Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[CH2:4][CH2:5][O:6][CH2:7][C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:17]=1[CH:18]=[O:19].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[OH:15][C:16]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:2][C:3]2[CH2:4][CH2:5][O:6][CH2:7][C:8]=2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:17]=1[CH:18]=[O:19]
Reactant: BrCC1=C(c2ccccc2)COCC1
Reactant: O=Cc1c(O)cccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: O=Cc1c(O)cccc1OCC1=C(c2ccccc2)COCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To a solution of 4-(bromomethyl)-5-phenyl-3,6-dihydro-2H-pyran (110 mg, 0.45 mmol) and 2,6-dihydroxybenzaldehyde (120 mg, 0.90 mmol) in DMF (3 mL) was added K2CO3 (120 mg, 0.90 mmol). After stirred at room temperature for 1 h, it was diluted with water and EtOAc, organic layer was separated, and the aqueous layer was extracted with EtOAc. Organic layer was combined, washed with brine, dried and concentrated to give crude product, which was purified by column (Hexanes/EtOAc=3:1) to give 2-hydroxy-6-((5-phenyl-3,6-dihydro-2H-pyran-4-yl)methoxy)benzaldehyde (120 mg). 1H NMR (400 MHz, CDCl3) δ (ppm) 11.92 (s, 1H), 10.36 (s, 1H), 7.35 (m, 4H), 7.18 (m, 2H), 6.49 (d, J=8.0 Hz, 1H), 6.13 (d, J=8.0 Hz, 1H), 4.48 (s, 2H), 4.32 (s, 2H), 3.95 (t, J=5.6 Hz, 2H), 2.41 (m, 2H); MS (ESI) m/z 309.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[CH3:15]O>[Pd]>[CH3:15][C:11]1[C:2]([CH3:1])=[C:3]([CH:8]=[C:9]([NH2:12])[CH:10]=1)[C:4]([OH:6])=[O:5]
Reactant: CO
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1C
Agent: [Pd]
Product: Cc1cc(N)cc(C(=O)O)c1C
Reaction time: 18 h

Procedure:
Combine methyl 2-methyl-5-nitrobenzoate (5.32 g, 27.2 mmol) and methanol (100 mL). Add 5% palladium-on-carbon (0.27 g). Hydrogenate on a pressure apparatus at 50 psi. After 18 hours, filter through celite to remove the catalyst and evaporate the filtrate in vacuo to give methyl 2-methyl-5-aminobenzoic acid: Rf=0.34 (silica gel, ethyl acetate/hexane 1/4).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]([O:16]C)=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.[OH-].[Na+].Cl>CO.O1CCCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=[O:15])[C:5]2[CH:6]=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1
Reactant: COC(=O)c1cc(Br)cc2c1ccn2C(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)n1ccc2c(C(=O)O)cc(Br)cc21
Temperature: 25 °C
Yield: 98.9 %

Procedure:
To a solution of methyl 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylate (0.52 g, 1.756 mmol) in methanol (15 mL) and tetrahydrofuran (3 mL) was added 3 M NaOH (1.756 mL, 5.27 mmol) via syringe drop wise (over 2 min). The solution was maintained at RT for 2 h, at which time LCMS showed only 12% conversion to product. Then 1.5 mL 3 M NaOH was added and the solution was maintained at RT overnight. LCMS showed complete conversion to product. Removed volatiles in vacuo and dissolved the residue in water and slowly acidified with 1 M HCl (solids precipitated). Extracted with EtOAc (2×), combined organics and dried over MgSO4. Filtered and concentrated in vacuo to give 6-bromo-1-(1-methylethyl)-1H-indole-4-carboxylic acid (0.50 g, 1.737 mmol, 99% yield) as a white solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:14])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2].[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)C(C)C)(C)C>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:14][C:31]([NH:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:32])=[CH:11][CH:12]=2)[C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH3:15])[CH2:6][C:5]1([CH3:23])[CH3:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(N)cc2C(C)(c2ccccc2)CC1(C)C
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1c2ccc(NC(=O)Nc3ccccc3)cc2C(C)(c2ccccc2)CC1(C)C
Reaction time: 18 h

Procedure:
A mixture of 1-acetyl-6-amino-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (10 mg), phenyl isocyanate (8.0 mg) and N,N-diisopropylethylamine (22 l) in tetrahydrofuran (1 ml) was stirred for 18 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in ethyl acetate and washed with 0.5 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in heptane/ethyl acetate=1/0=>0/1 (v/v) as eluent.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH2:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH2:14][CH2:13][CH:9]1[C:10](=[O:12])[NH:23][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)NCc1ccccc1
Yield: 85.7 %

Procedure:
Using General Procedure I Method A, N-(tert-butoxycarbonyl)-L-proline (1.0 g, 4.6 mmol) is coupled to benzylamine (0.55 g, 5.1 mmol) to give 1.2 g (86%) of 2-benzylcarbamoyl-pyrrolidine-1-carboxylic acid tert-butyl ester, which is submitted to the following step without further purification.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH2:6]([O:13][CH2:14][C:15]([N:17]([CH:19]([S:25][C:26]1[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=1)[C:20](=O)[CH:21]([CH3:23])[CH3:22])[CH3:18])=O)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>C(O)(=O)C>[CH2:6]([O:13][CH2:14][C:15]1[N:17]([CH3:18])[C:19]([S:25][C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=2)=[C:20]([CH:21]([CH3:23])[CH3:22])[N:5]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CC(C)C(=O)C(Sc1cc(Cl)cc(Cl)c1)N(C)C(=O)COCc1ccccc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CC(C)c1nc(COCc2ccccc2)n(C)c1Sc1cc(Cl)cc(Cl)c1
Reaction time: 1 h

Procedure:
In acetic acid was dissolved 2-benzyloxy-N-[1-(3,5-dichlorophenylthio)-3-methyl-2-oxobutyl]-N-methylacetamide (20), followed by addition of ammonium acetate, and the mixture was refluxed under heating. After 1 hour, the reaction mixture was concentrated under reduced pressure, neutralized with sodium hydroxide, and then, extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to give 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1H-methylimidazole (17a).
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH:4]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[N:6]=1.[Cl:11][C:12]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:13]=1[CH:14]=[C:15]([C:19](=O)[CH3:20])[C:16]([NH2:18])=[O:17]>CCO.O>[C:16]([C:15]1[CH:14]([C:13]2[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:12]=2[Cl:11])[N:3]2[CH:4]=[C:5]([S:7]([OH:10])(=[O:9])=[O:8])[N:6]=[C:2]2[NH:1][C:19]=1[CH3:20])(=[O:17])[NH2:18]
Reactant: CC(=O)C(=Cc1ccc(Cl)cc1Cl)C(N)=O
Reactant: Nc1nc(S(=O)(=O)O)c[nH]1
Solvent: O
Solvent: CCO
Product: CC1=C(C(N)=O)C(c2ccc(Cl)cc2Cl)n2cc(S(=O)(=O)O)nc2N1
Temperature: 80 °C

Procedure:
A suspension of 2-amino-1H-imidazole-4-sulfonic acid (82 mg, 0.5 mmol) and 2-(2,4-dichlorobenzylidene)-3-oxobutanamide (125 mg, 0.5 mmol) in 3:1 EtOH/H2O (2 mL) was heated to 80° C. for 14 h. After removal of solvent, the residue was dissolved in 1N NaOH and extracted with EtOAc (5 mL×2). The aqueous solution was then acidified with conc. HCl to pH=1. The precipitation which had formed was collected and further washed with H2O. After drying in vacuo, 6-carbamoyl-5-(2,4-dichlorophenyl)-7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-2-sulfonic acid was obtained a yellow solid (97 mg, 48%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]#[C:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:4][C:5]([CH3:9])=[CH:6][C:7]=1[Cl:8].O>CN(C=O)C.[Cu]I>[Cl:8][C:7]1[CH:6]=[C:5]([CH3:9])[N:4]=[C:3]2[CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[NH:1][C:2]=12
Reactant: Cc1cc(Cl)c(N)c(C#Cc2ccccc2)n1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Cl)c2[nH]c(-c3ccccc3)cc2n1
Temperature: 110 °C
Yield: 48.5 %

Procedure:
3-Amino-4-chloro-6-methyl-2-(2-phenylethynyl)pyridine (1.24 g, 5.1 mmol) was dissolved in anhydrous DMF (90 mL), CuI (150 mg, 0.8 mmol) was added and the mixture was heated at 110° C. for 18 h. The cooled mixture was poured into H2O (125 mL) and extracted with EtOAc (2×100 mL). The combined extracts were washed with H2O and brine, dried over MgSO4 and filtered through a plug of silica using CHCl3. The crude product was triturated with 20:1 hexanes:EtOAc, filtered, and dried under high vacuum to afford 600 mg (48%) of 7-chloro-5-methyl-2-phenylpyrrolo-[3,2-b]pyridine. 1H NMR (DMSO-d6; 500 MHz): δ 2.40 (s, 3), 7.05 (s, 1), 7.16 (s, 1), 7.38 (t, 1, J=5.2), 7.49 (m, 2), 8.02 (d, 2, J=7.2). MS m/z: 243 (M+H). This intermediate chloride (273 mg, 1.1 mmol) was taken up in 4:1 o-xylene/piperidine (10 mL) and heated to 140° C. in a Teflon-capped pressure tube for 7 d. The mixture was cooled to room temperature, diluted with H2O (125 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with H2O and brine, dried over MgSO4 filtered, and concentrated in vacuo. Chromatography on silica gel eluting with 10:1 CHCl3:MeOH afforded 244 mg (75%, 36% overall) of the title compound as a pale yellow solid. The product's 1H-NMR was identical to that obtained using Method A.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[CH:14]=[C:15]([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Reactant: O=C(O)c1ccc(Br)nc1
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1C
Yield: 101 %

Procedure:
Using 6-bromonicotinic acid (412 mg) and 1-(2,4,5-trimethylphenyl)piperazine (440 mg) and by the reaction and treatment in the same manner as in Preparation Example 118, the title compound (800 mg) was obtained.
Reaction SMILES: N#N.[CH3:3][C:4]1[O:5][C:6]([C:12]2[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=2)=[C:7]([C:9]([OH:11])=O)[N:8]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(C(C)C)C(C)C.[CH2:42]([O:44][CH2:45][C:46]1[N:47]=[C:48]([CH2:51][N:52]2[N:56]=[C:55]([NH2:57])[CH:54]=[N:53]2)[O:49][CH:50]=1)[CH3:43]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:42]([O:44][CH2:45][C:46]1[N:47]=[C:48]([CH2:51][N:52]2[N:56]=[C:55]([NH:57][C:9]([C:7]3[N:8]=[C:4]([CH3:3])[O:5][C:6]=3[C:12]3[CH:13]=[C:14]([CH3:18])[CH:15]=[CH:16][CH:17]=3)=[O:11])[CH:54]=[N:53]2)[O:49][CH:50]=1)[CH3:43]
Reactant: CCOCc1coc(Cn2ncc(N)n2)n1
Reactant: Cc1cccc(-c2oc(C)nc2C(=O)O)c1
Agent: CN(C)c1ccncc1
Agent: N#N
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOCc1coc(Cn2ncc(NC(=O)c3nc(C)oc3-c3cccc(C)c3)n2)n1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-methyl-5-(m-tolyl)oxazole-4-carboxylic acid (WO 2009/077990, p. 112) (42 mg, 0.20 mmol) in CH2Cl2 (1.0 mL) was treated at rt with DMAP (5.8 mg, 0.05 mmol), HOBt (31 mg, 0.23 mmol), EDC (91 mg, 0.48 mmol) and DIPEA (0.13 mL, 0.76 mmol) and the resulting mixture was stirred for 45 min at rt. A solution of 2-((4-(ethoxymethyl)oxazol-2-yl)methyl)-2H-1,2,3-triazol-4-amine (43 mg, 0.19 mmol) in CH2Cl2 (0.9 mL) was then added and the reaction mixture was stirred overnight at rt. The mixture was diluted with CH2Cl2 (10 mL) and the org. phase was washed with water (10 mL), dried over MgSO4, filtered and the solvents were removed under reduced pressure. Purification of the residue by FC (3:7 hept-EA) gave the title compound as a yellow oil: TLC: rf (7:3 hept-EA)=0.34. LC-MS-conditions 07: tR=0.91 min, [M+H]+=423.14.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7](/[C:10](/[CH3:16])=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+].O.O1CCCC1>[Fe].CO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7](/[C:10](/[CH3:16])=[CH:11]/[C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:9]=1
Reactant: COC(=O)/C=C(\C)c1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)/C=C(\C)c1ccc(N)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 93.8 %

Procedure:
Compound 6a (31.7 g), iron powder (41.1 g), ammonium chloride (18.1 g), and water (173 ml) were added to a mixed solution of tetrahydrofuran (280 ml) and methanol (280 ml) in a nitrogen atmosphere. The mixture was stirred at 70° C. for 1 hour. After the reaction mixture was allowed to cool, and filtered, the filtrate was separated with ethyl acetate and water. The organic layer was washed once with water and once with a saturated sodium chloride solution, and then dried over anhydrous sodium sulfate. The solvent was distilled off, and as a result, Compound 6b (25.7 g, 94%) was obtained as an orange solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH2:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Cl-].[NH4+].[CH2:16]1COCC1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[CH2:13])[C:9]2([CH3:16])[OH:12])=[CH:4][CH:3]=1
Reactant: C=C1CCc2ccc(Br)cc2C1=O
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [NH4+]
Product: C=C1CCc2ccc(Br)cc2C1(C)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
Anhydrous THF (200 mL) was added to a flame dried flask charged with anhydrous cerium (III) chloride (3.90 g, 15.8 mmol) under dry nitrogen. The mixture was vigorously stirred for 2 hours to provide an opaque suspension. The suspension was cooled to −78° C. Methyllithium (1.6 M in diethylether) (9.89 mL, 15.8 mmol) was added to the suspension of cerium(III) chloride to produce a bright yellow solution of methylcerium(III) dichloride. After stirring for 1 hour at −78° C., a solution of 7-bromo-2-methylene-3,4-dihydronaphthalen-1(2H)-one from step C1 (1.5 g, 6.33 mmol) in THF (20 mL) was added. The reaction mixture was allowed to stir for 30 min at −78° C., then it was poured into an Erlenmeyer flask charged with saturated aqueous ammonium chloride solution. The aqueous mixture was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified using silica gel column chromatography (10:1 Hex/EtOAc) to afford 7-bromo-1-methyl-2-methylene-1,2,3,4-tetrahydronaphthalen-1-ol (0.670 g, 2.66 mmol, 42% yield) as a clear viscous oil. 1H NMR (500 MHz, chloroform-d) δ 7.81 (d, J=2.0 Hz, 1H), 7.29 (dd, J=8.1, 2.1 Hz, 1H), 6.93 (d, J=8.1 Hz, 1H), 5.29-5.25 (m, 1H), 4.98 (d, J=1.2 Hz, 1H), 2.86-2.76 (m, 2H), 2.65-2.57 (m, 2H), 1.87-1.84 (m, 1H), 1.60 (s, 3H).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9][CH2:8][C:7](=[CH:10][C:11]([OH:13])=O)[CH2:6][CH2:5]1.C1(N=[C:28]=[N:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]2)CCCCC1.[OH-].[Na+]>CN(C)C=O.O>[CH3:20][N:3]([CH3:2])[C:4]1([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:5][CH2:6][C:7](=[CH:10][C:11]([NH:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]2[C:31]3[C:30](=[CH:35][CH:34]=[CH:33][CH:32]=3)[NH:29][CH:28]=2)=[O:13])[CH2:8][CH2:9]1
Reactant: CN(C)C1(c2ccccc2)CCC(=CC(=O)O)CC1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)C1(c2ccccc2)CCC(=CC(=O)NCCCCc2c[nH]c3ccccc23)CC1
Temperature: 0 °C
Reaction time: 96 h

Procedure:
(4-dimethylamino-4-phenylcyclohexylidene)acetic acid hydrochloride (592 mg, 2.0 mmol) in dry dimethylformamide (10 ml) under argon. The clear solution was cooled to 0° C. and dicyclohexylcarbodiimide (834 mg, 4.0 mmol) was added. The reaction mixture was stirred at RT for 4 d. Working up of the mixture was carried out by separating off the urea which had precipitated out and introducing the filtrate into a mixture of saturated NaCl solution (40 ml) and saturated NaHCO3 solution (10 ml). Still further urea thereby precipitated out and was separated off. 5 M sodium hydroxide solution (5 ml, 25 mmol) was added to the aqueous phase and the mixture was diluted with water (300 ml) and stored at 5° C. for 16 h. The product thereby precipitated out as a colourless solid in a yield of 45% (387 mg) with an m.p. of 77-88° C.
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1)#[N:2].C(N)(=[S:21])C>FC(F)(F)C(O)=O>[NH2:2][C:1](=[S:21])[CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[N:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:4]1
Reactant: CC(N)=S
Reactant: CCOC(=O)N1CCC(C#N)CN1C(=O)OCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)N1CCC(C(N)=S)CN1C(=O)OCC
Temperature: 50 °C

Procedure:
A mixture of 1,2-diethyl 4-cyanotetrahydro-1,2-pyridazinedicarboxylate (i.e the product of Step E) (5.5 g, 0.024 mol) and thioacetamide (5.5 g, 0.073 mol) in trifluoroacetic acid (about 10 mL) was heated at 50° C. for 20 h. The reaction mixture was cooled, and then partitioned between water and diethyl ether (about 30 mL). The layers were separated and the aqueous layer was extracted with diethyl ether (2×). The combined organic extracts were washed with water (about 30 mL), dried magnesium sulfate, filtered and concentrated under reduce pressure to an orange oil. The oil was adsorbed onto Celite® (diatomaceous filter aid), and then purified by silica gel column chromatography (25% to 60% gradient of ethyl acetate in petroleum ether as eluant) to provide the title compound as a yellow solid (3.97 g).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][C:19]=1[Cl:20].I[CH2:26][CH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.Cl>O1CCCC1.CN(C)P(N(C)C)(N(C)C)=O>[CH:27]1([CH2:26][CH:21]([C:16]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:14]([Cl:13])[CH:15]=2)[C:22]([OH:24])=[O:23])[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Reactant: ICC1CCCC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 80.8 %

Procedure:
A solution of diisopropylamine (13.36 mL, 101.89 mmol) in tetrahydrofuran (250 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.0M solution of n-butyllithium in hexanes (51 mL, 101.89 mmol). The reaction mixture was stirred at −78° C. for 15 min, at which time, a solution of 3,4-dichlorophenyl acetic acid (9.08 g, 44.3 mmol) in tetrahydrofuran (60 mL) and hexamethylphosphoramide (20 mL) was slowly added via a cannula. The bright yellow solution was allowed to stir at −78° C. for 1 h, at which time, a solution of iodomethylcyclopentane (11.17 g, 53.2 mmol) in hexamethylphosphoramide (10 mL) was added via a cannula. The reaction mixture was stirred at −78° C. for 1 h. The reaction mixture was then allowed to warm to 25° C. where it was stirred for 14 h. The reaction mixture was then acidified to pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid solution and extracted with ethyl acetate (3×50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, chloroform then 99/1 chloroform/methanol) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (10.28 g, 81%) as a white solid: mp 74.5-76.9° C.; EI-HRMS m/e calcd for C14H16Cl2O2 (M+) 286.0527, found 286.0534.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:15]([O:17][C:18]([C:20]1[C:24]([CH2:25][CH3:26])=[CH:23][N:22]([CH3:27])[C:21]=1[CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[O:19])[CH3:16]>ClCCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[N:22]([CH3:27])[C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:20]([C:18]([O:17][CH2:15][CH3:16])=[O:19])[C:24]=2[CH2:25][CH3:26])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c(CC)cn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCOC(=O)Cc1c(C(=O)OCC)c(CC)c(C(=O)c2ccc(Cl)cc2)n1C
Temperature: 25 °C
Reaction time: 10 h

Procedure:
A solution of 13.8 g. (0.0788 mole) of ρ-chlorobenzoyl chloride and 10.5 g. (0.0788 mole) of aluminum chloride in 120 ml. of 1,2-dichloroethane is added to a refluxing soluton of 21.8 (0.0788 mole) of ethyl 3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate. The mixture is heated under reflux for 10 hours and stirred at room temperature for an additional 10 hours. It is then poured into ice-hydrochloric acid. The organic layer is separated and the aqueous layer washed with 1,2-dichloroethane. The combined organics are washed successively with water, N,N-dimethylaminopropylamine, dilute HCl and brine. The colution is then dried over anhydrous magnesium solfate and the solven evaporated in vacuo. The residual red oil residue crystallized on standing. It is recrystallized twice from methanol to give ethyl (5-ρ-chlorobenzoyl)-3-ethoxycarbonyl-4-ethyl-1-methylpyrrole-2-acetate as a white solid, M.P. 72°-74° C.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([NH:13][N:14]([CH3:19])[C:15]([NH:17][CH3:18])=[S:16])=O.C([O-])(O)=O.[Na+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[N:17]([CH3:18])[C:15](=[S:16])[N:14]([CH3:19])[N:13]=1
Reactant: CNC(=S)N(C)NC(=O)c1ccc2ccccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cn1nc(-c2ccc3ccccc3c2)n(C)c1=S
Temperature: 25 °C

Procedure:
1-(2-Naphthoyl)-2,4-dimethyl-thiosemicarbazide (5.47 g, 2.00×10-2 mole) from Example 2 and 1 molar aqueous NaHCO3 (200 ml, 2.00×10-1 mole) were stirred and warmed to reflux. After refluxing for 17 hours the reaction was allowed to cool to room temperature. The precipitate was collected by filtration, water-washed, and dried by suction. The product was crystallized from isopropyl alcohol to yield off-white, matted needles: 3.9 g (76%) mp. 173°-175° C.
Reaction SMILES: [C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20](F)=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:5][CH2:4]1)#[N:2].[F:34][C:35]([F:40])([F:39])[C@@H:36]([OH:38])[CH3:37]>>[C:1]([C:3]1([NH:6][C:7]([C@@H:9]2[CH2:13][C@@H:12]([S:14]([C:17]3[CH:22]=[CH:21][C:20]([O:38][C@@H:36]([CH3:37])[C:35]([F:40])([F:39])[F:34])=[CH:19][C:18]=3[Cl:24])(=[O:16])=[O:15])[CH2:11][C@H:10]2[C:25]([N:27]2[CH2:31][CH2:30][C:29]([F:33])([F:32])[CH2:28]2)=[O:26])=[O:8])[CH2:4][CH2:5]1)#[N:2]
Reactant: N#CC1(NC(=O)[C@@H]2C[C@@H](S(=O)(=O)c3ccc(F)cc3Cl)C[C@H]2C(=O)N2CCC(F)(F)C2)CC1
Reactant: C[C@H](O)C(F)(F)F
Product: C[C@H](Oc1ccc(S(=O)(=O)[C@@H]2C[C@@H](C(=O)NC3(C#N)CC3)[C@H](C(=O)N3CCC(F)(F)C3)C2)c(Cl)c1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 134 using (1R,2R,4R)-4-(2-chloro-4-fluoro-benzenesulfonyl)-2-(3,3-difluoro-pyrrolidine-1-carbonyl)-cyclopentanecarboxylic acid (1-cyano-cyclopropyl)-amide (example 186 step 7) and (S)-1,1,1-trifluoro-propan-2-ol (CAS #: 3539-97-7). White solid (92%). MS (EI): 600.1 (M+H)+.