Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36]O)[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N-:66]=[N+:67]=[N-:68].[Li+].C(Br)(Br)(Br)Br>CN(C=O)C.CO>[CH2:1]([O:8][CH2:9][C@@:10]1([N:38]2[CH:46]=[C:44]([CH3:45])[C:42](=[O:43])[NH:41][C:39]2=[O:40])[O:33][C@H:13]([CH2:14][O:15][Si:16]([C:29]([CH3:32])([CH3:30])[CH3:31])([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C@@H:12]([CH2:34][CH2:35][CH2:36][N:66]=[N+:67]=[N-:68])[CH2:11]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Reactant: [N-]=[N+]=[N-]
Agent: BrC(Br)(Br)Br
Agent: [Li+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cn([C@@]2(COCc3ccccc3)C[C@H](CCCN=[N+]=[N-])[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O

Procedure:
Utilizing the conditions of Hetz et. al., J.C.S. Perkin 1 1980, 306, to a solution of compound 39 (1 eq) in DMF is added triphenylphosphine (1 eq) and lithium azide (5 eq) at room temperature. Carbon tetrabromide (1 eq) is added and the reaction mixture is stirred until judged complete by tlc. MeOH is added to quench the reaction mixture and the solvent is evaporated under reduced pressure. The residue is purified by silica gel chromatography to yield the title compound, 40.
Reaction SMILES: [CH2:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]#N)=[CH:10][C:9]([O:16][CH3:17])=[CH:8][CH:7]=2)[CH:2]=[CH2:3].[OH2:18].[OH-:19].[K+]>C(O)(=O)C>[CH2:1]([C:4]1[NH:5][C:6]2[C:11]([C:12]=1[CH2:13][C:14]([OH:19])=[O:18])=[CH:10][C:9]([O:16][CH3:17])=[CH:8][CH:7]=2)[CH:2]=[CH2:3]
Reactant: O
Reactant: [OH-]
Reactant: C=CCc1[nH]c2ccc(OC)cc2c1CC#N
Agent: [K+]
Solvent: CC(=O)O
Product: C=CCc1[nH]c2ccc(OC)cc2c1CC(=O)O

Procedure:
0.08 mole of 2-allyl-5-methoxy-3-indolyl acetonitrile is added to a mixture of 140 ml. of alcohol, 100 ml. of water and 4.3 g. of KOH. The mixture is refluxed 15 hours and then brought to room temperature. Glacial acetic acid (60 ml.) is added, and the solution is filtered through a talc filter. The filtrate is diluted with 500 ml. of water, and the precipitated 2-allyl-5-methoxy-3-indolyl acetic acid is separated by filtration and dried.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@:9]12[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]1)[CH:11]([C:18](Cl)=[O:19])[C:10]2=O.C(OC([N:29]([CH:37]1[CH2:39][CH2:38]1)[NH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=O)(C)(C)C.Cl.O1CCOCC1>ClCCCl>[CH:37]1([N:29]2[C:10]3[C@@:9]4([CH3:8])[C:15]([CH3:17])([CH3:16])[C@H:12]([CH2:13][CH2:14]4)[C:11]=3[C:18](=[O:19])[N:30]2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:39][CH2:38]1
Reactant: CC(C)(C)OC(=O)N(Nc1ccccc1)C1CC1
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC1(C)[C@@H]2CC[C@@]1(C)c1c2c(=O)n(-c2ccccc2)n1C1CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 42 %

Procedure:
Triethylamine (120 μL, 0.86 mmol) was added dropwise to a cooled (0° C.) solution of (1R,4R)-4,7,7-trimethyl-3-oxo-bicyclo [2.2.1]heptane-2-carbonyl chloride (Intermediate 20; 90 mg, 0.42 mmol) in 1,2-dichloroethane (1 mL) over 1 min. A solution of N-cyclopropyl-N′-phenyl-hydrazinecarboxylic acid tert-butyl ester (66 mg, 0.27 mmol) in 1,2-dichloroethane (4 mL) was added. The reaction mixture was stirred at 0° C. for 15 min, at room temperature for 15 min, and then in an oil bath at 50° C. for 90 min. The reaction mixture was cooled. A solution of HCl in dioxane (4 M; 4 mL, 16 mmol) was added and the mixture was heated in an oil bath at 100° C. for 1 h. A further portion of HCl in dioxane (4 M; 10 mL, 40 mmol) was added and the mixture was heated in an oil bath at 100° C. for 2 h. The solvent was evaporated. Dichloromethane (30 mL) was added and the mixture was washed with 1:1 water/brine (10 mL), dried (magnesium sulfate), filtered, evaporated, and purified using an ISCO 40 g column, eluting with 25-100% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated with dichloromethane and then petroleum ether. The residue was dried under high vacuum at 75° C. overnight to give (4S,7R)-1-cyclopropyl-7,8,8-trimethyl-2-phenyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (35 mg, 43%) as a light yellow solid. APCI(+)-MS (M+H) 309.
Reaction SMILES: [N:1]1[C:8](Cl)=[N:7][C:5]([Cl:6])=[N:4][C:2]=1[Cl:3].S([O-])([O-])(=O)=O.[Na+].[Na+].[C:17]([C:21]1[CH:22]=[C:23]([SH:32])[CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])([CH3:20])([CH3:19])[CH3:18].CC1C=C(C)N=C(C)C=1>CC(C)=O.ClC1C=CC=CC=1>[Cl:3][C:2]1[N:4]=[C:5]([Cl:6])[N:7]=[C:8]([S:32][C:23]2[CH:22]=[C:21]([C:17]([CH3:18])([CH3:19])[CH3:20])[C:26]([OH:27])=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:24]=2)[N:1]=1
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Solvent: CC(C)=O
Solvent: Cc1cc(C)nc(C)c1
Product: CC(C)(C)c1cc(Sc2nc(Cl)nc(Cl)n2)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 43.7 %

Procedure:
To a solution of 0.1 mol of cyanuric chloride in 120 ml of acetone are added 3 g of anhydrous sodium sulfate and the mixture is cooled to 0° C. A solution of 0.1 mol of 3,5-di-tert-butyl-4hydroxythiophenol in 25 ml of chlorobenzene is then run in. Afterwards 12.7 g of s-collidine are added dropwise at 5° C. over 20 minutes to the reaction mixture. The reaction is brought to completion by stirring for 30 minutes at 5° C. and for 2 hours at room temperature. The reaction mixture is then filtered and, after washing with 100 ml of acetone, the filtrate is stirred into a mixture of 400 g of ice and 900 ml of water, acidified with dilute hydrochloric acid (weakly acid reaction to litmus paper), and extracted repeatedly with ethyl acetate. Conventional working up and recystallisation from hexane/acetone gives 16.9 g of 2,4-dichloro-6-(3',5'-di-tert-butyl-4'-hydroxyphenylsulfanyl)-s-triazine.
Reaction SMILES: N1C=CC=CC=1.O=S(Cl)Cl.[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]O>C1COCC1>[Cl:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: OCCCCCCCCCl
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CCCCCCCCCl
Temperature: 60 °C
Reaction time: 24 h
Yield: 0.5 %

Procedure:
1 g (0.0015 mol, equivalent weight=666 gram per mole repeat unit) polymer 5 was placed into a 50 ml Schlenk and dissolved in THF anhydrous (30 ml). The Schlenk was connected to a trap with a NaOH solution (2M) for absorption of HCl and SO2. Then pyridine anhydrous 0.5 ml (0.0062 mol), and SOCl2 0.3 ml (0.0041 mol) were added dropwise at room temperature into the Schlenk. The temperature was slowly increased and maintained at 60° C. for 3 h. Excess of SOCl2 and THF were distilled off under vacuum at 50° C. for 30 minutes, the resulting crude acid chloride polymer. Then freshly distilled THF (30 ml) was added to dissolve the acylated polymer. After 30 minutes needed for complete dissolution of polymer, a solution of excess 8-chloro-1-octanol 1.05 ml (2 mol.eq, 0.0062 mol) was added dropwise to the polymer solution at room temperature under vigorous stirring, and allowed to stir for 24 h. The polymer was recovered by precipitating into distilled water. The product purification was made by dissolution in hot CH2Cl2, precipitation in ethanol and drying at 50° C. in vacuum oven to obtain Polymer 9 as a brown solid (1.39 g, yield 95%) with the following characteristics:
Reaction SMILES: F[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.C[Al](C)C.[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(Cl)[Cl:26]>C1(C)C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:13][S:14]([C:17]1[CH:24]=[CH:23][C:20]([C:21](=[NH:22])[NH:6][C:5]2[CH:7]=[CH:8][C:2]([Cl:26])=[CH:3][CH:4]=2)=[CH:19][CH:18]=1)(=[O:15])=[O:16]
Reactant: ClCCl
Reactant: CS(=O)(=O)c1ccc(C#N)cc1
Reactant: Nc1ccc(F)cc1
Agent: C[Al](C)C
Solvent: ClC(Cl)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(C(=N)Nc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
To a suspension of 4-fluoroaniline (4 mL, 40 mmol) in toluene (120 mL), trimethylaluminum (2M solution in toluene, 21 mL, 42 mmol) was added over 15 minutes. The reaction mixture was warmed to room temperature and stirred for 3 hours. A solution of 4-(methylsulfonyl)benzonitrile (7.65 g, 40 mmol) in methylene chloride (100 mL) was added over 10 minutes and the reaction mixture was heated to 70–75° C. After 48 hours, the reaction mixture was cooled to room temperature and poured over a slurry of silica gel in chloroform. After filtration, the residue was washed with a mixture of methylene chloride/methanol. The combined filtrates were concentrated in vacuo and the resulting crude intermediate (7.7 g) was purified by chromatography [silica gel, hexane/ethyl acetate, 25/75] to give 4-methylsulfonyl-N-[4-chlorophenyl]benzenecarboximidamide (4.1 g, 35%) as a white solid: mp (DSC) 182° C. Anal. Calc'd. for C14H13N2SO2F: C, 57.52; H, 4.48; N, 9.58; S, 10.97. Found: C, 57.37; H, 4.69; N, 9.21; S, 10.69.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C:6](=O)[CH2:7][CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C.[C:16]1(C=C[CH:21]=[C:19](O)[CH:18]=1)[OH:17].Cl>C(O)C>[OH:17][C:16]1[CH:13]=[C:12]2[C:21]([C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:15])=[CH:8][C:9](=[O:10])[O:11]2)=[CH:19][CH:18]=1
Reactant: Oc1cccc(O)c1
Reactant: CCOC(=O)CCC(=O)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: O=C(O)CCc1cc(=O)oc2cc(O)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A solution of 3-oxohexane-1,6-dioic acid diethyl ester (78.88 g), resorcinol (40.19 g) and ethanol (1 L) was saturated with hydrogen chloride gas during two hours at 0° C., tightly stoppered, let stand at room temperature over the weekend, shown by thin layer chromatography to contain unreacted 3-oxohexane-1,6-dioic acid diethyl ester, saturated again with hydrogen chloride gas during 45 minutes at 0° C., and let stand overnight at room temperature. Although thin layer chromatography still showed that the reaction was incomplete, the solution was partially (800 mL) stripped of volatiles and poured into ice-water. The resulting solid was collected by filtration and ethanol (300 mL) and aqueous sodium hydroxide solution (2.5N, 350 mL) were added. The mixture was stirred at room temperature and, when the reaction was complete, poured into hydrochloric acid (2N, 500 mL). A suspension of the resulting solid in methanol (300 mL) was stirred for 15 minutes at room temperature, cooled on ice and filtered. The resulting solid was washed with ether and dried affording 3-(7-hydroxy-4-coumarinyl)propionic acid (62.4 g, 73% yield).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[OH:7][C:8]([CH2:22][CH2:23][CH3:24])=[CH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)=[O:11].IC>CC(C)=O>[CH3:1][CH:9]([C:8](=[O:7])[CH2:22][CH2:23][CH3:24])[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:20])[F:21])[CH:13]=1)=[O:11]
Reactant: O=C([O-])[O-]
Reactant: CCCC(O)=CC(=O)c1cccc(C(F)(F)F)c1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCCC(=O)C(C)C(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 50.9 %

Procedure:
To a stirred suspension of potassium carbonate (596 mg) in acetone (7 mL), was added 3-hydroxy-1-(3-trifluoromethylphenyl)-hex-2-en-1-one (190 mg) followed by iodomethane (0.45 mL). The mixture was heated at reflux for 6 h, cooled to room temperature, and the solvent evaporated at reduced pressure. The resulting oil was dissolved in ethyl acetate (20 mL), washed with water (3×20 mL), dried over sodium sulphate and evaporated at reduced pressure to give the crude product as an oil. Flash silica chromatography afforded 2-methyl-1-(3-trifluoromethylphenyl)-hexane-1,3-dione as an oil (102 mg).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([C@@H:7]([NH2:11])[C:8]([OH:10])=[O:9])=[CH:3][CH:2]=1.C([O-])(O)=O.[Na+].[CH2:17]([O:19][C:20](Cl)=[O:21])[CH3:18].Cl>C1COCC1.O>[CH2:17]([O:19][C:20]([NH:11][C@H:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[C:8]([OH:10])=[O:9])=[O:21])[CH3:18]
Reactant: CCOC(=O)Cl
Reactant: N[C@@H](C(=O)O)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N[C@@H](C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
D-Phenylglycine (R) (85.2 mmol) was dissolved in anhydrous THF (260 mL) with NaHCO3 (256 mmol) in water (260 mL). Ethylchloroformate (0.235 mol) was added. After stirred at room temperature overnight, the reaction mixture was acidified to pH 3 with 1N HCl. The aqueous layer was extracted with EtOAc. The organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure to give (R)-2-(ethoxycarbonylamino)-2-phenylacetic acid 41 as a white solid in 82% yield. MS (ESI, EI+) m/z=224.2 (MH+).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[Cl:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([Cl:27])=[CH:29][CH:30]=3)[CH2:24][CH2:25]2)=[CH:4]1
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)c1ccc(Cl)cc1

Procedure:
The title compound, light brown solid (95 mg, 82%), MS (ISP) m/z=465.2 [(M+H)+], mp 203° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and 4-chloro-benzoic acid.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][C:15]=1[CH:24]=[O:25]
Reactant: N#Cc1ccc(F)cc1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: N#Cc1ccc(F)c(C=O)c1
Reaction time: 0.17 h
Yield: 44.7 %

Procedure:
Diisopropylamine (0.35 mL, 2.5 mmol) was dissolved in tetrahydrofuran (3.5 mL) and the temperature was adjusted to 0° C. Then, n-butyllithium (hexane solution) (1.24 mL, 2.0 mmol) was dropped thereto, followed by stirring for 10 minutes. Thereafter the reaction temperature was brought to −78° C. 4-Fluorobenzonitile (0.2 g, 1.65 mmol) was added thereto, stirring for 1 hour. Then, dimethylformamide (0.19 mL, 2.5 mmol) was dropped thereto, followed by stirring for 20 minutes and then the conventional treatment was performed. The residue was purified by thin-layer chromatography (hexane: ethyl acetate=8:1), to give 2-fluoro-5-cyanobenzaldehyde (0.11 g, 43.4%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([O:36][CH2:37][CH3:38])(=[O:35])[CH2:33][OH:34].[CH3:39][C:40]([CH3:47])([CH3:46])[C:41](=O)[CH2:42][C:43]#[N:44]>C1COCC1>[CH3:39][C:40]([CH3:47])([CH3:46])/[C:41](/[O:34][CH2:33][C:32]([O:36][CH2:37][CH3:38])=[O:35])=[CH:42]/[C:43]#[N:44]
Reactant: CC(C)(C)C(=O)CC#N
Reactant: CCOC(=O)CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)CO/C(=C\C#N)C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.5 %

Procedure:
A 0° C. solution of triphenylphosphine (2.72 g, 10.4 mmol, 1.3 equiv) in anh. THF (50 mL) was treated with diethyl azodicarboxylate (1.81 g, 10.4 mmol, 1.3 equiv), ethyl glycolate (1.08 g, 10.4 mmol, 1.3 equiv) and 4,4-dimethyl-3-oxopentanenitrile (1.00 g, 8.0 mmol). The resulting solution was allowed to warm to room temperature, stirred for 15 h and concentrated under reduced pressure. The residue was purified by flash chromatography (11 cm×22 cm SiO2, gradient from 5% EtOAc/hex to 8% EtOAc/hex) to afford (Z)-4,4-dimethyl-3-(ethoxycarbonylmethoxy)pentenenitrile (1.36 g, 80%) as a colorless oil: TLC (5% EtOAc/hexanes) Rf0.26; 1H NMR (CDCl3) δ1.12 (s, 9H), 1.28 (t, J=7.0 Hz, 3H), 4.24 (q, J=7.0 Hz, 2H), 4.55 (s, 1H), 5.00 (s, 2H); 13C NMR (CDCl3) δ13.9, 27.8, 38.2, 61.5, 67.1, 67.3, 117.0, 167.1, 180.7; CI-LRMS m/z (rel abundance) 212 (M+H, 100%). Anal. Calcd for C11H17NO3: C, 62.54; H, 8.11; N, 6.63. Found: C, 62.57; H, 7.90; N, 6.47.
Reaction SMILES: [NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:12])([CH3:11])[O:10][C:6]=2[C:5]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25]3([CH3:30])OCC[O:26]3)[CH2:18][C@H:17]2[O:31][CH3:32])=[O:14])=[CH:4][C:3]=1[Cl:33].S(=O)(=O)(O)O.N>>[OH2:10].[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](=[O:26])[CH3:30])[CH2:18][C@H:17]2[O:31][CH3:32])=[O:14])=[CH:4][C:3]=1[Cl:33].[NH2:1][C:2]1[C:7]2[CH2:8][C:9]([CH3:11])([CH3:12])[O:10][C:6]=2[C:5]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH2:24][C:25](=[O:26])[CH3:30])[CH2:18][C@H:17]2[O:31][CH3:32])=[O:14])=[CH:4][C:3]=1[Cl:33]
Reactant: CO[C@@H]1CN(CCCC2(C)OCCO2)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OC(C)(C)C2
Agent: N
Agent: O=S(=O)(O)O
Product: CO[C@@H]1CN(CCCC(C)=O)CC[C@@H]1NC(=O)c1cc(Cl)c(N)c2c1OC(C)(C)C2
Product: O
Reaction time: 2 h
Yield: 51.6 %

Procedure:
A mixture of 5.4 parts of cis-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-l-[3-(2-methyl-1,3-dioxolan-2-yl)propyl ]-4-piperidinyl]-2,2-dimethyl-7-benzofurancarboxamide and 85 ml of an aqueous sulfuric acid solution 1% was stirred for 2 hours at reflux temperature. After cooling, the reaction mixture was basified with ammonia and extracted with dichloromethane (2×). The combined extracts were dried, filtered and evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 95:5). The eluent of the desired fraction was evaporated and the residue was suspended in 2,2'-oxybispropane. The product was filtered off and dried, yielding 2.4 parts (51.6%) of cis-4-amino-5-chloro-2,3-dihydro-N-[3-methoxy-l-(4-oxopentyl)-4-piperidinyl]-2,2-dimethyl-7-benzofurancarboxamide hemihydrate; top. 137.7° C. (comp. 112).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([C:10](=[CH:16][NH:17][CH:18]2[CH2:20][CH2:19]2)[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[O:9])=[C:6](F)[C:5]([F:22])=[C:4]([F:23])[C:3]=1[F:24].[H-].[Na+]>O1CCOCC1>[CH:18]1([N:17]2[C:6]3[C:7](=[C:2]([CH3:1])[C:3]([F:24])=[C:4]([F:23])[C:5]=3[F:22])[C:8](=[O:9])[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16]2)[CH2:20][CH2:19]1
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1c(C)c(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(C)c2c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.8 %

Procedure:
Ethyl 2-(6-methyl-2,3,4,5-tetrafluorobenzoyl)-3-cyclopropylaminoacrylate (4.50 g) is dissolved in anhydrous dioxane (26 ml) and thereto 60% sodium hydride (580 mg) is gradully added under ice-cooling. After stirring at room temperature for 30 minutes, the reaction mixture is poured into ice-water and extracted with dichloromethane. The extract is dried over magnesium sulfate and concentrated. The residue is added with diethyl ether and crystals are filtered, which are recrystalized from dichloromethane-n-hexane to give ethyl 1-cyclopropyl-6,7,8-trifluoro-5-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylate (4.19 g), as white needles, m.p. 180°-183° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N+](=[CH2:17])=[N-]>C1COCC1.CCOCC>[NH2:1][C:2]1[CH:10]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: C=[N+]=[N-]
Reactant: Nc1cc(C(F)(F)F)ccc1C(=O)O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)c1ccc(C(F)(F)F)cc1N

Procedure:
To a solution of 2-amino-4-(trifluoromethyl)benzoic acid (5 g) in THF (85 ml) was added diazomethane (48.7 ml) in ether until completion of the reaction. Nitrogen was bubbled into the reaction mixture for 15 minutes to remove the excess of diazomethane and the solvent was removed under reduced pressure to provide a light brown solid (5.34 g). The compound was used in the next without purification. LRMS (ES+) m/z 220.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:31])[C:23]3[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=3)[C@@H:14]([CH3:32])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:37])C.Cl>O.C(Cl)Cl>[C:9]([N:8]([C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C@H:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[N:15]([C:22]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([NH2:30])=[O:37])=[CH:27][CH:28]=2)=[O:31])[C@@H:14]([CH3:32])[CH2:13]1)(=[O:11])[CH3:10]
Reactant: CCO
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C#N)cc2)c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C(N)=O)cc2)c2ccccc21

Procedure:
N-(4-chlorophenyl)-N-[(2S,4R)-1-(4-cyanobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide (143 mg, 0.33 mmol) and potassium hydroxide (55 mg, 1.00 mmol)) were dissolved in water (150 mL), ethanol (3 mL) and heated to 70° C. for 4 h. The slurry was portioned between 1N HCl (until acidic) and methylene chloride. The organic layer was collected, concentrated and subjected to flash chromatography (EtOAc to 20% MeOH, EtOAc) to afford the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH:19]=O)[CH:6]=1.[CH2:22]([NH2:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C([BH3-])#N.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([Br:18])=[CH:14][C:13]=2[CH2:19][NH:29][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=1
Reactant: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Reactant: NCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2CNCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
[3-(4-Bromo-2-formyl-phenoxy)-phenyl]-acetic acid methyl ester (0.151 g, 0.43 mmol), benzylamine (0.05 mL, 0.48 mmol), and sodium cyanoborohydride (0.041 g, 0.65 mmol) were combined in CH2Cl2 (3 mL). Acetic acid (2 drops) was added, and the reaction was stirred overnight at room temperature. The mixture was partitioned between CH2Cl2 and saturated aqueous NaHCO3, and the aqueous layer was separated and extracted twice with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated, and the residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to give the title compound.