Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:4]1[C:5]([OH:17])=[CH:6][C:7]2C[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH3:16])[C:12]=2[CH:13]=1)(=O)C.[OH-].S(OC)([O:22][CH3:23])(=O)=O>>[CH3:23][O:22][C:16]1[CH:9]=[CH:10][C:11]([C:12]2[CH:13]=[CH:4][C:5]([OH:17])=[CH:6][CH:7]=2)=[CH:14][CH:15]=1
Reactant: COS(=O)(=O)OC
Reactant: CCCC1CCCc2cc(O)c(C(C)=O)cc21
Agent: [OH-]
Product: COc1ccc(-c2ccc(O)cc2)cc1

Procedure:
4,4'-Dihydroxydiphenyl (1) (32 g 0.17 mol) was dissolved in 2M solution hydroxide solution (0.34 mol) and dimethyl sulphate (22 g 0.175 mol) was added slowly with stirring over half an hour. The sodium salt of the required product was filtered off and dried. The yield was 24 g. The sodium salt of the phenol (24 g) was treated with acetyl chloride (150 cm3), filtered and excess acetyl chloride removed. Work up gave 4- methoxy-4'-acetoxydiphenyl (4) (22 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([CH3:20])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([Sn](CCCC)(CCCC)C=C)CCC.[Li+].[Cl-]>C1(C)C=CC=CC=1.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:1]([N:8]1[CH2:23][CH2:22][N:11]2[C:12](=[O:21])[C:13]3[CH:14]=[C:15]([CH:20]=[CH2:24])[CH:16]=[CH:17][C:18]=3[CH2:19][C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: C=Cc1ccc2c(c1)C(=O)N1CCN(Cc3ccccc3)C[C@H]1C2
Temperature: 110 °C

Procedure:
Degassed mixture of (R)-2-benzyl-8-methyl-1,2,3,4,11,11a-hexahydro-pyrazino[1,2-b]isoquinolin-6-one (50 mg, 0.13 mmol), tributyl(vinyl)tin (64 mg, 0.20 mmol), dichlorobis(triphenylphosphine)palladium (9.1 mg, 0.013 mmol) and LiCl (27.5 mg, 0.65 mmol) in toluene (1 mL) was heated at 110° C. for 18 h to give dark brownish reaction mixture. The mixture was then cooled, diluted with ethyl acetate (10 mL) and filtered through bed of celite and rinsed with more ethyl acetate (20 mL). Filtrate was concentrated and purified by prep TLC (SiO2, 95:5, CH2Cl2:MeOH) to give (25 mg, 60%) as a faint yellow oil. MS (ESI) 319 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH2:13])[S:11][CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1.[C:15](OC(=O)C)(=[O:17])[CH3:16]>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[N:9]=[C:10]([NH:13][C:15](=[O:17])[CH3:16])[S:11][CH:12]=2)[CH:5]=[C:4]([Cl:14])[N:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Product: CC(=O)Nc1nc(-c2cc(Cl)nc(Cl)c2)cs1
Reaction time: 16 h
Yield: 93.8 %

Procedure:
7.38 g (0.03 mol) of [4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-amine and 70 ml of acetic anhydride are heated under reflux for 30 minutes, a solution initially forming but a precipitate then separating out. The reaction mixture is left to stand at room temperature for 16 hours, 200 ml of ice-water are then added and the mixture is filtered with suction. The residue is first washed several times with water and then digested with 200 ml of 5% strength aqueous sodium bicarbonate solution, and is filtered off with suction again. The product is dried at 50° C. under reduced pressure. 8.1 g (93.8% of theory) of N-[4-(2,6-dichloropyridin-4-yl)-thiazol-2-yl]-acetamide are obtained in this manner in the form of a solid substance of melting point 301° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[N+:9]([C:12]1[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=1)([O-:11])=[O:10].Cl>O>[N+:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Nc1cccc(O)c1
Agent: Cl
Solvent: O
Product: O=[N+]([O-])c1ccc(Nc2cccc(O)c2)cc1

Procedure:
A mixture of 32.4 g (0.3 mol) of m-aminophenol and p-nitrofluorobenzene (0.15 mol) was boiled under reflux for 10 days in 400 ml of water and then poured into dilute hydrochloric acid, followed by extraction with ethyl acetate, washing 2 to 3 times with dilute hydrochloric acid and then concentrated. The deposited crystals were washed with hot benzene, cooled and then filtered. The yield was 26 g and the melting point was 158°-160° C.
Reaction SMILES: [H-].[Na+].Br[C:4]1[N:5]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:6]2[N:7]=[C:8]([C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=3[Cl:28])[N:9]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[C:10](=[O:13])[C:11]=2[N:12]=1.[CH3:35][OH:36]>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([N:9]2[C:10](=[O:13])[C:11]3[N:12]=[C:4]([O:36][CH3:35])[N:5]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:6]=3[N:7]=[C:8]2[C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:22]=2[Cl:28])=[CH:15][CH:16]=1
Reactant: CO
Reactant: O=c1c2nc(Br)n(-c3ccccc3)c2nc(-c2ccc(Cl)cc2Cl)n1-c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: COc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n1-c1ccccc1
Temperature: 80 °C
Reaction time: 0.05 h

Procedure:
A microwave tube is charged with sodium hydride (24.0 mg, 1.0 mmol) and dry methanol. After the reaction mixture is stirred for 3 min, 8-Bromo-1-(4-chloro-phenyl)-2-(2,4-dichloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (8.0 mg, 0.015 mmol) is added. The tube is then capped and the mixture is heated in an oil bath for 3 h at 80° C. The reaction mixture is worked up by evaporating the solvent. The crude material is purified by flash chromatography. 1H NMR (CDCl3, 400 MHz) δ 7.63 (m, 4H), 7.43 (m, 1H), 7.28 (m, 4H), 7.11 (d, 2H), 7.03 (m, 1H), 4.25 (s, 3H). HPLC-MS calculated for C24H15Cl3N4O2 (M+H+) 497.0. Found: 497.0.
Reaction SMILES: [CH3:1][C:2]1O[C:6]([CH2:8][OH:9])=[CH:5][C:4](=[O:10])[C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1.Cl.[NH2:22][OH:23]>N1C=CC=CC=1>[CH3:1][C:2]1[N:22]([OH:23])[C:6]([CH2:8][OH:9])=[CH:5][C:4](=[O:10])[C:3]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=1
Reactant: NO
Reactant: COc1ccc(COc2c(C)oc(CO)cc2=O)cc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(COc2c(C)n(O)c(CO)cc2=O)cc1
Reaction time: 7 h
Yield: 30.8 %

Procedure:
To a solution of 4 g of 6-methyl-5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone in 50 ml of pyridine was added 5 g of hydroxylamine hydrochloride at room temperature. The mixture was stirred at 70° to 75° C. for 7 hours. After the reaction liquid was concentrated under reduced pressure, the residue was dissolved in 600 ml of chloroform and washed in succession with water and saturated aqueous sodium hydrogencarbonate solution. After drying the chloroform layer over anhydrous magnesium sulfate, the organic phase was dried and concentrated under reduced pressure. The concentrate was separated and purified by flash column chromatography (eluting solution; chloroform: methanol=20:1) using Wako Gel C-300 (manufactured by Wako Pure Chemical Industry Co., Ltd.) (100 g) to give 1.3 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH:21][C:20]([C:17]2[CH:18]=[CH:19][C:14]([O:13][CH2:12][O:11][CH3:10])=[CH:15][CH:16]=2)=[O:22])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: COCOc1ccc(C(C)=O)cc1
Product: COCOc1ccc(C(=O)C=Cc2ccc(Cl)cc2)cc1

Procedure:
By a procedure similar to that of example 1.59.1, starting from 4-chlorobenzaldehyde and p-methoxymethoxyacetophenone, 3-(4-chlorophenyl)-1-(4-methoxymethoxy-phenyl)prop-2-en-1-one was obtained as yellowish solid.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:23][OH:24])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:25]I>CN(C=O)C.CCOCC>[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12][CH:11]1[CH2:23][O:24][CH3:25])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 106.9 %

Procedure:
Sodium hydride (0.857 g, 21.42 mmol) was added portionwise to stirred Et2O (23.0 ml) at 25° C. under nitrogen. A solution of (1,4-dibenzylpiperazin-2-yl)methanol (1.411 g, 4.76 mmol) in DMF (8.0 ml) was added portionwise under nitrogen. The resulting suspension was stirred at room temperature for 1 h. A solution of methyl iodide (0.454 ml, 7.28 mmol) in Et2O (7.0 ml) was added dropwise to the reaction mixture at 10° C., under nitrogen. The resulting mixture was stirred at room temperature for 21 h. The reaction mixture was quenched with water (35 mL and extracted with Et2O (3×50 mL). The organic layers were combined and washed with water (50 mL), dried over MgSO4, filtered and evaporated to afford 1,4-dibenzyl-2-(methoxymethyl)piperazine (1.580 g, 107%) as a yellow oil. This was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][CH2:5][CH2:4][N:3]=1.S(C1C=CC(C)=CC=1)(O[CH3:14])(=O)=O>>[CH3:14][N:3]1[CH2:4][CH2:5][CH2:6][C:7]([CH3:9])([CH3:8])[C:2]1=[CH2:1]
Reactant: CC1=NCCCC1(C)C
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: C=C1N(C)CCCC1(C)C

Procedure:
A mixture of 5 g of 2,3,3-trimethyl-3,4,5,6-tetrahydropyridine and 12 g of methyl tosylate was reacted at 100° C. for 4 hours. The reaction mixture was cooled and extracted with water/chloroform. Then, 2 g of sodium hydroxide was added to the water layer and the mixture was stirred. The liquid was extracted with chloroform. The chloroform layer was concentrated to obtain a yellow liquid.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH:29]([CH3:31])[CH3:30])=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:32][CH2:33][C:34]([O:36]CC)=[O:35])=[CH:7][NH:8]2.Cl>C1COCC1.O>[F:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]2[N:17]=[C:16]([C:18]3[CH:19]=[N:20][C:21]([O:28][CH:29]([CH3:30])[CH3:31])=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=3)[O:15][N:14]=2)=[C:9]2[C:5]=1[C:6]([CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:7][NH:8]2
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4cnc(OC(C)C)c(C(F)(F)F)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)Oc1ncc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1C(F)(F)F
Temperature: 90 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Sodium hydroxide (30 mg) was added to a solution of ethyl 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoate (D49) (161 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-(4-fluoro-7-{5-[6-[(1-methylethyl)oxy]-5-(trifluoromethyl)-3-pyridinyl]-1,2,4-oxadiazol-3-yl}-1H-indol-3-yl)propanoic acid (E24) (93 mg) as a white solid. δH (DMSO-d6, 400 MHz): 1.38 (6H, d), 2.62 (2H, t), 3.05 (2H, t), 5.54 (1H, m), 6.98 (1H, dd), 7.26 (1H, d), 7.92 (1H, dd), 8.74 (1H, d), 9.32 (1H, d), 11.12 (1H, s), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −118.6, −62.8. MS (ES): C22H18F4N4O4 requires 478; found 479.1 (M+H+).
Reaction SMILES: [CH2:1]=[C:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4].[H][H]>C(O)C>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:3]([OH:5])=[O:4]
Reactant: C=C(CCCCCCC)C(=O)O
Reactant: [H][H]
Solvent: CCO
Product: CCCCCCCC(C)C(=O)O
Yield: 98.9 %

Procedure:
In a 200 ml autoclave, the inside atmosphere of which had previously been replaced with argon, were placed 3.0 g (17.6 mmoles) of 2-methylenenonanoic acid and 50 ml of ethanol. Then, 6.9 mg (0.007 mmole) of [Ru((-)-T-BINAP)](ClO4)2 prepared according to the same manner as in Referential Example 6 except using (-)-T-BINAP in place of (+)-T-BINAP was added to the mixture to perform hydrogenation for 15 hours at a hydrogen pressure of 30 kg/cm2 and at a reaction temperature of 20° C. Thereafter, the solvent was distilled off to provide 3.0 g of 2-methylnonanoic acid. The theoretical yield (hereafter simply referred to as "yield") was 100%.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.BrN1C(=O)CCC1=O.C(N(CC)C(C)C)(C)C>C1C=CC=CC=1>[CH3:1][C:2]1[O:3][C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1
Reactant: Cc1nc2c(o1)CCc1ccccc1C2=O
Agent: O=C1CCC(=O)N1Br
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: Cc1nc2c(=O)c3ccccc3ccc2o1

Procedure:
A stirred mixture of 9,10-dihydro-2-methyl-4H-benzo[5,6]cyclohepta[1,2-d]oxazol-4-one (9.52 g) (J. Med. Chem., 1974, 17, 1316) and N-bromosuccinimide (7.95 g) in benzene (200 ml) was irradiated with a 500 Watt halogen lamp for 2 h. The mixture was then treated with N,N-diisopropylethylamine (15.5 ml) and set at reflux for 1 hour. The mixture was then partitioned between ethyl acetate and water. The organic phase was collected, dried (MgSO4) and solvent evaporated under reduced pressure. Purification was by recrystallisation from ethyl acetate to give a buff solid.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][C@@H:10]([C@@H:13]([NH:15][CH2:16][CH2:17][F:18])[CH3:14])[CH2:9]1)C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[F:18][CH2:17][CH2:16][NH:15][C@H:13]([C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH3:14]
Reactant: C[C@H](NCCF)[C@@H]1CCN(Cc2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: C[C@H](NCCF)[C@@H]1CCNC1
Temperature: 25 °C

Procedure:
A solution of (S)-1-((R)-1-benzylpyrrolidin-3-yl)-N-(2-fluoroethyl)ethanamine (0.27 g, 1.08 mmol) and palladium hydroxide (0.27 g, 20 wt. % Pd on carbon, 50% wet) in ethanol (8.0 mL) is heated at 40° C. for 15 h under an atmosphere of hydrogen, and cooled to rt. The resulting mixture is filtered through a Büchner funnel on a layer of Celite washing with methanol. The filtrate is evaporated under reduced pressure to afford the title compound in quantitative yield (0.17 g). The residue obtained is used in the next reaction without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:8]3[C:9]([C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=3)=[CH:10][NH:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].ClC1C2C(=CC([N+]([O-])=O)=CC=2)N=CC=1[C:38](OCC)=[O:39].COC1C=CC(NN)=CC=1>>[CH3:38][O:39][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:9]3=[CH:10][NH:11][C:12]4[CH:13]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[CH:6][C:7]=4[C:8]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: O=c1c2c[nH]c3cc([N+](=O)[O-])ccc3c-2nn1-c1ccccc1
Reactant: CCOC(=O)c1cnc2cc([N+](=O)[O-])ccc2c1Cl
Agent: COc1ccc(NN)cc1
Product: COc1ccc(-n2nc3c4ccc([N+](=O)[O-])cc4[nH]cc-3c2=O)cc1

Procedure:
The title compound was prepared following the procedure described 12a using 11a and 4-methoxyphenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 3.76 (3H, s), 7.02 (2H, d, J=9.34 Hz), 8.02 (2H, d, J=9.06 Hz), 8.27 (1H, dd, J=8.79, 2.19 Hz), 8.39 (1H, d, J=8.79 Hz), 8.52 (1H, q, J=2.20 Hz), 8.88 (1H, d, J=6.04 Hz). m/z 337.3 (MH+).
Reaction SMILES: [CH:1]([N:4]1[CH:8]=[CH:7][C:6]([C:9](OCC)=[O:10])=[N:5]1)([CH3:3])[CH3:2].[Al].[Li].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(OCC)C.O1CCCC1>[CH:1]([N:4]1[CH:8]=[CH:7][C:6]([CH2:9][OH:10])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccn(C(C)C)n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al]
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)n1ccc(CO)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Commercially available ethyl 1-isopropyl-1H-pyrazole-3-carboxylate was dissolved in diethyl ether, the solution was cooled to 0° C., and a 1M lithium aluminum solution in tetrahydrofuran was added. After stirring for 3 hours, the reaction mixture was poured into a cold 30% aqueous Rochelle's salt solution and was allowed to stir for one hour. The resulting mixture was extracted twice with diethyl ether. The combined organic extracts were washed with 10% aqueous potassium carbonate solution and brine, dried over sodium sulfate, and concentrated under reduced pressure to yield the desired compound (54% yield).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([C:12]([NH:14][C@@H:15]1[CH2:20][CH2:19][CH2:18][CH2:17][C@@H:16]1[NH:21][C:22]([C:24]1[S:25][C:26]3[CH2:27][NH:28][CH2:29][CH2:30][C:31]=3[N:32]=1)=[O:23])=[O:13])=[CH:6]2.C(N(CC)CC)C.[C:40](OC(=O)C)(=[O:42])[CH3:41]>CN(C)C=O>[C:40]([N:28]1[CH2:29][CH2:30][C:31]2[N:32]=[C:24]([C:22]([NH:21][C@@H:16]3[CH2:17][CH2:18][CH2:19][CH2:20][C@@H:15]3[NH:14][C:12]([C:7]3[NH:8][C:9]4[C:5]([CH:6]=3)=[CH:4][C:3]([Cl:2])=[CH:11][CH:10]=4)=[O:13])=[O:23])[S:25][C:26]=2[CH2:27]1)(=[O:42])[CH3:41]
Reactant: O=C(N[C@@H]1CCCC[C@@H]1NC(=O)c1nc2c(s1)CNCC2)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(±)-cis-N1-[(5-Chloroindol-2-yl)carbonyl]-N2-[(4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl]carbonyl]-1,2-cyclohexanediamine hydrochloride (100 mg) was dissolved in N,N-dimethylformamide (3 ml), triethylamine (84 μl) and acetic anhydride (29 μl) were added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane and 1N hydrochloric acid were added to the residue to conduct liquid separation. The resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain the title compound (86 mg) as a pale yellow foamy substance.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@H:4]([CH2:6][C:7]1[C:15]2[C:10](=[C:11]([CH3:16])[CH:12]=[CH:13][CH:14]=2)[NH:9][CH:8]=1)[NH2:5].Cl.[CH3:19]O>CO>[CH3:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[NH:9][C:8]1[CH2:19][NH:5][C@H:4]([C:3]([O:2][CH3:1])=[O:17])[CH2:6][C:7]2=1
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2c(C)cccc12
Reactant: CO
Agent: Cl
Product: COC(=O)[C@@H]1Cc2c([nH]c3c(C)cccc23)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
3.02 g of 7-methyl-L-tryptophan methyl ester are dissolved in 20 ml of methanol, and 4 ml of 15% HCl-methanol are added thereto. The mixture is evaporated to remove the solvent. The residue is dissolved in 30 ml of methanol, and 2.86 g of 35% formalin are added thereto. The mixture is stirred at room temperature overnight. The mixture is evaporated to remove the solvent, and water is added to the residue. The aqueous solution is adjusted to pH 10 with 10% aqueous ammonia, and extracted with ethyl acetate. The extract is washed with water, dried and then evaporated to remove the solvent. The residue is recrystallized from chloroform. 2.0 g of methyl (3S)-8-methyl-1,2,3,4-tetrahydro-β-carboline-3-carboxylate are obtained as pale yellow prisms. Yield: 63%
Reaction SMILES: C(N)(=O)C.Br[CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[F-:18].[K+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.BrBr>S([O-])([O-])(=O)=S.[Na+].[Na+]>[F:18][CH:6]([CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCCCCCC(Br)C(=O)OCC
Reactant: [F-]
Agent: BrBr
Agent: CC(N)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Product: CCCCCCC(F)C(=O)OCC
Temperature: 80 °C
Yield: 38.4 %

Procedure:
--A mixture of acetamide (49 g) and ethyl 2-bromooctanoate 64 (100 ml, 0.464 mol) was heated at 80° C. (reaction temperature) with mechanical stirring under nitrogen until homogeneous. Anhydrous potassium fluoride (49.3 g, 0.84 mol) was added followed by tetrabutylammonium fluoride (3.25 ml). The mixture was heated for 5 h at 140° C. with rapid stirring and allowed to cool to 90° C. prior to pouring into ice (400 ml). The reaction vessel was rinsed with water and dichloromethane which were added to the ice mixture. The aqueous phase was extracted with dichloromethane (3 times); the combined organic solutions were dried (Na2SO4) and filtered. The solution was cooled to 5° C. under nitrogen and bromine (19.3 ml, 0.375 mol) was added. After 3 h saturated sodium thiosulfate solution (150 ml) was added. The organic phase was washed with sat. sodium bicarbonate solution (twice) and brine, dried (Na2SO4) and evaporated. The residue was distilled to give pure ethyl 2-fluorooctanoate 65 (33.9 g, 38%); b.p. 56-61° C. at 0.5 mm Hg; νmax /cm-1 (film) 2930, 2860, 1760, 1740, 1370, 1275, 1205, 1090 and 1030; δ 0.88 (3H, t, Me), 1.20-1.56 (11H, m), 1.75-2.13 (2H, m), 4.26 (2H, q, ) and 4.90(1H, 2JHF 46 and J8, CHF); m/z 190 (M+), 185, 168, 161, 143, 129, 113 and 106.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9](O)[CH:8]([CH3:14])[CH2:7][CH2:6]2.C([SiH](CC)CC)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([CH3:14])[CH2:7][CH2:6]2
Reactant: COc1ccc2c(c1)CCC(C)C2O
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COc1ccc2c(c1)CCC(C)C2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 6-methoxy-2-methyl-1,2,3,4-tetrahydronaphthalen-1-ol (8.24 g) and triethylsilane (9.2 mL, 74 mmol) in DCM (100 mL) at 0° C. is added boron trifloride-diethyl etherate (17.6 mL, 110 mmol) drop wise. After stirring for 10 min, the mixture is warmed to RT and stirred for 30 min. 10% K2CO3 solution is added and it is extracted with EtOAc. The organic layer is washed with brine, dried with MgSO4 and concentrated to give the title compound as a yellow oil, which is then used in the next step without purification.
Reaction SMILES: CN(C=O)C.[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH:15]([CH:19]([CH3:21])[CH3:20])[C:16]([OH:18])=[O:17])=[CH:12][C:11]=2[CH:22]=1.C([O-])([O-])=O.[K+].[K+].[O:29]([C:36]1[CH:37]=[C:38]([CH:41]=[CH:42][CH:43]=1)[CH2:39]Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CCOCC>[Cl:6][C:7]1[CH:8]=[CH:9][C:10]2[S:14][C:13]([CH:15]([CH:19]([CH3:20])[CH3:21])[C:16]([O:18][CH2:39][C:38]3[CH:41]=[CH:42][CH:43]=[C:36]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:37]=3)=[O:17])=[CH:12][C:11]=2[CH:22]=1
Reactant: CC(C)C(C(=O)O)c1cc2cc(Cl)ccc2s1
Reactant: BrCc1cccc(Oc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)c1cc2cc(Cl)ccc2s1
Reaction time: 15 h

Procedure:
A mixture of 20 ml DMF, 2-(5-chloro-2-benzothienyl)-3-methylbutanoic acid (0.5 g), K2CO3 (0.51 g) and 3-phenoxybenzyl bromide (0.44 g) is stirred, under nitrogen, for about 15 hours. The mixture is then taken up in ether, washed with water and brine, dried over Na2SO4 and solvent removed. The crude product is plated developing with 10% ether/hexane to give 3-phenoxybenzyl 2-(5-chloro-2-benzothienyl)-3-methylbutanoate.