Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][CH2:8][CH:9]([NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[F:27])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:6])([CH3:5])[CH3:4].[CH3:28]I>CN(C=O)C>[C:3]([O:7][CH2:8][CH:9]([N:17]([CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][C:20]=1[F:27])[CH3:28])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: CI
Reactant: CC(C)(C)OCC(NCc1ccc(C#N)cc1F)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(Cc1ccc(C#N)cc1F)C(COC(C)(C)C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirred suspension of sodium hydride (1.8 g, 0.038 mol) in dry DMF (10 mL) at 0° C., tert-butyl 3-tert-butoxy-2-[(4-cyano-2-fluorobenzyl)amino]propanoate (6.7 g, 0.019 mol) in DMF (20 mL) was added dropwise. The resulting mixture was allowed to stir for 20 min at RT. Methyl iodide (3.5 mL, 0.0057 mol) was then added dropwise at 000 and the mixture was allowed to stir for 3 hr at RT. The reaction mixture was quenched in ice water and extracted with ethyl acetate (250 mL). The organic layer was washed with water (3×100 mL), dried over sodium sulphate and concentrated under reduced pressure. The crude was purified by column chromatography using petroleum ether and ethyl acetate as eluent, affording the title compound as colorless liquid. 1H NMR (DMSO-d6, 400 MHz) δ 7.78 (d, J=9.8 Hz, 1H), 7.67 (t, J=2.5 Hz, 2H), 3.92 (d, J=15.2 Hz, 1H), 3.81-3.70 (d, J=15.0 Hz, 1H), 3.63 (m, 1H), 3.52 (m, 2H), 2.26 (s, 3H), 1.42 (s, 9H), 1.08 (s, 9H).
Reaction SMILES: [C:1]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:11][CH:10]=2)=[CH:3][CH:2]=1.Cl.[NH2:40][C@H:41]1[CH2:46][CH2:45][CH2:44][CH2:43][C@H:42]1[C:47]([O:49][CH2:50][CH3:51])=[O:48]>>[C:1]1([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:2]=[CH:3][C:4]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:27]=[CH:26][C:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:24][C:20]=3[C:21]([NH:40][C@@H:41]3[CH2:46][CH2:45][CH2:44][CH2:43][C@@H:42]3[C:47]([O:49][CH2:50][CH3:51])=[O:48])=[O:22])=[CH:13][CH:14]=2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)[C@@H]1CCCC[C@@H]1N
Reactant: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)O)c1
Agent: Cl
Product: CCOC(=O)c1ccc(OCCCc2ccc(OCc3ccc(-c4ccccc4)cc3)cc2)c(C(=O)N[C@@H]2CCCC[C@@H]2C(=O)OCC)c1

Procedure:
The compound is prepared in analogy to the process described in Example 6 from 2-{3-[4-(1,1′-biphenyl-4-ylmethoxy)phenyl]propoxy}-5-(ethoxycarbonyl)benzoic acid and ethyl cis-2-amino-1-cyclohexanecarboxylate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24](O)=[O:25])=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=2)[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[CH:40][C:34]([CH:31]4[CH2:33][CH2:32]4)=[CH:35][CH:36]=3)=[O:25])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: Nc1ccc(C2CC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(C4CC4)cc3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 23 %

Procedure:
The title compound was prepared following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.150 g, 0.399 mmol), thionyl chloride (2.0 mL), 4-cyclopropylaniline (Intermediate-50, 0.079 g, 0.598 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.62-0.63 (m, 2H), 0.90-0.92 (m, 2H), 1.56 (s, 6H), 1.89 (m, 1H), 3.09 (s, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.29-7.47 (m, 4H), 7.54 (d, J=8.4 Hz, 2H), 9.67 (s, 1H), 11.00 (s, 2H); MS [M+H]+: 491.28.
Reaction SMILES: O[CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1.S(Cl)([Cl:22])=O>C1(C)C=CC=CC=1>[Cl:22][CH2:2][C:3]1[N:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=2)[N:6]=[N:5][N:4]=1
Reactant: N#Cc1ccc(-n2nnnc2CO)cc1C(F)(F)F
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: N#Cc1ccc(-n2nnnc2CCl)cc1C(F)(F)F
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 4-[5-(hydroxymethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Intermediate 23, 30.0 g) in toluene (500 mL) was added thionyl chloride (14.5 g, 0.122 mol) at room temperature. The reaction was heated to reflux and stirred for 2 hours. The reaction mixture was concentrated under vacuum and diluted with DCM. The resulting solution was washed with ice-water, followed by aqueous NaHCO3. The organic was separated and washed with brine solution, dried over anhydrous Na2SO4 and concentrated under reduced pressure. The crude product was purified by triturating with ether (500 mL) and dried under vacuum to yield 4-[5-(chloromethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (23 g).
Reaction SMILES: [O-2].[Zn+2:2].[C:3]([OH:7])(=[O:6])[CH2:4][CH3:5]>>[C:3]([O-:7])(=[O:6])[CH2:4][CH3:5].[Zn+2:2].[C:3]([O-:7])(=[O:6])[CH2:4][CH3:5]
Reactant: CCC(=O)O
Agent: [O-2]
Agent: [Zn+2]
Product: CCC(=O)[O-]

Procedure:
The initial temperature of the zinc oxide and propionic acid were varied, as was the time at which the high-shear blades were engaged. Vent stack temperatures approximately six inches from the top of the mixer were monitored as a measure of the rate of reaction. Each batch was prepared by charging the mixer with 77 pounds of zinc oxide followed by spraying the dry zinc oxide with 140 pounds of propionic acid at nine pounds per minute. Starting material temperatures and the time at which the high-shear mixing blades ("choppers") were engaged are summarized below in Table 1.
Reaction SMILES: [PH2](O)=O.C(N1CCCCC1)C.[CH2:12]=[CH:13][S:14]([O:17][C:18]1[C:23]([F:24])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28])(=[O:16])=[O:15].I[CH:30]1[CH2:35][CH2:34][CH2:33][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:31]1.C(B(CC)CC)C>C(Cl)Cl>[F:24][C:23]1[C:22]([F:25])=[C:21]([F:26])[C:20]([F:27])=[C:19]([F:28])[C:18]=1[O:17][S:14]([CH2:13][CH2:12][CH:34]1[CH2:35][CH2:30][CH2:31][N:32]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:33]1)(=[O:16])=[O:15]
Reactant: C=CS(=O)(=O)Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1CCCC(I)C1
Agent: CCB(CC)CC
Agent: CCN1CCCCC1
Agent: O=[PH2]O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC(CCS(=O)(=O)Oc2c(F)c(F)c(F)c(F)c2F)C1
Temperature: 0 °C
Reaction time: 0 h

Procedure:
1-Ethylpiperidine hypophosphite (7.49 g, 41.8 mmol) were weighed into the reaction flask under an inert gas, and methylene chloride (38 ml) was added. The solution was cooled with ice-water, and 2,3,4,5,6-pentafluorophenyl 1-ethylenesulfonate (1.38 g, 5.02 mmol) [Org. Lett.; 2002; 4(15); 2549-2551] and tert-butyl 3-iodopiperidine-1-carboxylate (1.3 g, 4.18 mmol) was added at 0° C. Triethylborane solution (0.21 ml, 1 mol/l) was added to the reaction mixture and compressed air was then passed through the mixture for 10 sec. After stirring for 5 min the addition of triethylborane solution-compressed air was repeated with the same amount. Stir for 5 min, the addition of triethylborane solution-compressed air was then repeated with the same amount. The reaction mixture was washed with water (20 ml), sodium bicarbonate solution (20 ml, saturated 50% diluted) and saturated sodium chloride solution (20 ml), dried over sodium sulfate and concentrated in vacuo. The crude product was purified by column chromatography (silica gel) with hexane/diethyl ether (3:1). Yield: 0.5 g (26%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl[C:23]([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:24]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([NH:5][C:23](=[O:24])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:6]=[C:7]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:8]=1
Reactant: Nc1cc(F)cc(-c2cccnc2)c1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(F)cc(-c2cccnc2)c1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71.4 %

Procedure:
3-Fluoro-5-(pyrid-3-yl)aniline (1.05 g, 0.0050 mole) in dry dichloromethane was treated under argon with triethylamine (1.12 ml, 0.0080 mole) followed dropwise by phenyl chloroformate (0.97 ml, 0.0077 mole) and stirred at ambient temperature for 18 hours. The reaction mixture was washed (×2) with deionised water, dried (Na2SO4) and evaporated in vacuo to afford the title compound (1.1 g, 71%) as an off white solid.
Reaction SMILES: [Na:1].[SH:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5].[CH2:13]1[S:17](=[O:19])(=[O:18])[O:16][CH2:15][CH2:14]1>C(O)C>[Na:1].[S:17]([CH2:13][CH2:14][CH2:15][S:2][C:3]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:4]=1[NH2:5])([OH:19])(=[O:18])=[O:16]
Reactant: Nc1ccc([N+](=O)[O-])cc1S
Reactant: O=S1(=O)CCCO1
Agent: [Na]
Solvent: CCO
Product: Nc1ccc([N+](=O)[O-])cc1SCCCS(=O)(=O)O
Reaction time: 1 h

Procedure:
In a mixture of 50 ml. of ethanol and 0.46 g. of metallic sodium were dissolved 3.4 g. of 2-mercapto-4-nitroaniline and 2.44 g. of propanesultone were added thereto under stirring. Thereafter, heating was conducted at 40°-50° C. for 1 hour and the crystalline substance thus separated was recovered by filtration, washed with ethanol and acetone and then dried to give 2 g. of the desired product. m.p. 181°-193° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9](=[O:10])[C:8]3=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]3[C:6]2=[O:15])[CH2:3][CH2:2]1>CO.[BH4-].[K+].ClCCl>[OH:10][CH:9]1[C:8]2[C:7](=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6](=[O:15])[N:5]1[CH2:4][CH:1]1[CH2:2][CH2:3]1
Reactant: O=C1c2ccccc2C(=O)N1CC1CC1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: O=C1c2ccccc2C(O)N1CC1CC1
Temperature: 20 °C
Reaction time: 20 h
Yield: 94.4 %

Procedure:
3-Hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one is prepared as described in Example 1, starting with 4.3 g of N-cyclopropylmethylphthalimide in 40 cm3 of methanol and 1.2 g of potassium borohydride. The reaction mixture is stirred at a temperature in the region of 20° C. for 20 hours and is then cooled to a temperature in the region of 0° C. and distilled water is added dropwise. The precipitate obtained is filtered off and the solid obtained is then taken up in dichloromethane and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 4.1 g of 3-hydroxy-2-cyclopropylmethyl-2,3-dihydroisoindol-1-one are thus obtained in the form of a white powder (Rf=0.38, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (50/50 by volume)).
Reaction SMILES: [Br:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21](O)=[O:22])=[C:8]2[CH3:25])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=3)[C:9]([CH2:18][CH:19]([CH3:24])[CH2:20][C:21]([N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)=[O:22])=[C:8]2[CH3:25])=[CH:26][CH:27]=1
Reactant: CN1CCNCC1
Reactant: COc1ccc2c(c1)c(CC(C)CC(=O)O)c(C)n2Cc1ccc(Br)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)c(CC(C)CC(=O)N1CCN(C)CC1)c(C)n2Cc1ccc(Br)cc1

Procedure:
To a solution of the acid from Example 7, Step 6 (300 mg) in DMF (4 mL) was added triethylamine (0.13 mL), diethyl cyanophosphonate (0.13 mL) and 1-methylpiperazine (0.08 mL) at r.t. After 4 h the reaction mixture was diluted with EtOAc and the organic phase was washed with HCl 1M, 5% aqueous NaHCO3 and brine, dried (MgSO4) and evaporated. Flash chromatography of the residue (silica gel; CH2Cl2 /MeOH, 95:5) afforded the title compound as a white solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([N:17]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[CH:24][CH:23]=3)[C:18]2=[O:34])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:33][O:32][C:30]([CH2:29][CH2:28][C:25]1[CH:26]=[CH:27][C:22]([N:19]2[CH2:20][CH2:21][N:17]([CH:14]3[CH2:15][CH2:16][NH:11][CH2:12][CH2:13]3)[C:18]2=[O:34])=[CH:23][CH:24]=1)=[O:31]
Reactant: COC(=O)CCc1ccc(N2CCN(C3CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCc1ccc(N2CCN(C3CCNCC3)C2=O)cc1

Procedure:
Prepared by treating 1-(1-benzyloxycarbonyl-4-piperidinyl)-3-[4-(2-methoxycarbonyl-ethyl)-phenyl]-imidazolidin-2-one with hydrogen at 3 bars in the presence of 5% palladium/charcoal in methanol.
Reaction SMILES: [ClH:1].C([N:9]1[CH2:14][CH2:13][C:12]2([C:22]3[C:17](=[CH:18][CH:19]=[C:20]([CH2:23][CH3:24])[CH:21]=3)[C:16](=[O:25])[O:15]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[C].[Pd]>[ClH:1].[CH2:23]([C:20]1[CH:21]=[C:22]2[C:17]([C:16](=[O:25])[O:15][C:12]32[CH2:11][CH2:10][NH:9][CH2:14][CH2:13]3)=[CH:18][CH:19]=1)[CH3:24]
Reactant: CCc1ccc2c(c1)C1(CCN(Cc3ccccc3)CC1)OC2=O
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCc1ccc2c(c1)C1(CCNCC1)OC2=O
Reaction time: 1.5 h
Yield: 74.2 %

Procedure:
1′-benzyl-6-ethylspiro[isobenzofuran-1(3H),4′-piperidine]-3-one hydrochloride (400 mg) was dissolved in methanol (10 mL) and 10% palladium carbon was added. The mixture was stirred under a hydrogen atmosphere for 1.5 hours. After the palladium carbon was removed by filtration, the filtrate was concentrated to give a residue, which was subjected to crystallization with methanol-ethyl ether to give the subject compound (222 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH3:9])[N:3]=1.[NH3:10]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:10])[CH:5]=[C:4]([CH3:9])[N:3]=1
Reactant: N
Reactant: Cc1cc(Cl)nc(N)n1
Product: Cc1cc(N)nc(N)n1
Temperature: 25 °C

Procedure:
2,4-Diamino-6-methyl pyrimidine was prepared by a modified procedure of Gabriel and Coleman (Ber., volume 34, page 1253, 1901). A mixture of 2-amino-4-chloro-6-methyl pyrimidine (9.0 gm) and alcoholic ammonia (225 ml), were heated in a steel bomb at 180° C for 6 hours. The mixture was then filtered, and the filtrate was evaporated to dryness. The solid residue was dissolved in 60ml hot water. The solution was cooled to room temperature, and 40 gm of potassium hydroxide was then added. The product thus precipitated, was filtered, and crystallized from acetone, m.p. 183° C. Yield: 5.5gm. U.V. spectrum data corresponded to those reported by Curd and Rose (J.C.S., page 98, 1949).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][C:24](=O)[CH3:25])=[CH:18][CH:17]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:24]([CH3:25])[CH2:23][CH2:22][C:19]2[CH:18]=[CH:17][C:16]([Cl:15])=[CH:21][CH:20]=2)=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCc1ccc(Cl)cc1
Product: Cc1noc(-c2ccc(Br)cc2)c1NC(C)CCc1ccc(Cl)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 4-(4-chloro-phenyl)-butan-2-one.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[NH:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7]>C1(C)C=CC=CC=1>[C:9]([O:8][C:6]([NH:5][C@@H:4]([CH2:13][CH:14]([CH3:16])[CH3:15])[CH:3]=[O:2])=[O:7])([CH3:12])([CH3:11])[CH3:10]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Solvent: Cc1ccccc1
Product: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Under an argon gas stream, N-(tert-butoxycarbonyl)-L-leucine methyl ester (0.98 g, 4.0 mmol) was dissolved in toluene (7.1 ml), and cooled to -78° C. To the reaction solution, while keeping the temperature at -60 to -70° C., was added gradually aluminum diisobutyl hydride (toluene 1.0 M solution, 5.0 ml). After stirring at -78° C. for 30 minutes, thereby there was obtained (S)-2-(tert-butoxycarbonylamino)-4-methylpentanal.
Reaction SMILES: C([O:5][C:6]1[N:18]=[C:17]([C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[N:24]([CH3:28])[CH:23]=[CH:22]3)[C:16]([Cl:29])=[C:15]([O:30]C(C)(C)C)[C:7]=1[C:8]([O:10]C(C)(C)C)=[O:9])(C)(C)C.Cl.O1CCOCC1>>[Cl:29][C:16]1[C:15]([OH:30])=[C:7]([C:8]([OH:10])=[O:9])[C:6](=[O:5])[NH:18][C:17]=1[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[N:24]([CH3:28])[CH:23]=[CH:22]2
Reactant: Cn1ccc2cc(-c3nc(OC(C)(C)C)c(C(=O)OC(C)(C)C)c(OC(C)(C)C)c3Cl)ccc21
Agent: Cl
Solvent: C1COCCO1
Product: Cn1ccc2cc(-c3[nH]c(=O)c(C(=O)O)c(O)c3Cl)ccc21
Yield: 68.5 %

Procedure:
Following the procedure of Example 375 step 7, treatment of tert-butyl 2,4-di-tert-butoxy-5-chloro-6-(1-methyl-1H-indol-5-yl)nicotinate (27 mg, 0.055 mmol) with HCl in dioxane (4.0 M×1.0 mL, 4.0 mmol) provided 5-chloro-4-hydroxy-6-(1-methyl-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (12 mg, 68%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.C(OCC)C.[B:30](OC)([O:33]C)[O:31]C.Cl>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][C:10]=1[B:30]([OH:33])[OH:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COB(OC)OC
Reactant: FC(F)(F)c1ccc(OCc2ccccc2)c(I)c1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: OB(O)c1cc(C(F)(F)F)ccc1OCc1ccccc1
Temperature: -75 °C
Reaction time: 1 h

Procedure:
A solution of 4-benzyloxy-3-iodobenzotrifluoride (15.07 g, 39.85 mmol) in tetrahydrofuran (200 ml) was cooled to −40° C. with stirring under nitrogen. 2M isopropylmagnesium chloride in diethyl ether (39.85 ml, 79.7 mmol) was added dropwise and the mixture stirred at −40° C. for 40 minutes, then cooled to −75° C. Trimethyl borate (8.3 g, 9.2 ml, 79.7 mmol) was added at −75° C. over 10 minutes and the reaction stirred and allowed to reach 0° C. over 1 h. 1M hydrochloric acid (200 ml) was added and the mixture stirred vigorously for 1 h.
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH2:11])[CH2:4]2.[F:12][C:13]([F:26])([F:25])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[CH:20]=[CH:21]/[C:22](O)=[O:23]>>[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[CH:5]([NH:11][C:22](=[O:23])/[CH:21]=[CH:20]/[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:13]([F:25])([F:26])[F:12])[CH2:4]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)/C=C/c1ccccc1C(F)(F)F
Agent: Cl
Product: O=C(/C=C/c1ccccc1C(F)(F)F)NC1CN2CCC1CC2

Procedure:
Prepared as a free base by a method analogous to that described in Example 1 from racemic 1-azabicyclo[2.2.2]oct-3-ylamine dihydrochloride and E-3-(2-trifluoromethylphenyl)propenoic acid; MS (ES+) 325 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[N:5]=[C:4]([C:16]([O:18]C(C)C)=[O:17])[CH:3]=1.C(O)(C)C.[OH-].[K+]>O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9]2[CH:10]=[CH:11][C:12]([Cl:15])=[CH:13][CH:14]=2)[N:5]=[C:4]([C:16]([OH:18])=[O:17])[CH:3]=1
Reactant: CC(C)OC(=O)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: O=C(O)c1cc(Cl)c(Cl)c(-c2ccc(Cl)cc2)n1
Temperature: 40 °C
Yield: 109.2 %

Procedure:
To a 125 mL 3-neck round bottom flask fitted with a condenser, nitrogen inlet, overhead stirrer, thermometer and heating mantle was charged isopropyl 4,5-dichloro-6-(4-chlorophenyl)picolinate (7.6 g, 22.1 mmol) and isopropyl alcohol (70 mL). Reaction mixture was heated to 40° C. and potassium hydroxide (85%, 5.1 g, 77.4 mmol) and water (5 mL) were added. Solids precipitated from the mixture, and it became difficult to stir. The mixture was diluted with water (250 mL) to dissolve most of the solids and allowed to stir at room temperature. Concentrated HCl (12 N, 5.6 mL) was added dropwise to the reaction mixture to achieve a pH of ˜2 and solids precipitated from the mixture. The solids were isolated by vacuum filtration and washed with water (2×100 mL), then allowed to dry to give 7.3 g (108% yield by weight) of 4,5-dichloro-6-(4-chlorophenyl)picolinic acid as a white solid. 1H NMR (400 MHz, THF-d8/D2O) δ 8.19 (d, J=11.2 Hz, 1H), 7.84-7.73 (m, 2H), 7.50 (dd, J=10.3, 3.5 Hz, 2H); 13C NMR (101 MHz, THF-d8/D2O) δ 167.70, 156.03, 152.40, 143.60, 136.49, 134.76, 131.22, 129.24, 128.04, 124.71; mp=229° C.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1COCC1.[OH-].[Na+].Cl>CO>[CH:1]1([N:6]2[C:14]3[CH:13]=[CH:12][NH:11][C:10](=[O:15])[C:9]=3[C:8]([C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[S:19][CH:20]=3)=[N:7]2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc(-c2nn(C3CCCC3)c3cc[nH]c(=O)c23)cs1
Temperature: 25 °C
Reaction time: 96 h
Yield: 89.2 %

Procedure:
To a solution of methyl 4-(1-cyclopentyl-4-oxo-4,5-dihydro-1H-pyrazolo[4,3-c]pyridin-3-yl)thiophene-2-carboxylate (97 mg) obtained in Step E of Example 12 in a mixed solvent of THF (10 mL)/methanol (10 mL) was added 1N aqueous sodium hydroxide solution (2 mL) under ice-cooling, and the mixture was stirred at room temperature for 96 hr. To the reaction mixture was added 1N hydrochloric acid (2 mL) under ice-cooling, and the mixture was stirred, and extracted twice with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the title compound (83 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[S:9])[CH:2]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](=O)[CH2:16]Br)[CH3:12]>CO>[CH2:11]([O:13][C:14]([C:15]1[N:10]=[C:8]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[S:9][CH:16]=1)=[O:19])[CH3:12]
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=S)Nc1cccnc1
Solvent: CO
Product: CCOC(=O)c1csc(Nc2cccnc2)n1
Yield: 79.8 %

Procedure:
2-(Pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (200 mg) was prepared according to General Procedure B using pyridin-3-yl-thiourea (154 mg) and 3-bromo-2-oxo-propionic acid ethyl ester (200 mg) in methanol (2 mL). The crude product was used in subsequent steps without further purification.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c(OCC2CC2)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4ccc(OC)cc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-4-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f12) and commercially propionyl chloride the title compound is obtained as colorless solid.