Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH2:25])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1.[CH3:27][S:28](Cl)(=[O:30])=[O:29].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([C:16]4[C:24]5[C:19](=[CH:20][CH:21]=[CH:22][C:23]=5[NH:25][S:28]([CH3:27])(=[O:30])=[O:29])[NH:18][N:17]=4)[NH:13][C:12]=3[CH:26]=2)[CH2:4][CH2:3]1
Reactant: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(N)c45)[nH]c3c2)CC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCN(c2ccc3nc(-c4n[nH]c5cccc(NS(C)(=O)=O)c45)[nH]c3c2)CC1

Procedure:
3-[6-(4-Methylpiperazin-1-yl)-1H-benzoimidazol-2-yl]-1H-indazol-4-ylamine (1 equivalent), methanesulfonyl chloride (1.1 equivalent), and diisopropylethylamine (2 equivalents) in CH2Cl2 are stirred for 18 hours. The solvent is evaporated, and the resulting residue is purified by preparatory HPLC to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]([NH2:19])=O)=[CH:15][N:16]=2)[CH2:8][CH2:7]1.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>C(Cl)Cl>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:23]=[CH:22][CH:21]=[CH:20][C:4]=1[O:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[S:13][C:14]([C:17]#[N:19])=[CH:15][N:16]=2)[CH2:8][CH2:7]1
Reactant: NC(=O)c1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cnc(N2CCC(Oc3ccccc3C(F)(F)F)CC2)s1
Reaction time: 0.08 h

Procedure:
A suspension of 2-{4-[2-(trifluoromethyl)phenoxy]piperidin-1-yl}-1,3-thiazole-5-carboxamide (4 g, 10.8 mmol) in CH2Cl2 (100 mL) was cooled with an ice-acetone bath. Tf2O (2.0 mL, 11.9 mmol) was then added dropwise over about 10 min. The mixture was stirred for 5 min and then the cooling bath was removed. After further stirring at room temperature for 15 min, the mixture was quenched with water and extracted twice with CH2Cl2. The combined CH2Cl2 extracts were washed twice with diluted brine, dried (Na2SO4) and concentrated. The crude material was purified by column chromatography on silica gel (eluting with 40% EtOAc/hexanes) to give the title compound as a pale yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:29]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:30])[C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25]O)[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:51]=[N+:52]=[N-:53].[Na+]>ClCCl.O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]([C:14]2[CH:19]=[CH:18][C:17]([N:20]3[CH2:24][C@H:23]([CH2:25][N:51]=[N+:52]=[N-:53])[O:22][C:21]3=[O:27])=[CH:16][C:15]=2[F:28])[C:29]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[O:30])[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CO)OC3=O)cc2F)C1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CC[C@@H](N(C(=O)OCc2ccccc2)c2ccc(N3C[C@H](CN=[N+]=[N-])OC3=O)cc2F)C1
Temperature: 25 °C

Procedure:
To a solution 3.36 g of (3R)-3-{benzyloxycarbonyl-[2-fluoro-4-{(5R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl}-phenyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester (10.8 mmol) and 2.05 ml of triethylamine (10.8 mmol) in 40 ml of dichloromethane, was added at 0° C. 0.805 ml of methanesulfonyl chloride (10.8 mmol). The reaction was stirred at rt. and monitored by TLC. The reaction was diluted with water and washed with water and brine. The org. layer was dried over Mg sulfate, filtered and the filtrate evaporated. The solid residue was dissolved in 10 ml of DMF and 1.38 g sodium azide (10.8 mmol) was added and the mixture stirred under inert gas at 80° C. for 20 hrs. The DMF was evaporated, the residue dissolved in ethyl acetate, washed with water and brine, dried over Mg sulfate, filtered and evaporated.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[C:27]([Si:28]([CH3:31])([CH3:30])[CH3:29])=[C:26]([F:32])[C:25]([F:33])=[CH:24][C:23]=1[C:34]1[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=1.CI>C1COCC1.O>[F:21][C:22]1[C:27]([Si:28]([CH3:31])([CH3:29])[CH3:30])=[C:26]([F:32])[C:25]([F:33])=[C:24]([CH3:1])[C:23]=1[C:34]1[O:35][CH2:36][C:37]([CH3:40])([CH3:39])[N:38]=1
Reactant: CC1(C)COC(c2cc(F)c(F)c([Si](C)(C)C)c2F)=N1
Reactant: CC(C)NC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CI
Product: Cc1c(F)c(F)c([Si](C)(C)C)c(F)c1C1=NC(C)(C)CO1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 90.6 %

Procedure:
A solution of 0.64 mL (4.57 mmol) of diisopropylamine in 20 mL of dry THF under argon was cooled to -78° C. and treated with 2.1 mL (4.20 mmol) of 2.0N n-butyllithium. The LDA solution was stirred at -78° C. for 15 minutes, then warmed to 0° C. To this solution was added a solution of 1.05 g (3.5 mmol) of 2-(2,4,5- trifluoro-3-trimethylsilylphenyl)-4,4-dimethyl-2-oxazoline in 5 mL of THF; the reaction mixture was stirred at 0° C. for 45 minutes, then quenched with 1.50 g (10.6 mmol) of methyl iodide. The solution was stirred at room temperature for 3 hours and diluted with water. The organic layer was washed with water, dried over magnesium sulfate, and concentrated to give 1.00 g of the title compound as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][N:11]3[C:16]([C:17]=2[CH3:18])=[C:15]([CH:19]2[CH2:21][CH2:20]2)[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12]3=[O:27])=[CH:4][CH:3]=1.CI.[C:30](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH:19]1([C:15]2[CH:14]=[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:12](=[O:27])[N:11]3[C:16]=2[C:17]([CH3:18])=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][CH3:30])=[CH:7][CH:6]=2)[CH:9]=[CH:10]3)[CH2:21][CH2:20]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(N)cc3)ccn2c1=O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CI
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NC)cc3)ccn2c1=O
Temperature: 70 °C
Reaction time: 17 h
Yield: 30.8 %

Procedure:
50 mg of ethyl 8-(4-aminophenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 2) was dissolved in 2 ml of DMF. 20 mg of methyl iodide and 29 mg of potassium carbonate were added to the obtained solution, and they were stirred at 70° C. for 17 hours. Water was added to the reaction mixture. After the extraction with chloroform, the organic layer was dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by the silica gel column chromatography (eluent: chloroform/ethyl acetate=9/1) to obtain 16 mg of ethyl 1-cyclopropyl-9-methyl-8-(4-methylaminophenyl)-4-oxo-4H-quinolizine-3-carboxylate.
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5].[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>C(Cl)Cl>[C:9]1([C:8]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[S:1][CH2:2][CH:3]([CH3:7])[C:4]([OH:6])=[O:5])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(CS)C(=O)O
Solvent: ClCCl
Product: CC(CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O

Procedure:
A solution of 3-mercapto-2-methylpropanoic acid (1.2 g.) and tritylchloride (2.9 g.) in methylene chloride (50 ml.) is kept at room temperature for 2 hours. The mixture is warmed in a steam bath for 20 minutes and then evaporated to dryness in vacuo and the residue is dissolved in saturated aqueous sodium bicarbonate and the solution is washed with ethyl acetate. The aqueous phase is acidified to pH 3 and extracted with ethyl acetate. The organic layer is dried and concentrated to dryness to give 3-triphenylmethylthio-2-methylpropanoic acid. Rf 0.8 (Silica gel, Benzene/acetic acid 3:1).
Reaction SMILES: [CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:27][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@@H]1CCN(C(=O)OC)[C@@H](C2CCCCC2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1C1CCCCC1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 1.03 mmol) (from example 79, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (41.1 mg, 1.03 mmol) dissolved in water (0.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.063 mL, 1.03 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h 20 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5 mL, 30.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase was dried over Na2SO4 and evaporated to yield a yellow oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (170 mg, 53%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.82-1.08 (m, 2H), 1.08-1.32 (m, 3H), 1.45-1.83 (m, 8H), 1.89-2.02 (m, 1H), 2.12-2.23 (m, 1H), 2.79-3.04 (m, 2H), 3.70 (s, 3H), 3.87-4.83 (m, 2H), 5.64 (s, 1H). MS m/z 309 (M+H)+
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([OH:21])=[N:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:22](I)[CH3:23].O>CN(C)C=O>[CH2:3]([N:10]1[CH:14]=[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:12]([O:21][CH2:22][CH3:23])=[N:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCI
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)nc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccccc2)nc1OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
Sodium hydride (60%, oily, 1.20 g) was added to a solution of ethyl 1-benzyl-3-hydroxy-1H-pyrazol-4-ylacetate (7.81 g) in N,N-dimethylformamide (100 ml) at 0° C., which was stirred at room temperature for 15 minutes. Ethyl iodide (2.40 ml) was added to the mixture, which was stirred at room temperature for 1 hour. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 1-benzyl-3-ethoxy-1H-pyrazol-4-ylacetate (7.52 g, yield 87%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([C:21](=[O:38])[CH:22]([N:24]2[CH2:29][CH2:28][C:27]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)([OH:30])[CH2:26][CH2:25]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13]>C(O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:21]([OH:38])[CH:22]([N:24]2[CH2:25][CH2:26][C:27]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)([OH:30])[CH2:28][CH2:29]2)[CH3:23])[CH:7]=[CH:8][C:9]=1[O:10][Si:11]([CH:12]([CH3:13])[CH3:14])([CH:15]([CH3:17])[CH3:16])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C(=O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(F)cc2)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C(O)c1ccc(O[Si](C(C)C)(C(C)C)C(C)C)c(F)c1)N1CCC(O)(c2ccc(F)cc2)CC1
Reaction time: 0.17 h

Procedure:
A mixture of sodium borohydride (0.027 g, 0.717 mmol) and ethanol (10 mL) was stirred 10 min and then 1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-one (0.371 g, 0.717 mmol in 10 mL of ethanol) was added. The reaction was stirred at ambient temperature overnight. The mixture was concentrated and the residue was partitioned between ethyl acetate and water. The phases were separated and the organic phase was washed with brine, dried over calcium sulfate and concentrated. The residue was flash chromatographed on silica gel (0.75×3 inches packed in hexane) with elution proceeding as follows: 10% ethyl acetate/hexane (200 mL), nil; 10% ethyl acetate/hexane (100 mL) and 20% ethyl acetate/hexane (200 mL), to give 0.22 g (59%) of (1R*, 2R*)-1-(3-fluoro-4-triisopropylsilyloxyphenyl)-2-(4-(4-fluorophenyl)-4-hydroxypiperidin-1-yl)-propan-1-ol. A sample recrystallized from ether had: mp 159-160° C.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=1.[C:10]1(B(O)O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C>[C:10]1([C:2]2[O:6][C:5]([C:7]([OH:9])=[O:8])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(O)c1ccc(Br)o1
Reactant: OB(O)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(-c2ccccc2)o1
Temperature: 150 °C
Yield: 55.5 %

Procedure:
A solution of 5-bromofuran-2-carboxylic acid (381 mg, 2 mmol), phenylboronic acid (488 mg, 4 mmol) in DMF (3 ml) was place in a microwave reaction tube and treated with a 2 M K3PO4 (aq) (2 ml, 4 mmol). The solution was purged with nitrogen for 10 minutes before adding Pd(PPh3)4 (1.5 mg) catalyst. The mixture was again purged with nitrogen for 5 minutes before the reaction tube was sealed. The mixture was heated in a microwave oven at 150° C. for 30 minutes. The reaction mixture was filtered and the filtrate poured into 1N HCl (100 ml) with stirring. The precipitate was filtered and air-dried to give 209 mg of 5-phenylfuran-2-carboxylic acid. MS (ES−) found: (M−H)−=187.13.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.[OH-:18].[K+]>O1CCOCC1>[CH:9]1([NH:8][C:6]2[N:7]=[C:2]([OH:18])[CH:3]=[CH:4][C:5]=2[N+:15]([O-:17])=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1NC1CCCCC1
Agent: [K+]
Solvent: C1COCCO1
Product: O=[N+]([O-])c1ccc(O)nc1NC1CCCCC1
Temperature: 100 °C

Procedure:
To a solution of 6-chloro-N-cyclohexyl-3-nitropyridin-2-amine (2.16 g, 8.45 mmol) dissolved in dioxane (845 mL) was added 3 M aqueous potassium hydroxide (8.5 mL). The reaction mixture was heated at 100° C. until LCMS showed the starting material was entirely consumed. The reaction mixture was cooled to room temperature and then diluted with water. 1 N HCl was added until the solution turned acidic and a solid was formed. The solid was filtered, washed with water, and dried under vacuum to afford the title compound as a yellow solid (1.58 g). LCMS m/z=238.30 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:33])/[CH:5]=[C:6](\[CH3:32])/[CH:7]=[CH:8]/[C@@H:9]1[CH2:11][C@@:10]1([C:13]1[CH:14]=[C:15]([C:24]2[C:29]([CH3:30])=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:31])[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=1)[CH3:12])C.C(O)C.[OH-].[Na+]>CCCCCC>[CH3:30][C:29]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:31])[C:24]=1[C:15]1[C:16]2[O:20][CH2:19][C:18]([CH3:22])([CH3:21])[C:17]=2[CH:23]=[C:13]([C@@:10]2([CH3:12])[CH2:11][C@H:9]2/[CH:8]=[CH:7]/[C:6](/[CH3:32])=[CH:5]/[C:4]([OH:33])=[O:3])[CH:14]=1
Reactant: CCOC(=O)/C=C(C)/C=C/[C@@H]1C[C@]1(C)c1cc(-c2c(C)cccc2C)c2c(c1)C(C)(C)CO2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Product: CC(/C=C/[C@@H]1C[C@]1(C)c1cc(-c2c(C)cccc2C)c2c(c1)C(C)(C)CO2)=C\C(=O)O

Procedure:
Following General Procedure H and using 5-{(1S, 2S)-2-[7-(2,6-dimethyl-phenyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-3-methyl-penta-2E,4 Edienoic acid ethyl ester (Compound 23, 0.109 g, 0.24 mmol), ethanol (15 mL), and 5M aqueous sodium hydroxide (1 mL) followed by flash column chromatography using 25% in hexane as the eluent, and reverse phase HPLC, the title compound was obtained (0.049 g, 50%) as a white solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([CH:7]=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1>C(O)C.[C].[Pd]>[S:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C=CC1CCSCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCC1CCSCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
In 150 ml of ethanol is dissolved 10 g of ethyl 3-(4-thianyl)acrylate, and a catalytic reduction reaction is carried out at ordinary temperature and at atmospheric pressure using 9 g of 10% palladium-carbon (50% in water) as a catalyst. The reaction mixture is stirred at room temperature for 20 minutes and at 50° C. for 8 hours, and the catalyst is removed by filtration. Nine (9) g of 10% palladium-carbon (50% in water) is added anew to the filtrate, followed by stirring at 50° C. for one day. The catalyst is removed by filtration, and the filtrate is concentrated under reduced pressure to give 9.1 g of ethyl 3-(4-thianyl)propionate as an oily material.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:25])[C:22](=O)[CH3:23])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.Cl.[CH3:27][O:28][NH2:29]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:25])/[C:22](=[N:29]/[O:28][CH3:27])/[CH3:23])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:17])[F:18])=[CH:4][CH:3]=1
Reactant: CC(=O)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Reactant: CON
Agent: Cl
Solvent: CO
Product: CO/N=C(\C)C(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-[5-(4-Chloro-phenyl)-6-(2,2,2-trifluoro-ethoxy)-pyridin-3-yl]-2-oxo-propionamide (0.063 g, 169 μmol) was dissolved in methanol (1.00 mL). O-Methyl hydroxylamine hydrochloride (70.6 mg, 845 μmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated and the residue was partitioned between water and ethyl acetate; the organic phase was dried with MgSO4 and concentrated in vacuo to deliver 67 mg (89%) of the title compound as white solid; LC-MS (UV peak area/ESI) 99.0%, 402.0825 (M+H)+.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].O[C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[F:5][C:4]([F:7])([F:6])[S:1]([O:8][C:17]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20])(=[O:3])=[O:2]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)c1ccc(C)cc1O
Solvent: c1ccncc1
Product: COC(=O)c1ccc(C)cc1OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.3 %

Procedure:
Triflic anhydride (170 ml; 1.01 mol) was added to a solution of methyl 2-hydroxy-4-methylbenzoate (153 g; 0.92 mol) in pyridine (1.5 l), at 0° C., The mixture was stirred at ambient temperature overnight. After evaporation of the pyridine, the residue was acidified to pH 3.5 with 6N HCl and extracted with ether. The organic phase was evaporated and the residue purified by flash column chromatography eluting with a gradient of 0-5% ethyl acetate/petroleum ether to give methyl 2-trifluoromethylsulfonyloxy-4-methylbenzoate (245 g; 90%).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH:25]1[CH2:30][CH2:29][CH:28]([CH2:31][OH:32])[CH2:27][CH2:26]1>CN(C=O)C.CS(C)=O.CO>[OH:32][CH2:31][CH:28]1[CH2:29][CH2:30][N:25]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH2:26][CH2:27]1
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Reactant: OCC1CCNCC1
Solvent: CO
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(N3CCC(CO)CC3)n2n1
Temperature: 25 °C
Yield: 62.4 %

Procedure:
A solution of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 81 mg, 0.235 mmol) and piperidin-4-ylmethanol (35 mg, 0.294 mmol) in DMF (1 mL) was stirred at 100° C. for 3 h. After cooling to room temperature, the mixture was diluted with a few drops of DMSO and methanol, and was then purified by preparatory HPLC (25-35% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a white solid (62.1 mg, 62%). Melting point (164.0-169.5° C.). 1H NMR (DMSO-d6) δ: 10.86 (s, 1H), 7.99 (d, J=8.6 Hz, 2H), 7.60 (d, J=8.6 Hz, 2H), 7.27 (s, 1H), 6.17 (s, 1H), 4.50 (d, J=12.1 Hz, 2H), 3.33 (d, J=6.3 Hz, 2H), 2.99-3.11 (m, 2H), 2.38 (s, 3H), 1.79-1.87 (m, 2H), 1.67-1.78 (m, 1H), 1.45 (s, 6H), 1.28-1.42 (m, 2H); ESI-MS: m/z 424.3 (M+H)+.
Reaction SMILES: N.[C:2]([OH:11])(=[O:10])/[CH:3]=[CH:4]/[CH:5]=[CH:6]/[C:7]([OH:9])=[O:8]>O1CCOCC1>[C:2]([OH:11])(=[O:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8]
Reactant: O=C(O)/C=C/C=C/C(=O)O
Agent: N
Solvent: C1COCCO1
Product: O=C(O)CCCCC(=O)O

Procedure:
For reference, effect of temperature and time of catalytic reduction on reaction yield are studied using a 500 mL Parr reactor, 50 psi NH3, dioxane (0.07M, 1 wt %) and 5 wt % 5% Pd/Al2O3 catalyst are studied using trans,trans-muconic acid as the substrate. The trans,trans-muconic acid is hydrogenated in situ by the catalyst to form adipic acid. Initial hydrogen pressure is 200 psi, so that the total initial pressure after charging with hydrogen is 250 psi. Results are shown in Table 5A. The time listed includes the beginning of heating a room temperature to the time at which the reaction is cooled down. The temperature ramp time from room temperature to 250° C. is 45-60 min. At 225° C. (entry 3), adipamide is the main product as hydrogenation is relatively slow at this temperature. Also observed is the presence of monoamide, showing amidification is not complete. Increasing reaction temperature to 250° C. (entry 1) results in complete amidification and increases rate of hydrogenation of adipamide to an intermediate 6-aminohexanamide which cyclizes to form caprolactam. Increasing reaction time to 3 h (entry 2) results in complete reduction of the adipamide but also increases the reduction of caprolactam to HMI. The reaction is heated to 250° C. for a time that allows formation of caprolactam without undesired production of HMI. ND=not detected. t, t-MA=trans,trans-muconic acid.
Reaction SMILES: [NH2:1][N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[C:3]1=O.C(O[C:18](=[NH:27])[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=1)C>>[CH3:13][O:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[C:3]1=[N:27][C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=3)=[N:1][N:2]1[CH2:11][CH2:10]2
Reactant: CCOC(=N)c1cccc(OC)c1
Reactant: COc1ccc2c(c1)CCN(N)C2=O
Product: COc1cccc(-c2nc3n(n2)CCc2cc(OC)ccc2-3)c1

Procedure:
The compound is prepared according to the procedure of Example 1 from 2-amino-6-methoxy-3,4-dihydro-1(2H)-isoquinolinone (prepared according to the procedure described in Belgian Pat. No. 780,885; m.p. 101°-3° C.) and m-methoxybenzimidic acid ethyl ester; m.p. 132°-3° C.