Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][NH:32][C:33]([CH2:35][N:36]([S:44]([CH3:47])(=[O:46])=[O:45])[C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1)=[O:34]>>[CH3:28][N:29]([CH3:48])[CH2:30][CH2:31][NH:32][C:33]([CH2:35][N:36]([C:37]1[CH:42]=[CH:41][C:40]([NH:43]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][C:9]([O:15][CH3:16])=[C:10]([O:13][CH3:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:38]=1)[S:44]([CH3:47])(=[O:46])=[O:45])=[O:34]
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(OC)c(OC)cc21)c1ccccc1
Reactant: CN(C)CCNC(=O)CN(c1ccc(N)cc1)S(C)(=O)=O
Product: COc1cc2c(cc1OC)/C(=C(/Nc1ccc(N(CC(=O)NCCN(C)C)S(C)(=O)=O)cc1)c1ccccc1)C(=O)N2

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenyl-methylidene)-5,6-dimethoxy-2-indolinone and N-[(2-dimethylamino-ethylamino)-carbonylmethyl]-N-methylsulphonyl-p-phenylenediamine
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[C:5]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[C:9]([CH2:24][C:25](=[O:27])[CH3:26])[C:8]=2[CH:28]=1.O>C1COCC1>[Cl:3][C:4]1[C:5]([O:29][C:30](=[O:34])[N:31]([CH3:33])[CH3:32])=[CH:6][C:7]2[O:12][C:11](=[O:13])[C:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([N+:21]([O-:23])=[O:22])[CH:16]=3)=[C:9]([CH2:24][CH:25]([OH:27])[CH3:26])[C:8]=2[CH:28]=1
Reactant: CC(=O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(O)Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2cc(OC(=O)N(C)C)c(Cl)cc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 93.5 %

Procedure:
Sodium borohydride (49 mg, 1.30 mmol) was added to a solution of dimethylcarbamic acid 6-chloro-3-(3-nitrobenzyl)-2-oxo-4-(2-oxopropyl)-2H-1-benzopyran-7-yl ester (compound 7f-1-3CO) (300 mg, 0.65 mmol) in anhydrous THF (5.0 mL), and the mixture was stirred at 0° C. for 2 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate, and the title compound (280 mg, 93%) was obtained as a pale yellow powder.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=O)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:25][C:26]1[CH:27]=[C:28]2[C:36](=[CH:37][CH:38]=1)[NH:35][C:34]1[CH2:33][CH2:32][CH:31]([N:39]([CH3:41])[CH3:40])[CH2:30][C:29]2=1>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([NH:25][C:26]3[CH:27]=[C:28]4[C:36](=[CH:37][CH:38]=3)[NH:35][C:34]3[CH2:33][CH2:32][CH:31]([N:39]([CH3:41])[CH3:40])[CH2:30][C:29]4=3)=[O:12])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc5[nH]ccc5c4)cc3c2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.9 %

Procedure:
To a solution of 43.5 mg (0.27 mMol) indole-5-carboxylic acid in 1.5 mL dimethylformamide were added 44.3 mg (0.27 mMol) carbonyldiimidazole resulting in immediate gas evolution. The reaction mixture was stirred for 4 hours at room temperature and then 60.0 mg (0.26 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole were added. After 3 days the reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 4:1 dichloromethane:2% ammonium hydroxide in methanol. Fractions shown to contain product were combined and concentrated under reduced pressure to give 66.7 mg (69%) of 6-(indol-5-oyl)amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole. The compound was converted to its corresponding hydrochloride salt, crystallizing from ethanol:diethyl ether.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[C:13](Cl)[CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:22][CH2:23][F:24])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C>CO.[Pd]>[CH2:1]([O:3][C:4]([CH:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[O:19][CH3:20])[N:11]([CH2:22][CH2:23][F:24])[C:10]=2[CH2:9][CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCc2c1c1c(OC)ccc(Cl)c1n2CCF
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCCc2c1c1c(OC)cccc1n2CCF
Reaction time: 18 h
Yield: 87.7 %

Procedure:
8-chloro-9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (15) (5.3 g, 15.0 mmol) was dissolved in methanol (180 mL) and triethylamine (1.8 g, 18.0 mmol, 2.5 mL) and 10% Pd/C (2 g in methanol (20 mL)) were added. The mixture was placed on the Parr hydrogenator and shaken for 18 h under a hydrogen atmosphere. The reaction was filtered through a pad of celite, washed with methanol and the solvent was removed in vacuo. The residue was dissolved in ethyl acetate (300 mL) and washed with 10% aqueous potassium carbonate (200 mL), dried over magnesium sulfate and concentrated in vacuo to give 4.2 g (88%) of 9-(2-Fluoroethyl)-5-methoxy-2,3,4,9-tetrahydro-1H-carbazole-4-carboxylic acid ethyl ester (16) as a light brown solid. The structure was confirmed by 13C NMR (75 MHz, CDCl3): δC 14.3, 20.6, 21.8, 27.6, 40.3, 43.3 (d, JCF=23 Hz), 54.9, 60.1, 82.0 (d, JCF=165 Hz), 99.8, 102.1, 107.3, 117.2, 121.8, 134.9, 137.6, 153.8, and 176.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([NH2:21])[C:14]=2[N:13]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24]>>[C:1]([O:5][C:6](=[O:22])[N:7]([CH2:9][CH2:10][CH2:11][C:12]1[NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([NH:21][C:23](=[O:25])[CH3:24])[C:14]=2[N:13]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCCc1nc2c(N)cccc2[nH]1)C(=O)OC(C)(C)C
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc2[nH]c(CCCN(C)C(=O)OC(C)(C)C)nc12

Procedure:
A solution of 3.66 g of [3-(4-amino-1H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid tert-butyl ester in 40 mL of acetic anhydride was refluxed for 2 h. The excess of acetic anhydride was evaporated off and the residue was treated with 16 mL of EtOH and IM-NaOH until pH 10 then extracted with EtOAc. The organic phase was dried over anh. Na2SO4 and concentrated in vacuo. Purification by CC using EtOAc/MeOH 100/1 to 90/1 yielded 1.86 g of [3-(4-acetylamino-1H-benzoimidazol-2-yl)-propyl]-methyl-carbamic acid tert-butyl ester as yellow foam.
Reaction SMILES: [Br:1]Br.[Br:3][C:4]1[C:13]2[S:14][C:15]([CH3:18])=[C:16]([CH3:17])[C:12]=2[C:11]([C:19]2[CH:24]=[CH:23][C:22]([OH:25])=[C:21]([N+:26]([O-:28])=[O:27])[CH:20]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[CH:9]2.C([O-])(=O)C.[K+].O>C(O)(=O)C>[Br:1][C:23]1[CH:24]=[C:19]([C:11]2[C:12]3[C:16]([CH3:17])=[C:15]([CH3:18])[S:14][C:13]=3[C:4]([Br:3])=[C:5]3[C:10]=2[CH:9]=[CH:8][CH:7]=[CH:6]3)[CH:20]=[C:21]([N+:26]([O-:28])=[O:27])[C:22]=1[OH:25]
Reactant: BrBr
Reactant: Cc1sc2c(Br)c3ccccc3c(-c3ccc(O)c([N+](=O)[O-])c3)c2c1C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1sc2c(Br)c3ccccc3c(-c3cc(Br)c(O)c([N+](=O)[O-])c3)c2c1C
Reaction time: 0.17 h
Yield: 59.5 %

Procedure:
A solution of bromine (0.040 mL, 0.756 mmol) in acetic acid (0.5 mL) was added dropwise to a stirred suspension of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-nitro-phenol (0.20 g, 0.467 mmol), potassium acetate (0.228 g, 2.335 mmol) in acetic acid (4 mL). After 10 min, water was added and the reaction mixture was extracted with ether. Silica gel was added to the ether phase and the solvent was removed. The adsorbate was flashed (gradient: 95:5 to 85:15) to provide the title compound as a yellow solid (0.141 g, 60%): mp 129-130° C.: NMR (DMSO-d6); δ11.30 (s, 1H), 8.22 (d, J=8 Hz, 1H), 8.03 (s, 1H), 7.96 (s, 1H), 7.67 (quintuplet, J=4 Hz, 1H), 7.51 (d, J=4 Hz, 2H), 2.45 (s, 3H), 1.65 (s, 3H); MS (EI): 2 bromine isotope pattern 505 (40%), 507 (100%), 509 (50%); Anal. Calc. for C20H13Br2NO3S: C, 47.36; H, 2.58; N, 2.76. Found: C, 47.18; H, 2.55; N, 2.63.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].[CH3:9][NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>CC(C)=O.[Ag]=O>[CH3:9][N:10]([C:6]1[CH:7]=[CH:8][C:1](=[O:2])[C:3](=[O:4])[CH:5]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccccc1
Reactant: Oc1ccccc1O
Agent: O=[Ag]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CN(C1=CC(=O)C(=O)C=C1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2.2 g (0.02 mole) catechol and 2.0 g (0.019 mole) N-methylaniline were dissolved in 80 ml acetone. Then 18.8 g (0.08 mole) silver oxide was added followed by 20 g of anhydrous sodium sulfate. The mixture was stirred at room temperature for 10 minutes and filtered. The residue was washed with several portions of acetone totaling 50 ml. The filtrate was diluted with ligroin (bp 60°-80° C.) and the solid was filtered and washed with ligroin to give 2.6 g (60%). Thin-layer chromatography on Eastman Chromogram silica gel sheets showed essentially a single spot with traces of impurities.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH:13]2[C:25]([NH2:27])=[O:26])=[CH:4][CH:3]=1.[H][H]>[Pd].CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:28]2[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=2)[CH2:9][CH2:10][CH2:11][N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH:13]2[C:25]([NH2:27])=[O:26])=[CH:4][CH:3]=1
Reactant: [H][H]
Reactant: NC(=O)C1CN(Cc2ccccc2)CCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: NC(=O)C1CNCCN1CCCC(c1ccc(F)cc1)c1ccc(F)cc1
Yield: 66.4 %

Procedure:
A mixture of 14.8 parts of 1-[4,4-bis(4-fluorophenyl)butyl]-4-(phenylmethyl)-2-piperazinecarboxamide and 200 parts of methanol was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10%. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (85:15 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2,2'-oxybispropane, yielding 7.9 parts (66.4%) of 1-[4,4-bis(4-fluorophenyl)butyl]-2-piperazinecarboxamide; m.p. 113.6° C. (intermediate 53).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][N:5]([CH:14]1[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]1)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[CH3:25][C:26]1([CH3:35])[CH2:31]C(O)[CH2:29][C:28]([CH3:34])([CH3:33])[NH:27]1.CC(C)([O-])C.[K+].CO>CCCCCCC>[CH3:25][C:26]1([CH3:35])[CH2:31][CH:1]([O:2][C:3](=[O:24])[CH2:4][N:5]([CH:14]2[CH2:19][C:18]([CH3:21])([CH3:20])[NH:17][C:16]([CH3:23])([CH3:22])[CH2:15]2)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[CH2:29][C:28]([CH3:34])([CH3:33])[NH:27]1
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCCCN(CC(=O)OC)C1CC(C)(C)NC(C)(C)C1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CO
Product: CCCCCCCCN(CC(=O)OC1CC(C)(C)NC(C)(C)C1)C1CC(C)(C)NC(C)(C)C1
Yield: 73.6 %

Procedure:
To the same flask as used in Example 1 were added 34 g (0.1 mole) of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-octylglycine methyl ester, 17.3 g (0.11 mole) of 2,2,6,6-tetramethyl-4-piperidinol, 1.2 g of potassium tert-butoxide and 100 g of heptane. The temperature was raised with stirring, and reaction was carried out at 98° to 105° C. for 6 hours, during which methanol was removed from the reaction system by means of the Deanstark trap. After completion of the reaction, water was added to the reaction solution to dissolve the product in the heptane layer. The heptane layer was separated, and heptane in the layer was removed by distillation to obtain 34.3 g of N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-octylglycine(2,2,6,6-tetramethyl-4-piperidinyl)ester as a pale brown oily product. Yield, 74% based on N-(2,2,6,6-tetramethyl-4-piperidinyl)-N-octylglycine methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[CH:5](O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2].[Na].[CH2:33]([SH:35])[CH3:34]>>[CH2:1]([O:3][C:4](=[O:31])[CH:5]([S:35][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][N:15]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:9][CH:8]=1)[CH3:2]
Reactant: CCCCCCCN(CCc1ccc(CC(O)C(=O)OCC)cc1)C(=O)OC(C)(C)C
Reactant: CCS
Agent: [Na]
Product: CCCCCCCN(CCc1ccc(CC(SCC)C(=O)OCC)cc1)C(=O)OC(C)(C)C

Procedure:
Synthesized from 3-{4-[2-(tert-butoxycarbonyl-heptyl-amino)-ethyl]-phenyl}-2-hydroxy-propionic acid ethyl ester using a procedure analogous to that used for Example 50 and substituting the sodium salt of ethanethiol as the nucleophile to give an approximate 1:1 mixture of ethyl and methyl ester as a clear film (23 mg, 43%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][CH:9](OS(C)(=O)=O)[CH2:8][C@H:7]1[C:16](=[O:23])[NH:17][C:18]1([C:21]#[N:22])[CH2:20][CH2:19]1)=[O:5])[CH3:2].[C:24]1([SH:30])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:1]([O:3][C:4]([C@@H:6]1[CH2:10][C@H:9]([S:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][C@H:7]1[C:16](=[O:23])[NH:17][C:18]1([C:21]#[N:22])[CH2:19][CH2:20]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)[C@@H]1CC(OS(C)(=O)=O)C[C@H]1C(=O)NC1(C#N)CC1
Reactant: Sc1ccccc1
Product: CCOC(=O)[C@@H]1C[C@H](Sc2ccccc2)C[C@H]1C(=O)NC1(C#N)CC1

Procedure:
The reaction of the mixture of (1R,2R,4R) and (1R,2R,4S)-2-(1-cyano-cyclopropylcarbamoyl)-4-methanesulfonyloxy-cyclopentanecarboxylic acid ethyl ester from step 3 with thiophenol performed in analogy to example 1, step 5, yielded a crude material which was purified on silica using n-heptane/EtOAc (3:2) to give in the first fraction the desired (1R,2R,4R)-2-(1-cyano-cyclopropylcarbamoyl)-4-phenylsulfanyl-cyclopentanecarboxylic acid ethyl ester as a colorless oil. MS: 359.2 (M+H)+.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12](O)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:24])[CH3:23])[CH2:18][CH2:17]1.[CH3:25][S:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[Br:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[C:8]([C:12]([N:32]3[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH2:31]3)=[O:13])[NH:9]2)=[CH:5][C:4]=1[O:15][CH:16]1[CH2:21][CH2:20][N:19]([CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:17]1
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: Cl
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCN(S(C)(=O)=O)CC4)[nH]c3cc2Br)CC1
Yield: 45 %

Procedure:
The title compound was synthesized in analogy to example 1, from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride (example 1, intermediate a) and 1-methylsulfonyl-piperazine to afford the title compound as a light-yellow solid (45%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]3[C:19](=[O:20])[CH2:18][O:17][C:16]3=[O:21])[C:5]=12.N1CCCC1.[C:27]1([CH2:33][CH2:34][CH:35]=O)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(O)C>[C:27]1([CH2:33][CH2:34][CH:35]=[C:18]2[O:17][C:16](=[O:21])[N:15]([CH2:14][CH2:13][CH2:12][CH2:11][O:10][C:6]3[C:5]4[N:4]([CH:3]=[CH:2][N:1]=4)[CH:9]=[CH:8][CH:7]=3)[C:19]2=[O:20])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: O=CCCc1ccccc1
Reactant: O=C1COC(=O)N1CCCCOc1cccn2ccnc12
Solvent: CCO
Solvent: C1CCNC1
Product: O=C1OC(=CCCc2ccccc2)C(=O)N1CCCCOc1cccn2ccnc12
Temperature: 60 °C
Reaction time: 0.33 h

Procedure:
1.45 g (5 mmol) of 3-[4-(imidazo[1,2-a]pyridin-8-yloxy)butyl]oxazolidine-2,4-dione and 20 ml of ethanol were placed in a reaction flask, followed by stirring at 60° C. for 20 minutes, to dissolve the starting materials. After this mixture was kept standing to 50° C., an ethanol solution of 0.05 ml (0.5 mmol) of pyrrolidine was added. Next, an ethanol solution of 0.66 ml (5 mmol) of 3-phenylpropionaldehyde was added, followed by refluxing for 19 hours. 3.5 hours later, 0.66 ml (5 mmol) of 3-phenylpropionaldehyde and 0.05 ml (0.5 mmol) of pyrrolidine were added. After the reaction mixture was cooled, the solvent was distilled off, followed by extraction with dichloromethane and water. After the organic layer was dried with sodium sulfate, the solvent was distilled off. The residue was eluted by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 15 mg (0.74%, yellow oily substance) of the desired product.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[CH2:11][CH:10]([N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])[CH2:9][CH2:8]2)=[O:2].[BH4-].[Na+].Cl>C(O)C.O>[CH2:17]([N:13]([CH2:14][CH2:15][CH3:16])[CH:10]1[CH2:9][CH2:8][C:7]2[C:12](=[C:3]([CH2:1][OH:2])[CH:4]=[CH:5][CH:6]=2)[CH2:11]1)[CH2:18][CH3:19]
Reactant: CCCN(CCC)C1CCc2cccc(C=O)c2C1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(CO)c2C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 8-formyl-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (1 gm, 3.86 mMol) in ethanol (15 mL) was added sodium borohydride (500 mg, 13.2 mMol), and the solution was stirred for 18 hours at room temperature. The reaction mixture was then diluted with water and made acidic with 10% hydrochloric acid. The aqueous was extracted once with diethyl ether, and the organic phase was discarded. The remaining aqueous phase was made basic with concentrated ammonium hydroxide and extracted with dichloromethane. The combined extracts were dried over sodium sulfate and concentrated in vacuo to give a colorless oil. Purification by flash chromatography (3% methanol in dichloromethane+tr. NH4OH) gave the title compound as a colorless, viscous oil (780 mg 77%). The fumarate salt was formed and crystallized (ethanol/diethyl ether) to give colorless crystals (m.p.=151°-152° C.).
Reaction SMILES: O[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[Br:16].C(N(S(F)(F)[F:23])CC)C>ClCCl>[F:23][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:7][C:6]=1[Br:16]
Reactant: CCN(CC)S(F)(F)F
Reactant: OCCOc1ccc(OC(F)(F)F)cc1Br
Solvent: ClCCl
Product: FCCOc1ccc(OC(F)(F)F)cc1Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 20.9 %

Procedure:
To a cooled (-78° C.) suspension of 2-(2-hydroxyethoxy)-5-(trifluoromethoxy)bromobenzene (Description 30; 8.9 g, 30 mmol). in dichoromethane (80 ml) was added diethylaminosulphur trifluoride (3.88 ml, 31.5 mmol). The solution was stirred at ambient temperature for 2 h., then quenched by the dropwise addition of water (100 ml). The organic layer was separated, washed with brine (100 ml), dried (MgSO4), and evaporated in vacuo. Purification in silica, eluting with 15%-20% ethyl acetate in hexane gave the title compound as a clear oil (1.9 g, 15%). 1H NMR (360 MHz, CDCl3) δ4.23 (1H, m), 4.31 (1H, m), 4.37 (1H, m), 4.86 (1H, m), 6.90 (1H, m), 7.15 (1H, m), and 7.47 (1H, t, J 0.7 Hz).
Reaction SMILES: [C:1]([N:4]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH:23]=[CH:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2]>CCO.C(Cl)Cl.[Pd]>[C:1]([N:4]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)[C@H:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:19][CH:18]=2)=[O:16])[C@@H:7]([CH3:28])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(C=CC(=O)O)cc2)c2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(CCC(=O)O)cc2)c2ccccc21
Reaction time: 1 h
Yield: 99 %

Procedure:
(2S,4R)-3-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-propionic acid was prepared from (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid. A solution of (2S,4R)-3-(4-{4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-acrylic acid (50 mg, 0.102 mmol) in EtOH (2 ml) and CH2Cl2 (10 drops for solubility) was subjected to Pd-C (10%, ca. 50 mg) and 1 atm H2 gas. After 1 hour, the mixture was filtered, concentrated and subjected to silica gel chromatography (2% MeOH in EtOAc to 10% MeOH in EtOAc), to afford the title compound (50 mg, 99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([S:7]C(=O)C)[CH2:4][C@H:3]1[CH2:11][O:12]C(=O)C.C[O-].[Na+].[ClH:19]>CO>[ClH:19].[CH3:1][N:2]1[CH2:6][C@@H:5]([SH:7])[CH2:4][C@H:3]1[CH2:11][OH:12]
Reactant: CC(=O)OC[C@@H]1C[C@H](SC(C)=O)CN1C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](S)C[C@H]1CO

Procedure:
To a solution of (2S,4S)-1-methyl-2-acetoxymethyl-4-acetylthiopyrrolidine (231 mg) in methanol (2.4 ml), a solution of sodium methoxide (130 mg) in methanol (1.4 ml) was added at room temperature under nitrogen stream, and the resultant mixture was stirred at the same temperature for 19 minutes. The reaction mixture was combined with conc. hydrochloric acid (375 mg), followed by removal of the solvent. The residue was dissolved in a mixture of chloroform and methanol (4:1) and dried over magnesium sulfate. Removal of the solvent gave (2S,4S)-1-methyl-2-hydroxymethyl-4-mercaptopyrrolidine hydrochloride.
Reaction SMILES: [C:1]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH2:15])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([NH:15][CH:12]1[CH2:11][CH2:10][CH:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:14][CH2:13]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](N)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(NS(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 22 h
Yield: 67.7 %

Procedure:
The trans-N-boc-1,4-cyclohexanediamine (1.00 g, 4.67 mmol) was dissolved in DCM (50 mL). Next, TEA was added (1.301 mL, 9.33 mmol), followed by methanesulfonyl chloride (0.397 mL, 5.13 mmol). The reaction was allowed to stir at rt for 22 h. The reaction mixture was partitioned between DCM (100 mL) and water (25 mL). The phases were separated and the aqueous phase was extracted with DCM (50 mL). Combined organic layer was dried over MgSO4 for 20 h overnight. Filtered and evaporated to dryness to give the title compound of Step A as a solid (0.924 g). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.32 (s, 8H), 2.89 (s, 3H), 1.83-1.91 (m, 1H), 1.70-1.78 (m, 1H), 1.37 (s, 9H).