Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13](=[O:17])OCC)[C:6]([O:18][CH3:19])=[N:5]2.[N:20]1[CH:25]=[CH:24][CH:23]=[N:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([NH:12][C:13]([N:29]1[CH2:30][CH2:31][N:26]([C:21]3[N:20]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH2:27][CH2:28]1)=[O:17])[C:6]([O:18][CH3:19])=[N:5]2
Reactant: CCOC(=O)Nc1nc2ccc(Cl)cc2nc1OC
Reactant: c1cnc(N2CCNCC2)nc1
Product: COc1nc2cc(Cl)ccc2nc1NC(=O)N1CCN(c2ncccn2)CC1
Yield: 90 %

Procedure:
Ethyl N-(6-chloro-3-methoxyquinoxalin-2-yl)carbamate and 1-(2-pyrimidyl)piperazine were reacted by the same way with the example 106 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 3.69-3.73 (m, 4H), 3.98 (s, 4H), 4.16 (s, 3H), 6.54-6.55 (m, 1H), 7.28-7.49 (m, 1H), 7.63-7.75 (m, 2H), 8.33 (d, J=4.8 Hz, 2H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23]=[C:24]=[S:25])(=O)C1C=CC=CC=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:24](=[S:25])[NH2:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCN(C(N)=S)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
1.37 g (6.85 mmol) of 1,4-diazepane-1-carboxylic acid tert-butyl ester and 1.12 g (6.85 mmol) of benzoyl isothiocyanate were dissolved in 13 ml of THF and stirred at 50° C. for 2 h. The solvent was subsequently distilled off, and the residue was taken up in 34 ml of methanol and 3.4 ml of water, and 1.89 g of potassium carbonate were added. The mixture was boiled under reflux overnight and then filtered off. The filtrate was evaporated, slurried in 80 ml of water and extracted 3 times with 20 ml of EA each time. The organic phase was dried over sodium sulfate, filtered, evaporated, digested using a little PE and EA and filtered off with suction.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6]([CH2:8][CH2:9][C:10]([OH:12])=O)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.C(Cl)(=O)OCC.[NH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH2:8][CH2:9][C:10]([N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)=[O:12])=[O:7])=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: O=C(O)CCC(=O)c1ccc(F)cc1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(CCC(=O)N1CCCCC1)c1ccc(F)cc1
Reaction time: 0.42 h
Yield: 54.7 %

Procedure:
To a solution of 15 g of β-p-fluorobenzoyl-propionic acid and 8.0 g of triethylamine in 100 ml of tetrahydrofuran, was gradually added 8.3 g of ethyl chlorocarbonate while the reaction mixture was kept below 0°C. After being stirred for 25 minutes at a temperature below 0°C, the mixture was added with 6.5 g of piperidine and stirred for another 2 hours. Then the precipitate formed was filtered off and the filtrate was concentrated to dryness under reduced pressure. The residue was recrystallized from hexane to obtain 11 g of 1-(β-p-fluorobenzoylpropionyl)piperidine, melting at 70° - 71°C.
Reaction SMILES: [C:1]([OH:4])(=[S:3])[CH3:2].[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.CO.[Si:25]([O:42][CH2:43][C@H:44](I)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1(C)C=CC=CC=1>[C:1]([S:3][C@H:44]([CH2:43][O:42][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])(=[O:4])[CH3:2]
Reactant: COC(=O)CC[C@@H](I)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: CC(O)=S
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)SC(C)=O
Reaction time: 18 h

Procedure:
Thioacetic acid (1 mL, 13.2 mmol) was added to 20 mL of toluene under a nitrogen atmosphere. A 1M solution of tetrabutylammonium hydroxide in methanol (11 mL, 11 mmol) with a washing of 1 mL methanol was added to the thioacetic acid solution. The methanol was removed azeotropically with toluene and residual salt redissolved in 30 mL toluene. The salt solution with a washing of 20 mL toluene was added to a solution of 8 (4.75 g, 9.6 mmol) in 50 mL toluene and stirred under nitrogen for 18 hours. After removal of solvent and precipitated salts, the crude product was purified by flash chromatography with 6:1 hexane/ethyl acetate. Yield 3.47 g (81%) of a viscous oil [α]D25 -16.0° (C=0.7, CDCl3); FAB MS 445 (M+H)+, 387 (M-t-butyl)+ ; 1H NMR (CDCl3) δ 7.65 (m, 4, ArH), 7.4 (m, 6, ArH), 3.8 (m, 1, H-4), 3.7 (s, 3, OCH2), 3.7 (m, 2, CH2), 2.35 (m, 2, CH2), 2.3 (s, 3, acetyl CH2), 2.2 (m, 1, H-2), 1.9 (m, 1, H-2), 1.05 (s, 9, t-butyl).
Reaction SMILES: FC(F)(F)C(O)=O.C([O:12][C:13](=[O:26])[CH2:14][C:15]1[CH:16]=[N:17][C:18]([N:21]2[CH:25]=[N:24][N:23]=[N:22]2)=[N:19][CH:20]=1)(C)(C)C>ClCCl>[N:21]1([C:18]2[N:17]=[CH:16][C:15]([CH2:14][C:13]([OH:26])=[O:12])=[CH:20][N:19]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: CC(C)(C)OC(=O)Cc1cnc(-n2cnnn2)nc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)Cc1cnc(-n2cnnn2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trifluoroacetic acid (36 mL, 467 mmol) was added slowly to a solution of tert-butyl[2-(1H-tetrazol-1-yl)pyrimidin-5-yl]acetate (9.80 g, 37.4 mmol) in dichloromethane (36 mL) at RT. The reaction mixture was stirred at RT overnight then evaporated. The residue was triturated with ether:hexane (1:1) (100 mL). The solid was triturated with acetonitrile to afford title compound: 1H NMR 600 MHz (CD3OD) 10.01 (s, 1H); 8.94 (s, 2H); 3.88 (s, 2H); LC/MS (M+Na)+ at 229, (M+1)+ at 207, and (M+1-N2)+ at 179.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH2:6][C:5]2([CH3:20])[CH3:19].N1C=CC=CC=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([S:33](Cl)(=[O:35])=[O:34])[CH:28]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][S:33]([C:29]1[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=1)(=[O:35])=[O:34])[CH2:6][C:5]2([CH3:20])[CH3:19]
Reactant: O=S(=O)(Cl)c1cccnc1
Reactant: CC1(C)CC(c2ccccc2N)Nc2ccc(Cl)cc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)CC(c2ccccc2NS(=O)(=O)c2cccnc2)Nc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a stirred solution of 2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydroquinolin-2-yl)aniline (100 mg, 0.35 mmol) in dichloromethane (5 mL) was added pyridine (0.6 mL) and pyridine-3-sulfonyl chloride (112 mg, 0.35 mmol) at ice-bath. The reaction mixture was stirred at room temperature for 6 h. The reaction mixture was washed with water. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed by brine, dried over anhydrous sodium sulfate, concentrated in vacuum. The residue was purified by HPLC to give pyridine-3-sulfonic acid [2-(6-chloro-4,4-dimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-amide. LC/MS m/e obsd. (ESI+) [(M+H)+] 427.90.
Reaction SMILES: [O:1]1[CH2:27][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH:20]=[CH:19][CH:18]=3)=[CH:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1.[CH3:28][NH:29][CH3:30]>C(O)C>[C:17]1([C:9]2[C:8]3[C:13](=[CH:14][C:5]([O:4][CH2:3][CH:2]([OH:1])[CH2:27][N:29]([CH3:30])[CH3:28])=[CH:6][CH:7]=3)[O:12][C:11]([CH3:16])([CH3:15])[CH:10]=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: CC1(C)C=C(c2cccc3ccccc23)c2ccc(OCC3CO3)cc2O1
Reactant: CNC
Solvent: CCO
Product: CN(C)CC(O)COc1ccc2c(c1)OC(C)(C)C=C2c1cccc2ccccc12
Reaction time: 48 h

Procedure:
7-(2,3-Epoxypropoxy)-2,2-dimethyl-4-(1-naphthyl)-2H-chromene (4.4g., 0.012 moles) was dissolved in a solution of dimethylamine in ethanol (28ml., ~40% solution) and left to stand at room temperature for 48 hours. Removal of solvent gave the title product as an orange oil which was converted to the hydrochloride salt. Recrystallization from acetone gave a white solid (3.13g., 64%) m.p. 185-187° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH3:11][OH:12]>>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:12][CH3:11])=[O:6]
Reactant: CO
Reactant: O=C(Cl)c1cccc(F)c1
Product: COC(=O)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
To a 1-liter flask fitted with a stirrer, addition funnel, condenser, and drying tube containing diethyl ether (200 ml) and methanol (anhd.; 64 g,; 2.0 moles] is added dropwise m-fluorobenzoyl chloride (317 g,; 2.0 moles) at room temperature over a 3 hour period. Additional methanol (10 ml) is added and the reaction mixture is stirred at room temperature overnight. The reaction mixture is then filtered through a bed of silicic acid and the solvent removed under vacuum to afford 285 grams of methyl 3-fluorobenzoate (92.5% yield). This was identical to the product prepared in Example 2A.
Reaction SMILES: [CH2:1]([O:5][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][O:7]1)[CH2:2][C:3]#[CH:4].C([Li])CCC.[P:17](Cl)([O:22][CH2:23][CH3:24])([O:19][CH2:20][CH3:21])=[O:18].C(=O)(O)[O-].[Na+]>O1CCCC1>[O:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH:6]1[O:5][CH2:1][CH2:2][C:3]#[C:4][P:17](=[O:18])([O:22][CH2:23][CH3:24])[O:19][CH2:20][CH3:21]
Reactant: CCOP(=O)(Cl)OCC
Reactant: C#CCCOC1CCCCO1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOP(=O)(C#CCCOC1CCCCO1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of tetrahydro-2-(3-butynyloxy)2H-pyran (20 g, 0.13 mol) in anhydrous tetrahydrofuran (200 ml) is cooled in a dry ice-acetone bath and treated dropwise with n-butyllithium (2.5M in hexane, 0.13 mol) in tetrahydrofuran (20 ml). The anion is stirred for 30 minutes and treated with diethyl chlorophosphate in tetrahydrofuran added via a slow stream. The reaction mixture is stirred 15 minutes and then warmed to room temperature overnight. A saturated aqueous solution of sodium bicarbonate (125 ml) is added and the mixture extracted with ethyl acetate (2×150 ml). The organic layer is separated, dried (magnesium sulfate), filtered and evaporated. The residue is chromatographed over silica gel and eluted with ethyl acetate in chloroform to give the title compound.
Reaction SMILES: S(O[CH2:9][C:10]([CH3:23])([N+:20]([O-:22])=[O:21])[CH2:11]OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.C(N(C(C)C)C(C)C)C.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(#N)C>[CH3:23][C:10]1([N+:20]([O-:22])=[O:21])[CH2:9][N:40]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:11]1
Reactant: CC(COS(=O)(=O)C(F)(F)F)(COS(=O)(=O)C(F)(F)F)[N+](=O)[O-]
Reactant: NCc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC1([N+](=O)[O-])CN(Cc2ccccc2)C1
Temperature: 80 °C
Reaction time: 12 h

Procedure:
A solution of 2-methyl-2-nitro-1,3-propanediol ditriflate [the product of step 1] (4.0 g, 10 mmol) in acetonitrile (70 ml) is cooled to 0° C.-5° C. and N-ethyl-diisopropylamine (3.23 g, 25 mmol) is added, followed by benzylamine (1.60 g, 15 mmol) and the mixture is stirred at a temperature of 80° C. for 12 hours. The cooled reaction mixture concentrated under reduced pressure, dissolved in ethyl acetate and transferred to a separating funnel. This is then washed with water (2×) and brine, dried (Na2SO4), filtered, and concentrated. The crude liquid product is used in the next step without further purification. The crude product is purified by chromatography using a 3:1 mixture of Hexane: Ethyl acetate as eluant; the product is obtained as an oil. 1H-NMR (CDCl3): 7.3 (m, 5H), 3.75 (d, 2H), 3.68 (s, 2H), 3.42 (d, 2H), 1.88 (s, 3H).
Reaction SMILES: C(N(CC)CC)C.Cl.[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH2:21].[I:22][C:23]1[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>ClCCl>[Cl:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[CH2:19][CH2:20][NH:21][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=1[I:22]
Reactant: O=C(Cl)c1ccccc1I
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccccc1I
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 87.3 %

Procedure:
N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide was prepared according to method C with triethylamine (1.19 mL; 8.48 mmol), 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.800 g; 3.90 mmol) and 2-iodobenzoyl chloride (0.968 g; 3.56 mmol) in dichloromethane (75 mL). The mixture was stirred for 20 minutes at room temperature and was evaporated to dryness. The crude material was purified by flash chromatography on silica gel (eluent 1 to 10% ethyl acetate in dichloromethane) to furnish 1.32 g (92%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-2-iodobenzamide as a white solid.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH:11]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([NH:8][C:9](=[O:28])[C@@H:10]([CH2:19][O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[NH2:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](COCc1ccccc1)C(=O)NCc1ccccc1
Temperature: 40 °C
Reaction time: 2 h
Yield: 69.9 %

Procedure:
To a solution of N-benzyl-O-benzyl-N2-Boc-D-serinamide (3 g) and dichloromethane (15 mL), trifluoroacetic acid (15 mL) was added. The solution was stirred for 2 hours at 40° C. for completion of reaction. The solution was concentrated under vacuum to remove solvents and subsequently water was added. The aqueous layer was basified to pH 8-10 with 5% sodium hydroxide. The aqueous layer was extracted with ethyl acetate and the combined organic layer was washed with brine solution. Organic layer was concentrated under vacuum to obtain an oily residue solidify by n-Hexane to give 1.55 g of N-benzyl-O-benzyl-D-serinamide.
Reaction SMILES: [CH:1]([C@@H:14]1[CH2:20][C@H:19]2[C@H:17]([O:18]2)[CH2:16][O:15]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][O:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH2:28])=[CH:25][CH:24]=1>CO>[CH:1]([C@H:14]1[O:15][CH2:16][C@H:17]([OH:18])[C@H:19]([NH:28][CH2:27][C:26]2[CH:29]=[CH:30][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[CH2:20]1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CN)cc1
Reactant: c1ccc(C(c2ccccc2)[C@@H]2C[C@@H]3O[C@@H]3CO2)cc1
Solvent: CO
Product: COc1ccc(CN[C@@H]2C[C@@H](C(c3ccccc3)c3ccccc3)OC[C@@H]2O)cc1

Procedure:
(1R,4S,6S)-4-benzhydryl-3,7-dioxa-bicyclo[4.1.0]heptane 28b (0.021 g, 0.079 mmol) was reacted with p-methoxybenzylamine (0.22 g, 1.58 mmol) (Procedure E) to yield (3R,4R,6S)-6-benzhydryl-4-(4-methoxy-benzylamino)-tetrahydropyran-3-ol, (−)-29g 0.02 g (63%, [α]D=(−)63.75, c=1, MeOH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[C:5]2([C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=1)O.C([SiH](CC)CC)C.B(F)(F)F.CCOCC>C(Cl)CCl>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([CH3:12])[CH:5]2[C:14]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([F:22])[CH:15]=1
Reactant: COc1cc(F)cc(C2(O)c3cc(Br)ccc3C(=O)N2C)c1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCCl
Product: COc1cc(F)cc(C2c3cc(Br)ccc3C(=O)N2C)c1

Procedure:
To a well stirred suspension of 5-Bromo-3-(3-fluoro-5-methoxy-phenyl)-3-hydroxy-2-methyl-2,3-dihydro-isoindol-1-one (106 mg; 0.29 mmol) in ethylene dichloride (1 ml) at 0° C. is added Triethylsilane (84 mg; 0.72 mmol) and Boron Trifluorid etherate (54 μl; 0.43 mmol). It is let to come to ambient temperature and stirred for 1 hour. The reaction mixture is then purified by using reversed phase chromatography under basic conditions.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][S:16][CH3:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:35])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[F:26])[CH:12]([CH3:18])[CH2:13][CH2:14][CH2:15][S:16]([CH3:17])=[O:35])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CSCCCC(C)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(CCCS(C)=O)C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
The 2-[1-[(4-chlorophenyl)sulfonyl]-2-methyl-5-(methylthio)pentyl]-1,4-difluorobenzene (Isomer 43-B) (175 mg, 0.418 mmol) obtained in Example 43 was dissolved in methylene chloride (10 ml). Under ice cooling, 3-chloroperbenzoic acid (87 mg, 0.50 mmol) was added. The resulting mixture was stirred at room temperature for 14 hours. The residue obtained by concentrating the reaction mixture under reduced pressure was purified silica gel chromatography (methylene chloride:methanol=40:1) to yield a white solid. The resulting solid was washed with diethyl ether, whereby the title compound (118 mg, 65%) was obtained as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12].Br[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22].C(N(CC)CC)C>C(OCC)(=O)C>[CH3:14][O:13][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([NH:1][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([NH:23][CH2:24][CH:25]([CH3:26])[CH3:27])=[O:22])[CH:3]=1)[N:10]=[CH:9][CH:8]=[C:7]2[CH3:12]
Reactant: CC(C)CNC(=O)CCCCCBr
Reactant: COc1cc(N)c2nccc(C)c2c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1cc(NCCCCCC(=O)NCC(C)C)c2nccc(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.2 %

Procedure:
A stirred mixture of 22.6 g (0.120 mole) of 8-amino-6-methoxy-4-methylquinoline and 29.6 g (0.118 mole) of 6-bromo-N-(2-methyl-1-propyl)-hexanamide was heated in an oil bath (130° ) while 12.2 g (16.8 ml; 0.120 mole) of triethylamine was added dropwise over 30 minutes. The temperature of the bath was kept at 130° for 30 minutes, at 150° for 60 minutes, between 150° and 190° for 30 minutes, and at 190° for 30 minutes. The mixture was cooled to room temperature then diluted with 25 ml of ethyl acetate. The solid that separated was collected on a filter, extracted with boiling ethyl acetate (3×100 ml), then discarded. The filtrate and extracts were combined, then concentrated in vacuo to a solid; yield 44 g. The solid was dissolved in 130 ml of dichloromethane and purified by elution chromatography on a column (8 cm dia× 40 cm) of silica gel (1000 g; activity III) using 1 l of dichloromethane-ether (1:1), followed by 2 l of ether, as eluents. The fractions (100 ml each) containing pure product were combined then concentrated in vacuo. The fractions containing mixtures were concentrated in vacuo then triturated with diethyl ether to yield 25.4 g (60.2%) of crude product. The product was suitable for further transformation. Analytically pure compound was readily obtained (84% recovery) by recrystallization from methylene chloride and ether; mp 111°-112°.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)O1.[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:27]=[CH:26][C:25](I)=[CH:24][CH:23]=1)[OH:21].C([O-])([O-])=O.[Cs+].[Cs+]>C(COC)OC.O.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>[NH2:18][C@H:19]([CH2:29][F:30])[C@@H:20]([C:22]1[CH:23]=[CH:24][C:25]([C:9]2[CH:10]=[CH:11][C:12]([C:15]#[N:16])=[N:13][CH:14]=2)=[CH:26][CH:27]=1)[OH:21]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: N[C@H](CF)[C@H](O)c1ccc(I)cc1
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: [Cs+]
Solvent: COCCOC
Solvent: O
Product: N#Cc1ccc(-c2ccc([C@@H](O)[C@H](N)CF)cc2)cn1
Temperature: 90 °C
Yield: 51 %

Procedure:
To a solution of 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine-2-carbonitrile (0.5 g, 2.17 mmol) in dimethoxyethane (10 mL) and water (3 mL) is added (1R,2S)-2-Amino-3-fluoro-1-(4-iodo-phenyl)-propan-1-ol (0.65 g, 2.20 mmol) and Cs2CO3 (2.15 g, 6.59 mmol), and degassed with nitrogen followed by addition of Pd(PPh3)4 (0.25 g, 0.21 mmol) and heated the reaction mixture to 90° C. for 1.5 hours. Solvent is evaporated in vacuo, to get crude material purified by column chromatography eluting in 2.5 to 3% methanol in CH2Cl2 to afford the title compound (0.3 g) as impure. 1H NMR (400 MHz, DMSO-d6) δ: 3.09-3.18 (m, 1H), 3.48 (s, 1H), 4.24-4.28 (m, 0.5H), 4.36-4.41 (m, 1H), 4.49-4.52 (m, 0.5H), 4.64 (d, J=6.16 Hz, 1H), 7.53 (d, J=8.16 Hz, 2H), 7.59 (d, J=8.24 Hz, 2H), 7.76 (d, J=8.2, 1H), 8.0 (dd, J1=8.16 Hz, J2=2.32 Hz, 1H), 8.93 (d, J=1.76 Hz, 1H). LC-MS (m/z): [M+H]=272.00.
Reaction SMILES: [CH3:1][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([C@H:28]([CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:29][C:30]([O:32]C)=[O:31])=[CH:24][CH:23]=2)=[CH:7][CH:6]=1)([CH3:4])[CH3:3].C1COCC1.CCO.[OH-].[Na+]>>[CH3:4][C:2]([C:5]1[C:10]([C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[F:19])=[CH:9][C:8]([CH2:20][O:21][C:22]2[CH:23]=[CH:24][C:25]([C@@H:28]([CH:34]=[C:35]([CH3:37])[CH3:36])[CH2:29][C:30]([OH:32])=[O:31])=[CH:26][CH:27]=2)=[CH:7][CH:6]=1)([CH3:1])[CH3:3]
Reactant: COC(=O)C[C@@H](C=C(C)C)c1ccc(OCc2ccc(C(C)(C)C)c(-c3cc(OC)ccc3F)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(F)c(-c2cc(COc3ccc([C@@H](C=C(C)C)CC(=O)O)cc3)ccc2C(C)(C)C)c1
Reaction time: 15 h
Yield: 86.1 %

Procedure:
To a stirred solution of 16.2 (0.047 g, 0.09 mmol) in THF (2.00 mL, 0.10 mmol) and EtOH (2.00 mL, 0.10 mmol) at 23° C. was added a 1 M solution of sodium hydroxide (1 mL, 1 mmol). Stirring was continued for 15 hours. The resulting reaction was concentrated in vacuo. 1 N HCl was added to bring the pH to 1, and the resulting mixture was extracted with EtOAc, dried over MgSO4, and concentrated. The crude product was purified by silica gel flash chromatography (0-20% EtOAc/hexane) to afford compound 14 (38 mg, 82% yield) as a colorless oil. MS ESI (neg.) m/e: 489.2 (M−H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:8]=2)[CH:3]=[CH:2]1.[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1/[CH:28]=[CH:29]/[N+:30]([O-:32])=[O:31]>ClCCl>[F:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH:28]([C:3]1[C:4]2[C:9](=[CH:8][C:7]([NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH2:29][N+:30]([O-:32])=[O:31]
Reactant: O=C(Nc1ccc2cc[nH]c2c1)OCc1ccccc1
Reactant: O=[N+]([O-])/C=C/c1ccccc1F
Solvent: ClCCl
Product: O=C(Nc1ccc2c(C(C[N+](=O)[O-])c3ccccc3F)c[nH]c2c1)OCc1ccccc1
Temperature: 105 °C
Yield: 80.7 %

Procedure:
Benzyl 1H-indol-6-ylcarbamate (0.981 g, 3.68 mmol) and (E)-1-fluoro-2-(2-nitrovinyl)benzene (0.770 g, 4.60 mmol) were suspended and well mixed in dichloromethane (15 mL). The suspension was concentrated under vacuum to dryness. The solid mixture was then heated at 105° C. under nitrogen for 7 hr. The mixture was subjected to ISCO (120 g silica gel, solid loading, 20-45% ethyl acetate) to afford the desired product (1.287 g, 2.97 mmol, 81% yield) as a white solid.