Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([S:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8])=[CH:5][C:4]=1[O:16][S:17]([CH3:20])(=[O:19])=[O:18].C(Cl)CCl.[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:25][C:26]1[CH:27]=[N+:28]([O-:51])[CH:29]=[C:30]([Cl:50])[C:31]=1[CH2:32][C@@H:33]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH:42]([F:44])[F:43])=[C:37]([O:45][CH2:46][CH:47]2[CH2:49][CH2:48]2)[CH:36]=1)[O:12][C:11](=[O:13])[CH2:10][S:9][C:7](=[O:8])[C:6]1[CH:14]=[CH:15][C:3]([O:2][CH3:1])=[C:4]([O:16][S:17]([CH3:20])(=[O:19])=[O:18])[CH:5]=1
Reactant: [O-][n+]1cc(Cl)c(C[C@H](O)c2ccc(OC(F)F)c(OCC3CC3)c2)c(Cl)c1
Reactant: COc1ccc(C(=O)SCC(=O)O)cc1OS(C)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc(C(=O)SCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)cc1OS(C)(=O)=O
Temperature: 25 °C
Reaction time: 48 h
Yield: 23.7 %

Procedure:
To a solution of 2-(4-methoxy-3-(methylsulfonyloxy)benzoylthio)acetic acid (0.150 g, 0.468 mmol) in dry DCM (12 ml), EDC (0.090 g, 0.468 mmol) and DMAP (0.057 g, 0.468 mmol) were added followed by (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-hydroxyethyl)pyridine 1-oxide (0.197 g, 0.468 mmol) and the reaction was stirred at RT for 48 hours. The mixture was partitioned between DCM and HCl 1N; the organic phase was washed with NaHCO3 sat. sol., and dried over Na2SO4. The solvent was removed and the crude was purified by preparative HPLC to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(4-methoxy-3-(methylsulfonyloxy)benzoylthio)-acetoxy)ethyl)pyridine 1-oxide (0.080 g, 0.111 mmol, 23.64% yield, MS/ESI+ 722.38 [MH]+, [αD]=−34.72, c=0.5, DCM).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][Si](C(C)(C)C)(C)C)[CH:12]=2)[S:6]1(=[O:26])=[O:25])([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[S:6]1(=[O:25])=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)N1C(=O)C=C(c2cccc(O[Si](C)(C)C(C)(C)C)c2)S1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)N1C(=O)C=C(c2cccc(O)c2)S1(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
A solution of 4.08-A (1.39 g, 3.5 mmol) in tetrahydrofuran (14 mL) at 0° C. was treated with tetra-n-butylammonium fluoride (1.1 g, 4.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 30 min and diluted with ethyl acetate (150 mL) and washed with 0.1 N HCl (100 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered, and concentrated to give a crude residue which was purified using flash column chromatography (100% hexane to 30% ethyl acetate/hexane) to yield 4.08-B as a white solid (0.95 g, 96%). 1H NMR (500 MHz, CDCl3): δ 7.39 (dd, J=7.8, 7.8 Hz, 1H), 7.34–7.32 (m, 1H), 7.26–7.24 (m, 1H), 7.05–7.02 (m, 1H), 6.63 (s, 1H), 5.3 (br s, 1H), 1.73 (s, 9H); LCMS found for C13H16NO4S (M+H)+: m/z=282.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[C:9]([Cl:14])=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[CH:4][N:3]=1.Cl.[CH3:16][NH2:17].C([O-])([O-])=O.[K+].[K+].CS(C)=O>O>[Cl:14][C:9]1[C:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH3:16])[CH:7]=2)=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Clc1cc(-c2cccnc2Cl)ncn1
Reactant: CN
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: CNc1cc(-c2cccnc2Cl)ncn1
Temperature: 80 °C

Procedure:
4-Chloro-6-(2-chloro-pyridin-3-yl)-pyrimidine (450 mg, 1.99 mmol), methylamine hydrochloride (202 mg, 2.99 mmol), K2CO3 (550 mg, 3.98 mmol) and DMSO (3.0 mL) were combined. The mixture was heated overnight at 80° C. in a sealed tube. The cooled mixture was diluted with water (300 mL) and the resulting solid was filtered, washed with water and dried to yield the title compound. MS m/z=221 [M+1]+. Calc'd for C10H9ClN4: 220.66.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.[O:11]([CH2:18][CH2:19][C:20](O)=[O:21])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[C:20](=[O:21])[CH2:19][CH2:18][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(O)CCOc1ccccc1
Reactant: COC(=O)[C@@H]1CCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1CCCN1C(=O)CCOc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.2 %

Procedure:
Proline methyl ester hydrochloride (3.4 g), 3-phenoxypropionic acid (3.4 g) and triethylamine (2.8 ml) were suspended in dry methylene chloride (30 ml). To the cooled suspension, WSCD HCl (N-ethyl-N',N'-dimethylaminopropyl-carbodiimide hydrochloride) (3.9 g) was added. Under cooling, the mixture was stirred for 1 hour, and after allowing the mixture to warm to room temperature, it was again stirred for 18 horus. The stirred mixture was washed successively with water, 1N HCl, water, saturated aqueous sodium bicarbonate and brine. After drying over anhydrous magnesium sulfate, the solvent was distilled off under vacuum. The resulting crude product was purified by medium-pressure liquid column chromatography on silica gel (solvent: chloroform) to obtain the end compound as an oil (3.7 g).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:36]=[CH:35][C:17]([C:18]([NH:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[NH:27]C(=O)OC(C)(C)C)=[O:19])=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[C:4]([CH3:37])=[N:3]1.O.Cl.[OH-].[Na+]>CO>[NH2:27][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[NH:20][C:18](=[O:19])[C:17]1[CH:35]=[CH:36][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([CH2:7][C:5]3[C:4]([CH3:37])=[N:3][N:2]([CH3:1])[CH:6]=3)[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3NC(=O)OC(C)(C)C)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1nn(C)cc1CN1CCC(c2ccc(C(=O)Nc3ccccc3N)cc2)CC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 85.6 %

Procedure:
tert-Butyl (2-{[4-(1-{1,3-dimethyl-1H-pyrazol-4-ylmethyl}piperidin-4-yl)benzoyl]amino}phenyl)carbamate (Method 6 below; 92.3 g, 183.3 mmol) was slurried in methanol (754 ml) and water (141 ml) and cooled to 0-5° C. Concentrated hydrochloric acid was added maintaining the temperature below 20° C. The reaction mixture was stirred for 20 hours at ambient temperature. The reaction was cooled to 0-5° C. and aqueous sodium hydroxide solution added maintaining the temperature at below 20° C. until a pH of 12-14 is obtained. The reaction mixture was heated to reflux temperature for 30 minutes before cooling to 20° C. over about 4 hours. The product was collected by filtration and washed with aqueous methanol before being dried in vacuo at 45° C. to constant weight to give the title compound (63.3 g 86%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=2[C:26]2[CH:31]=[C:30]([O:32][C:33]3[C:38]4[N:39]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[S:41][C:37]=4[CH:36]=[CH:35][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[CH:18][C:17]=2[C:26]2[N:27]=[CH:28][N:29]=[C:30]([O:32][C:33]3[C:38]4[N:39]=[C:40]([NH:42][C:43](=[O:45])[CH3:44])[S:41][C:37]=4[CH:36]=[CH:35][CH:34]=3)[CH:31]=2)[CH2:10][CH2:9]1
Reactant: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCN(C(=O)OC(C)(C)C)CC4)ncn3)cccc2s1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)Nc1nc2c(Oc3cc(-c4ccc(C(F)(F)F)cc4NCC4CCNCC4)ncn3)cccc2s1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-({2-[6-(2-acetylamino-benzothiazol-4-yloxy)-pyrimidin-4-yl]-5-trifluoromethyl-phenylamino}-methyl)-piperidine-1-carboxylic acid tert-butyl ester, (Example 160), (0.20 g, 0.30 mmol) in CH2Cl2 (10 mL) was added trifluoroacetic acid (30 mL, Aldrich). The reaction mixture was allowed to stir for 3 h at room temperature and then concentrated in vacuum. The residue was dissolved in EtOAc (30 mL), washed with satd NaHCO3 (2×30 mL), dried over Na2SO4, filtered and concentrated in vacuum. Purification by silica gel chromatography (2:1, EtOAc:hexanes) afforded the title compound as yellow film. MS (ESI, pos. ion) m/z: 543 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([S:24]([NH2:27])(=[O:26])=[O:25])=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.ClCCl>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([S:24]([NH:27][C:11]([C:10]2[CH:9]=[CH:8][C:7]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:16])=[CH:15][CH:14]=2)=[O:13])(=[O:25])=[O:26])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C(=O)O)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(C(=O)NS(=O)(=O)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A 5-liter, 3-necked, round-bottomed flask was equipped with a mechanical stirrer and nitrogen inlet. dichloromethane (2 liters) was placed in the reaction flask and terephthalic acid mono-t-butyl ester (127.5 g), 4-dimethylaminopyridine (70.06 g), and 4-chlorobenzenesulfonamide (110.04 g) were added in that order using dichloromethane (400 ml) to wash down the solids. 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (110.10 g) was added in portions over 10 min using dichloromethane (100 ml) to wash down the solid. After the reaction mixture was stirred overnight at room temperature, it was evaporated. The residue was partitioned between ethyl acetate and water. The organic solution was washed (20% (w/v) aqueous citric acid, saturated aqueous NaHCO3, brine), dried (Na2SO4), and evaporated to a white solid. After drying in a vacuum oven at 50° C., the ester (227 g, 100%) was obtained in a sufficiently pure state to be used directly for the next step; TLC, Rf =0.43, methanol:chloroform (15:85). (Further purification was possible by recrystallization from ethanol:water; mp above 300° C.).
Reaction SMILES: C(OC(=O)[NH:10][C:11]1([C:14]2[S:15][CH:16]=[N:17][N:18]=2)[CH2:13][CH2:12]1)C1C=CC=CC=1.CCOCC.[BrH:25]>C(O)(=O)C>[BrH:25].[S:15]1[CH:16]=[N:17][N:18]=[C:14]1[C:11]1([NH2:10])[CH2:13][CH2:12]1
Reactant: O=C(NC1(c2nncs2)CC1)OCc1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: NC1(c2nncs2)CC1
Reaction time: 0.5 h

Procedure:
(1-1,3,4-Thiadiazol-2-yl-cyclopropyl)-carbamic acid benzyl ester (0.2 g, 0.73 mmol) was dissolved in 48% HBr in acetic acid (5 mL) and allowed to stir for 30 min. Et2O was then added and the majority of the liquid decanted off. The remaining residue was concentrated under reduced pressure to give 1-1,3,4-thiadiazol-2-yl-cyclopropylamine hydrobromide (0.12 g, 0.54 mmol) as an orange gum, m/z 142.4 [M+H]+.
Reaction SMILES: [CH2:1]([N:5]1[CH2:10][CH2:9][C:8]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)([OH:11])[CH2:7][CH2:6]1)[CH2:2][C:3]#[CH:4].I[C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1>C(N)CCC.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:24][C:23]1[CH:25]=[CH:26][C:20]([C:4]#[C:3][CH2:2][CH2:1][N:5]2[CH2:10][CH2:9][C:8]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)([OH:11])[CH2:7][CH2:6]2)=[CH:21][CH:22]=1
Reactant: C#CCCN1CCC(O)(c2ccc(Cl)cc2)CC1
Reactant: Nc1ccc(I)cc1
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCCCN
Product: Nc1ccc(C#CCCN2CCC(O)(c3ccc(Cl)cc3)CC2)cc1
Yield: 20.8 %

Procedure:
A solution of 1-(3-butynyl)-4-(4-chlorophenyl)-4-hydroxypiperidine (263 mg, 1.00 mmol), 4-iodoaniline (208 mg, 0.950 mmol) and 50 mg of tetrakis(triphenylphosphine) palladium in 10 mL of butylamine is allowed to reflux for 20 hr. The solvent is evaporated in vacuo to give a residue, which is purified by flash chromatography giving the product as an off white solid (70 mg, 21%): mp 134-136° C.; 1H NMR (CDCl3) 1.59 (m, 2 H), 1.90 (m, 2 H), 2.47 (m, 6 H), 2.67 (m, 2 H), 3.59 (S, 1 H), 3.87 (bs, 2 H), 6.46 (d, J=8.1 Hz, 1 H), 7.02 (d, J=8.1 Hz, 2 H), 7.14 (d, J=8.4 Hz, 2 H), 7.33 (d, J=8.4 Hz, 2 H).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[NH:8][C:7]2=[N:9][CH:10]=[CH:11][C:6]2=[C:5]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)[N:4]=1.CCN(CC)CC.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1COCC1.CN(C1C=CN=CC=1)C>[C:25]([N:9]1[C:7]2[N:8]=[C:3]([N:2]([CH3:17])[CH3:1])[N:4]=[C:5]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[C:6]=2[CH:11]=[CH:10]1)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN(C)c1nc(-c2ccco2)c2ccnc-2[nH]1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)c1nc(-c2ccco2)c2ccn(C(=O)c3ccccc3)c2n1
Yield: 28.6 %

Procedure:
A solution of N,N-dimethyl-4-(2-furyl)-1H-pyrrolo[2,3-d]pyrimidine-2-amine (181 mg, 0.8 mmol) in THF (3 mL) was treated with Et3N, (111 μL, 0.8 mmol), benzoyl chloride (93 μL, 0.8 mmol) and a catalytic amount of DMAP, stirred at room temperature for 16 h, quenched with water, extracted with EtOAc, dried (MgSO4), concentrated in vacuo and purified by chromatography (EtOAc:Heptane, 1:9 then Heptane:DCM, 2:1) to give the title compound (76 mg) as a yellow solid.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8](O)=[O:9])([CH3:4])([CH3:3])[CH3:2].[C:19]([C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]=1[OH:35])[C:26]([O:28][CH2:29][CH2:30][NH2:31])=[O:27])([CH3:22])([CH3:21])[CH3:20].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[C:19]([C:23]1[CH:24]=[C:25]([CH:32]=[C:33]([C:36]([CH3:39])([CH3:38])[CH3:37])[C:34]=1[OH:35])[C:26]([O:28][CH2:29][CH2:30][NH:31][C:8](=[O:9])[C:7]1[CH:11]=[C:12]([C:15]([CH3:16])([CH3:17])[CH3:18])[C:13]([OH:14])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=1)=[O:27])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)c1cc(C(=O)OCCN)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)NCCOC(=O)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc(C(C)(C)C)c1O

Procedure:
To a stirred solution of 25 grams (0.1 mole) of 3,5-di-t-butyl-4-hydroxybenzoic acid and 29.3 grams (0.1 mole) of N-(3,5-di-t-butyl-4'hydroxybenzoyloxyethyl)amine in 100 milliliters of drytetrahydrofuran was added dropwise a solution of 20.6 grams (0.1 mole) of dicyclohexylcarbodiimide in 75 milliliters of dry tetrahydrofuran. The mixture was stirred for several hours and the white solid (dicyclohexyl urea) was filtered off and discarded. Evaporation of the filtrate gave a product which was recrystallized from 1:1 benzene-hexane to give N-(3',5'di-t-butyl-4'-hydroxybenzoyloxyethyl)-3,5-di-t-butyl-4-hydroxybenzamide; melting point 185°-187° C. When tested by the procedure of Example 2, the sample containing this compound lasted 1,000 hours, about 3.3 times as long as the control.
Reaction SMILES: [CH:1]1([C:7]([NH2:9])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:11].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[CH:1]1([C:7](=[S:11])[NH2:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=O)C1CCCCC1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: NC(=S)C1CCCCC1
Temperature: 115 °C
Reaction time: 8 h
Yield: 281.2 %

Procedure:
25.0 g Cyclohexanecarboxamide were dissolved in 200 ml toluene. 8.74 g phosphorus pentasulfide were added, followed by the addition of 33.0 g sodium bicarbonate. The reaction mixture was warmed to 115° C. and stirred overnight. The reaction mixture was filtered over a celite pad, washed with dichloromethane. The filtrate evaporated under reduced pressure. The residue was dissolved in 250 ml dichloromethane and the organic layer was washed three times with 100 ml water and twice with 100 ml brine. The aqueous layer was extracted five times with 100 ml dichloromethane. The combined organic layers were dried over MgSO4 and the solvent removed under reduced pressure. The resulting residue was purified by chromatography with the eluent dichloromethane:ethyl acetate=1:1 to obtain 7.92 g Cyclohexanecarbothioic acid amide as a yellow solid.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]([OH:5])=[O:4].S(Cl)(Cl)=O.[CH3:15]O>>[CH3:1][CH:2]([CH2:6][CH:7]([CH3:10])[CH2:8][CH3:9])[C:3]([O:5][CH3:15])=[O:4]
Reactant: CO
Reactant: CCC(C)CC(C)C(=O)O
Solvent: O=S(Cl)Cl
Product: CCC(C)CC(C)C(=O)OC
Reaction time: 8 h

Procedure:
The product of part (i) above (385 mg) in methanol (10 ml) was treated dropwise with thionyl chloride 0.4 ml, 5.5 mmol) at 0° C. and then the solution was stood at room temperature overnight. The excess methanol was removed by distillation at atmospheric pressure, and the residue was distilled to give the title compound (216 mg), [α]19 +33° (liquid, 1=0.1 dm, d22 =0.871), lit1 [α]23 +D D 32.2° (liquid 1=0.2 dm), υmax (CHBr3) 1725 cm-1 (ester), δ(CDCl3) 3.67 (s, 3H, CO2CH3), 2.57 (m, 1H, CH2CHCH2), 1.33 and 1.13 (m, 1H each, CH2CH3), 1.16 (d, J7 Hz, 3H, C--2H3), 0.89 (d, J7 Hz, 3H, C--4CH3), 0.87 (t, J7 Hz, 3H, CH2CH3) lit2 (NMR spectrum).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([O:9][CH3:10])=[O:8].[OH-].[Na+].[Br:13]Br>C(O)(=O)C.[Zn]>[Br:13][C:6]1[C:2]([CH3:1])=[C:3]([C:7]([O:9][CH3:10])=[O:8])[S:4][CH:5]=1
Reactant: COC(=O)c1sccc1C
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)c1scc(Br)c1C
Temperature: 85 °C
Reaction time: 6 h

Procedure:
A solution of methyl 3-methylthiophene-2-carboxylate (20 g, 103 mmol, 1.0 eq) and sodium hydroxide (12.3 g, 307 mmol, 3 eq) in acetic acid (75 mL) was heated to 60° C. Bromine (46.9 g, 294 mmol, 2.85 eq) was added drop wise at such a rate so as to maintain the temperature of the reaction mixture at <85° C. The resulting mixture was stirred at 85° C. for 6 h. The solution was then allowed to cool to 50° C. and zinc dust (15.4 g, 236 mmol, 2.3 eq) was added in 3 gram portions to the reaction such that the exotherm was controlled to remain below 85° C. The resulting mixture was stirred at 85° C. for 1 h, and then filtered hot through a small bed of celite. Water (300 mL) was added and the mixture was extracted with hexane (300 mL). The organic phase was washed with water, then concentrated to dryness to give 27 g (89%) an off white oil which slowly crystallized upon standing at room temperature. 1HNMR (400 MHz, CDCl3) δ 7.43 (s, 1H), 3.87 (s, 3H), 2.56 (s, 3H)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Br:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][C:10]=1[Br:30])[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)Cc1nc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)sc1Br
Reaction time: 8 h
Yield: 21.9 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-bromosuccinimide (0.024 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.013 g, 21%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][N:16]=[CH:15]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:21](Cl)([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([C:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[N:16]=[CH:15]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(Nc1ccc2[nH]ncc2c1)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc2c(cnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1)OCc1ccccc1

Procedure:
5-Benzyloxycarbonylaminoindazole (0.534 g, 2 mmol) was stirred with trityl chloride (0.556 g, 2 mmol) and tetrabutylammonium iodide (0.074 g, 0.2 mmol) in tetrahydrofuran (5 ml) and triethylamine (0.42 ml, 3 mmol) for 3 days at room temperature. Solvent was removed under vacuum, and the solid residue was triturated with methanol (3 ml). The solid was washed with a mixture of methanol-water (5:1, ca. 15 ml) and dried under vacuum to afford the desired product. Yield 0.73 g (72%). 1H NMR.
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH3:28])([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([N+:25]([O-])=O)=[CH:21][N:20]=1)[CH2:9][CH2:8]2)(=[O:3])[CH3:2].[H][H]>CO.C1C=CC=CC=1.[Pd]>[C:1]([O:4][C:5]1[C:6]([CH3:29])=[C:7]2[C:12](=[C:13]([CH3:16])[C:14]=1[CH3:15])[O:11][C:10]([CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([NH2:25])=[CH:21][N:20]=1)([CH3:28])[CH2:9][CH2:8]2)(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc([N+](=O)[O-])cn1)O2
Agent: [Pd]
Solvent: c1ccccc1
Solvent: CO
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)CCC(C)(COc1ccc(N)cn1)O2

Procedure:
6 g of 6-acetoxy-2,5,7,8-tetramethyl-2-(5-nitropyridin-2-yloxymethyl)chroman (prepared as described in Preparation 36) were dissolved in a mixture of 80 ml of methanol and 15 ml of benzene, and, in the presence of 1.5 g of 10% w/w palladium-on-carbon, were catalytically reduced at room temperature for about 20 hours under about 1 atmosphere (about 1 bar) pressure of hydrogen. The catalyst was filtered off, and the filtrate was condensed by evaporation under reduced pressure, to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:15][CH2:16][CH2:17][Cl:18])=[CH:5][C:6]([N+:12]([O-])=O)=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:11]=[C:7]([C:8]([OH:10])=[O:9])[C:6]([NH2:12])=[CH:5][C:4]=1[O:15][CH2:16][CH2:17][Cl:18]
Reactant: [H][H]
Reactant: COc1cc(C(=O)O)c([N+](=O)[O-])cc1OCCCl
Agent: [Pd]
Solvent: CO
Product: COc1cc(C(=O)O)c(N)cc1OCCCl
Temperature: 40 °C
Yield: 98.6 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 3.76 g (13.5 mmol) of 5-methoxy-4-(2-chloroethoxy)-2-nitrobenzoic acid (purity: 99%) obtained in Reference Example III-16, 40 mL of methanol, and 0.4 g of 5 wt. % palladium/carbon (containing 49% water). The resulting mixture was heated to 40° C. under stirring, and further heated to the same temperature for 4 hours, while hydrogen was introduced into the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, to precipitate a crystalline product. The crystalline product was dried under reduced pressure, to give 3.27 g (isolated yield: 98.1%, purity: 99% in terms of area percentage determined by high performance liquid chromatography) of 5-methoxy-4-(2-chloroethoxy)anthranilic acid as a white crystalline product.