Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[CH2:11][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:13][CH:14]=2)=[CH:2]1.[CH2:22]([Zn]CC)C.ICI>C(Cl)Cl.CCCCCC>[NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]23[CH2:22][CH:14]2[CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]3)=[CH:2]1
Reactant: CC[Zn]CC
Reactant: CC(C)(C)OC(=O)N1CC=C(c2c[nH]c3ncccc23)C1
Solvent: ClCCl
Solvent: ICI
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)N1CC2CC2(c2c[nH]c3ncccc23)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-2,5-dihydro-1H-pyrrole-1-carboxylate (700 mg, 2.5 mmol) in DCM (20 mL), was added dropwise at 0° C. under nitrogen atmosphere diethylzinc (6.13 mL of a 1M solution in hexane, 6.1 mmol) and diiodomethane (0.79 mL, 9.8 mmol). The mixture was warmed to RT and stirred at RT overnight. The mixture was then cooled with an ice bath and quenched with a saturated aqueous solution of ammonium chloride. The mixture was extracted with DCM, dried over sodium sulphate and concentrated in vacuo. The residue was triturated in diisopropylether and the resulting precipitate was filtered and then purified by column chromatography (DCM/MeOH 95:5) to afford the title compound as a yellow solid (100 mg).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([O:15][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])([CH3:18])=[O:17])[CH3:14].[CH3:26][C:27]1[CH:37]=[CH:36][C:30]([CH:31]=[CH:32][N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1.[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:26][C:27]1[CH:28]=[CH:29][C:30]([CH:31]([CH2:32][N+:33]([O-:35])=[O:34])[CH2:18][P:16]([CH:19]([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])(=[O:17])[O:15][CH2:13][CH3:14])=[CH:36][CH:37]=1
Reactant: CCOC(OCC)P(C)(=O)OCC
Reactant: Cc1ccc(C=C[N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(OCC)P(=O)(CC(C[N+](=O)[O-])c1ccc(C)cc1)OCC
Reaction time: 0.17 h

Procedure:
The starting material may be prepared as follows: To a solution of 8.7 g of diisopropylamine in 40 ml of tetrahydrofuran at -78° C. under an atmosphere of nitrogen are added 53.6 ml of a 1.6M solution of n-butyllithium in hexane. This solution is then stirred for a period of 10 minutes at this temperature, after which time a solution of 15.0 g of ethyl(diethoxymethyl)methylphosphinate in 20 ml of tetrahydrofuran is added. This mixture is then stirred for a period of 1 hour at -78° C. after which time a solution of 11.6 g of 4-methyl-β-nitrostyrene in 20 ml of tetrahydrofuran is introduced. This mixture is then allowed to warm to room temperature when 40 ml of a saturated ammonium chloride solution is added. The aqueous layer is then extracted with 2×25 ml of diethyl ether and the organic extracts are combined and dried over magnesium sulphate. The solvent is then evaporated under reduced pressure and the crude product chromatographed on silica gel using ethyl acetate as an eluent to give ethyl 2-(4-methylphenyl)-3-nitropropyl(diethoxymethyl)phosphinate as a viscous oil, 31P=+42.5 and +42.1 ppm (CDCl3).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:28][CH3:29])=[C:6]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[CH:26]=[CH:25][O:24][N:23]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][C:9]2=[O:27])[CH:7]=1.[Br-].[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[Zn+].[Cl-].[NH4+]>C1COCC1.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>[O:24]1[CH:25]=[CH:26][C:22]([NH:21][S:18]([C:14]2[CH:13]=[C:12]3[C:17](=[CH:16][CH:15]=2)[N:8]([C:6]2[CH:7]=[C:2]([C:32]4[CH:33]=[CH:34][CH:35]=[CH:36][N:31]=4)[CH:3]=[CH:4][C:5]=2[O:28][CH3:29])[C:9](=[O:27])[CH:10]=[CH:11]3)(=[O:20])=[O:19])=[N:23]1
Reactant: COc1ccc(Br)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Reactant: [Zn+]c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [Cl-]
Solvent: C1CCOC1
Product: COc1ccc(-c2ccccn2)cc1-n1c(=O)ccc2cc(S(=O)(=O)Nc3ccon3)ccc21
Temperature: 60 °C

Procedure:
To a vial charged with 1-(5-bromo-2-methoxyphenyl)-N-(isoxazol-3-yl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.100 g, 0.210 mmol) and Pd(Ph3P)4 (0.024 g, 0.021 mmol) in THF (1.050 ml) was added pyridin-2-ylzinc(II) bromide (0.5M in THF) (2.100 ml, 1.050 mmol). The reaction was sealed and heated to 60° C. for 6.5 h. After cooling to RT, ammonium chloride (sat. aq) was added and the product extracted (×3) with DCM. The organics were dried via phase separator and concentrated in vacuo. The crude material was purified via MPLC, eluting with 20-100% ethyl acetate in heptanes to yield desired product, contaminated with triphenylphosphine oxide. The material was triturated in diethyl ether and filtered to yield N-(isoxazol-3-yl)-1-(2-methoxy-5-(pyridin-2-yl)phenyl)-2-oxo-1,2-dihydroquinoline-6-sulfonamide (0.070 g, 0.148 mmol, 70.3% yield) as a light yellow solid. MS (ESL pos. ion) m/z: [M+1] 475.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.74 (s, 3 H) 6.44 (d, J=1.76 Hz, 1 H) 6.79-6.85 (m, 2 H) 7.31 (t, J=5.85 Hz, 1 H) 7.42 (d, J=8.81 Hz, 1H) 7.52-7.67 (m, 2 H) 7.97 (d, J=8.01 Hz, 1 H) 8.06 (d, J=2.28 Hz, 1 H) 8.23 (d, J=9.64 Hz, 1 H) 8.31-8.41 (m, 2 H) 8.59-8.64 (m, 1 H) 8.72 (d, J=1.87 Hz, 1 H) 11.59-11.69 (m, 1 H).
Reaction SMILES: Cl.Cl.[C:3]([C:7]1[N:11]=[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[NH:9][N:8]=1)([CH3:6])([CH3:5])[CH3:4].Cl.Cl.N1C=NC=N1.C(N(CC)CC)C.[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37]>CN(C)C1C=CN=CC=1.C1COCC1>[CH3:34][N:35]([CH3:39])[C:36]([N:9]1[C:10]([S:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[N:11][C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])=[N:8]1)=[O:37]
Reactant: CN(C)C(=O)Cl
Reactant: CC(C)(C)c1n[nH]c(SCc2ccccn2)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: c1nc[nH]n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(C(C)(C)C)nc1SCc1ccccn1

Procedure:
Ten g of 3-t-butyl-5-(pyrid-2-yl-methylthio)-1H-1,2,4-triazole dihydrochloride, 0.5 g (4.1 mmole) of 1,2,4-triazole dihydrochloride, 0.5 g (4.1 mmole) of 4-dimethylaminopyridine, 10 g (100 mmole) of triethylamine, 3.5 g of dimethylcarbamoyl chloride and 100 ml of THF were refluxed for two hours. The mixture was concentrated in vacuo, and partitioned between ether and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the solvent was removed in vacuo to yield 1-dimethylcarbamoyl-3-t-butyl-5-(pyrid-2-yl-methylthio)-1H-1,2,4triazole, an oil.
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[N:6]=[C:7]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][N:8]2[C:9](=[O:11])[CH:10]=1.[CH:17](=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CO>[CH3:16][C:15]1[C:7]2=[N:6][C:5](/[CH:4]=[CH:17]/[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:10][C:9](=[O:11])[N:8]2[CH:12]=[CH:13][CH:14]=1
Reactant: Cc1cc(=O)n2cccc(C)c2n1
Reactant: O=Cc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cccn2c(=O)cc(/C=C/c3ccccc3)nc12
Yield: 26.6 %

Procedure:
To a solution of 1.1g of sodium methoxide and 25ml of absolute methanol is added 1.1g of 2,9-dimethyl-4H-pyrido-[1,2-a]pyrimidin-4-one, followed by 2.2g of benzaldehyde. The mixture is heated and stirred under reflux for 15 hours and concentrated on a rotary evaporator in vacuo at 45°C. The residual material is distributed between 100ml of chloroform and 50ml of water. The two solutions are separated and the chloroform solution is washed with saturated aqueous sodium chloride, dried, filtered, and the filtrate concentrated. The residual material is recrystallized from 100ml of cyclohexane to yield 0.44g of the title compound, melting point 150°-152°C.
Reaction SMILES: [CH2:1]([C:3]1[C:4]([NH:11][C@@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].C1C2C(=CC=CC=2)[C@H](N)[C@@H]1O>>[CH2:1]([C:3]1[C:4]([NH:11][C@H:12]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][C@H:13]2[OH:21])=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Agent: N[C@H]1c2ccccc2C[C@H]1O
Product: CCc1cnc(CC)c(N[C@H]2c3ccccc3C[C@H]2O)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting (1S,2R)-(−)-cis-1-amino-2-indanol and making non-critical variations provided the title compound as a light purple solid. MS (ESI+) for C17H21N3O m/z 284.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8](Cl)[CH3:9].[Na].[CH3:21][SH:22]>CO>[Cl:1][C:2]1[C:3]([NH:11][CH:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])=[N:4][CH:5]=[N:6][C:7]=1[CH:8]([S:22][CH3:21])[CH3:9]
Reactant: CS
Reactant: CC(Cl)c1ncnc(NC(C)c2ccccc2)c1Cl
Agent: [Na]
Solvent: CO
Product: CSC(C)c1ncnc(NC(C)c2ccccc2)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
In 30 ml of methanol was dissolved 1.20 g of 5-chloro-6-(1-chloroethyl)-4-(1-phenylethylamino)pyrimidine, and to the mixture was added 2.89 g of a methanethiol sodium salt 15% aqueous solution. The mixture was stirred at room temperature for 3 hours.
Reaction SMILES: [C:1]1(=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:7][C@H:8]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]1.CO.C1(C)C=CC=CC=1.[BH4-].[Na+]>O>[CH:1]1([NH:7][C@H:8]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: O=C1CCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NC2CCCC2)C1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Cyclopentanone (12.7 ml, 143 mmol) was added to tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (26.6 g, 143 mmol) in a mixture methanol:toluene 3:1 (600 ml:200 ml) and the reaction mixture was stirred at room temperature for 1.5 hours under nitrogen. The mixture was then evaporated to 50 ml, azeotroped three times with methanol:toluene 3:1 (600 ml:200 ml) and concentrated in vacuo. The reaction mixture was taken up in methanol (250 ml), cooled down to 0° C. and sodium borohydride (7.5 g, 200.2 mmol) was added portionwise. After completion of the reaction, water (50 ml) was added and the solvent was evaporated. The residue was diluted with more water (150 ml) and extracted three times with dichloromethane (250 ml). The organic phases were combined, dried over magnesium sulfate, and concentrated in vacuo to provide the title compound as a gum, 36.1 g (99.4%).
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[N:6][CH:5]=1.[NH2:32][CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:32][CH:33]5[CH2:38][CH2:37][O:36][CH2:35][CH2:34]5)=[O:31])=[CH:5][N:6]=4)[CH:14]=3)=[C:19]([C:20]([F:22])([F:21])[F:23])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Product: O=C(NC1CCOCC1)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)nc1
Yield: 99.7 %

Procedure:
As described for Example 38b, 6-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-nicotinic acid methyl ester (100 mg, 0.23 mmol), was converted, using 4-aminotetrahydropyran (96.35 μL, 0.9 mmol) instead of cyclopropanemethylamine, to the title compound (115 mg, 99%) which was obtained as a white solid. MS: m/e=501.8 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([C:21](C)([CH3:25])[C:22](O)=O)[C:17]=3[CH:27]=2)[C:3]1=[O:28].N1C2C(=CC=CC=2)C=CC=1>C(OCC)(=O)C>[CH:21]([C:18]1[C:17]2[CH:27]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:9])([F:11])[F:10])[N:2]([CH3:1])[C:3]3=[O:28])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)([CH3:25])[CH3:22]
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(C)(C)C(=O)O)c3c2)c1=O
Solvent: CCOC(C)=O
Solvent: c1ccc2ncccc2c1
Product: CC(C)c1nsc2ccc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)cc12
Temperature: 140 °C
Reaction time: 0.25 h
Yield: 35.8 %

Procedure:
A mixture of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-α,α-dimethyl-1,2-benzisothiazole-3-acetic acid (2.00 g, 0.00484 mol) and quinoline (20.0 ml) is heated to 140° C. with stirring. After 15 minutes, the mixture is cooled to room temperature, diluted with ethyl acetate, washed sequentially with 2 N hydrochloric acid, saturated sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to a yellow solid. The solid is recrystallized from hexanes:methylene chloride to give the title compound as an off-white solid (0.640 g, 35.8%, mp 139-140° C.) which is identified by NMR and IR spectral analyses.
Reaction SMILES: [CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:18]([NH2:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[OH-].[Na+]>O1CCCC1.C(O)(=O)C>[CH2:1]([C:8]1([N:15]([CH3:17])[CH3:16])[CH2:13][CH2:12][CH:11]([NH:20][CH2:18][CH3:19])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN
Reactant: CN(C)C1(Cc2ccccc2)CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCNC1CCC(Cc2ccccc2)(N(C)C)CC1
Reaction time: 8 h
Yield: 72.5 %

Procedure:
15.0 g 4-benzyl-4-dimethylamino-cyclohexanone (see example 3) were dissolved in 225 ml analytical grade tetrahydrofuran, and 2.89 g ethylamine followed by 8.40 ml glacial acetic acid were added, while stirring in an ice-bath. 19.2 g sodium triacetoxyborohydride were then added in portions in the course of 15 minutes and the mixture was subsequently stirred overnight. For working up, 110 ml two molar sodium hydroxide solution were added dropwise (pH>10) and the mixture was extracted three times with 200 ml diethyl ether each time. The combined organic phases were washed twice with 200 ml water each time, dried over sodium sulfate and filtered and the filtrate was concentrated. The crude product obtained (15.7 g) was chromatographed over silica gel with methanol with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 14.1 g of the still significantly contaminated product were obtained, and were chromatographed again over silica gel with methanol with the addition of one percent by volume of aqueous ammonia solution (25 wt. %). 12.1 g 1-benzyl-N′-ethyl-N,N-dimethyl-cyclohexane-1,4-diamine were obtained as a cis/trans mixture.
Reaction SMILES: [CH2:1]([N:8]1[C:12](Br)=[CH:11][N:10]=[C:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+].CO>CC([O-])=O.CC([O-])=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Pd+2].COCCOC>[CH2:1]([N:8]1[C:12]([C:19]2[CH:18]=[CH:17][C:16]([F:15])=[CH:21][C:20]=2[F:22])=[CH:11][N:10]=[C:9]1[CH3:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1F
Reactant: Cc1ncc(Br)n1Cc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: CO
Product: Cc1ncc(-c2ccc(F)cc2F)n1Cc1ccccc1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
Heat a mixture of 1-benzyl-2-methyl-5-bromo-1H-imidazole (4.71 g, 18.7 mmol), 2,4-difluorophenyl boronic acid (6.92 g, 43.8 mmol), bis(acetato)bis(triphenylphosphine)-palladium(II) (1.4 g, 1.875 mmol), 2N Na2CO3 (19 mL, 38 mmol), MeOH (19 mL) and 1,2-dimethoxyethane (120 mL) to reflux for 18 h. Cool to RT. Add water and EtOAc and separate the layers. Dry organic layer over MgSO4, filter, and concentrate. Purify the residue (silica gel chromatography, eluting with EtOAc:CH2Cl2 mixtures) to give the desired compound (3.59 g).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.CSC.[C:12]([O:15][C:16]1[C:17]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:18][C:19]2[O:23][C:22]([CH2:25][CH2:26]/[CH:27]=[C:28](\[CH3:31])/[CH2:29]O)([CH3:24])[CH2:21][C:20]=2[C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:14])[CH3:13]>ClCCl>[C:12]([O:15][C:16]1[C:17]([C:37]([CH3:40])([CH3:39])[CH3:38])=[CH:18][C:19]2[O:23][C:22]([CH2:25][CH2:26]/[CH:27]=[C:28](\[CH3:31])/[CH2:29][Cl:1])([CH3:24])[CH2:21][C:20]=2[C:32]=1[C:33]([CH3:36])([CH3:35])[CH3:34])(=[O:14])[CH3:13]
Reactant: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CO)O2
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)Oc1c(C(C)(C)C)cc2c(c1C(C)(C)C)CC(C)(CC/C=C(\C)CCl)O2
Reaction time: 0.25 h
Yield: 71.7 %

Procedure:
N-Chlorosuccinimide (150 mg) was suspended in dichloromethane (4 ml). After adding dimethyl sulfide (0.1 ml) dropwise at -5° C., the suspension was stirred for 15 min. Subsequently, a solution of 5-acetoxy-4,6-di-tert-butyl-2-(5-hydroxy-4-methyl-3(E)-pentenyl)-2-methyl-2,3-dihydrobenzofuran (0.4 g) in dichloromethane (1 ml) was added dropwise and the resulting mixture was stirred at -5° C. for 90 min. After the end of the reaction, dichloromethane was distilled off under reduced pressure and the concentrate was purified by silica gel chromatography (25% ethyl acetate in n-hexane) to afford 5-acetoxy-2-(5-chloro-4-methyl-3(E)-pentenyl)-4,6-di-tert-butyl-2-methyl-2,3-dihydrobenzofuran [0.3 g (yield, 70%)] as a colorless oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][C:7]1[CH:8]=[C:9]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:40][CH3:41])([C:25]3[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([CH2:37][CH3:38])([OH:36])[CH2:34][CH3:35])=[C:27]([CH3:39])[CH:26]=3)[CH2:23][CH3:24])=[CH:18][C:17]=2[CH3:42])[C:10]([OH:15])=[C:11]([O:13][CH3:14])[CH:12]=1.[Cl-].[NH4+]>CO.O1CCCC1>[CH2:23]([C:22]([C:19]1[CH:20]=[CH:21][C:16]([C:9]2[C:10]([OH:15])=[C:11]([O:13][CH3:14])[CH:12]=[C:7]([CH2:6][C:5]([OH:43])=[O:4])[CH:8]=2)=[C:17]([CH3:42])[CH:18]=1)([C:25]1[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([CH2:34][CH3:35])([OH:36])[CH2:37][CH3:38])=[C:27]([CH3:39])[CH:26]=1)[CH2:40][CH3:41])[CH3:24]
Reactant: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)OC)cc(OC)c3O)c(C)c2)cc1C)CC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CCC(O)(/C=C/c1ccc(C(CC)(CC)c2ccc(-c3cc(CC(=O)O)cc(OC)c3O)c(C)c2)cc1C)CC
Temperature: 25 °C
Reaction time: 8 h
Yield: 12.5 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.301 mL, 0.301 mmol) was added to a solution of (4′-{1-ethyl-1-[4-((E)-3-ethyl-3-hydroxy-1-pentenyl)-3-methyl-phenyl]-propyl}-6-hydroxy-5-methoxy-2′-methyl-biphenyl-3-yl)-acetic acid methyl ester (Example 179-(1); 33.6 mg, 0.050 mmol) in methanol-tetrahydrofuran (1:1, 4 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform:methanol=10:1) to give the target compound as a colorless oil (3.4 mg, 10%).
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:6]([CH3:21])[C:5]=1[C:22]([O:24]CC)=[O:23]>CO>[Br:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:11]=2)[N:6]([CH3:21])[C:5]=1[C:22]([OH:24])=[O:23]
Reactant: CCOC(=O)c1c(Br)c2cc(OCc3ccccc3)ccc2n1C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1c(C(=O)O)c(Br)c2cc(OCc3ccccc3)ccc21
Yield: 96.3 %

Procedure:
A solution of potassium hydroxide (17.0 g, 303 mmol) in 3.0 L of 50% aqueous methanol is treated with ethyl 3-bromo-1-methyl-5-(phenylmethoxy)-1 H-indole-2-carboxylate (55.4 g, 143 mmol). The mixture is stirred at reflux for 5 hours, than decanted while warm from any insoluble material into 600 mL of hot water. The warm solution is quickly acidified with 100 mL of 4.0N HCl. An additional 1.0 L of cold water is added, and the mixture is stirred for 1 hour. The precipitated solid is filtered, stirred in 1.0 L of 25% methanol-water, and refiltered, to give 49.6 g (96%) of product, suitable for further synthesis. A sample recrystallized from aqueous acetonitrile has mp 210° C.-dec.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[S:8][C:9]([C:11]3[C:16]([F:17])=[CH:15][C:14](I)=[CH:13][C:12]=3[Cl:19])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[C:20](=[O:27])([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[NH2:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>C1(C)C=CC=CC=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:19][C:12]1[CH:13]=[C:14]([NH:21][C:20](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:15]=[C:16]([F:17])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([Cl:1])=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1
Reactant: Fc1cc(I)cc(Cl)c1-c1nc2ccnc(Cl)c2s1
Reactant: CC(C)(C)OC(N)=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1cc(F)c(-c2nc3ccnc(Cl)c3s2)c(Cl)c1
Temperature: 90 °C
Yield: 78.9 %

Procedure:
A mixture of 4-chloro-2-(2-chloro-6-fluoro-4-iodo-phenyl)thiazolo[5,4-c]pyridine (715 mg, 1.682 mmol), tert-butyl carbamate (394 mg, 3.365 mmol), Pd2(dba)3 (77 mg, 0.084 mmol), and XantPhos (97 mg, 0.168 mmol) in toluene (17 mL) and K3PO4 (2.65 mL, 1.27 M) was heated at 90° C. under nitrogen for 20 hours. The reaction mixture was diluted with water, extracted with EtOAc (2×). The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel flash chromatography (0-25% EtOAc/hexane) to give the title compound (550 mg, 78.9% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.48 (d, J=5.6 Hz, 1H), 7.95 (d, J=5.6 Hz, 1H), 7.46-7.33 (m, 2H), 6.70 (s, 1H), 1.55 (s, 9H). LCMS (ESI) m/z 414.1 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]=[O:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:22])([F:21])[F:20].[BH4-].[Na+]>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:10]=2[C:11]#[N:12])=[CH:4][C:3]=1[C:19]([F:20])([F:21])[F:22]
Reactant: N#Cc1cc(C=O)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: N#Cc1cc(CO)ccc1Oc1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 89.4 %

Procedure:
To the solution of 2-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}-5-formylbenzonitrile (1.59 g, 4.88 mmol) in ethanol (45 ml), was added NaBH4 (0.203 g, 5.37 mmol). The solution was stirred at room temperature under nitrogen for 1.5 h. After removing the solvent, the residue was dissolved in DCM, then washed with water twice. The solvent was dried over Na2SO4, concentrated to afford the title compound (1.43 g, 89% yield) as a white solid. LCMS: rt=3.31 min, [M+H+]=328