Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:10]=2)/[C:5]/1=[CH:30]/[C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)(=[O:3])[CH3:2].C(O)C.[H][H]>C(Cl)Cl>[C:1]([N:4]1[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][C:8]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:9]([O:14][CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:10]=2)[C@@H:5]1[CH2:30][C:31]1[CH:36]=[C:35]([O:37][CH3:38])[C:34]([O:39][CH3:40])=[C:33]([O:41][CH3:42])[CH:32]=1)(=[O:3])[CH3:2]
Reactant: COc1cc(/C=C2/c3cc(OCc4ccccc4)c(OCc4ccccc4)cc3CCN2C(C)=O)cc(OC)c1OC
Reactant: [H][H]
Solvent: ClCCl
Solvent: CCO
Product: COc1cc(C[C@H]2c3cc(OCc4ccccc4)c(OCc4ccccc4)cc3CCN2C(C)=O)cc(OC)c1OC
Yield: 92.1 %

Procedure:
In 1.5 ml of methylene chloride was dissolved 100.8 mg (0.178 mmol) of (Z)-N-acetyl-6,7-dibenzyloxy-1-(3,4,5-trimethoxyphenylmethylene)-1,2,3,4-tetrahydroisoquinoline, and 7.5 ml of ethanol was further added thereto. A separately prepared solution of 2.9 mg (1.7×10-3 mmol) of Ru2Cl4 ((S)-(-)-BINAP)2N(C2H5)3 in 1.5 ml of methylene chloride was added to the above prepared solution, and the mixture was transferred to an autoclave. The mixture was subjected to hydrogenation at 23° C. for 62 hours at a hydrogen pressure of 4 kg/cm2 while stirring. After completion of the reaction, the solvent was removed by distillation, and the residue was purified by silica gel column chromatography (silica gel: 15 g, eluent: ethyl acetate/hexane=3:1 by volume) to give 92.8 mg (0.164 mmol) of (S)-N-acetyl-6,7-dibenzyloxy-1-(3,4,5-trimethoxyphenylmethyl)-1,2,3,4-tetrahydroisoquinoline in a yield of 92%. The optical rotation [α]D24 of this product was +62.8° (c=0.92, CHCl3).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:26]=[N:25][N:24]=2)[CH:19]=[CH:20][CH:21]=[O:22])=[CH:13][CH:12]=1>O1CCCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)=[C:18]([C:23]2[N:27]([CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33])[N:26]=[N:25][N:24]=2)[CH:19]=[CH:20][CH:21]([OH:22])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:13][CH:12]=1
Reactant: COCCOCn1nnnc1C(C=CC=O)=C(c1ccc(F)cc1)c1ccc(F)cc1
Reactant: CCOC(=O)CC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)CC(O)C=CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1COCCOC
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Ethyl acetoacetate dianion (2.6 mL of a freshly prepared 1M solution as described in Example 10) was added to a solution of 5,5-bis(4-fluorophenyl)-4-[1-(2-methoxyethoxy)methyl-1H-tetrazol-5-yl]-2,4-pentadienal (1.1 g, 2.6 mmoles) in 15 mL of tetrahydrofuran at -40° C. After stirring for 2 hours, analytical TLC eluted with 25% (v/v) ethyl acetate in hexane showed starting aldehyde and therefore, another 1.2 mL of dianion solution was added. The reaction mixture was allowed to warm to 0° C. and then quenched with 1N HCl. The mixture was extracted with methylene chloride, dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with 1% (v/v) methanol in methylene chloride to give 0.9 g of the title compound as an oil. MS (CI): m/e=557 for (M+H)+ ;
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH:15]([N:18]3C(=O)C4=CC=CC=C4C3=O)[CH2:14]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>C(O)C.O.NN>[NH2:18][CH:15]1[CH2:16][CH2:17][N:13]([CH2:12][CH2:11][C:5]2[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:14]1
Reactant: COc1ccc(CCN2CCC(N3C(=O)c4ccccc4C3=O)C2)cc1OC
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(CCN2CCC(N)C2)cc1OC
Yield: 100.3 %

Procedure:
1.03 g of N-(1-(2-(3,4-dimethoxyphenyl)ethyl)pyrrolidin-3-yl)phthalimide was dissolved in 50 ml of ethanol, to which 2 ml of hydrazine monohydrate was added and refluxed under heating for 14 hours. The solvent was distilled off and an aqueous diluted solution of sodium hydroxide was added to the residue and extracted with chloroform. After drying with anhydrous magnesium sulfate, the solvent was distilled off, to obtain 0.68 g of the above-captioned compound (yield: 100%).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:16][CH2:17][C:18](Br)=[O:19]>C(OCC)(=O)C>[Br:16][CH2:17][C:18]([NH:1][C:2]1[S:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1)=[O:19]
Reactant: O=C(Br)CBr
Reactant: Nc1ncc([N+](=O)[O-])s1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: O=C(CBr)Nc1ncc([N+](=O)[O-])s1

Procedure:
To a stirred solution of 2-amino-5-nitrothiazole (725.7 mg) in ethyl acetate (50 mL) in the presence of saturated sodium carbonate (10 mL) at 0° C., is added bromoacetyl bromide (434.3 uL), and additional bromoacetyl bromide is added to complete the reaction. The organic layer is separated, washed with 3 N HCl solution, followed by brine and dried over sodium sulfate and concentrated in vacuo to give a brown oil. The crude product is purified by silica gel column chromatography (40% ethyl acetate/hexanes) to give a solid (950 mg). ESI MS m/z 266 (M+H+); 1H NMR (400 MHz, CDCl3) δ 8.26 (s, 1H), 3.98 (s, 2H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:17][C:18](I)([F:20])[F:19].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([C:18]([F:20])([F:19])[F:17])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)I
Agent: O=S(=O)([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C1CCN(Cc2ccccc2)CC1C(F)(F)F
Reaction time: 0.25 h

Procedure:
1-benzylpiperidin-4-one (12 g, 63.5 mmole) was added to the stirred suspension of sodium hydride (3.0 g, 127.0 mmole) in tetrahydrofuran (100 ml) at −5° C. The reaction mixture was stirred for 15 min, trifluoromethyl iodide (25 g, 127.0 mmole) was bubbled over a period of 4 hr at −5° C. and stirring continued for 1 hr. The resulting mixture was stirred for 16 hr at ambient temperature, saturated sodium sulphate solution (20 ml) was added and diluted with ethyl acetate (200 ml). Ethyl acetate layer was separated, dried (Na2SO4) and concentrated to furnish crude product, which was purified through column chromatography. Elute from hexane afforded l-benzyl-3-trifluoromethylpiperidin-4-one as oil and 20% ethyl acetate in hexane gave the unreacted 1-benzylpiperidin-4-one (9.5 g). Yield 2.1 g (44%, based on reacted 1-benzyl piperidin-4-one), C13H14F3NO, m/z 258 (M+1), PMR (CDCl3): 2.54 (2H, m, H6), 3.02 (2H, m, H2), 3.6 (3H, m, H3 & H5), 4.36 (2H, s, N—CH2), 7.28 (5H, m, ArH).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][CH:8]=O)=[CH:4][CH:3]=1.C([O-])=O.[Na+].Cl.[NH2:17]O.O>C(O)=O>[F:1][C:2]1[CH:11]=[CH:10][C:5]([CH:6]=[CH:7][C:8]#[N:17])=[CH:4][CH:3]=1
Reactant: O=CC=Cc1ccc(F)cc1
Reactant: NO
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O
Solvent: O=CO
Product: N#CC=Cc1ccc(F)cc1
Yield: 70.4 %

Procedure:
p-Fluorocinnamaldehyde (9.0 g.) was refluxed for 1 hr. in 98% formic acid containing sodium formate (10 g.) and hydroxylamine hydrochloride (7 g.). The solution was cooled and poured into water (275 ml.), giving a solid. This was washed well with water, leaving p-fluorocinnamonitrile (6.21 g., 70%), m.p. 64°-65°, λmax. (EtOH) 271 nm ε 22500.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[CH:11][C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([O:19][CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:15][CH:14]=2)[CH2:6][CH2:5][CH2:4]1.Cl.[CH2:34](OCC)C>C(Cl)Cl>[ClH:1].[ClH:1].[CH:3]1([C:7]2[N:8]=[N:9][C:10]([O:26][CH:27]3[CH2:28][CH2:29][N:30]([CH3:34])[CH2:31][CH2:32]3)=[CH:11][C:12]=2[C:13]2[CH:14]=[CH:15][C:16]([O:19][CH:20]3[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]3)=[CH:17][CH:18]=2)[CH2:6][CH2:5][CH2:4]1
Reactant: CCOCC
Reactant: c1cc(-c2cc(OC3CCNCC3)nnc2C2CCC2)ccc1OC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CN1CCC(Oc2cc(-c3ccc(OC4CCCCC4)cc3)c(C3CCC3)nn2)CC1

Procedure:
To a solution of 3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-6-(piperidin-4-yloxy)-pyridazine dihydrochloride (0.17 mmol, 0.08 g) and aqueous formaldehyde (37%, 0.83 mmol, 0.07 mL) in dry DCM (1 mL) was added macroporous resin-bound triacetoxyborohydride (loading 2.36 mmol/gram, 1.0 mmol, 0.42 g). The mixture was shaken for 12 hours. The reaction was placed directly onto a 4 g SiO2 cartridge and the column was eluted with 0-6% (2N NH3 in MeOH) in DCM to give 3-cyclohexyl-4-(4-cyclohexyloxy-phenyl)-6-(1-methyl-piperidin-4-yloxy)-pyridazine. The neutral amine was treated with 2N HCl in diethyl ether (1 mL) and DCM (1 mL). The volatiles were removed under reduced pressure and the salt was triturated with diethyl ether and filtered to provide the title compound (0.05 g). LCMS: m/z 423 [M+1]. 1H NMR (400 MHz, CD3OD) δ 7.26-7.47 (3H, m), 7.02-7.11 (2H, m), 5.35-5.60 (1H, m), 4.37-4.48 (1H, m), 3.97-4.13 (1H, m), 3.67 (1H, d), 3.23-3.53 (2H, m), 2.92 (3H, s), 1.95-2.62 (12H, m), 1.75-1.92 (3H, m), 1.29-1.68 (6H, m).
Reaction SMILES: S(Cl)(Cl)=O.[ClH:5].[CH:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][N:18]=[C:13]3[S:12][C:11]=2[C:19]([OH:21])=O)[CH2:9][CH2:8][CH2:7]1>C(OCC)C>[CH:6]1([C:10]2[N:14]3[CH2:15][CH2:16][CH2:17][N:18]=[C:13]3[S:12][C:11]=2[C:19]([Cl:5])=[O:21])[CH2:9][CH2:8][CH2:7]1
Reactant: Cl
Reactant: O=C(O)C1=C(C2CCC2)N2CCCN=C2S1
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Product: O=C(Cl)C1=C(C2CCC2)N2CCCN=C2S1
Yield: 115.6 %

Procedure:
To 20 ml of thionyl chloride was suspended 5.0 g of 3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carboxylic acid obtained in Example 1, followed by reflux under heating for 30 minutes. Under cooling, an anhydrous diethylether was added dropwise to the reaction mixture to precipitate. The crystals were collected by filtration and washed with anhydrous diethylether to yield 5.4 g of 3-cyclobutyl-6,7-dihydro-5H-thiazolo[3,2-a]pyrimidine-2-carbonyl chloride as a pale yellow crystals. To the mixture of 60 ml of pyridine and 20 ml of dimethyl formamide was suspended 2.7 g of the crystal. To the mixture was added 1.5 g of 3,5-dichloroaniline and 60 mg of dimethylaminopyridine, followed by stirring at 70° C. for 17 hours. The solvent was removed under reduced pressure to obtain a residue. Addition of water to the residue caused precipitation of the crystals and the crystals were collected by filtration. After washing with cold methanol, the crystals were suspended to saturated hydrogenchloride ethanol solution. After washing with diethylether, the crystals were collected by filtration to obtain 1.2 g of the titled compound.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[CH2:15][N:14]([S:16]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)(=[O:18])=[O:17])[CH2:13][CH2:12][N:11]1[C:24]1[CH:29]=[CH:28][C:27]([C:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32])=[CH:26][CH:25]=1)C1C=CC=CC=1.C(Cl)Cl.B(Cl)(Cl)Cl>CO>[F:34][C:31]([F:32])([F:33])[C:30]([C:27]1[CH:28]=[CH:29][C:24]([N:11]2[CH2:12][CH2:13][N:14]([S:16]([C:19]3[S:20][CH:21]=[CH:22][CH:23]=3)(=[O:17])=[O:18])[CH2:15][CH:10]2[CH2:9][OH:8])=[CH:25][CH:26]=1)([OH:36])[CH3:35]
Reactant: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2COCc2ccccc2)cc1)C(F)(F)F
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: CC(O)(c1ccc(N2CCN(S(=O)(=O)c3cccs3)CC2CO)cc1)C(F)(F)F
Temperature: -78 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A 250 mL round-bottomed flask was charged with 2-(4-(2-((benzyloxy)methyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-1,1,1-trifluoro-2-propanol (2.93 g, 5.43 mmol) and CH2Cl2 (50 mL) and cooled to −78° C. A 1.0 M solution of BCl3 (1M in CH2Cl2, 7.31 mL, 7.31 mmol, Sigma-Aldrich, St. Louis, Mo.) was added slowly to the mixture and the reaction was stirred for 1 h at −78° C. After this time, MeOH (25 mL) was added and the mixture was warmed to room temperature. After the MeOH was removed in vacuo, diethyl ether (100 mL) was added. The resulting precipitate was collected by filtration, dried under reduced pressure to yield 1,1,1-trifluoro-2-(4-(2-(hydroxymethyl)-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (2.17 g) as a mixture of four isomers.
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3.[OH-].[K+].[CH2:25](I)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CS(C)=O.O>[CH2:25]([O:1][C@H:2]1[CH2:7][CH2:6][C@H:5]2[C@H:8]3[C@H:18]([CH2:19][CH2:20][C@:3]12[CH3:4])[C@:16]1([CH3:17])[C@H:11]([N:12]([CH3:22])[C:13](=[O:21])[CH2:14][CH2:15]1)[CH2:10][CH2:9]3)[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CN1C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3CC[C@@H]12
Reactant: CCCCCCI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCCCCO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4N(C)C(=O)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 8 h

Procedure:
To a solution of 17β-hydroxy-4-methyl-5α-4-azaandrostan-3-one (102 mg, 0.336 mmol) in DMSO (3 ml) was added powdered KOH (300 mg) followed by n-hexyliodide (400 μl). After stirring the reaction mixture overnight, the reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with water, then brine, then dried (MgSO4), and concentrated in vacuo. The residue was then purified by preparative thin layer chromatography to afford the title compound, characterized by H1NMR.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[C:3]([N:5]=[C:6](OCC)[CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=O.O.[NH2:19][NH2:20]>CO>[C:2]([C:3]1[N:5]=[C:6]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:20][N:19]=1)([CH3:17])([CH3:16])[CH3:1]
Reactant: NN
Reactant: CCOC(=O)CC(=NC(=O)C(C)(C)C)OCC
Solvent: O
Solvent: CO
Product: CCOC(=O)Cc1nc(C(C)(C)C)n[nH]1
Reaction time: 24 h
Yield: 59.4 %

Procedure:
Ethyl 3-[(2,2-Dimethylpropanoyl)imino]-3-ethoxypropanoate (Preparation 117, 40 g, 0.165 mol) was dissolved in methanol (250 mL) and hydrazine hydrate (9.6 mL, 0.196 mol) was added at 0° C. The reaction mixture was stirred for 24 hours. The solvents concentrated in vacuo. The residue was dissolved in water (200 mL), and the solution was extracted with chloroform (3×100 mL). The combined organic extracts were dried over MgSO4 and evaporated to afford the title compound (20.7 g, 59%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8]([NH2:10])=[S:9])[CH:2]=1.[CH2:11]([O:13][C:14](=[O:19])[C:15](=O)[CH2:16]Br)[CH3:12]>CO>[CH2:11]([O:13][C:14]([C:15]1[N:10]=[C:8]([NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[S:9][CH:16]=1)=[O:19])[CH3:12]
Reactant: NC(=S)Nc1cccnc1
Reactant: CCOC(=O)C(=O)CBr
Solvent: CO
Product: CCOC(=O)c1csc(Nc2cccnc2)n1
Yield: 79.8 %

Procedure:
2-(Pyridin-3-ylamino)-thiazole-4-carboxylic acid ethyl ester (200 mg) was prepared according to General Procedure B using pyridin-3-yl-thiourea (154 mg) and 3-bromo-2-oxo-propionic acid ethyl ester (200 mg) in methanol (2 mL). The crude product was used in subsequent steps without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([F:9])[CH:3]=1.Br[C:11]1[C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:20])[C:14]([O:21][CH3:22])=[CH:13][CH:12]=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[C:16]([C:17]([OH:19])=[O:18])=[C:15]([F:20])[C:14]([O:21][CH3:22])=[CH:13][CH:12]=2)=[C:4]([F:9])[CH:3]=1
Reactant: COc1ccc(Br)c(C(=O)O)c1F
Reactant: Oc1ccc(Br)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2ccc(Br)cc2F)c(C(=O)O)c1F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78.3 %

Procedure:
To a 1 L RB was added 4-bromo-2-fluorophenol (18.85 mL, 169 mmol), 6-bromo-2-fluoro-3-methoxybenzoic acid (40 g, 161 mmol), copper (I) trifluoromethanesulfonate toluene complex (4.16 g, 8.03 mmol), ethyl acetate (1.6 mL, 16.06 mmol) and cesium carbonate (105 g, 321 mmol) in dry toluene (300 mL). The reaction mixture was stirred at rt for 15 min and heated at 110° C. for overnight. The toluene was decanted and the resulting green sticky precipitate was washed with excess hexanes and then acidified by addition of 6N aqueous HCl. The resulting solution was added water and extracted with EtOAc 3×. The light brown organic phase was then washed by brine and dried by MgSO4. The solution was filtered and concentrated in vacuo to give the crude material 6-(4-bromo-2-fluorophenoxy)-2-fluoro-3-methoxybenzoic acid (45.4 g, 126 mmol, 79% yield) as a brown solid. It was used for next step without further purification.
Reaction SMILES: [F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([O:24]C)=O.[NH3:31]>CO>[F:1][CH:2]([F:30])[O:3][C:4]1[CH:29]=[CH:28][CH:27]=[CH:26][C:5]=1[CH2:6][O:7][C:8]1[CH:12]=[C:11]([N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[CH:17][C:16]=3[N:15]=[CH:14]2)[S:10][C:9]=1[C:22]([NH2:31])=[O:24]
Reactant: N
Reactant: COC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)F
Solvent: CO
Product: NC(=O)c1sc(-n2cnc3cnccc32)cc1OCc1ccccc1OC(F)F

Procedure:
In a similar manner as described for example 38, 110 mg of methyl 3-{[2-(difluoromethoxy)benzyl]oxy}-5-(1H-imidazo[4,5-c]pyridin-1-yl)thiophene-2-carboxylate and 20 ml of a saturated solution of ammonia in methanol yield the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19]3[N:23]([C:24]4[CH:28]=[CH:27][O:26][N:25]=4)[CH:22]=[N:21][N:20]=3)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:29]([F:32])([F:31])[F:30].C1C(=O)N([Br:40])C(=O)C1>C(Cl)(Cl)(Cl)Cl.C(Cl)Cl.C([O-])(O)=O.[Na+]>[Br:40][C:22]1[N:23]([C:24]2[CH:28]=[CH:27][O:26][N:25]=2)[C:19]([C:13]2[C:12]([NH:11][S:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:29]([F:32])([F:31])[F:30])[CH:4]=3)(=[O:9])=[O:10])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=2)=[N:20][N:21]=1
Reactant: O=S(=O)(Nc1cc(Cl)cnc1-c1nncn1-c1ccon1)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: O=S(=O)(Nc1cc(Cl)cnc1-c1nnc(Br)n1-c1ccon1)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
4-Chloro-N-[5-chloro-2-(4-(isoxazol-3-yl)-4H-1,2,4-triazol-3-yl)pyridin-3-yl]-3-(trifluoromethyl)benzenesulfonamide (80 mg) in CCl4/DCM (3 mL/1 mL) was charged with NBS (30 mg). The resulting mixture was stirred at room temperature for 6 h. The reaction mixture was diluted with sat NaHCO3 and extracted EtOAc (50 mL×2), the combined organic layer was concentrated under reduced pressure. The residue was purified through automated normal-phase chromatography (10% to 100% gradient of EtOAc-Hexane), and followed by preparative HPLC (10% to 90% gradient of MeCN-water) and dried (Lyophilizer) to afford the title compound. 1H NMR (400 MHz, CDCl3) δ 11.6 (br, 1H), 8.60 (d, 1H), 8.46 (s, 1H), 8.27 (s, 1H), 8.19 (d, 1H), 7.98 (dd, 1H), 7.62 (d, 1H), 6.63 (d, 1H). MS (ES) [M+H]+ expected 584.0, found 584.0.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH:7]([NH:11][S:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:4])([CH3:3])[CH3:2].[F:29][C:30]1[CH:35]=[CH:34][C:33]([N:36]=[C:37]=[O:38])=[CH:32][CH:31]=1.CCN(CC)CC>C(OCC)C>[C:1]([O:5][C:6](=[O:28])[CH:7]([NH:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([O:27][C:37](=[O:38])[NH:36][C:33]3[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=3)=[CH:25][CH:26]=2)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH:8]([CH3:10])[CH3:9])([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1)C(=O)OC(C)(C)C
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(C)C(NS(=O)(=O)c1ccc(-c2ccc(OC(=O)Nc3ccc(F)cc3)cc2)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 57 %

Procedure:
2-(4′-Hydroxy-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester (300 mg, 0.74 mmol, 1 equiv.) was dissolved in diethyl ether (7.5 mL), followed by the addition of 4-fluorophenylisocyanate (101 mg, 0.74 mmol, 1 equiv.) and Et3N (1 mL). The reaction mixture was stirred at room temperature for 50 min. Solid precipitated from the reaction mixture. Solid was collected by filtration and washed with ether to yield 2-[4′-(4-Fluoro-phenylcarbamoyloxy)-biphenyl-4-sulfonylamino]-3-methyl-butyric acid tert-butyl ester in 57% yield (228 mg).
Reaction SMILES: [CH2:1]([C:4]1[N:5]=[C:6]([Cl:15])[C:7]2[C:12]([C:13]=1[OH:14])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:25].[Na+].OO>O1CCCC1>[Cl:15][C:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:13]([OH:14])=[C:4]([CH2:1][CH2:2][CH2:3][OH:25])[N:5]=1
Reactant: [OH-]
Reactant: C=CCc1nc(Cl)c2ccccc2c1O
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: OCCCc1nc(Cl)c2ccccc2c1O
Reaction time: 8 h
Yield: 71.7 %

Procedure:
To a stirred solution of 3-allyl-1-chloroisoquinolin-4-ol (670 mg, 3.05 mmol) in dry tetrahydrofuran (5 mL) at room temperature was added 0.5 M in THF solution of 9-BBN (18.30 mL, 9.15 mmol) and the mixture was stirred for overnight. 3N NaOH (9.15 mL, 27.5 mmol) and H2O2 (2.83 mL, 30.5 mmol) were then added to the mixture. The mixture was stirred for 45 min before quenching with sat. NaCl solution. 1 N HCl was then added to the solution to adjust PH<7. The reaction was extracted with EtOAc. The organic layer was washed with brine, dried and concentrated to afford a yellow oil that was purified by silica gel chromatography using 20-40% EtOAc/hexane to obtain 1-chloro-3-(3-hydroxypropyl)isoquinolin-4-ol (520 mg, 70%) as product. MS: MS m/z 238.0 (M++1).
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]2[C:3]=1[CH2:4][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([O:17]CC1C=CC=C(OC3C=CC=CC=3)C=1)=[O:16])[CH2:6]2.[OH-].[K+].C(O)C>O>[F:13][C:8]1[C:9]([F:12])=[C:10]([F:11])[C:2]([F:1])=[C:3]2[C:7]=1[CH2:6][N:5]([CH:14]([CH:32]([CH3:34])[CH3:33])[C:15]([OH:17])=[O:16])[CH2:4]2
Reactant: CC(C)C(C(=O)OCc1cccc(Oc2ccccc2)c1)N1Cc2c(F)c(F)c(F)c(F)c2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)C(C(=O)O)N1Cc2c(F)c(F)c(F)c(F)c2C1

Procedure:
A mixture of m-phenoxybenzyl 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoate (0.4 g), potassium hydroxide (0.134 g), ethanol (8 ml) and water (2 ml) is heated to reflux for 4 hours. After cooling, the reaction mixture is concentrated under vacuum and 50 ml of water is added. This mixture is washed with ether (3×). The aqueous phase is carefully adjusted to pH 7 and then extracted with ether (3×). The combined ether extracts are washed with water, dried and solvent removed under vacuum to yield 2-(4,5,6,7-tetrafluoro-2-isoindolinyl)-3-methylbutanoic acid, a white powder.