2)c(OCC(N)=O)nn(C)c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 839.2 %

Procedure:
A solution of (4-(2,6-diethyl-4-methylphenyl)-5-benzyloxy-2-methyl-3(2H)-pyridazinone-6-yl)oxyacetic acid (530 mg, 1.53 mmol), thionyl chloride (290 mg, 2.43 mmol) and DMF (10 mg) in toluene (15 ml) was stirred at 50° C. for 45 minutes. The reaction solution was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in THF (5 ml), and aqueous ammonia (2 ml) was slowly added under ice-cooling. After the reaction solution was stirred at room temperature for 30 minutes, the reaction solution was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated under reduced pressure to give 500 mg of Compound (I-35-1) (yield: 94%).
Reaction SMILES: [OH:1][C:2]1[CH2:3][C:4]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29]C(=O)[O-])=[CH:25][CH:24]=2)([CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17]C(=O)[O-])=[CH:13][CH:12]=2)[O:5][C:6](=[O:8])[CH:7]=1.[C:33]([C:37]1[CH:42]=[C:41]([CH2:43][OH:44])[C:40]([CH3:45])=[CH:39][C:38]=1[S:46]S(C1C=CC(C)=CC=1)(=O)=O)([CH3:36])([CH3:35])[CH3:34].C([O-])([O-])=O.[K+].[K+].CN(C=O)C>CCOC(C)=O.C(O)(=O)C>[NH2:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][CH2:21][C:4]2([CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=3)[O:5][C:6](=[O:8])[C:7]([S:46][C:38]3[CH:39]=[C:40]([CH3:45])[C:41]([CH2:43][OH:44])=[CH:42][C:37]=3[C:33]([CH3:36])([CH3:35])[CH3:34])=[C:2]([OH:1])[CH2:3]2)=[CH:28][CH:27]=1
Reactant: O=C([O-])Nc1ccc(CCC2(CCc3ccc(NC(=O)[O-])cc3)CC(O)=CC(=O)O2)cc1
Reactant: Cc1ccc(S(=O)(=O)Sc2cc(C)c(CO)cc2C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1cc(SC2=C(O)CC(CCc3ccc(N)cc3)(CCc3ccc(N)cc3)OC2=O)c(C(C)(C)C)cc1CO
Reaction time: 8 h

Procedure:
The title compound was prepared as described in General Method 9 using 0.38 g (0.69 mmol) of (1,1-dimethylethyl)[(3,6-dihydro-4-hydroxy-6-oxo-2H-pyran-2,2-diyl)bis[2, 1-ethanediyl-(4,1-phenylene)]biscarbamate prepared in Example OO, 0.35 g (0.96 mmol) of toluene-4-thiosulfonic acid S-(2-tert-butyl-4-hydroxymethyl-5-methyl-phenyl) ester (prepared in Example FFF), 0.58 g (4.2 mmol) of K2CO3, and 5 mL of DMF. The reaction mixture was stirred overnight, and then poured into glacial acetic acid (5 mL) and EtOAc (20 mL). After standard workup, the residue was chromatographed on silica gel, eluting with 1:1 hexane:EtOAc, to give the BOC-protected intermediate. This material was dissolved in CH2Cl2, cooled in an ice bath, and treated with a steady stream of gaseous HCl for 10 minutes. The solvent was evaporated. The residue was suspended in H2O which was then made basic to pH 11.5 with 10% NaOH and stirred for 20 minutes. The solution was made basic to pH 6.5 with HOAc and extracted with EtOAc (3×50 mL). The combined extracts were washed with brine, dried (MgSO4), and concentrated to give the title compound, m.p. 144-146° C. 1H NMR (DMSO-d6) δ 1.43 (s, 9 H), 1.81 (s, 3 H), 1.95 (m, 4 H), 2.42 (m, partially obscured by DMSO, 4 H), 2.87 (br s, 2 H), 4.30 (s, 2 H), 4.90 (br s, 1 H), 6.45 (d, 4 H), 6.65 (s, 1 H), 6.80 (d, 4 H), 7.20 (s, 1 H).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@H:10]([C@@H:13]([OH:17])[CH2:14][O:15][CH3:16])[CH2:9]1)=O)(C)(C)C.[H-].[Na+].[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1F.CCO>CN(C=O)C.Cl>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:17][C@H:13]([C@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:14][O:15][CH3:16]
Reactant: COC[C@H](O)[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: Fc1ccc(Cl)cc1Cl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COC[C@H](Oc1ccc(Cl)cc1Cl)[C@H]1CCNC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(S)-3-((R)-1-Hydroxy-2-methoxyethyl)pyrrolidine-1-carboxylic acid t-butyl ester (10.0 mg, 40.8 μmol) was dissolved in DMF (0.1 mL). NaH (1.5 mg, 61.1 μmol) was slowly added and the mixture was stirred at room temperature for 15 minutes. Then, 2,4-dichloro-1-fluorobenzene (20.2 mg, 122 μmol) was added. The mixture was stirred at 100° C. for 1 hour, then cooled to room temperature. The mixture was concentrated then dissolved in 1.2M HCl in EtOH (1.0 mL, 1.2 mmol) and stirred overnight at room temperature. The product was concentrated and purified by preparative HPLC to yield the title compound as a mono-TFA salt (12.8 mg, 99% purity). MS m/z: [M+H]+ calcd for C13H17Cl2NO2, 290.06. found 290.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:15])[S:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[N:16]1([C:21](N2C=CN=C2)=[S:22])[CH:20]=[CH:19][N:18]=[CH:17]1>C(#N)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:15][C:21]([N:16]3[CH:20]=[CH:19][N:18]=[CH:17]3)=[S:22])[S:12][C:13]=2[CH3:14])=[CH:7][CH:8]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COc1ccc(-c2nc(N)sc2C)cc1
Solvent: CC#N
Product: COc1ccc(-c2nc(NC(=S)n3ccnc3)sc2C)cc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 87 %

Procedure:
To 4-(4-methoxyphenyl)-5-methylthiazol-2-amine (0.98 g, 4.45 mmol) in acetonitrile (25 mL) was added di(1H-imidazol-1-yl)methanethione (1.03 g, 5.78 mmol). The reaction was stirred at 50° C. for 3 hours. The reaction was cooled to room temperature and the precipate was filtered. The powder was washed with acetonitrile (2×10 mL) and dried to yield racemic N-(4-(4-methoxyphenyl)-5-methylthiazol-2-yl)-1H-imidazole-1-carbothioamide (1.28 g, 3.87 mmol, 87% yield) as a yellow powder. The product was taken directly to the next step.
Reaction SMILES: S(Cl)(Cl)=O.[Cl:5][C:6]1[CH:14]=[C:13]([I:15])[CH:12]=[C:11]([Cl:16])[C:7]=1[C:8]([OH:10])=O.[NH2:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C1COCC1>[Cl:16][C:11]1[CH:12]=[C:13]([I:15])[CH:14]=[C:6]([Cl:5])[C:7]=1[C:8]([NH:17][C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:10]
Reactant: Nc1ccncc1
Reactant: O=C(O)c1c(Cl)cc(I)cc1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccncc1)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.8 %

Procedure:
Thionyl chloride (20 mL) was added to 2,6-dichloro-4-iodobenzoic acid (1.5 g, 4.73 mmol) and the mixture was heated to reflux for 5 h under nitrogen. After cooling the mixture was concentrated under reduced pressue. Toluene (10 mL) was added and the mixture was concentrated under reduced pressure again to remove residual thionyl chloride. The residue was dissolved in anhydrous THF (20 mL) and this was added dropwise to a cooled (0° C.) solution of 4-aminopyridine (0.53 g, 5.68 mmol) and triethylamine (1.32 mL, 9.46 mmol) in anhydrous THF (20 mL). After addition was complete, the mixture was stirred at room temperature under nitrogen overnight. The reaction was poured onto the ice water (50 mL) and extracted with EtOAc (2×50 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexanes/EtOAc=3:1) to afford the desired product (1.8 g, yield: 97%.) 1HNMR (DMSO-d6, 400 MHz): 611.14 (s, 1H), 8.47 (dd, J=1.6, 4.8 Hz, 2H), 8.03 (d, J=2.0 Hz, 2H), 7.59 (dd, J=1.6, 4.8 Hz, 2H). LCMS (ESI) m/z: 393.0 [M+H+].
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1.IC.[C:14](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:14][O:1][C:2]1[CH:6]=[C:5]([C:7]([O:9][CH3:10])=[O:8])[N:4]([CH3:11])[N:3]=1
Reactant: COC(=O)c1cc(O)nn1C
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1cc(OC)nn1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A mixture of methyl 3-hydroxy-1-methyl-1H-pyrazole-5-carboxylate (2.34 g, 15.0 mmol), iodomethane (3.19 g, 22.5 mmol), potassium carbonate (4.15 g, 30.0 mmol) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 18 hr. The mixture was diluted with water (50 mL), and extracted with ethyl acetate (50 mL×3). The organic layer was washed with water (10 mL×2), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=100/0→50/50) to give the title compound (2.01 g, yield 79%) as a white solid.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+]>C1COCC1.CO.O>[C:1]([C:3]1[C:4]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1-c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2c(C(=O)O)sc(N3CCOCC3)c2C#N)cc1
Temperature: 50 °C
Reaction time: 6 h
Yield: 84.3 %

Procedure:
To a suspension of ethyl 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylate (0.077 g, 0.21 mmol) in THF/MeOH/water (1:1:1) (6 mL) was added sodium hydroxide (0.2 g, 5 mmol). The reaction mixture was allowed to stir at 50° C. for 6 h and was concentrated. The residue was acidified to pH 1-2 with 1N HCl and was extracted with EtOAc. The organic solutions were combined, washed with brine, dried over MgSO4, filtered and concentrated to give 4-cyano-3-(4-methoxyphenyl)-5-morpholin-4-ylthiophene-2-carboxylic acid (77) (0.061 g, 86%). LCMS: (FA) ES+ 345. 1H NMR (400 MHz, d6-DMSO) δ: 7.27-7.31 (m, 2H), 6.95-6.99 (m, 2H), 3.80 (s, 3H), 3.76-3.78 (m, 4H) and 3.56-3.58 (m, 4H).