Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][C:6]=1[C:7]([OH:9])=O)([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[N:24][C:23]=2[CH:33]=1>O1CCCC1>[Cl:18][C:19]1[CH:20]=[CH:21][C:22]2[S:26][C:25]([N:27]3[CH2:28][CH2:29][N:30]([C:7]([C:6]4[CH:10]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:12]=[CH:13][C:5]=4[O:4][CH:1]([CH3:2])[CH3:3])=[O:9])[CH2:31][CH2:32]3)=[N:24][C:23]=2[CH:33]=1
Reactant: Clc1ccc2sc(N3CCNCC3)nc2c1
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)N1CCN(c2nc3cc(Cl)ccc3s2)CC1

Procedure:
Prepared in analogy to example 1.1 b) from 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.2) and 5-chloro-2-piperazin-1-yl-benzothiazole in tetrahydrofuran. The crude material was purified by chromatography (SiO2, heptane/ethyl acetate), and the residue was then triturated in ether to yield the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1)[CH3:6].[OH-].[Li+].Cl>C1CCC(O)CC1.O>[F:1][C:2]1[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:3]=1[O:4][CH:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=1)[CH3:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccc(F)cc2F)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: OC1CCCCC1
Product: CC(Oc1ccc(F)cc1F)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.5 %

Procedure:
To the solution of methyl 4-(1-(2,4-difluorophenoxy)ethyl)benzoate (151 mg, 0.54 mmol) in meth anol/water (50 mL) was added lithium hydroxide (50 mg, 2.1 mmol), the solution was stirred at room temperature for 12 hours. Then the solution was acidified by hydrogen chloride (1 N/mol) pH to 6, extracted with dichloromethane (50 mL*3), evaporated the solvent and the residue was purified by column chromatography (silica gel, Petroleum ether/ethyl acetate=5:1) to give 4-(1-(2,4-difluorophenoxy)ethyl)benzoic acid (127 mg, 88%)
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:11]=[CH:10][C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18].O>CS(C)=O>[CH2:18]([N:7]1[C:8](=[O:9])[CH:10]=[CH:11][N:4]([CH3:3])[C:5]1=[O:6])[CH2:17][CH2:16][CH2:15][CH:14]=[CH2:13]
Reactant: C=CCCCCBr
Reactant: Cn1ccc(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C=CCCCCn1c(=O)ccn(C)c1=O
Reaction time: 0.25 h
Yield: 71.8 %

Procedure:
3-(5,6-Oxidohexyl)-1-methyluracil was synthesized as follows: A mixture of sodium hydride (86 mg, 3.6 mmol) and 1-methyluracil (500 mg, 4 mmol) in dimethyl sulfoxide (25 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (647 mg, 4 mmol) was added. After stirring for 20 hours, the reaction mixture was poured into water (50 ml) and extracted with 20% ethanol-dichloromethane (3×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (20 ml) and dried over sodium sulfate. The solvent was evaporated under vacuum to give a residue which was purified by column chromatography (silica, ethyl acetate) to give 3-(5-hexenyl)-1-methyluracil (598 mg, 72% yield).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:12][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:12][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:2]=1[OH:1]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(C)cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-hydroxy-4-methylbenzoic acid (1.52 g, 10 mmol) in toluene (6 mL) and methanol (2 mL) at 0° C. is added trimethylsilyldiazomethane (2 M in hexane, 6 mL, 12 mmol) dropwise. The mixture is then warmed up to ambient temperature and it is stirred for 2 h. The solvent is removed under reduced pressure and the residue is purified by flash chromatography to give the title compound as a colorless oil.
Reaction SMILES: CO[C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[CH:13][CH:12]=[CH:11]2)=[CH:6][C:5]=1[OH:15].[CH:17]1([Mg]Cl)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.[NH4+].[Cl-]>C1COCC1>[CH:17]1([C:3]([CH:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)([OH:16])[C:4]2[CH:9]=[CH:8][C:7]([N:10]3[CH:11]=[CH:12][CH:13]=[CH:14]3)=[CH:6][C:5]=2[OH:15])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: COC(=O)c1ccc(-n2cccc2)cc1O
Reactant: Cl[Mg]C1CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Oc1cc(-n2cccc2)ccc1C(O)(C1CCCCC1)C1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of 217 mg of 2-Hydroxy-4-pyrrol-1-yl-benzoic acid methyl ester in 4 ml of THF, 2 ml of a solution of cyclohexylmagnesium chloride in THF (2 M) was added slowly at room temperature. The reaction mixture was then heated to reflux for 4 h. After cooling to room temperature it was hydrolized with ice. Saturated aqueous NH4Cl was added until the white precipitate was dissolved. The aqueous phase was extracted with ether. The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was used in the next reaction step. Yield: 504 mg.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12].[CH2:13]([OH:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[CH2:13]([O:20][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([F:11])[C:3]=1[CH3:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: OCc1ccccc1
Reactant: Cc1c(F)ccc([N+](=O)[O-])c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1c(OCc2ccccc2)ccc([N+](=O)[O-])c1F
Temperature: 100 °C
Yield: 33.3 %

Procedure:
1,3-difluoro-2-methyl-4-nitrobenzene (16 g, 0.092 mol), benzyl alcohol (10 g, 0.092 mol) and K2CO3 (25.3 g, 0.18 mol) were combined in DMF (250 mL) and heated to 100° C. overnight. The mixture was poured into water and extracted with EtOAc (3×200 mL). The combined organics were washed with brine, dried (Na2SO4), concentrated in vacuo and purified by column chromatography on silica gel to give 1-benzyloxy-3-fluoro-2-methyl-4-nitrobenzene (8 g, 33% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.04 (t, J=8.8 Hz, 1H), 7.30-7.46 (m, 5H), 7.08 (d, J=9.2 Hz, 1H), 5.28 (s, 2H), 2.13 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:17]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)=[CH:16][C:4]=1[C:5]([C:7]1[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[CH:9][C:8]=1[CH3:15])=[O:6].[BH4-].[Na+]>C(O)C.O>[CH3:15][C:8]1[CH:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[C:7]=1[CH:5]([C:4]1[CH:16]=[C:17]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH:18]=[CH:19][C:3]=1[O:2][CH3:1])[OH:6]
Reactant: COc1ccc(-n2ccnc2)cc1C(=O)c1c(C)cc(C)cc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(-n2ccnc2)cc1C(O)c1c(C)cc(C)cc1C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a suspension of 4 g of 2-methoxy-5-(1-imidazolyl)-2',4',6'-trimethylbenzophenone in 20 ml of ethanol is added a solution of 0.9 g of sodium borohydride in 5 ml of water. After the whole mixture is stirred at 70°-75° C. for 1.5 hours, the reaction mixture is poured into ice-cold water. The crystals precipitated are filtered off and recrystallized from ethanol to give 2.9 g of α-(2,4,6-trimethylphenyl)-2-methoxy-5-(1-imidazolyl)benzenemethanol as white crystals, melting at 187°-188° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[O:17][CH3:18])=O)[C:5](F)=[N:6][CH:7]=1.O.[NH2:20][NH2:21]>C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[O:17][CH3:18])=[N:21][NH:20][C:5]2=[N:6][CH:7]=1
Reactant: NN
Reactant: COc1ccccc1C(=O)c1cc(Br)cnc1F
Solvent: CCO
Solvent: O
Product: COc1ccccc1-c1n[nH]c2ncc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
To a solution of (5-bromo-2-fluoro-pyridin-3-yl)-(2-methoxy-phenyl)-methanone (1.9 g, 6.1 mmol) in ethanol (125 ml), hydrazine monohydrate (691 μl, 12.2 mmol) was added and the resulting solution was allowed to stir at room temperature overnight. Solvent was removed under reduced pressure and the product was precipitated out by addition of water to afford 5-bromo-3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridine (1.1 g, 58% yield). 1H NMR (500 MHz, DMSO-d6) δ 3.84 (s, 3H), 7.07 (m, 1H), 7.20 (d, 1H), 7.45 (m, 1H), 7.62 9d, 1H), 8.34 (s, 1H), 8.60 (s, 1H). MS: m/z 304+306 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([OH:9])=[C:4]([F:10])[CH:3]=1.[CH2:11](Cl)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>>[CH2:11]([O:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[CH:3][C:4]=1[F:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: ClCc1ccccc1
Reactant: Oc1c(F)cc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1cc(Br)cc(F)c1OCc1ccccc1

Procedure:
A stirred mixture of 4-bromo-2,6-difluorophenol (36 g, 0.172 mole), benzylchloride (21.77 g, 0.172 mole), and potassium carbonate (25 g, 0.18 mole) in demethylformamide (300 ml) was heated at 80°-90° for four hours. After cooling, the solvent was evaporated and ether added to the residue. The insoluble inorganic salts were removed by filtration, and solvent evaporated from the filtrate. The oily residue was subjected to bulb-to-bulb vacuum distillation on Kugelrohr apparatus to give the desired product as a nearly colorless oil (41 g, 80 percent): R.I.=1.5602 @25° C.; NMR (CDCl3) was consistent with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]([OH:9])=O.Cl.[NH2:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19].N1C=CC=CC=1>O=S(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[CH2:13][CH3:14])[CH:5]=[CH:6][C:7]([NH:16][N:17]1[CH2:23][C:21](=[O:22])[NH:20][C:18]1=[O:19])=[O:9]
Reactant: NN1CC(=O)NC1=O
Reactant: CCc1ccc(C=CC(=O)O)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1ccc(C=CC(=O)NN2CC(=O)NC2=O)cc1Cl

Procedure:
3-Chloro-4-ethylcinnamic acid (50 g, 0.24 mole) in SOCl2 (100 ml) was heated under reflux for about 1 hour. The excess SOCl2 was removed in vacuo and the residue flushed with benzene. The acid chloride was treated with 1-aminohydantoin hydrochloride (40 g, 0.26 mole) and pyridine (300 ml) and the reaction mixture heated on a steam bath for 4 hours. The reaction mixture was poured onto HCl/ice to precipitate the product. (40 g, 55%). Several recrystallizations from CH3NO2 provided analytical material which melted at 231°-234°.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[C:10]([O:14][CH3:15])(=[O:13])[CH:11]=[CH2:12]>C1CCN2C(=NCCC2)CC1.O1CCCC1>[N:1]1([CH2:12][CH2:11][C:10]([O:14][CH3:15])=[O:13])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C=CC(=O)OC
Reactant: c1ccc2[nH]cnc2c1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COC(=O)CCn1cnc2ccccc21
Yield: 91.5 %

Procedure:
A solution of 10.0 g (84 mmol) of benzimidazole, 22.7 ml (250 mmol) of methyl acrylate and 3 drops of DBU in 50 ml of tetrahydrofuran was heated at reflux for 2 days. The resulting solution was concentrated in vacuo, and the residue was purified by silica gel chromatography using 3% methanol in chloroform to provide 15.7 g (92%) of the desired compound (Rf 0.58, 10% methanol in chloroform).
Reaction SMILES: [O:1]=[C:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[CH:27]=[CH:26][C:25]2[C:20](=[CH:21][CH:22]=[C:23]([S:28][CH2:29][CH2:30][CH2:31]Cl)[CH:24]=2)[CH:19]=1.O>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28][CH2:29][CH2:30][CH2:31][N:7]1[CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3][C:2]1=[O:1])[CH:22]=[CH:21]2
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Reactant: ClCCCSc1ccc2cc(Cl)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(CCCSc2ccc3cc(Cl)ccc3c2)C(=O)C1
Yield: 92.4 %

Procedure:
tert-Butyl 3-oxopiperazine-1-carboxylate (2.0 g) was dissolved in DMF (30 mL), and sodium hydride (0.5 g) was added thereto. With ice cooling, 2-chloro-6-((3-chloropropyl)thio)naphthalene (2.7 g) was added thereto, and the mixture was mixed at 60° C. for 3 hours. The reaction solution was poured into water, then extracted with chloroform, and the extract was dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified with a silica gel column to give the title compound (4.0 g) as a pale brown oily matter.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([N:6]([C:20]([CH:22]3[CH2:24][CH2:23]3)=[O:21])[C@@H:7]([CH3:19])[CH2:8][N:9]2C(OC(C)(C)C)=O)=[CH:4][CH:3]=1.C(O)C.Cl>O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5](=[CH:4][CH:3]=1)[N:6]([C:20]([CH:22]1[CH2:23][CH2:24]1)=[O:21])[C@@H:7]([CH3:19])[CH2:8][NH:9]2
Reactant: C[C@H]1CN(C(=O)OC(C)(C)C)c2cc(Br)ccc2N1C(=O)C1CC1
Agent: Cl
Solvent: CCO
Solvent: O
Product: C[C@H]1CNc2cc(Br)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Yield: 93.3 %

Procedure:
A 200-mL round bottomed flask fitted with a nitrogen inlet, magnetic stir bar, and condenser was charged with (S)-tert-butyl 7-bromo-4-(cyclopropanecarbonyl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (5.74 g, 14.52 mmol), ethanol (100 mL), water (25 mL), and 6 M hydrochloric acid solution (2.66 mL, 15.97 mmol). The reaction mixture was heated to 50° C. for 24 h and then cooled to room temperature. The ethanol was removed under reduced pressure, the residue was extracted into dichloromethane (100 mL), and the extract was concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel (eluting with 3:2 hexanes-ethyl acetate) to afford (S)-(6-bromo-2-methyl-3,4-dihydroquinoxaline-1(2H)-yl)(cyclopropyl)methanone (4.00 g, 93%) as an off-white solid. MS (ESI, pos. ion) m/z 295, 297 [M+1]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[N+:8]([C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1)([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:15]2[CH:16]=[C:11]([N+:8]([O-:10])=[O:9])[CH:12]=[CH:13][CH:14]=2)[CH:3]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: Brc1cccnc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=[N+]([O-])c1cccc(-c2cccnc2)c1

Procedure:
To 3-bromopyridine (8.53 g, 54 mmol) in ethyleneglycol dimethylether (180 ml) is added 3-nitrophenylboronic acid (10 g, 59.95 mmol), aqueous potassium carbonate (90 ml, 2M) and tetrakis(triphenylphosphine)palladium (0.5 g, 0.43 mmol). The mixture is refluxed gently in a nitrogen atmosphere overnight. The cooled reaction mixture is filtered and water (600 ml) is added to the filtrate. The precipitate is filtered off and washed with water. This crude product is dissolved in hot water (400 ml) with addition of hydrochloric acid (25 ml, 4 M). The mixture is filtered while still hot. The filtrate is cooled in an ice bath and pure 3-(3-pyridyl)-nitrobenzene is precipitated by addition of 12 M NaOH. Yield 9.14 g (85%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5](Br)[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:8]2.C[O-].[Na+].CO.[C:33](OCC)(=[O:35])C>CO.CCCCCC>[F:1][C:2]([F:27])([F:26])[C:3]1[CH:4]=[C:5]([O:35][CH3:33])[CH:6]=[C:7]2[C:11]=1[C:10](=[O:12])[N:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=1)[CH2:8]2
Reactant: CCOC(C)=O
Reactant: O=C1c2c(cc(Br)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CO
Product: COc1cc2c(c(C(F)(F)F)c1)C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Temperature: 100 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
A mixture of 7-trifluoromethyl-5-bromo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.060 g, 0.15 mmol), and 30% sodium methoxide-methanol (0.21 mL) in methanol (4 mL) was stirred at 100° C. for 1 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 7-trifluoromethyl-5-methoxy-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.043 g, 70%). 1H NMR (300 MHz, CDCl3): δ (ppm) 3.88 (s, 3H), 4.25 (s, 2H), 4.76 (s, 2H), 7.02 (s, 1H), 7.17 (d, 2H), 7.28 (s, 1H), 7.37 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20])([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19]([C:21]1[CH:25]=[CH:24][S:23][CH:22]=1)=[O:20])=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: CC(C)NNC(=O)c1ccsc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(NC(=O)c1ccsc1)C(=O)COc1ccc(F)cc1Br
Yield: 66.4 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (226 mg, 0.91 mmol) and thiophene-3-carboxylic acid N′-isopropyl-hydrazide (200 mg, 1.09 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.40 mL, 2.28 mmol) and PyBroP (636 mg, 1.37 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was washed with brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 30-50% ethyl acetate/hexanes gradient to afford the product as a solid (251 mg, 66%).
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[CH2:12][NH:11][CH:10]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:9]2([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])[C:18]#[N:19])[CH:5]=[CH:6][CH:7]=1.Br[CH2:30][C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C)C=O>[C:34]([O:33][C:31](=[O:32])[CH2:30][N:11]1[CH2:12][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])[C@:9]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:21]=2[F:27])([C:18]#[N:19])[C@@H:10]1[CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)CC1NCC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)C[C@@H]1N(CC(=O)OC(C)(C)C)C[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 66 h
Yield: 66.2 %

Procedure:
To a solution of rac-(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-2-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (2.5 g, 5.9 mmol) in N,N-dimethylformamide (50 mL) was added tert-butyl bromoacetate (2.5 g, 12.8 mmol) and Cs2CO3 (5 g, 15.4 mmol). The reaction mixture was stirred at room temperature for 66 h. Water was added. The mixture was extracted with ethyl acetate. The organic layer was separated, and aqueous layer was extracted with ethyl acetate. The organic layers were combined, washed with water twice, dried over MgSO4, then concentrated. The residue was purified by chromatography (EtOAc:hexanes=1:10) to give rac-[(2S,3R,4S)-4-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-2-(2,2-dimethyl-propyl)-pyrrolidin-1-yl]-acetic acid tert-butyl ester as a white foam (2.1 g, 66%).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][OH:9])=[CH:5][CH:4]=1.[H-].[Na+].Cl[CH2:15][C:16]([OH:18])=[O:17].O>CS(C)=O>[CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([CH2:7][CH2:8][O:9][CH2:15][C:16]([OH:18])=[O:17])=[CH:5][CH:4]=1
Reactant: O=C(O)CCl
Reactant: CSc1ccc(CCO)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ccc(CCOCC(=O)O)cc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 46.1 %

Procedure:
6.27 g of 4-methylthiophenethyl alcohol in 100 ml of dimethyl sulfoxide were treated with 3.58 g of a 50% sodium hydride dispersion in mineral oil and the mixture was stirred at 60° C. for 10 minutes. 3.53 g of chloroacetic acid were added and the heating was continued at 80° C. for 3 hours while stirring. The mixture was cooled, poured into water and washed with ethyl acetate. The aqueous phase was acidified to pH 1 with concentrated hydrochloric acid and extracted with ethyl acetate. The organic phase was separated, washed well with water, dried over sodium sulfate, filtered and evaporated to dryness. The residue was recrystallized from toluene/hexane to give 3.89 g (46%) of 2-(4-methylthiophenyl)ethoxyacetic acid of melting 58°-60° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.[OH-].[K+].[CH:18]([C:20]1[CH:21]=[N:22][CH:23]=[N:24][CH:25]=1)=[CH2:19]>CN1CCCC1=O.O>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:19][CH2:18][C:20]3[CH:21]=[N:22][CH:23]=[N:24][CH:25]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: C=Cc1cncnc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CN1CCc2c(c3cc(Cl)ccc3n2CCc2cncnc2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of 8-Chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.15 g, 0.68 mmol) in N-methyl 2-pyrolidone (1.0 mL) was added powdered potassium hydroxide (0.19 g, 3.4 mmol) and allowed to stir for 10 min at RT. 5-vinyl pyrimidine (0.177 g, 1.7 mmol) was added and stirred for further 5 h at 60 deg C. After completion (TLC), reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (3×100 mL). The organic layer was dried over anhydrous sodium sulphate and concentrated under reduced pressure. The crude was purified through column chromatography (7% MeOH:DCM in silica 100-200 mesh, Diameter of column—2.5 cm, Height of silica—approx. 5 inch), Then further purified by preparative TLC, to give the desired compound as yellow oil (0.030 g, 14% yield). 8-Chloro-2-methyl-5-(2-pyrimidin-5-yl-ethyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (0.025 g, 0.076 mmol) was dissolved in THF (1.0 mL). A solution of oxalic acid dihydrate (0.0096 g, 0.076 mol) in THF (1.0 mL) was added and stirred for 30 min at RT, precipitate obtained was filtered and dried to give oxalate salt as off white solid (0.025 g, 78% yield).