Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[C@H:14]([CH3:25])[CH2:13]3)[CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O>[C:26]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[C@H:14]([CH3:25])[CH2:13]3)[CH2:9]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: C[C@@H]1CN(C2CN(C(c3ccccc3)c3ccccc3)C2)CCN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H]1CN(C2CN(C(c3ccccc3)c3ccccc3)C2)CCN1C
Temperature: 0 °C
Yield: 90.2 %

Procedure:
To a mixed solution of tert-butyl(2R)-4-(1-(diphenylmethyl)azetidin-3-yl)-2-methylpiperazine-1-carboxylate (476 mg, 1.13 mmol) described in Production Example 5-1 and THF (10.0 mL) was added lithium aluminum hydride (171 mg, 4.52 mmol) at 0° C., and the resultant mixture was stirred under reflux for 1 hour and 55 minutes. The reaction mixture was cooled to 0° C., water (171 μL) and a 5 N aqueous sodium hydroxide solution (171 μL) were added thereto, and water (513 μL) was additionally added thereto. The reaction mixture was filtrated using Celite and then washed with ethyl acetate. A filtrate was concentrated under a reduced pressure and the resultant residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=2:1) to give the title compound (342 mg, yield: 90%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]([O:8][CH3:9])=[O:7])[C:3]([C:10]([O:12][CH3:13])=[O:11])=[CH:2]1.C(OCC)(=O)C.[H][H]>CO.[Rh]>[O:1]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH:3]([C:10]([O:12][CH3:13])=[O:11])[CH2:2]1
Reactant: [H][H]
Reactant: COC(=O)c1cocc1C(=O)OC
Agent: [Rh]
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)C1COCC1C(=O)OC
Reaction time: 8.5 h
Yield: 98.7 %

Procedure:
Dimethyl 3,4-furandicarboxylate (5.20 g, 28.0 mmol) was combined with 5% Rhodium/C in methanol (30 mL) and ethyl acetate (10 mL) in a Parr shaker bottle. The reaction was charged to 50 psi hydrogen and was shaken for 8.5 h. The reaction was filtered over celite, concentrated in vacuo to give the dimethyl 3,4-tetrahydrofuran dicarboxylate (5.2 g, 100%) as an oil MS (M−CH3OH)+=156.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(CC(=O)C)(=O)C.C(OCCOC(=O)C)(=O)C>C([O-])(=O)CC.[Pd+2].C([O-])(=O)CC>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=3[C:6]=2[CH:7]=1
Reactant: Cc1ccc(Oc2ccc(C)cc2)cc1
Agent: [Pd+2]
Agent: CCC(=O)[O-]
Solvent: CC(=O)CC(C)=O
Solvent: CC(=O)OCCOC(C)=O
Product: Cc1ccc2oc3ccc(C)cc3c2c1
Yield: 18.7 %

Procedure:
This example was carried out under the same conditions as in Example 1 except that 15.0 g of 4,4'-dimethyldiphenyl ether, 0.038 g (0.15 m. mole) of palladium propionate, 0.015 g (0.15 m. mole) of acetylacetone and 5 ml of ethylene glycol diacetate were employed. As a result, 2.78 g (14 m. moles) of 2,8-dimethyldibenzofuran and 0.78 g (2.0 m. moles) of the dimer also obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[N:6]=[CH:5]2.C(Cl)Cl.[I:22]N1C(=O)CCC1=O>>[OH:1][C:2]1[C:3]([I:22])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C@:12]1([CH3:18])[CH2:16][O:15][C:14](=[O:17])[NH:13]1)[N:6]=[CH:5]2
Reactant: C[C@@]1(c2ncc3cc(O)ccc3n2)COC(=O)N1
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: C[C@@]1(c2ncc3c(I)c(O)ccc3n2)COC(=O)N1
Yield: 84.1 %

Procedure:
(R)-4-(6-Hydroxy-quinazolin-2-yl)-4-methyl-oxazolidin-2-one (330.0 mg, 0.001346 mol) was dissolved in methylene chloride (500 mL, 8 mol), (heterogeneous) followed by N-iodosuccinimide (302.8 mg, 0.001346 mol) at 23° C. The reaction mixture was then sonicated for 30 seconds, and all the solvent was removed under vacuum (rotavap). The residue was purified via chromatography (SiO2, 20 gm, 0-100% ethyl acetate/hexanes) to give 420 mg of desired product (84%). 1H NMR (MeOD) δ: 9.50 (s, 1H), 7.90 (d, J=9.0 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H), 4.99 (d, J=8.8 Hz, 1H), 4.48 (d, J=8.8 Hz, 1H), 1.79 (s, 3H). MS (M+1): 372.00.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[CH3:9][S-:10].[Na+].O>CN(C)C=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([S:10][CH3:9])=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: C[S-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 94.5 %

Procedure:
Commercially available 2,5-dibromo pyridine (6.01 g, 25.4 mmol) was dissolved in N,N-dimethylformamide (50 mL), and sodium thiomethoxide (2.20 g, 31.4 mmol) was added, followed by stirring at 0° C. for 3.5 hours under nitrogen atmosphere. The reaction solution was brought back to room temperature, water (250 mL) was added, and extraction was carried out with diethyl ether (250 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: ethyl acetate/hexane=3%-5%) to afford the desired compound (4.90 g, yield 94%) as a white solid.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:9][NH:10][C@H:11]1[C@H:20]([O:21][CH3:22])[CH2:19][C:18]2[C:13](=[CH:14][C:15]([C:23](=[O:25])[NH2:24])=[CH:16][CH:17]=2)[C:12]1([CH3:27])[CH3:26])(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:7][C@H:8]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:9][NH:10][C@@H:11]1[C:12]([CH3:27])([CH3:26])[C:13]2[CH:14]=[C:15]([C:23]([NH2:24])=[O:25])[CH:16]=[CH:17][C:18]=2[CH2:19][C@H:20]1[O:21][CH3:22]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC[C@@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1NC[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 187.2 %

Procedure:
A solution of [(R)-1-benzyl-2-(trans-7-carbamoyl-3-methoxy-1,1-dimethyl-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-ethyl]-carbamic acid tert-butyl ester (2.20 g, 3.36 mmol) in DCM (20 mL) under an atmosphere of nitrogen was cooled to 0° C. and 4.0 M HCl in 1,4-dioxane (3.36 mL, 13.4 mmol) was added dropwise. The clear solution was stirred and allowed to warm to room temperature. After 3 h, the reaction flask was stored at −20° C. for 4 days. The reaction mixture was allowed to warm to room temperature and the solvents were evaporated under reduced pressure to give the title compound as an off-white solid (2.4 g).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])[NH2:8])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Cl:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>CCOCC>[C:1]([C:5]1[CH:6]=[C:7]([NH:8][C:28](=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][Cl:23])[CH:9]=[C:10]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:11]=1[OH:12])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)CCCCCl
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)c1cc(NC(=O)CCCCCl)cc(C(C)(C)C)c1O
Temperature: 0 °C
Reaction time: 15 h
Yield: 100 %

Procedure:
To a stirred mixture of 3.6 g (16 mmol) of 3,5-di-tert-butyl-4-hydroxyaniline and 1.3 g (16 mmol) of pyridine in 50 ml of ether cooled to 0° C. there was slowly added 2.5 g (16 mmol) of 5-chlorovalerylchloride. The reaction mixture was allowed to warm to 25° C. and stirred for 15 hours following which the mixture was diluted with 100 ml of ether, washed with water, dried over anhydrous magnesium sulfate and concentrated to 5.8 g of solid. The solid was triturated in hexane and filtered to yield 5.5 g (16 mmol) of N-(3,5-di-tert-butyl-4-hydroxyphenyl)-5-chlorovaleramide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1.[NH2:27][C:28]1[CH:29]=[C:30]([CH3:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=1>CO.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:27][C:28]2[CH:29]=[C:30]([CH3:36])[C:31](=[O:35])[N:32]([CH3:34])[CH:33]=2)[C:9]2[C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:11][N:12]([CH:18]3[CH2:20][CH2:19]3)[C:13]=2[C:14]([F:17])([F:16])[F:15])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(O)c1ccc(Cl)cc1
Reactant: Cc1cc(N)cn(C)c1=O
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1nn(C2CC2)c(C(F)(F)F)c1C(Nc1cc(C)c(=O)n(C)c1)c1ccc(Cl)cc1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-cyclopropyl-5-(trifluoromethyl)-1H-pyrazole-3-carboxylate (Step 40.2) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2) at RT for 4 days. tR: 1.22 min (LC-MS 2); ESI-MS: 509 [M+H]+ (LC-MS 2); Rf=0.32 (5% MeOH/CH2Cl2).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1.Br[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13]>CN(C=O)C>[C:14]1([C:12](=[O:13])[CH2:11][O:3][C:4]2[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(CBr)c1ccccc1
Reactant: Oc1cccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(COc1cccnc1)c1ccccc1
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a suspension NaH (0.8 g, 60%, 20 mmol) in DMF (15 mL) was added a solution of 3-hydroxylpyridine (1.9 g, 20 mmol) in DMF (10 mL) at ° C. under nitrogen. After the mixture was stirred 15 min, a solution of 2-bromoacetophenone (3.98 g, 20 mmol) in DMF (10 mL) was added dropwise. The resulting mixture was stirred for 5 h until the starting material consumed. Water was added to quench the reaction and the aqueous phase was extracted with CH2Cl2 (3×40 mL). The combined organic phases were washed with brine, dried over MgSO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography eluted by hexane:ethyl acetate (1:1) and the correct product was obtained as a white solid; mp 81-82° C.; yield 75% (3.19 g); H NMR (400 MHz, CDCl3): d 5.40 (s, 2H, OCH2), 7.28 (m, 2H, Ar), 7.59 (m, 2H, Ar), 7.67 (m, 1H, Ar), 8.03 (m, 2H, Ar), 8.32 (m, 1H, Ar), 8.43 (m, 1H, Ar); CNMR (100 MHz, CDCl3): δ 70.8, 121.7, 123.9, 128.1, 129.0, 134.2, 134.3, 138.2, 143.1, 154.4, 193.6; IR ν (cm−1) 3054, 3007, 2988, 2963, 2898, 1702, 1579, 1486, 1450, 1422, 1275, 1263, 1233, 1090, 974, 815, 765, 751.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[F:13])[C:6]([O:8]C)=[O:7])[CH3:2].[OH-].[Li+]>[Pd].CO.CO.O1CCCC1.O>[F:13][C:12]1[CH:11]=[CH:10][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1cc(C(=O)OC)ccc1F
Agent: [Pd]
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCc1cc(C(=O)O)ccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
(4-fluoro-3-ethylbenzoyl chloride was prepared in 5 steps from 3-bromo-4-fluorobenzoic acid. 3-bromo-4-fluorobenzoic acid was converted to methyl 3-bromo-4-fluorobenzoate by treatment with trimethylsilyl diazomethane (1.5 equivalents) in benzene/methanol (4/1) at room temperature. Subsequent reaction with tributyl(vinyl) tin (1.2 equivalents) in DMF in the presence of catalytic dichlororbis(triphenylphosphine)palladium(II) (0.1 equivalents) at 80° C. under an argon atmosphere, followed by aqueous work up and standard chromatography (10% ethyl acetate/hexanes), yielded methyl 4-fluoro-3-vinylbenzoate. Hydrogenation of the vinyl group by treatment of this material with palladium on carbon (10% palladium on carbon, 10% by mass) in methanol under an hydrogen atmosphere then afforded methyl 3-ethyl-4-fluorobenzoate. This material was dissolved in methanol/tetrahydrofuran/water (2/1/1) then lithium hydroxide (5.0 equivalents) was added and reaction mixture stirred at room temperature for 2 hours. The mixture was concentrated, the residue acidified with a 1N HCl aqueous solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 4-fluoro-3-ethylbenzoic acid. This material was directly converted to 4-fluoro-3-ethylbenzoyl chloride by treatment with thionyl chloride (2.2 equivalents) in dichloromethane at room temperature for 2 hours followed by removal of the volatiles in vaccuo). The rest of the procedures were followed as indicated in general procedure B to afford N-(4-chlorophenyl)-N-[(2S,4R)-1-(3-ethyl-4-fluorobenzoyl)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]acetamide.
Reaction SMILES: C([Li])CCC.C[Si](C)(C)N[Si](C)(C)C.[CH:15]1([C:18]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)=[O:19])[CH2:17][CH2:16]1.Cl.[C:28]([O:31][CH2:32][CH3:33])(=[O:30])[CH3:29]>CCCCCC.O1CCCC1>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([C:18]([CH:15]2[CH2:16][CH2:17]2)([OH:19])[CH2:29][C:28]([O:31][CH2:32][CH3:33])=[O:30])=[CH:25][CH:24]=1
Reactant: CCOC(C)=O
Reactant: O=C(c1ccc(Cl)cc1)C1CC1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)CC(O)(c1ccc(Cl)cc1)C1CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
13.8 ml (22.14 mmol) of a 1.6N solution of n-butyllithium in hexane were added dropwise to a solution of 4.7 ml (22.14 mmol) of hexamethyldisilazane in 17 ml of tetrahydrofuran at −20° C., and the mixture was stirred at 0° C. for 30 min and then cooled again to −78° C. 2.17 ml (22.14 mmol) of ethyl acetate were added, and the mixture was stirred for 30 min and, after addition of 2.00 g (11.07 mmol) of 4-chlorophenyl cyclopropyl ketone, dissolved in 17 ml of tetrahydrofuran, stirred at −78° C. for a further hour. The reaction solution was mixed with 1N hydrochloric acid and ethyl acetate, and the phases were separated. The organic phase was washed successively with 0.5N hydrochloric acid, water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. After purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) the acetonitrile was removed in a rotary evaporator, and the aqueous phase was extracted several times with diethyl ether. The combined organic phases were washed with saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. 2.54 g (99% of theory) of the title compound were obtained.
Reaction SMILES: Cl[S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3].[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[N:15]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH2:23])[N:13]=1.N1C=CC=CC=1>ClCCl>[CH3:19][O:18][C:16]1[CH:17]=[C:12]([O:11][CH3:10])[N:13]=[C:14]([O:20][C:21]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:22]=2[NH:23][S:2]([CH2:5][C:6]([O:8][CH3:9])=[O:7])(=[O:4])=[O:3])[N:15]=1
Reactant: COC(=O)CS(=O)(=O)Cl
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2N)n1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)CS(=O)(=O)Nc1c(F)cccc1Oc1nc(OC)cc(OC)n1
Reaction time: 8 h

Procedure:
Methyl (chlorosulfonyl)acetate (13.0 g) in dichloromethane (20 ml) was aaded dropwise with stirring and cooling to 2-(4,6-dimethoxypyrimidin-2-yloxy)-6-fluoroaniline (20 g) and pyridine (6.3 g) in dichloromethane (120 ml). After stirring for 2 hours, the mixture was allowed to stand at room temperature overnight. Washing with dilute hydrochloric acid and water, dryiny over magnesium sulfate, and running down, gave an oil which was triturated with ether. The resulting off-white solid was separated by filtration to qive 20.4 of the desired product, mp 111°-114° C.
Reaction SMILES: Br[C:2]1[C:3](=[O:28])[NH:4][C:5]2[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=[C:9]([S:12]([NH:15][CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)(=[O:14])=[O:13])[C:10]=2[CH:11]=1.[N:29]1[CH:34]=[CH:33][CH:32]=[C:31](B(O)O)[CH:30]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(COC)OC>O>[CH:16]1([NH:15][S:12]([C:9]2[C:10]3[CH:11]=[C:2]([C:31]4[CH:30]=[N:29][CH:34]=[CH:33][CH:32]=4)[C:3](=[O:28])[NH:4][C:5]=3[CH:6]=[C:7]([C:21]3[C:22]([CH3:27])=[N:23][O:24][C:25]=3[CH3:26])[CH:8]=2)(=[O:14])=[O:13])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(Br)c(=O)[nH]c2c1
Reactant: OB(O)c1cccnc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: COCCOC
Solvent: O
Product: Cc1noc(C)c1-c1cc(S(=O)(=O)NC2CCCC2)c2cc(-c3cccnc3)c(=O)[nH]c2c1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of 3-bromo-N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-1,2-dihydroquinoline-5-sulfonamide (45 mg, 0.1 mmol), 3-pyridine boronic acid (25 mg, 0.2 mmol), cesium carbonate (100 mg, 0.3 mmol), Peppsi-iPr (4 mg, 5 mol %), dimethoxyethane (2 mL) and water (1 mL) was stirred at 100° C. for 2 hours. The reaction mixture was concentrated before being purified by preparative HPLC to give N-cyclopentyl-7-(3,5-dimethylisoxazol-4-yl)-2-oxo-3-(pyridin-3-yl)-1,2-dihydroquinoline-5-sulfonamide as a yellow powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][C:16]=2[C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19]([O:24][CH3:25])[CH:18]=2)[C:10](OC)=[O:11])=[CH:5][CH2:4][CH2:3]1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:1][C:2]1([CH3:26])[C:6]([C:7]2[CH:8]=[C:9]([CH2:10][OH:11])[CH:14]=[CH:15][C:16]=2[C:17]2[C:22]([F:23])=[CH:21][N:20]=[C:19]([O:24][CH3:25])[CH:18]=2)=[CH:5][CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2=CCCC2(C)C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(-c2ccc(CO)cc2C2=CCCC2(C)C)c(F)cn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To methyl 3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)benzoate 66.12B (295 mg, 830 μmol) was added THF. The mixture was cooled to 0° C., and LAH (1660 μL, 1660 μmol) was added dropwise. The reaction was stirred at room temperature for 1 hour, and was quenched with water and a small amount of Rochelle's salt solution. Purification with silica gel chromatography afforded (3-(5,5-dimethylcyclopent-1-enyl)-4-(5-fluoro-2-methoxypyridin-4-yl)phenyl)methanol 66.12C (201 mg) as an oil (74%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Br)#[N:18].[OH-].[Na+].C(O)C>O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:21][C:20]2[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=2[C:17]#[N:18])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: N#Cc1ccccc1CBr
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)(C)c1cc(SCc2ccccc2C#N)cc(C(C)(C)C)c1O
Yield: 18.9 %

Procedure:
A solution of 2.00 g (8.39 mmole) of 2,6-di-t-butyl-4-mercaptophenol, 1.65 g (8.39 mmole) of o-cyanobenzyl bromide, 5 ml of 1.68N sodium hydroxide and 75 ml of ethanol was heated at reflux for 48 hours. The reaction mixture was poured into water and was extracted with diethyl ether. The ether extract was washed with water, dried with magnesium sulfate and evaporated to give the crude product as an oil. The oil was purified by silica gel chromatography, eluting with a mixture of ethyl acetate and hexane, followed by recrystallization from hexane to give 0.56 g of white 2,6-di-t-butyl-4-[(2-cyanophenyl) methylthio]phenol, m.p. 79°-82° C. Analysis: Calculated for C22H27NOS: %C, 74.7; %H, 7.7; %N, 4.0; Found: %C, 74.6; %H, 7.9; %N 3.6.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[CH:5]2.[C:13](O)(=[O:15])C.C(O)(=O)C.IC1C=CC=CC=1.CS(O)(=O)=O>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([OH:12])=[N:7][CH:6]=[C:5]2[O:15][CH3:13]
Reactant: Oc1nccc2cc(F)ccc12
Reactant: CC(=O)O
Agent: CS(=O)(=O)O
Solvent: Ic1ccccc1
Solvent: CO
Product: COc1cnc(O)c2ccc(F)cc12
Temperature: 70 °C
Reaction time: 3 h
Yield: 67.6 %

Procedure:
6-fluoroisoquinolin-1-ol (1 g, 6.13 mmol), iodobenzene diacetate (2.172 g, 6.74 mmol) and MeOH (15 ml) were added to a sealed tube. To the mixture was added methanesulfonic acid (0.477 ml, 7.36 mmol). The threaded stopper was affixed to the vessel and the mixture was heated first to 70° C. for 4 h and then to 130° C. for 3 h. The mixture was concentrated in vacuo to remove half of methanol, then 5 mL of water was added and the solid was collected by filtration and washed thoroughly with 1:1 methanol/water then dried in vacuo to give 6-fluoro-4-methoxyisoquinolin-1-ol (800 mg, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.27 (dd, J=9.0, 5.8 Hz, 1H), 7.49 (dd, J=10.0, 2.5 Hz, 1H), 7.46-7.42 (m, 1H), 6.83 (d, J=6.3 Hz, 1H), 3.81 (s, 3H); MS m/z 194.1 (M++1).
Reaction SMILES: [CH3:1][CH:2]([Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[O:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=1)[CH3:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[Br:44]Br.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)C.C(#N)C.O>[Br:44][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([O:5][Si:4]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:2]([CH3:3])[CH3:1])=[CH:7][CH:8]=1
Reactant: CC(C)[Si](Oc1ccc(CO)cc1)(C(C)C)C(C)C
Reactant: BrBr
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(CBr)cc1)(C(C)C)C(C)C
Temperature: 0 °C

Procedure:
To a solution of (4-{[tris(1-methylethyl)silyl]oxy}phenyl)methanol (Step 2, 1.0 g, 3.56 mmol) in diethyl ether (20 mL) and acetonitrile (7.5 mL) was added triphenylphosphine (0.94 g, 3.57 mmol) and imidazole (243 mg, 3.57 mmol). After being cooled to 0° C., a solution of bromine (184 μL, 3.56 mmol) in diethyl ether (2.5 mL) was added dropwise. The reaction mixture was stirred at rt over night. Then water was added, and it was extracted with ethyl acetate. The organic extract was washed with water and brine, dried over anhydrous magnesium sulfate and filtered. After evaporation of the solvent, the crude material was treated with pentane. Precipitated triphenylphosphine oxide (TPPO) was removed by filtration. The solvent was evaporated in vacuo. The product thus obtained (1.42 g) still contained some TPPO (as judged by tlc) but was used for subsequent reactions without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([CH2:10][C:11]([OH:13])=O)=[CH:7][CH:8]=[CH:9][C:2]1=2.C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:26][NH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:26][N:27]([C@@H:28]1[CH2:33][CH2:32][CH2:31][CH2:30][C@H:29]1[N:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1)[C:11](=[O:13])[CH2:10][C:6]1[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)Cc1cccc2sccc12
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCCC1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1cccc2sccc12)[C@@H]1CCCC[C@H]1N1CCCCC1
Yield: 71.6 %

Procedure:
A stirred solution of benzo[b]thiophene-4-acetic acid (0.50 g, 2.6 mmol) and carbonyl di-imidazole (0.46 g, 2.8 mmol) in tetrahydrofuran (5 ml) was heated with a solution of trans-(±)-N-methyl-2-(1-piperidinyl)cyclohexanamine (0.46 g, 2.3 mmol) in tetrahydrofuran (2 ml). This mixture was heated to reflux for five minutes, concentrated in vacuo, poured into saturated aqueous sodium bicarbonate (30 ml) and extracted with dichloromethane (2×20 ml) to give an oil which on trituration with diethyl ether gave trans-(±)-N-methyl-N-[2-(1-piperidinyl)cyclohexyl]benzo[b]thiophene-4-acetamide as a crystalline solid (610 mg, 72%); VmaxC=0 (liquid film) 1635 cm-1.