Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=2[NH:12][C:11](=[S:20])[CH2:10][N:9]=1.[OH-].[Na+].CO.Cl.Cl[CH2:27][CH2:28][N:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:29]1([CH2:28][CH2:27][S:20][C:11]2[CH2:10][N:9]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:14]3[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=3[N:12]=2)[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: S=C1CN=C(c2ccccc2Cl)c2cc(Cl)ccc2N1
Reactant: ClCCN1CCCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCC(SCCN1CCCCCC1)=N2
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 7.5 g of 1,3-dihydro-5-(2-chlorophenyl)-7-chloro-2H-1,4-benzodiazepine-2-thione in a solvent mixture comprising 30 ml of a 10% aqueous sodium hydroxide solution and 30 ml of methanol is added dropwise under ice cooling with stirring an aqueous solution of 7.0 g of 1-chloro-2-(perhydroazepin-1-yl)ethane hydrochloride over a period of about 10 minutes, and the resulting mixture is stirred at room temperature for 4 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The extract is rinsed with a 5% aqueous sodium hydroxide solution, washed with water and dried. Thereafter the solvent is distilled off to obtain an oily residue of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7-chloro-3H-1,4-benzodiazepine. The oily product thus obtained is treated, according to usual procedure, with 2.74 g of fumaric acid and recrystallized from isopropyl alcohol to obtain 9.9 g of 2-(2-perhydroazepin-1-ylethylthio)-5-(2-chlorophenyl)-7 -chloro-3H-1,4-benzodiazepine fumarate, m.p. 170°-171° C.
Reaction SMILES: [C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]([SiH3:17])(Cl)[Cl:15]>C(OCC)C>[C:1]([O:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][SiH2:17][CH:14]([Cl:15])[Cl:13])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OCCCCCCCl
Reactant: [SiH3]C(Cl)(Cl)Cl
Solvent: CCOCC
Product: CC(C)(C)OCCCCCC[SiH2]C(Cl)Cl
Temperature: 25 °C
Yield: 84 %

Procedure:
Grignard reagent, a t-butoxyhexylmagnesium chloride solution (0.14 mol) was obtained by reacting t-butoxyhexylchloride with Mg(O) in the presence of diethyl ether (Et2O) as a solvent. Trichloromethylsilane (24.7 ml, 0.21 mol) was added to the Grignard reagent at −100° C. and the mixture was stirred at room temperature for at least 3 hours and then filtered. The filtrate was dried in a vacuum to obtain t-butoxyhexyldichloromethylsilane (yield 84%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([N+:10]([O-])=O)=[CH:4][C:5]([F:9])=[C:6]([O-:8])[CH:7]=1.[K+].[NH4+].[Cl-]>CCO.O.CO.C(OCC)(=O)C.[Fe]>[NH2:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([OH:8])=[C:5]([F:9])[CH:4]=1
Reactant: O=[N+]([O-])c1cc(F)c([O-])cc1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: Nc1cc(F)c(O)cc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 85.4 %

Procedure:
To a solution of potassium 5-chloro-2-fluoro-4-nitrophenolate (1.0 g, 4.35 mmol, Yuxiang) in 95% EtOH (22 mL) and H2O (8 mL) was added Fe (0.97 g, 17.4 mmol) and NH4Cl (1.86 g, 34.8 mmol). The mixture was stirred at rt for 10 hours, then diluted with methanol (100 mL) and ethyl acetate (100 mL). Filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water (50 mL) and ethyl acetate (50 mL). The organic phase was separated and the water phase was extracted with ethyl acetate (50 mL×2). The combined organic layers were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo to give the title compound as a pale solid (0.6 g, 85.3%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]=12.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:8](=[O:10])[C:7]2[C:2]([F:1])=[CH:3][CH:4]=[CH:5][C:6]=2[NH2:12])=[CH:18][CH:17]=1
Reactant: O=c1[nH]c2cccc(F)c2c(=O)o1
Reactant: COc1ccc(N)cc1
Product: COc1ccc(NC(=O)c2c(N)cccc2F)cc1
Yield: 81.7 %

Procedure:
Using the procedure described in Example 91, Part B, 6-fluoroisatoic anhydride (11 mmol) and 4-methoxyaniline (11 mmol) yielded 2.34 g (84%) of the title compound.
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:16])[CH2:12][CH:13](O)[CH:14]=1)([OH:3])=[O:2].[SH:17][CH2:18][CH2:19][OH:20].C[O-].[Na+].C(O)(=O)C>CO>[C:1]([CH2:4][CH2:5][CH2:6][CH2:7]/[CH:8]=[CH:9]\[C:10]1[C:11](=[O:16])[CH2:12][CH:13]([S:17][CH2:18][CH2:19][OH:20])[CH:14]=1)([OH:3])=[O:2]
Reactant: O=C(O)CCCC/C=C\C1=CC(O)CC1=O
Reactant: OCCS
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)CCCC/C=C\C1=CC(SCCO)CC1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2.24 g. (10 mmols) of 2-(6-carboxy-2-cis-hexenyl)-4-hydroxycyclopent-2-en-1-one (U.S. Pat. No. 3,952,033) and 0.82 g (10.5 mmols) of β-mercaptoethanol in 50 ml of methanol is added 10.5 ml of N/1 sodium methoxide in methanol solution during 30 minutes at room temperature. After the addition the solution is stirred at room temperature for 1 hour and treated with 4.8 g of glacial acetic acid (80 mmols). The solution is concentrated to volume of 10 ml, treated with 30 ml of brine, and extracted with ethyl acetate. The extract is washed with brine, dried over magnesium sulfate, and concentrated.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4](O)=O.[NH2:10][C@H:11](C(O)=O)[CH2:12]CC(O)=O.N1CCC[C@H]1C(O)=O.N[C@H](C(O)=O)C(C)C.NCC(O)=O.C(SSC[C@H](N)C(O)=O)[C@H](N)C(O)=O.N[C@H](C(O)=O)[C@@H](C)O.N[C@H](C(O)=O)CC(C)C.N[C@H](C(O)=O)CO>>[NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:12][CH2:11][NH2:10]
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Reactant: N[C@@H](CC(=O)O)C(=O)O
Agent: CC(C)C[C@H](N)C(=O)O
Agent: CC(C)[C@H](N)C(=O)O
Agent: C[C@@H](O)[C@H](N)C(=O)O
Product: NCCCC[C@H](N)C(=O)O

Procedure:
1.04 (1), aspartic acid: 2.09 (2), glutamic acid: 2.02 (2), proline: 3.10 (3), valine: 1.90 (2), glycine: 1.95 (2), cystine: 0.44 (0.5), threonine: 3.11 (3), leucine: 1.99 (2), serine: 1.98 (2).
Reaction SMILES: N[C:2]1[C:6]([C:7]#[N:8])=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[S:4][C:3]=1[C:15]([O:17][CH3:18])=[O:16].[I:19]CI.N(OCCCCC)=O>C(#N)C>[C:7]([C:6]1[C:2]([I:19])=[C:3]([C:15]([O:17][CH3:18])=[O:16])[S:4][C:5]=1[N:9]1[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)#[N:8]
Reactant: ICI
Reactant: COC(=O)c1sc(N2CCOCC2)c(C#N)c1N
Agent: CCCCCON=O
Solvent: CC#N
Product: COC(=O)c1sc(N2CCOCC2)c(C#N)c1I
Temperature: 80 °C
Reaction time: 96 h
Yield: 46.2 %

Procedure:
To a solution of methyl 3-amino-4-cyano-5-morpholin-4-ylthiophene-2-carboxylate (3.4 g, 12.6 mmol) in ACN (110 mL) was added diiodomethane (10.5 mL, 130.2 mmol) and amyl nitrite (1.1 mL, 77.7 mmol). The reaction mixture was allowed to stir at 80° C. for 4 days and was concentrated. The residue was purified by column chromatography to give methyl 4-cyano-3-iodo-5-morpholin-4-ylthiophene-2-carboxylate (2.2 g, 46%). LCMS: (FA) ES+ 379.0. 1H NMR (400 MHz, d6-DMSO) δ: 3.76 (s, 3H), 3.72-3.75 (m, 4H) and 3.56-3.61 (m, 4H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[N:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=O.C(N(CC)CC)C.[CH3:27][N:28]1[C:32](=[O:33])[CH2:31][C:30]([CH3:34])=[N:29]1.CC(C)(O)C#N>C(Cl)(=O)C(Cl)=O>[OH:33][C:32]1[N:28]([CH3:27])[N:29]=[C:30]([CH3:34])[C:31]=1[C:9]([C:8]1[C:7]([CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[N:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][CH:12]=1)=[O:11]
Reactant: CC1=NN(C)C(=O)C1
Reactant: COCCOCc1nc(C(F)(F)F)ccc1C(=O)O
Agent: CC(C)(O)C#N
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Product: COCCOCc1nc(C(F)(F)F)ccc1C(=O)c1c(C)nn(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
1.0 g (0.004 mol) of 2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinic acid is dissolved in 10 ml of oxalyl chloride. Three drops of dimnethylformamide are added, and the mixture is stirred at room temperature for 1 hour. The mixture is then concentrated using a rotary evaporator, and the residue (2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinoyl chloride) is taken up in 10 ml of methylene chloride. At a temperature of 0° C., 0.84 ml (0.006 mol) of triethylamine and 0.45 g (0.004 mol) of 2,5dimethyl-2,4-dihydropyrazol-3one are added. After 2 hours at a temperature of 22° C., the solvent is removed using a vacuum rotary evaporator, and the residue that remains is dissolved in 10 ml of acetonitrile and, to rearrange the intermediate (2,5-dimethyl-2H-pyrazol-3-yl 2-(2-methoxyethoxymethyl)-6-trifluoromethylnicotinate), admixed with 0.1 ml of acetone cyanohydrin and 1.13 ml (0.008 mol) of triethylamine. The reaction solution is stirred at room temperature for four hours and then concentrated. The syrup that remains is chromatographed on silica gel. The viscous oil obtained by eluting with a mixture of toluene, ethyl alcohol, dioxane, triethylamine and water (100:40:20:20:5 parts by volume) is dissolved in ethyl acetate and washed successively with 10% hydrochloric acid and water. The organic solution is dried over Na2SO4 and concentrated, giving 0.93 g of (5-hydroxy-1,3-dimethyl-1H-pyrazol-4yl)-[2-(2-methoxyethoxymethyl)-6-trifluoromethylpyridin-3-yl]methanone in the form of a viscous oil.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[Br:13])C.[OH-].[Na+].CCOCC>ClC1C=CC=CC=1>[Br:13][C:8]1[C:7]2[O:6][CH:5]=[CH:4][C:12]=2[CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(COc1ccccc1Br)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: Clc1ccccc1
Solvent: CCOCC
Product: Brc1cccc2ccoc12
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A stirred mixture of polyphosphoric acid (˜5 g) and chlorobenzene (8 mL) was heated at reflux and a solution of 1-(2,2-diethoxyethoxy)-2-bromobenzene (2.62 g, 9.0 mmol) in chlorobenzene (3 mL) was added dropwise over 10 min. The mixture was heated at reflux for 1.5 h. The mixture was allowed to cool to rt and 1 M aq NaOH (20 mL) was added, followed by ether (175 mL). The mixture was washed with water (2×20 mL) and brine (20 mL), and dried over MgSO4. Evaporation of the solvent left a residue which was purified by a chromatography on a 140-g silica cartridge eluted with hexanes and a 0-10% EtOAc in hexanes gradient. Appropriate fractions were pooled and concentrated to afford 7-bromobenzofuran (0.65 g, 38% from 2-bromophenol) as a clear colorless oil.
Reaction SMILES: [O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30](O)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-:29])=[O:28])=[CH:23][CH:22]=2)=[O:18])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)(OCC)=O.[NH:48]1[CH2:53][CH2:52][O:51][CH2:50][CH2:49]1>O1CCCC1>[O:1]([CH2:8][C:9]1[S:15][CH:14]2[CH:11]([C:12](=[O:33])[N:13]2[C:16](=[C:30]([N:48]2[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)[CH3:31])[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([N+:27]([O-:29])=[O:28])=[CH:25][CH:26]=2)=[O:18])[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CC(O)=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21
Agent: CCOP(=O)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=C(C(=O)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)C2N=C(COc3ccccc3)SC21)N1CCOCC1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a stirred solution of p-nitrobenzyl α-(3-phenoxymethyl-7-oxo-4-thia-2,6-diazabicyclo(3,2,0)hept-2-en-6-yl)-α-(1-hydroxyethylidene)acetate (4.69 g.) in tetrahydrofuran (60 ml.) under a nitrogen atmosphere at 0°-5° C. was added triethylamine (1.6 ml.) followed by dropwise addition of ethyl dichlorophosphate (1.36 ml.) over 5 minutes. After stirring for 3 hours at 20° C., the reaction mixture was cooled to 0° C. and morpholine (4.0 ml.) was added dropwise over 10 minutes with the reaction temperature maintained at 0°-5° C. After stirring for 3 hours at this temperature, the tetrahydrofuran was evaporated and the residue dissolved in dichloromethane. The resulting solution was washed with water and then with saturated sodium chloride solution, dried with magnesium sulphate and evaporated to give the title compound as a pale yellow foam in essentially quantitative yield. The product obtained was a mixture of geometric isomers (ca. 1:1.4) about the enamine double bond and was identical to that produced in example 8.
Reaction SMILES: [CH2:1]([N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]2([CH2:10][CH2:9][N:8](C)[CH2:7][CH2:6]2)[C:4]1=[O:18])[CH3:2]>C1(C)C=CC=CC=1.CCOC(C)=O.[Zn]>[CH2:1]([N:3]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:5]2([CH2:6][CH2:7][NH:8][CH2:9][CH2:10]2)[C:4]1=[O:18])[CH3:2]
Reactant: CCN1C(=O)C2(CCN(C)CC2)c2ccccc21
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCN1C(=O)C2(CCNCC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
To a stirred solution of 1-ethyl-1′-methylspiro[indoline-3,4′-piperidin]-2-one (0.0046 mol) in toluene (41.6 mL) was added 2,2,2 trichloro ethyl chloroformate (6.23 mL, 0.046 mol) at 0° C. and the reaction mixture was heated at reflux for 18 h. Progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT, diluted with EtOAc (2×50 mL) and washed with water (2×12 mL) and brine (12 mL). The organic portions were combined, dried over Na2SO4 and evaporated under reduced pressure. The crude product was taken up in acetic acid (12.0 mL) and Zn (4.1 g, 0.062 mol) and was added portion wise at 0° C. The reaction mixture was allowed to stir at RT for 1 h. Progress of the reaction was monitored by TLC. The reaction mixture was filtered through Celite® (diatomaceous earth) and washed with EtOAc (2×20 mL), basified using saturated NH4OH solution (15.0 mL) and extracted with DCM (2×40 mL). the organic portions were combined, dried over Na2SO4 and evaporated under reduced pressure to obtain crude 1-ethylspiro[indoline-3,4′-piperidin]-2-one (42%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([Br:24])=[C:13]([CH:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)[OH:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].ClCCl>[CH2:1]([O:8][C:9]1[C:10]([O:25][CH3:26])=[CH:11][C:12]([Br:24])=[C:13]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[O:16])[CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(Br)c(C(O)c2ccc(C)cc2)cc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: COc1cc(Br)c(C(=O)c2ccc(C)cc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.8 %

Procedure:
A mixture of 5-benzyloxy-2-bromo-4-methoxyphenyl)-p-tolylmethanol (reference example 9-1) (1.27 g), manganese dioxide (2.67 g) and dichloromethane (30 mL) was stirred at room temperature overnight. Insoluble materials were removed by celite (registered mark) filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.11 g).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[OH:23])[CH:19]([CH2:24][C:25]([OH:27])=[O:26])[CH2:18][CH2:17]2)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.O.[CH3:29]O>>[CH3:29][O:26][C:25](=[O:27])[CH2:24][CH:19]1[C:20]2[C:16](=[CH:15][C:14]([C:6](=[O:13])[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[C:22]([OH:23])[CH:21]=2)[CH2:17][CH2:18]1
Reactant: CO
Reactant: O=C(O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)CC1CCc2cc(C(=O)c3ccccc3)c(O)cc21

Procedure:
0.5 ml of concentrated sulphuric acid is added to a solution of 1.4 g of 5-benzoyl-6-hydroxy-indane-1-acetic acid in 300 ml of absolute methanol and the mixture is heated to the reflux temperature for 8 hours, with exclusion of water. The reaction mixture is then evaporated in vacuo to a volume of 5 ml and partitioned between 20 ml of water and twice 20 ml of ether. The organic phases are combined, washed until neutral, dried over sodium sulphate and evaporated in vacuo. Distillation of the evaporation residue in a high vacuum gives, in the fraction boiling at 180° C./0.04 mm, 5-benzoyl-6-hydroxyindane-1-acetic acid methyl ester as a yellow oil which is identical with the product described in Example 22.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1C(C1C=C(C)C=CC=1N1C=NC(C(F)(F)F)=N1)=O.[F:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[C:36]([C:42]([OH:44])=O)=[N:37][C:38]([CH3:41])=[CH:39][CH:40]=2)=[CH:31][CH:30]=1>>[NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:42]([C:36]1[C:35]([C:32]2[CH:31]=[CH:30][C:29]([F:28])=[CH:34][CH:33]=2)=[CH:40][CH:39]=[C:38]([CH3:41])[N:37]=1)=[O:44]
Reactant: Cc1ccc(-n2cnc(C(F)(F)F)n2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)c1
Reactant: Cc1ccc(-c2ccc(F)cc2)c(C(=O)O)n1
Product: Cc1ccc(-c2ccc(F)cc2)c(C(=O)N2CCC[C@@H](C)[C@H]2CN)n1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(5-methyl-2-(3-(trifluoromethyl)-1H-1,2,4-triazol-1-yl)phenyl)methanone in Example A51, starting from 3-(4-fluorophenyl)-6-methylpicolinic acid. ESI-MS (m/z): 342 [M+1]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[N:7]=1>C(O)C.O=[Mn]=O>[N:4]1[C:5]2[CH:11]=[CH:10][CH:9]=[CH:8][C:6]=2[NH:7][C:3]=1[CH:2]=[O:1]
Reactant: OCc1nc2ccccc2[nH]1
Agent: O=[Mn]=O
Solvent: CCO
Product: O=Cc1nc2ccccc2[nH]1
Reaction time: 48 h

Procedure:
A mixture of 2-Hydroxymethyl-benzimidazole (11.9 g) and MnO2 (59.5 g in ethanol (250 mL) was vigorously stirred for 2 days. The reaction was concentrated in vacuo, hot dimethylformamide was added and the mixture wasfiltered through celite. After removal of the solvent in vacuo the tan solid was triturated with ethanol to afford 2-Benzimidazolecarboxaldehyde as a tan powder.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20][C:21]([NH:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=S)[NH:17][N:16]=2)=[C:11]([F:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.[CH:48]1([NH2:53])[CH2:52][CH2:51][CH2:50][CH2:49]1>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18]([NH:20][C:21]([NH:53][CH:48]3[CH2:52][CH2:51][CH2:50][CH2:49]3)=[N:23][C:24](=[O:35])[C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)[NH:17][N:16]=2)=[C:11]([F:36])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CCCC1
Reactant: O=C(NC(=S)Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: O=C(N=C(Nc1cc(-c2ccc(OCc3ccccc3)cc2F)n[nH]1)NC1CCCC1)c1ccc(C(F)(F)F)cc1
Temperature: 50 °C
Reaction time: 0.75 h
Yield: 53 %

Procedure:
N-((3-(4-(Benzyloxy)-2-fluorophenyl)-1H-pyrazol-5-yl)carbamothioyl)-4-(trifluoromethyl)benzamide (154 mg, 0.3 mmol) and EDCI (63 mg, 0.33 mmol) were suspended in THF (4 mL) and cyclopentylamine (0.044 mL, 0.45 mmol) was added. The resulting mixture was stirred at 50° C. for 45 minutes, then concentrated onto silica gel and purified by chromatography (gradient: 9:1 hexanes:EtOAc to 6:4 hexanes:EtOAc) to provide the title compound in 53% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11](=[O:29])[C@@H:10]([CH2:30][C:31]([OH:33])=[O:32])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH3:39][C:40](=[CH2:42])[CH3:41]>C(Cl)Cl>[C:40]([O:32][C:31](=[O:33])[CH2:30][C@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[N:12]([C@@H:21]([CH2:27][CH3:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:11]1=[O:29])([CH3:42])([CH3:41])[CH3:39]
Reactant: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Reactant: C=C(C)C
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: CCOC(=O)[C@H](CC)N1C(=O)[C@@H](CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred solution of 1.14 g (2.3 mmol) of 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-ethoxy-1-oxobutan-2-yl)-2-oxopiperidin-3-yl)acetic acid (Example 3) in DCM (21.0 mL) was added sulfuric acid (0.247 mL, 4.63 mmol) followed by isobutylene (4.42 mL, 46.3 mmol) at −78° C. The reaction vessel was sealed and the mixture was slowly warmed to rt and vigorously stirred for 3 days. After cooling to −78° C., the tube was opened and the reaction was quenched with aqueous saturated NaHCO3 to pH 8. The organic solvent was removed under reduced pressure, and the remaining mixture was extracted (2×EtOAc). The combined organic layers were washed with sat. NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes) to provide the title compound as a foam.
Reaction SMILES: [C:1]([C:4]1[C:5]([C:19](=O)[CH3:20])=[C:6]([CH3:18])[N:7]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([Cl:17])[CH:11]=2)[C:8]=1[CH3:9])(=O)[CH3:2].[NH2:22][NH2:23]>>[Cl:17][C:12]1[CH:11]=[C:10]([N:7]2[C:8]([CH3:9])=[C:4]3[C:5]([C:19]([CH3:20])=[N:22][N:23]=[C:1]3[CH3:2])=[C:6]2[CH3:18])[CH:15]=[CH:14][C:13]=1[OH:16]
Reactant: NN
Reactant: CC(=O)c1c(C(C)=O)c(C)n(-c2ccc(O)c(Cl)c2)c1C
Product: Cc1nnc(C)c2c(C)n(-c3ccc(O)c(Cl)c3)c(C)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-[4-acetyl-1-(3-chloro-4-hydroxy-phenyl)-2,5-dimethyl-1H-pyrrol-3-yl]-ethanone (340 mg, 1.0 mmol) was added hydrazine (50 μL). After stirring at rt for 1 h, the reaction mixture was poured into ice water (25 mL). The resulting precipitate was filtered, washed with diethyl ether (20 mL), and then dried under vacuum to afford 2-chloro-4-(1,4,5,7-tetramethyl-pyrrolo[3,4-d]pyridazin-6-yl)-phenol as a pale yellow solid: 1H NMR (CD3OD, 500 MHz) δ 7.34 (br s, 1H), 7.08 (m, 2H), 2.83 (s, 6H), 2.52 (s, 6); MS (ESI) 302 (M+H)+.
Reaction SMILES: [CH2:1]([CH:3]1[C:7](=[O:8])[N:6]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:5][C:4]1([C:18]([O:20]C)=[O:19])[CH3:17])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[CH2:1]([CH:3]1[C:7](=[O:8])[N:6]([C@@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[CH2:5][C:4]1([C:18]([OH:20])=[O:19])[CH3:17])[CH3:2]
Reactant: CCC1C(=O)N([C@H](C)c2ccccc2)CC1(C)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC1C(=O)N([C@H](C)c2ccccc2)CC1(C)C(=O)O
Temperature: 60 °C
Reaction time: 5.5 h

Procedure:
To a solution of the methyl 4-ethyl-3-methyl-5-oxo-1-[(R)-1-phenylethyl]pyrrolidin-3-yl-carboxylate (stereoisomer A) produced in Reference Example 32 (10.63 g, 36.7 mmol) in tetrahydrofuran (330 mL) and methanol (110 mL), 2N aqueous solution of sodium hydroxide (110 mL, 220 mmol) was added at room temperature, and the mixture was stirred in an oil bath at 60° C. for 5.5 hours. The reaction mixture was concentrated under reduced pressure, and after adding concentrated hydrochloric acid to the concentrate in an ice bath for acidification, the mixture was extracted with chloroform (300 mL+2×100 mL). The organic layers were combined, and dried with anhydrous sodium sulfate. After removing the dessicating agent by filtration, the solvent was removed by distillation under reduced pressure to obtain 11.46 g (quantitative) of the crude title compound as a pale brown solid. The crude product was used in the subsequent reaction with no further purification.