Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2Cl)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:26]1([CH2:32][CH2:33][NH2:34])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([C@@H:8]1[CH2:19][N:18]2[C:10]([C:11]3[NH:12][C:13]([CH:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[N:14][C:15]=3[N:16]=[C:17]2[NH:34][CH2:33][CH2:32][N:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCN1CCCCC1
Reactant: ClC1=Nc2nc(C3CCCC3)[nH]c2C2=N[C@H](Cc3ccccc3)CN12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: c1ccc(C[C@@H]2CN3C(NCCN4CCCCC4)=Nc4nc(C5CCCC5)[nH]c4C3=N2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 102.9 %

Procedure:
Compound 67a (100 mg, 0.240 mmol) obtained in Example 67 was dissolved in tetrahydrofuran (2 mL), and to the solution were added 2-piperidinoethylamine (61 μL, 0.480 mmol, 2.0 equivalents) and N,N-diisopropylethylamine (344 μL, 0.960 mmol, 4.0 equivalents) and the mixture was stirred at 80° C. for 2 hours. The reaction mixture was concentrated, and then the residue was purified by silica gel column chromatography (chloroform:methanol=90:10, chloroform: a 7 mol/L ammonia/methanol solution=90:10). To the product was added diisopropyl ether, and the deposited crystals were collected by filtration and dried to obtain the title compound (110 mg, 94%) as white crystals.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].[Cl:5][C:6]1[C:7]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:8][C:9](CC#N)=[N:10][CH:11]=1.S(=O)(=O)(O)O>O>[Cl:5][C:6]1[C:7]([CH:15]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][CH:28]=2)(=[O:26])=[O:25])[C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])=[CH:8][C:9]([CH2:2][C:1]([OH:4])=[O:3])=[N:10][CH:11]=1
Reactant: CC(=O)O
Reactant: N#CCc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C(O)Cc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 86 %

Procedure:
To an acetic acid (2 ml) solution of [5-chloro-4-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]acetonitrile (113 mg, 0.25 mmol) was added a mixture of water (2 ml) and concentrated sulfuric acid (2 ml) at room temperature. The resulting mixture was stirred at 100° C. for 2 hours. After the reaction mixture was cooled to room temperature, water was added thereto. The resulting mixture was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure. The residue thus obtained was washed with a mixed solvent of diethyl ether/hexane and then, collected by filtration to give the title compound (101 mg, 0.21 mmol, 86%) as a white solid.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH:3]=[N:2]1.[CH3:13][O:14][CH2:15]Cl>CN(C=O)C>[CH3:13][O:14][CH2:15][N:1]1[CH:5]=[C:4]([C@@H:6]2[CH2:11][CH2:10][CH2:9][CH2:8][C@H:7]2[OH:12])[CH:3]=[N:2]1
Reactant: COCCl
Reactant: O[C@@H]1CCCC[C@H]1c1cn[nH]c1
Solvent: CN(C)C=O
Product: COCn1cc([C@@H]2CCCC[C@H]2O)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
To a solution of the (1R,2S)-2-(1H-pyrazol-4-yl)cyclohexanol (170 mg, 1.02 mmol) prepared in Example 169b in DMF (5.0 mL), chloromethyl methyl ether (0.078 mL, 1.02 mmol) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was vacuum concentrated, and the residue was then purified with silica gel chromatography (hexane/ethyl acetate=7:3) to yield the title compound (132 mg, 61%) as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]=2[O:22]C(=O)C(C)(C)C)=[C:4]([CH3:29])[CH:3]=1.[CH2:30]([Sn](CCCC)(CCCC)C#CC)[CH2:31][CH2:32]C>C1(C)C=CC=CC=1>[CH3:8][C:6]1[CH:7]=[C:2]([C:30]#[C:31][CH3:32])[CH:3]=[C:4]([CH3:29])[C:5]=1[CH:9]1[C:13](=[O:14])[CH:12]([CH2:15][CH:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[CH2:11][C:10]1=[O:22]
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Reactant: Cc1cc(Br)cc(C)c1C1=C(OC(=O)C(C)(C)C)CC(CC2CCOCC2)C1=O
Solvent: Cc1ccccc1
Product: CC#Cc1cc(C)c(C2C(=O)CC(CC3CCOCC3)C2=O)c(C)c1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
To a degassed solution of rac-2,2-dimethylpropionic acid 2-(4-bromo-2,6-dimethylphenyl)-3-oxo-4-(tetrahydropyran-4-ylmethyl)cyclopent-1-enyl ester (0.20 g, 0.43 mmol) in toluene (4 ml) under a nitrogen atmosphere is added tributyl(1-propynyl)tin (0.39 ml, 1.29 mmol) and tetrakistriphenylphosphine palladium(0) (0.10 g, 0.086 mmol). The reaction mixture is then heated at 130°C. under microwave irradiation for 45 minutes, followed by quenching with distilled water (20 ml) and extraction with ethyl acetate (50 ml×2). The combined organic fractions are washed with water, brine, dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo. The residue is then dissolved in methanol (1.0 ml) and 2N sodium hydroxide solution (0.5 ml) is added followed by stirring at 25°C. for 3 hours. The solvent is evaporated in vacuo and the crude product is diluted with distilled water, acidified with 2N hydrochloric acid then extracted with ethyl acetate (50 ml×3). The combined organic fractions are washed with water, brine, dried over sodium sulphate, filtered and the filtrate is concentrated in vacuo to afford rac-2-(2,6-dimethyl-4-prop-1-ynylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione.
Reaction SMILES: [CH:1]([C:4]1([OH:18])[CH2:9][CH2:8][CH:7]([NH:10]C(=O)OC(C)(C)C)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:19].O1CCOCC1>O1CCOCC1>[ClH:19].[NH2:10][CH:7]1[CH2:8][CH2:9][C:4]([CH:1]([CH3:3])[CH3:2])([OH:18])[CH2:5][CH2:6]1
Reactant: CC(C)C1(O)CCC(NC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)C1(O)CCC(N)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a mixture of tert-butyl (4-isopropyl-4-hydroxycyclohexyl)carbamate (Preparation Example 250) (0.392 g) and dioxane (3 mL), 26% hydrogen chloride-dioxane (2.0 mL) was added under ice cooling and stirred at room temperature for 18 hours. The precipitated solid was collected by filtration to give 4-amino-1-isopropylcyclohexanol hydrochloride (0.190 g) as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=O.[CH2:8]([O:10][CH:11]([O:13][CH2:14][CH:15]=[O:16])[CH3:12])[CH3:9]>C1(C)C=CC=CC=1>[CH2:8]([O:10][CH:11]([O:13][C:14](=[CH:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)[CH:15]=[O:16])[CH3:12])[CH3:9]
Reactant: CCOC(C)OCC=O
Reactant: O=Cc1cccs1
Solvent: Cc1ccccc1
Product: CCOC(C)OC(C=O)=Cc1cccs1
Yield: 20.5 %

Procedure:
Except to use a reaction time of 36 hours at ambient temperature, and to use toluene as eluant on chromatography, thiophene-2-carbaldehyde (3.1 ml., 3.74 g., 0.083 mol) and 2-[1-(ethoxy)ethoxy)acetaldehyde (4.0 g., 0.030 mol) were converted to instant title product as a yellow solid 1.39 g., crystallized from hexane, 109 mg.; 1H-nmr: 1.14 (t, 3H), 1.52 (d, 3H), 3.75 (m, 2H), 6.01 (q, 1H), 6.99 (s, 1H), 7.15 (m, 1H), 7.53 (m, 2H), 9.40 (s, 1H).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=O)[CH3:2].[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16]>C(O)=O.CO>[Cl:13][C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[N:16]=[C:1]([C:4]1[N:5]=[C:6]([C:10](=[N:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[Cl:13])[CH3:11])[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: Cc1cc(C)c(N)c(Cl)c1
Reactant: CC(=O)c1cccc(C(C)=O)n1
Solvent: CO
Solvent: O=CO
Product: CC(=Nc1c(C)cc(C)cc1Cl)c1cccc(C(C)=Nc2c(C)cc(C)cc2Cl)n1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
In a 200 ml round bottom flask, 2.0 g of 2,6-diacetylpyridine (M=163.176 g/mol, 0.0123 mol) and 75 ml of methanol were placed. Next 3.81 g of 2-chloro-4,6-dimethylaniline (M=155.627 g/mol, 0.0245 mole) and three drops of formic acid were added and the solution stirred at room temperature under nitrogen for four days, at which time no precipitate had formed. The reaction then was refluxed for 24 h. GC analysis indicated that the reaction was incomplete. Refluxing was continued for a total of 1 week. Solvent was stripped from the reaction mixture via rotary evaporator. Flash chromatography through a basic alumina column (eluted with hexane/ethyl acetate 20:1) lead to isolation of an oil. The oil was then crystallized from methanol/methylene chloride to receive pale yellow crystals.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][C:14]1([CH3:25])[O:19][CH:18]([CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:17][CH2:16][CH2:15]1.[Cl:26][CH2:27][CH2:28][CH2:29]I.[Cl-].[NH4+]>C1COCC1.O.C(OCC)(=O)C.CN(C)P(N(C)C)(N(C)C)=O>[Cl:26][CH2:27][CH2:28][CH2:29][CH:20]([CH:18]1[CH2:17][CH2:16][CH2:15][C:14]([CH3:25])([CH3:13])[O:19]1)[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)CC1CCCC(C)(C)O1
Reactant: ClCCCI
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(CCCCl)C1CCCC(C)(C)O1
Temperature: -30 °C
Reaction time: 0.25 h

Procedure:
n-Butyl lithium (2.64 M solution in hexane, 1.1 ml) was added dropwise to a solution of diisopropylamine (0.45 ml) in THF (6 ml), and the reaction solution was stirred at −30° C. for 15 minutes. The reaction solution was cooled to −78° C. Hexamethylphosphoramide (0.75 ml) and a solution of methyl 2-(6,6-dimethyltetrahydropyran-2-yl)acetate (500 mg) in THF (3 ml) were sequentially added dropwise to the reaction solution, and the reaction solution was stirred at the same temperature for 20 minutes. 1-Chloro-3-iodopropane (0.43 ml) was added dropwise to the resulting reaction solution. The reaction solution was gradually heated, and then a saturated ammonium chloride solution was added to the reaction solution. Ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The resulting organic layer was sequentially washed with 1 N hydrochloric acid, water, a saturated sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 278 mg of methyl 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)valerate.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[NH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:16][CH2:15]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([NH:13][C@H:14]2[CH2:15][CH2:16][C@H:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][CH2:19]2)=[O:12])=[CH:6][CH:7]=1
Reactant: N[C@H]1CC[C@H](c2ccccc2)CC1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(CCc1ccc(O)cc1)N[C@H]1CC[C@H](c2ccccc2)CC1
Reaction time: 8 h

Procedure:
A mixture of 3-(4-hydroxyphenyl)propionic acid 7 (0.48 g, 2.9 mmol), amine 5 (0.50 g, 2.9 mmol), EDC (0.67 g, 3.5 mmol), and HOBT (0.39 g, 2.9 mmol) in DMF (5 mL) was stirred under an atmosphere of nitrogen overnight. The reaction mixture was partitioned between H2O (25 mL) and EtOAc (50 mL). The organic layer was washed with H2O, 3N HCl (25 mL), H2O (25 mL), and saturated NaCl (25 mL). After drying (Na2SO4), concentration under reduced pressure gave (a) trans-3-(4-hydroxyphenyl)-N-(4-phenylcyclohexyl)propionamide (0.65 g, 69%) which was used without further purification: 1H NMR (300 MHz, CD3OD) δ 7.28-7.06 (m, 5H), 3.74-3.60 (m, 1H), 2.80 (t, J=4 Hz, 2H), 2.51-2.36 (m, 3H), 1.97-1.82 (m, 4H), 1.67-1.51 (m, 2H), 1.40-1.21 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][C:10]=1[C:16]1[CH:21]=[C:20](Cl)[N:19]=[C:18]([NH2:23])[N:17]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=1>>[NH2:23][C:18]1[N:19]=[C:20]([NH:24][C:25]2[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][OH:33])=[CH:27][CH:26]=2)[CH:21]=[C:16]([C:10]2[CH:11]=[C:12]([Cl:15])[CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:17]=1
Reactant: Nc1nc(Cl)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Reactant: Nc1ccc(CCO)cc1
Product: Nc1nc(Nc2ccc(CCO)cc2)cc(-c2cc(Cl)ccc2OCc2ccccc2)n1
Yield: 71 %

Procedure:
Following the method described in Example 72, 4-(2-benzyloxy-5-chloro-phenyl)-6-chloro-pyrimidin-2-ylamine and 2-(4-amino-phenyl)-ethanol provided the title compound (71% yield). 1H NMR (CD3OD) δ 2.85 (t, 2H, J=6.9 Hz, CH2), 3.78 (t, 2H, J=6.9 Hz, CH2), 5.27 (s, 2H, CH2), 6.42 (s, 1H, Ar), 7.28-7.30 (m, 2H, Ar), 7.32-7.36 (m, 2H, Ar), 7.39 (d, 4H, J=6.3 Hz, Ar), 7.58 (d, 2H, J=8.4 Hz, Ar), 7.68-7.70 (m, 2H, Ar).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)=[CH:20][CH:19]=1)[CH3:27]
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Reactant: CCOC(=O)CN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [Na].[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5](Cl)[N:4]=1.[CH2:13]([OH:16])[CH2:14][CH3:15]>>[NH2:2][C:3]1[N:11]=[C:10]2[C:6]([NH:7][CH:8]=[N:9]2)=[C:5]([O:16][CH2:13][CH2:14][CH3:15])[N:4]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCCO
Agent: [Na]
Product: CCCOc1nc(N)nc2nc[nH]c12
Temperature: 85 °C

Procedure:
Sodium (0.68 g, 29.5 mmol Aldrich lot #9621CL) was added in portions to anhydrous propanol (25 mL). Upon complete dissolution 2-amino-6-chloropurine (1 g, 5.9 mmol, Sigma lot #69F4064) was added and the reaction heated in an 85° C. oil bath under a nitrogen atmosphere for 20 hours. The solution was cooled and neutralized with Dowex 50W×12 (H+ form) (BioRad, 140-270 mesh), an acidic ion exchange resin. The resin was filtered, the filtrate collected and adsorbed onto silica gel column and eluted with CHCl3 /MeOH (9:1, v/v). Combination and evaporation of appropriate fractions gave 0.89 g of slightly impure material. Adsorption of this material onto silica gel followed by elution with EtOAc/MeOH (10:1, v/v) gave, after evaporation of combined product fractions, 0.76 g, (3.9 mmol; 67%). mp=198°-200° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[C:5]([Cl:12])=[CH:4][C:3]=1[NH2:13].[C:14](OCC)(=[O:20])[C:15](OCC)=[O:16]>>[Cl:12][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][C:6]=1[C:8]([F:9])([F:10])[F:11])[NH:1][C:15](=[O:16])[C:14](=[O:20])[NH:13]2
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1N
Product: O=c1[nH]c2cc(Cl)c(C(F)(F)F)cc2[nH]c1=O
Reaction time: 5 h
Yield: 86 %

Procedure:
A mixture of 1,2-diamino-4-chloro-5-trifluoromethylbenzene (13.4 g, 63.6 mmol) and diethyl oxalate (100 ml) was heated at reflux under nitrogen with stirring for 5 h. After being cooled, the solid which formed was filtered off and washed well with ether to afford a pale orange solid (14.5 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:17][CH:18]([CH3:27])[CH2:19][C@@H:20]([C:22]1[S:23][CH:24]=[CH:25][N:26]=1)[NH2:21]>>[CH3:17][CH:18]([CH3:27])[CH2:19][C@H:20]([NH:21][C:14]([C:12]1[CH:11]=[CH:10][CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)=[O:16])[C:22]1[S:23][CH:24]=[CH:25][N:26]=1
Reactant: CC(C)C[C@H](N)c1nccs1
Reactant: O=C(O)c1cccc(-c2cccc(Cl)c2)n1
Product: CC(C)C[C@H](NC(=O)c1cccc(-c2cccc(Cl)c2)n1)c1nccs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-(3-chlorophenyl)-2-pyridinecarboxylic acid (CAN 863704-38-5) and (S)-α-(2-methylpropyl)-2-thiazolemethanamine as starting materials, MS (LC/MS): 386.1 [M+H]+.
Reaction SMILES: [Cl:1][C:2]([Cl:35])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[N+:30]([O-])=O)=[CH:9][CH:8]=1.[Cl-].[NH4+]>O1CCCC1.C(O)C.O.[Fe]>[Cl:35][C:2]([Cl:1])([Cl:34])[CH2:3][O:4][C:5](=[O:33])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)Nc3ccc(Br)cn3)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1cc(C(=O)Nc2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Temperature: 25 °C
Yield: 95.3 %

Procedure:
A mixture of the product of Example 364C (1.63 g, 2.63 mmol), iron powder (0.737 g, 13.1 mmol, 5 equiv., from Acros, electrolytically reduced, reagent, powder), and ammonium chloride (0.211 g, 3.94 mmol, 1.5 equiv.) in tetrahydrofuran/ethanol/water (30/30/10 mL) was heated under reflux for 2.5 hours. The reaction mixture was cooled to room temperature and filtered through Celite, rinsing the Celite pad with 50 mL of ethanol. The resulting filtrate was evaporated under reduced pressure and the residue was partitioned between ethyl acetate (100 mL) and water (100 mL). The aqueous phase was washed with ethyl acetate (2×100 mL). The combined organic phases were washed with brine (50 mL), dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure to give the title compound (1.48 g, 95%) as a faintly yellow solid.
Reaction SMILES: N[C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6].[OH-].[Na+].N([O-])=O.[Na+].Cl.C([O-])(=O)C.[Na+].CCOC([S-])=[S:32].[K+]>O>[SH:32][C:2]1[C:3]([CH3:15])=[C:4]([CH:8]=[CH:9][C:10]=1[S:11]([CH3:14])(=[O:13])=[O:12])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=S)[S-]
Reactant: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1N
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: Cc1c(C(=O)O)ccc(S(C)(=O)=O)c1S
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
11.0 g (48.0 mmol) of 3-amino-2-methyl-4-methylsulfonylbenzoic acid (synthesis described by T. L. Siddall et al. in Pest Management Science (2002), 58 (12), 1175-1186) was added to a solution of 2.03 g (50.9 mmol) of NaOH in 60 ml of water. 3.31 g (48.0 mmol) of sodium nitrite were then added. At 5-8° C., the solution was added dropwise to a mixture of concentrated HCl and ice. The mixture was stirred at this temperature for 15 minutes and then neutralized with sodium acetate. The content was then added dropwise to a solution, kept at 70-80° C., of 21.54 g (134.3 mmol) of potassium ethyl xanthogenate in 80 ml of water. The mixture was stirred at 80° C. for 15 minutes and then, at RT, acidified for work-up with 1M HCl. After five minutes, the mixture was decanted and 85 ml of 10% strength aqueous sodium hydroxide solution were added to the residue. The mixture was heated and distillate formed was removed with the aid of a distillation assembly, so that an internal temperature of 100° C. could be reached. After the mixture had been heated at this temperature for 1.25 h, HPLC analysis showed that the reaction had gone to completion. 21 ml of a saturated aqueous sodium bisulfite solution were then added, and the mixture was heated at 100° C. for 10 minutes. For work-up, the cooled reaction mixture was acidified with 1M HCl, cooled to 0-5° C. and filtered under an atmosphere of nitrogen. What was isolated were 10 g of a solid; a 1H-NMR spectrum showed the identity of the product.
Reaction SMILES: C1(S([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([C:19]4[NH:23][CH:22]=[N:21][N:20]=4)[CH:18]=[C:13]3[C:12]([C:24]3[CH:28]=[CH:27][O:26][CH:25]=3)=[CH:11]2)(=O)=O)C=CC=CC=1.[OH-].[Na+]>CCO>[O:26]1[CH:27]=[CH:28][C:24]([C:12]2[C:13]3[C:14](=[N:15][CH:16]=[C:17]([C:19]4[NH:23][CH:22]=[N:21][N:20]=4)[CH:18]=3)[NH:10][CH:11]=2)=[CH:25]1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccoc2)c2cc(-c3nnc[nH]3)cnc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: c1nnc(-c2cnc3[nH]cc(-c4ccoc4)c3c2)[nH]1
Temperature: 90 °C
Yield: 28.4 %

Procedure:
A mixture of 40 (60 mg, 0.15 mmol), EtOH (1.54 mL) and 10% aq. NaOH (767 μL) were heated at 90° C. for 45 min then cooled and poured onto water (11 mL) and extracted with ethyl acetate (4×10 mL). The combined organic extracts were dried (MgSO4), concentrated and the residue purified by preparative LCMS (column LUNA 10μ C18(2) 00G-4253-V0 250×50 mm) using water—acetonitrile (0.1% AcOH) as eluent (in gradient; flow 80 mL/min) to give the product as a white solid (10.7 mg, 28%); 1H NMR (400 MHz, CDCl3+2 drops CD3OD) δ 6.70 (d, J=1.0 Hz, 1H), 7.45 (s, 1H), 7.49 (t, J=1.5 Hz, 1H), 7.89 (s, 1H), 8.16 (bs, 1H), 8.75 (d, J=1.9 Hz, 1H), 8.92 (s, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7])[CH2:3][CH2:2]1.[H][H]>CO.[Pt]>[NH2:13][C:12]1[C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1cccc([N+](=O)[O-])c1C1CC1
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Nc1cccc(C(=O)O)c1C1CC1
Reaction time: 3 h
Yield: 94.7 %

Procedure:
A solution of 2-cyclopropyl-3-nitrobenzoic acid (0.63 g, 3.04 mmol) and 5% Pt/C (0.59 g, 0.152 mmol) in methanol (10 mL) was charged with 40 psi of hydrogen and shaken for 3 hours. The catalyst was removed by filtration and washed with methanol (10 mL). The filtrate was concentrated under reduced pressure to give 3-amino-2-cyclopropylbenzoic acid (0.51 g, 94.1%) as a solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>C(#N)C>[CH3:34][C:28]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8](=[O:12])[CH2:7][CH2:6][CH2:5][C:4]=2[C:3]=1[CH2:13][CH2:14][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)([CH3:35])[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: O=C1CCCc2c1ccc(O)c2CCc1ccccc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc2c(c1CCc1ccccc1)CCCC2=O
Yield: 96 %

Procedure:
A mixture of 6-hydroxy-5-(2-phenylethyl)-3,4-dihydro-1(2H)-naphthalenone (2.00 g, 7.5 mmol), potassium carbonate (2.08 g, 15.0 mmol), and acetonitrile (15 mL) was heated to reflux, whereupon ethyl 2-bromo-2-methylpropanoate (1.2 mL, 8.3 mmol) was added. The mixture was stirred at reflux for 2.5 h, whereupon further potassium carbonate (1.04 g, 7.5 mmol) and ethyl 2-bromo-2-methylpropanoate (1.2 mL, 8.3 mmol) were added. The mixture was stirred at reflux for a further 22 h and was then filtered and concentrated. The residue was purified by dry-flash column chromatography (SiO2, 5-30% ethyl acetate-hexane) to give ethyl 2-methyl-2-{[5-oxo-1-(2-phenylethyl)-5,6,7,8-tetrahydro-2-naphthalenyl]oxy}propanoate as a pale yellow oil, 2.75 g, 96% yield. NMR spectrum was consistent with structure. MS EI: M+• 380.1985 (M+• 380.1988). 2. 6-(2-Hydroxy-1,1-dimethylethoxy)-5-(2-phenylethyl)-1,2,3,4-tetrahydro-1-naphthalenol