Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)([CH3:5])[C:3]#[N:4].CC(C[AlH]CC(C)C)C>C1(C)C=CC=CC=1>[Cl:12][C:8]1[CH:7]=[C:6]([C:2]([NH2:1])([CH3:5])[CH2:3][NH2:4])[CH:11]=[CH:10][CH:9]=1
Reactant: CC(N)(C#N)c1cccc(Cl)c1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(N)(CN)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of compound 2-amino-2-(3-chloro-phenyl)-propionitrile (8.0 g) in toluene (60 mL) was cooled to −78° C. and DIBAL-H solution (132 mL of a 1M solution in toluene) was added to it drop wise under nitrogen. The reaction mixture was slowly warmed to room temperature and then left at stirring for 17 h. Reaction was monitored by TLC. After completion, the reaction mixture was quenched with 30 mL methanol and then 100 mL water. All solvents were evaporated and the crude mass was taken in 50 mL water and acidified to pH=1 with 1M HCl. Organic impurities were extracted with ethyl acetate and the aqueous layer was basified to pH=14 with 30% NaOH solution. The free diamine, 2-(3-chloro-phenyl)-propane-1,2-diamine, was extracted with dichloromethane, dried over sodium sulfate, filtered and concentrated (4.2 g). The material was used crude in the next reaction step. MS (ESI): 185.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH:13]=2)=[CH:4][CH:3]=1>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ccc(F)cc2)CC1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97 %

Procedure:
A solution of Example 6B (2 g, 7.2 mmol) in ethanol (30 mL) was treated with 10% Pd/C (200 mg) and shaken at room temperature under 60 psi of H2 for 4 hours. The mixture was filtered and the filter cake was washed with ethanol. The filtrate was concentrated to provide the desired product (1.95 g, 96%). MS (CI) m/e 280 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1.[CH3:15][N:16]([CH3:29])[C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([CH3:28])[CH:20]=1)=[O:18]>>[Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:23](=[O:24])[C:22]2[CH:26]=[CH:27][C:19]([C:17]([N:16]([CH3:29])[CH3:15])=[O:18])=[CH:20][C:21]=2[CH3:28])=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: Cc1cc(C(=O)N(C)C)ccc1C(=O)O
Product: Cc1cc(C(=O)N(C)C)ccc1C(=O)Nc1ccc(Cl)c(-c2ccccn2)c1

Procedure:
In a sealed tube, 1.94 g of dimethyl 2-bromoterephthalate was dissolved in 4 mL of HMPA and degassed with nitrogen prior to adding 1.1 mL of tetramethyl tin and 0.077 g of palladium tetrakistriphenylphosphene. After sealing the tube, the reaction was heated to 65° C. for 16 h. The reaction was then partitioned into ethylether and water and extracted. The organic layers were washed with 5% ammonium hydroxide, 1N HCl, again with 5% ammonium hydroxide, and finally with water. Filtration of the solvent through sodium sulfate and evaporation gave 1.44 g of crude dimethyl 2-methylterephthalate. 210 mg of dimethyl 2-methylterephthalate was hydrolyzed via Procedure M to give 4-(methoxycarbonyl)-3-methylbenzoic acid. Silica gel chromatography was performed (0% to 70% EtOAc gradient in Hexanes) to yield 115 mg of 4-(methoxycarbonyl)-3-methylbenzoic acid. 4-(methoxycarbonyl)-3-methylbenzoic acid was then coupled to dimethylamine hydrochloride via Procedure G. The crude methyl 4-(dimethylcarbamoyl)-2-methylbenzoate was then hydrolyzed via Procedure M to give 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid. 4-chloro-3-(pyridin-2-yl)aniline was coupled to 110 mg of 4-(dimethylcarbamoyl)-2-methylbenzoic acid via Procedure G to yield N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4,N4,2-trimethylterephthalamide. MS (Q1) 394 (M)+.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]([O:7]C)=O.[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH:29]=O)[S:24][CH:25]=1>>[Cl:20][C:21]1[N:22]=[C:23]([C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=2)[CH2:29][N:1]2[CH:2]([C:10]3[C:11]([O:18][CH3:19])=[N:12][CH:13]=[CH:14][C:15]=3[O:16][CH3:17])[CH2:3][CH:4]([CH3:9])[C:5]2=[O:7])[S:24][CH:25]=1
Reactant: COC(=O)C(C)CC(N)c1c(OC)ccnc1OC
Reactant: O=Cc1cccc(-c2nc(Cl)cs2)c1
Product: COc1ccnc(OC)c1C1CC(C)C(=O)N1Cc1cccc(-c2nc(Cl)cs2)c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of methyl 4-amino-4-(2,4-dimethoxypyridin-3-yl)-2-methylbutanoate with synthesized 3-(4-chlorothiazol-2-yl)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.81 min.; [M+H]+: 443.85 g/mol.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8](=[O:15])OCC(Cl)(Cl)Cl)=[CH:3][N:2]=1.[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:16]1([C:22]2[N:26]=[C:25]([N:27]3[CH2:32][CH2:31][N:30]([C:8]([NH:7][C:4]4[CH:5]=[CH:6][N:1]=[N:2][CH:3]=4)=[O:15])[CH2:29][CH2:28]3)[S:24][N:23]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccnnc1)OCC(Cl)(Cl)Cl
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: O=C(Nc1ccnnc1)N1CCN(c2nc(-c3ccccc3)ns2)CC1
Yield: 40.5 %

Procedure:
A solution of 2,2,2-trichloroethyl pyridazin-4-ylcarbamate (100 mg, 0.370 mmol), 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (88.9 mg, 0.370 mmol), diisopropylethylamine (0.0645 ml, 0.370 mmol) and dimethylsulfoxide (2 ml) was stirred at 70° C. for 12 hours, the reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired product (55.0 mg, 40.4%) as a solid.
Reaction SMILES: [CH:1]1([N:4]2[C:8]([N:9]3[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]3)=[C:7]([N+:23]([O-])=O)[CH:6]=[N:5]2)[CH2:3][CH2:2]1.[C:26]([O:30][C:31]([NH:33][C:34]1[S:38][C:37]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=2[F:45])=[N:36][C:35]=1[C:46](O)=[O:47])=[O:32])([CH3:29])([CH3:28])[CH3:27]>>[F:45][C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[C:37]1[S:38][C:34]([NH:33][C:31](=[O:32])[O:30][C:26]([CH3:28])([CH3:27])[CH3:29])=[C:35]([C:46](=[O:47])[NH:23][C:7]2[CH:6]=[N:5][N:4]([CH:1]3[CH2:3][CH2:2]3)[C:8]=2[N:9]2[CH2:15][CH2:14][CH2:13][C@@H:12]([NH:16][C:17](=[O:22])[C:18]([F:21])([F:20])[F:19])[CH2:11][CH2:10]2)[N:36]=1
Reactant: O=C(N[C@@H]1CCCN(c2c([N+](=O)[O-])cnn2C2CC2)CC1)C(F)(F)F
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)O
Product: CC(C)(C)OC(=O)Nc1sc(-c2ccccc2F)nc1C(=O)Nc1cnn(C2CC2)c1N1CCC[C@@H](NC(=O)C(F)(F)F)CC1
Yield: 76 %

Procedure:
Following the procedure for Example 506 starting with (R)—N-(1-(1-cyclopropyl-4-nitro-1H-pyrazol-5-yl)azepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(2-fluorophenyl)thiazole-4-carboxylic acid gave (R)-tert-butyl 2-(2-fluorophenyl)-4-(1-cyclopropyl-5-(4-(2,2,2-trifluoroacetamido)azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate as a cream solid (370 mg, 76%). 1H-NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 8.69 (s, 1H), 8.12-8.00 (m, 1H), 7.45-7.30 (m, 1H), 7.28-7.15 (m, 3H), 6.40-6.27 (m, 1H), 4.30-4.15 (m, 1H), 3.43-3.15 (m, 5H), 2.25-1.75 (m, 6H), 1.55 (s, 9H), 1.35-1.15 (m, 2H), 1.10-0.95 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:4]([NH:6][C:7]1[S:15][C:10]2[CH2:11][O:12][CH:13]([CH3:14])[C:9]=2[C:8]=1[C:16]([O:18]CC)=[O:17])=[O:5].[OH-].[K+].Cl>C(O)C.O>[F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:27])([F:26])[F:28])[C:3]=1[C:4]([NH:6][C:7]1[S:15][C:10]2[CH2:11][O:12][CH:13]([CH3:14])[C:9]=2[C:8]=1[C:16]([OH:18])=[O:17])=[O:5]
Reactant: CCOC(=O)c1c(NC(=O)c2c(F)cccc2C(F)(F)F)sc2c1C(C)OC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1OCc2sc(NC(=O)c3c(F)cccc3C(F)(F)F)c(C(=O)O)c21
Temperature: 25 °C

Procedure:
A mixture of Example 1B (334 mg, 0.800 mmol) and solid potassium hydroxide (337 mg, 6.00 mmol) in ethanol (4 mL) and water (1 mL) were heated to reflux for 1 hour. After cooling to room temperature, 1 N aqueous HCl was added dropwise to adjust the mixture to pH 1. The mixture was extracted with ethyl acetate (3×10 mL). The combined extracts were dried over magnesium sulfate, filtered, and concentrated under reduced pressure to provide the title compound. LC-MS (ESI+) m/z 390 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:11]([O-])=O)[CH:3]=1>C(O)C.[C].[Pd]>[NH2:11][C:4]1[CH:3]=[C:2]([F:1])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: O=C(O)c1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1cc(F)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
To a solution of 4-fluoro-2-nitrobenzoic acid (22.5 g, 0.1 mol) in ethanol (200 mL), 10% palladium-carbon (1.0 g, 50% hydrate) was added, and the mixture was stirred at room temperature under hydrogen atmosphere for 4 hours. The solution was filtered to remove the catalyst, and the filtrate was concentrated under reduced pressure to give the title compound (8.38 g, 100% yield).
Reaction SMILES: [C@@H:1]12[O:11][CH2:10][C@@H:8]([O:9]1)[C:6](O)=[C:4](O)[C@@H:2]2[OH:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]([CH:39]=[C:40]([O:42][CH3:43])[CH:41]=1)[C:36](O)=[O:37].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:43][O:42][C:40]1[CH:39]=[C:35]([CH:34]=[C:33]([O:32][CH3:31])[CH:41]=1)[C:36]([O:3][C@@H:2]1[CH:4]=[CH:6][C@H:8]2[CH2:10][O:11][C@@H:1]1[O:9]2)=[O:37]
Reactant: OC1=C(O)[C@H](O)[C@@H]2OC[C@H]1O2
Reactant: COc1cc(OC)cc(C(=O)O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(OC)cc(C(=O)O[C@@H]2C=C[C@H]3CO[C@@H]2O3)c1
Yield: 83.8 %

Procedure:
1.28 g (10.0 mmol) of 1,6-anhydro-β-D-threo-hex-3-enopyranose, 5.25 g (20.0 mmol) of triphenyl phosphine, and 3.64 g (20.0 mmol) of 3,5-dimethoxybenzoic acid were added to 16 ml of dry THF, and a solution obtained by dissolving 3.48 g (20.0 mmol) of diethylazodicarboxylate in 16 ml of dry THF was gradually dropped in the above mixture in a nitrogen-sealed ice-water bath. The resultant solution was stirred at room temperature for 45 hours. The solvent was distilled from the reaction solution at a reduced pressure. Triphenyl phosphine oxide as a byproduct was eliminated from the residue using a silica gel column (eluent: chloroform). The solvent was distilled from the resultant eluate at a reduced pressure, and the residue was purified using a silica gel column (hexane:ethyl acetate=5:1) to obtain 2.45 g (yield: 83.7%) of 1,6-anhydro-3,4-dideoxy-2-O-(3,5-dimethoxybenzoyl)-β-D-erythro-hex-3-enopyranose. This product was recrystallized from a solvent mixture of hexane and diethyl ether.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[Cl:24][C:25]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=[O:28]>>[Cl:24][C:25]1[C:33]([F:34])=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]([NH:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2)=[O:28]
Reactant: O=C(O)c1cccc(F)c1Cl
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc(F)c2Cl)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 2-Chloro-3-fluoro-benzoic acid.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[NH2:12][C:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=2)[N:15]([CH3:26])[N:14]=1>>[F:25][C:22]([F:23])([F:24])[C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH3:26])[N:14]=[C:13]2[NH:12][C:2]1[CH:11]=[N:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1ccncc1Br
Reactant: Cn1nc(N)c2cc(C(F)(F)F)ccc21
Product: Cn1nc(Nc2cnccc2C(=O)O)c2cc(C(F)(F)F)ccc21
Yield: 44 %

Procedure:
The title compound was prepared in 44% yield from methyl 3-bromoisonicotinate and 3-amino-5-trifluoromethyl-1-methyl-indazole according to the general procedure for Example 6. 1H NMR (400 MHz, DMSO-d6): δ 4.05 (3H, s), 7.72-7.83 (3H, m), 7.99 (1H, s), 8.21 (1H, d, J=5.0 Hz), 9.64 (1H, s), 10.69 (1H, br s), 14.12 (1H, br s). [M+H] calc'd for C15H11F3N4O2, 337; found 337.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:4]=[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][C:8]([C:17]3[S:21][C:20]([N:22]([CH:30]([CH3:32])[CH3:31])C(=O)OC(C)(C)C)=[N:19][CH:18]=3)=[CH:7][N:6]2[CH:33]=1>C(O)(C(F)(F)F)=O>[CH:30]([NH:22][C:20]1[S:21][C:17]([C:8]2[CH:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:5]3[N:6]([CH:33]=[C:3]([CH2:2][OH:1])[N:4]=3)[CH:7]=2)=[CH:18][N:19]=1)([CH3:32])[CH3:31]
Reactant: CC(C)N(C(=O)OC(C)(C)C)c1ncc(-c2cc(-c3ccccc3)c3nc(CO)cn3c2)s1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1ncc(-c2cc(-c3ccccc3)c3nc(CO)cn3c2)s1

Procedure:
A solution of tert-butyl 5-(2-(hydroxymethyl)-8-phenylimidazo[1,2-a]pyridin-6-yl)thiazol-2-yl(isopropyl)carbamate (75 mg) in 4 ml of TFA was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was made basic with 1 N NaOH and extracted into CH2Cl2. The solvent was removed under vacuum and the residue purified by column chromatography on silica gel using ethyl acetate as eluent to give (6-(2-(isopropylamino)thiazol-5-yl)-8-phenylimidazo[1,2-a]pyridin-2-yl)methanol as a light yellow solid. LCMS (Conditions C): 1.82 min (RT); (M+H)+=365.31 (100%). 1H NMR, 400 MHz, CDCl3/CD3OD: δ 8.08 (d, 1 H), 7.89 (m, 2 H), 7.61-7.31 (m, 6 H), 4.74 (s, 2 H), 3.71 (m, 1 H), 1.32 (d, J=6.4 Hz, 6 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][C:17]3([F:26])[C:18](=O)[NH:19][C:20]=2[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:44])=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([Cl:34])[CH:29]=1)[CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]2[CH:16]3[CH2:25][CH2:24][CH2:23][C:17]3([F:26])[C:18](=[S:44])[NH:19][C:20]=2[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N(CCCc1ccc2c(c1)NC(=O)C1(F)CCCC21)Cc1cccc(Cl)c1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N(CCCc1ccc2c(c1)NC(=S)C1(F)CCCC21)Cc1cccc(Cl)c1

Procedure:
A solution of 100 mg (0.21 mmol) of 7-[3-(N-tert-butoxycarbonyl-3-chlorobenzylamino)propyl]-3a-fluoro-1,2,3,3a,5,9b-hexahydrocyclopenta[c]quinolin-4-one and 223 mg (0.55 mmol) of Lawesson's reagent in 15 ml of THF is refluxed for 1.5 hours. After concentration by evaporation in a vacuum, the residue is purified by column chromatography with hexane-ethyl acetate: 80 mg of product.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:39])=[O:38])[C@H:16]([CH2:47][CH:48]([NH2:50])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1.CCN(CC)CC.[C:59](Cl)(=[O:61])[CH3:60]>C(Cl)Cl.O>[CH3:1][O:2][CH2:3][C@H:4]([CH3:51])[CH2:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C@@H:14]2[C@@H:19]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]4[O:30][CH2:29][CH2:28][N:27]([CH2:31][CH2:32][CH2:33][O:34][CH3:35])[C:26]=4[CH:36]=3)[CH2:18][N:17]([S:37]([C:40]3[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=3)(=[O:38])=[O:39])[C@H:16]([CH2:47][C@H:48]([NH:50][C:59](=[O:61])[CH3:60])[CH3:49])[CH2:15]2)=[CH:10][CH:9]=1
Reactant: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](CC(C)N)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COCCCN1CCOc2ccc(CO[C@H]3CN(S(=O)(=O)c4ccc(C)cc4)[C@H](C[C@@H](C)NC(C)=O)C[C@@H]3c3ccc(COC[C@@H](C)COC)cc3)cc21
Reaction time: 1 h

Procedure:
To a solution of 1.0 mmol of (R and S)-2-[(2S,4R,5R)-4-[4-((S)-3-methoxy-2-methyl-propoxymethyl)-phenyl]-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-1-(toluene-4-sulfonyl)-piperidin-2-yl]-1-methyl-ethylamine, 4.0 mmol of Et3N in 25 ml of CH2Cl2 are added 2.0 mmol of acetyl chloride at 0° C. and the resulting mixture is stirred for 1 h. The reaction mixture is diluted with water and extracted with CH2Cl2. The organic phases are combined, dried over Na2SO4 and concentrated under reduced pressure. The resulting diastereomeric mixture is separated by flash chromatography (SiO2 60 F) to afford:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.[Li]CCCC.[CH3:16][Si:17]([CH3:30])([CH3:29])[CH2:18][CH2:19][O:20][CH2:21][N:22]1[CH:26]=[CH:25][N:24]=[C:23]1[C:27]#[N:28].Cl[C:32]([O:34][CH2:35][CH3:36])=[O:33]>C1COCC1>[CH2:35]([O:34][C:32]([C:26]1[N:22]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:30])([CH3:29])[CH3:16])[C:23]([C:27]#[N:28])=[N:24][CH:25]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)Cl
Reactant: C[Si](C)(C)CCOCn1ccnc1C#N
Agent: CC1(C)CCCC(C)(C)N1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(C#N)n1COCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 48 %

Procedure:
To a solution of 2,2,6,6-tetramethyl-piperidine (0.365 mL, 2.17 mmol) in 4 mL of THF at −50° C. was added n-BuLi (1.08 mL, 2.17 mmol, 2M in pentane) and the mixture allowed to stir for 10 min at 0° C. The mixture was cooled to −50° C. and a solution of 1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carbonitrile (prepared in the previous step) (0.440 g, 1.97 mmol) in 2 mL of THF was added and the reaction stirred for 1 h at −50° C. and then ethyl chloroformate (0.210 mL, 2.17 mmol) was added. After 10 min at −50° C. the reaction was quenched with brine (20 mL) and extracted with EtOAc (2×20 mL) and the organic layer dried (Na2SO4) and concentrated. The title compound was eluted from a 20-g SPE column with 20% EtOAc/hexanes to give 0.280 g (48%) of a colorless oil. 1H-NMR (CDCl3, 400 MHz): δ 7.81 (s, 1H), 5.89 (s, 2H), 4.40 (q, J=7.1 Hz, 2H), 3.65 (m, 2H), 1.41 (t, J=7.1 Hz, 3H), 0.96 (m, 2H), 0.00 (s, 9H). Mass spectrum (ESI, m/z): Calcd. for C13H21N3O3Si, 296.1 (M+H), found 295.5.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9]C)[CH2:5][C:6]#[N:7])C.[CH3:11][C:12]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:13]=1[CH:14]=O.C[O-].[Na+]>CO>[CH3:9][O:8][CH:4]([O:3][CH3:1])/[C:5](=[CH:14]/[C:13]1[CH:16]=[CH:17][CH:18]=[C:19]([CH3:20])[C:12]=1[CH3:11])/[C:6]#[N:7]
Reactant: CCOC(CC#N)OCC
Reactant: Cc1cccc(C=O)c1C
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(OC)/C(C#N)=C/c1cccc(C)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3,3-bis(ethyloxy)propanenitrile (2.3 g, 20 mmol) and 2,3-dimethylbenzaldehyde (2.1 g, 16 mmol) in methanol (10 mL) was added a 25-30% of sodium methoxide in methanol over 20 minutes. The reaction mixture was stirred at room temperature overnight. Most of solvent was evaporated in vacuo and the residue was dissolved with ethyl acetate (30 mL) and water (15 mL). The two layers were separated. Organic layer was separated, washed with brine (15 mL), dried and concentrated in vacuo. The residue was then purified to give product. It was used in next step. (1.55 g, 33%); 1H NMR (600 MHz, DMSO-d6) δ ppm 2.20 (s, 3H) 2.28 (s, 3H) 3.37 (s, 6H) 5.13 (s, 1H) 7.17-7.22 (m, 1H) 7.27 (d, J=7.55 Hz, 1H) 7.39-7.45 (m, 1H) 7.79 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][CH2:13][CH2:14][OH:15])[CH:9]([OH:16])[CH2:8][CH2:7]2.N1C=CN=C1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>CN(C)C=O.O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH:10]([CH2:12][CH2:13][CH2:14][O:15][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:9]([OH:16])[CH2:8][CH2:7]2
Reactant: OCCCC1c2c(Br)cccc2CCC1O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCCC1c2c(Br)cccc2CCC1O
Temperature: 25 °C
Yield: 107.1 %

Procedure:
A solution of 8-bromo-1,2,3,4-tetrahydro-1-(3-hydroxypropyl)-2-hydroxynaphthalene (B-3, 29.15 g, 0.10 mol) and imidazole (17.02 g, 0.25 mol) in dimethylformamide (70 mls) was cooled in ice, and t-butyldimethylsilyl chloride (17.3 g, 0.115 mol) was added with stirring. The mixture was allowed to warm to room temperature slowly. After stirring for a total of 18 hours, crushed ice (30 mls) was added, and the mixture was stirred at ambient temperature for 0.5 hour. The mixture was diluted with water (300 mls) and extracted twice with 1:1 diethylether/hexane. The extracts were washed twice with water and once with brine. The solution was dried (MgSO4), and the solvent was removed under vacuum to leave the title compound as an oil (B-4, 42.78 g, 100%). NMR (CDCl3, TMS)δ0.083, 0.099 (twos,6H,Si-CH3), 0.91 (s,9H,Si-tBu), 1.50-1.60(m, 1H), 1.8-2.0(m,5H), 2.8-3.0(m,2H), 3.19 (d,J=4.3 Hz, 1H), 3.48(m,5 lines, 1H), 3.65-3.85 (m,2H), 4.0-4.13 (m,1H), 6.86(t,J=7.6 Hz, 1H), 6.93 (br. d,J=7.6 Hz, 1H), 7.30 (br. d,J=7.5 Hz,1H). IR (Major peaks)3411, 3057, 1592, 1559, 1472, 1463, 1438, 1256, 1100, 1067, 835, 774. CI Mass spec. m+at m/z 399,401.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([S:26]([C:29]([F:32])([F:31])[F:30])(=[O:28])=[O:27])=[CH:5][C:6]2[CH2:12][CH2:11][N:10](C(=O)C(F)(F)F)[CH2:9][CH:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:7]=2[CH:25]=1.[OH-].[Na+]>CO>[CH3:1][O:2][C:3]1[C:4]([S:26]([C:29]([F:31])([F:30])[F:32])(=[O:28])=[O:27])=[CH:5][C:6]2[CH2:12][CH2:11][NH:10][CH2:9][CH:8]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:7]=2[CH:25]=1
Reactant: COc1cc2c(cc1S(=O)(=O)C(F)(F)F)CCN(C(=O)C(F)(F)F)CC2c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cc2c(cc1S(=O)(=O)C(F)(F)F)CCNCC2c1ccccc1

Procedure:
8-Methoxy-1-phenyl-3-trifluoroacetyl-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (5 g, 0.01 m) dissolved in methanol is treated with 40% aqueous sodium hydroxide and stirred. The mixture is concentrated in vacuo and partitioned between ethyl acetate and water to give 8-methoxy-1-phenyl-7-trifluoromethylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].[CH3:14][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI.C(OCC)(=O)C.CCCCCC>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CSc1ccc(CC(=O)O)cc1F
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccc(C(C)C(=O)O)cc1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 31 %

Procedure:
2-(3-Fluoro-4-(methylthio)phenyl)acetic acid (3 g, 0.01 mol) was dissolved in dry THF (60 mL) and the mixture was cooled to −78° C. Lithium bis(trimethylsilyl)amide (45 mL, 3 eq) was added at −78° C. and the mixture was stirred for 1 h at the same temperature. Methyl iodide (0.93 mL, 1 eq) was added at −78° C., the mixture was allowed to come to room temperature and stirred for 3 h at the same temperature. Progress of the reaction was monitored by TLC (50% ethyl acetate/hexane, Rf˜0.5). Although the reaction had not been completed the mixture was worked-up. The reaction contents were quenched with saturated ammonium chloride solution at 0° C. The contents were acidified with diluted HCl, the organic layer was separated and the aqueous layer was extracted with ethyl acetate (2×50 mL). the combined extract was dried over sodium sulfate, concentrated under reduced pressure and the crude product obtained was purified by column chromatography (10% ethyl acetate/hexane) to yield 2-(3-fluoro-4-(methylthio)phenyl)propanoic acid as an yellow solid (1 g, 31%).