Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][O:6][N:7]=[CH:8][CH2:9][CH2:10][CH2:11][N:12]1[C:24]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[C:16]([NH2:25])[C:15]=2[N:14]=[C:13]1[CH2:26][CH2:27][CH3:28].C(O)(=O)C.[OH-].[Na+]>C(O)C>[NH2:25][C:16]1[C:15]2[N:14]=[C:13]([CH2:26][CH2:27][CH3:28])[N:12]([CH2:11][CH2:10][CH2:9][CH2:8][NH:7][O:6][CH3:5])[C:24]=2[C:23]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[N:17]=1
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCCC=NOC
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCCCNOC
Temperature: 0 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
Sodium cyanoborohydride (5.40 g, 86 mmol) was added to a mixture of 4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyraldehyde O-methyloxime (5.60 g, 17.2 mmol), acetic acid (30 mL), and ethanol (75 mL) and stirred for 1 hour. The reaction mixture was cooled to 0° C. and the pH was adjusted to 8 with 25% sodium hydroxide solution. The reaction mixture was then concentrated under reduced pressure and diluted with dichloromethane (200 mL) and saturated aqueous sodium bicarbonate solution (75 mL). The layers were separated and the aqueous layer was extracted with dichloromethane (2×75 mL). The combined organics were washed with water (2×50 mL), dried over potassium carbonate, filtered, and concentrated under reduced pressure to afford 5.2 g of N-[4-(4-amino-2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]-O-methyl-hydroxylamine as a light brown solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4](B(O)O)=[CH:3][CH:2]=1.Br[C:11]1[CH:12]=[C:13]([C:17]([NH:19][C:20]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:21]=2[C:22]([O:24][CH3:25])=[O:23])=[O:18])[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].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.CO.C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:20]([NH:19][C:17]([C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH:12]=2)=[O:18])=[C:21]([CH:26]=1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: OB(O)c1ccncc1
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(Br)c1
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: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(Cl)ccc1NC(=O)c1cccc(-c2ccncc2)c1
Yield: 32.3 %

Procedure:
0.67 g (5.4 mmol) of 4-pyridine boronic acid, 1.0 g (2.7 mmol) of methyl 2-{[(3-bromophenyl)carbonyl]amino}-5-chlorobenzoate, 313 mg (0.27 mmol) of tetrakis(triphenylphosphine)palladium(0), and 0.58 g (5.4 mmol) of sodium carbonate were heated under reflux in a mixed solvent of 4 mL of water, 23 mL of toluene, and 6.7 mL of methanol for 7.5 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. Ethyl acetate was added, and solids were collected by filtration. Subsequently, the organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, and the solvent was then distilled off under reduced pressure. The obtained crude product was separated and purified by silica gel column chromatography, thereby giving 320 mg of methyl 5-chloro-2-({[3-(pyridin-4-yl)phenyl]carbonyl}amino)benzoate (yield: 32%).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[OH-].[Na+].[C:12]1([CH3:22])[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][CH:13]=1.Cl>O.C(#N)C>[S:18]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])([C:15]1[CH:16]=[CH:17][C:12]([CH3:22])=[CH:13][CH:14]=1)(=[O:20])=[O:19]
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2cc(C)c(=O)[nH]c2=O)cc1
Temperature: 2.5 °C
Reaction time: 0.83 h
Yield: 97.4 %

Procedure:
To a mechanically stirred solution of 200.0 g thymine (1.586 mol) in a mixture of 1.33 l water and 65 g sodium hydroxide (1.6 mol) under nitrogen atmosphere were added simultaneously a solution of 378.1 g p-toluenesulphonyl chloride (1.98 mol) in 1.0 l acetonitrile over 60 min and a solution of 95.16 g NaOH (2.38 mol) in 0.330 l water added over 65 min while cooling the reaction in a water bath from an initial temperature of 40° C. to about 35° C. The reaction was stirred an additional 50 min following completion of the additions, and then cooled to 0-5° C. The reaction mixture was then acidified by adding 242 g conc. HCl (2.45 mol) over 10 min. The reaction mixture was stirred an additional 20 min at 0-5° C. followed by vacuum filtration. The solid was vacuum dried at 55° C. overnight. 433.1 g 1-tosylthymine (97% yield, white crystals) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11](C(O)=O)[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1.[F:25][C:26]([F:30])([F:29])[S:27]Cl>CCOCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([S:27][C:26]([F:30])([F:29])[F:25])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2cc(C(=O)O)[nH]c2-c2ccc(OC)cc2)cc1
Reactant: FC(F)(F)SCl
Solvent: CCOCC
Product: COc1ccc(-c2cc(SC(F)(F)F)[nH]c2-c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.3 g (1 m mole) of 4,5-bis(4-methoxyphenyl)pyrrole-2-carboxylic acid in 5 ml ether/5 ml THF at -78° was added as a gas 0.3 g of trifluoromethanesulfenyl chloride. After 15 minutes, TLC showed no evidence of reaction, so a large excess of trifluoromethanesulfenyl chloride was added and the mixture was allowed to warm slowly to room temperature overnight, with a dry ice condenser attached for the first few hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by chromatography on 100 g Silic AR CC-7 to give after recrystallization from hexane 0.15 g (40%) of 4,5-bis(4-methoxyphenyl)-2-(trifluoromethylthio)pyrrole, identical to material obtained by Method A.
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[CH:6]=1)([F:4])[CH3:3]>CC(O)=O.CCOC(C)=O.[Zn]>[F:1][C:2]([C:5]1[CH:6]=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1)([F:4])[CH3:3]
Reactant: CC(F)(F)c1cccc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(F)(F)c1cccc(N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(1,1-difluoroethyl)-3-nitrobenzene (2.75 g, 14.7 mmol) in AcOH (30 mL) was added zinc (10.0 g, 153 mmol). The reaction mixture was allowed to stir at rt overnight. The mixture was diluted with EtOAc (40 mL) and filtered through Celite. The filtrate was concentrated. The residue was diluted with DCM (20 mL), washed with saturated NaHCO3 (20 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was purified by column chromatography to give 3-(1,1-difluoroethyl)benzenamine as light brown oil. 1H NMR (300 MHz, DMSO) δ 7.21 (dd, 1H), 6.89 (s, 1H), 6.80 (d, 1H), 6.79 (d, 1H), 186 (t, 3H); LCMS: ES+ 158.1.
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]([CH2:24][OH:25])[CH:19]=[C:20]([CH2:22][OH:23])[CH:21]=2)[CH2:13][O:12][CH2:11]1>C(#N)C>[Br:8][C:19]1[C:20]([CH2:22][OH:23])=[CH:21][C:16]([O:15][CH2:14][C:10]2([CH3:9])[CH2:13][O:12][CH2:11]2)=[CH:17][C:18]=1[CH2:24][OH:25]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(COc2cc(CO)cc(CO)c2)COC1
Solvent: CC#N
Product: CC1(COc2cc(CO)c(Br)c(CO)c2)COC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
NBS (212 mg) is added to ((5-((3-Methyloxetan-3-yl)methoxy)-1,3-phenylene)dimethanol (270 mg) in acetonitrile (5 mL) and the resulting mixture is stirred at room temperature for 3 h. The solvent is evaporated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 50:50→0:100) to give the title compound. LC (method 7): tR=0.76 min; Mass spectrum (ESI−): m/z=315 [M−H]−.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([C:12]([OH:14])=[O:13])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH2:15](O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.[C:24]1([CH3:34])[CH:29]=[CH:28][C:27]([S:30]([OH:33])(=[O:32])=[O:31])=[CH:26][CH:25]=1>C1C=CC=CC=1>[S:30]([C:27]1[CH:28]=[CH:29][C:24]([CH3:34])=[CH:25][CH:26]=1)([OH:33])(=[O:32])=[O:31].[CH2:15]([O:13][C:12](=[O:14])[C@@H:3]([CH2:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH2:2])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N[C@H](CCc1ccccc1)C(=O)O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: O
Solvent: c1ccccc1
Product: N[C@H](CCc1ccccc1)C(=O)OCc1ccccc1
Yield: 83.7 %

Procedure:
A solution of D-Homophenylalanine hydrochloride (1.7 g, 7.93 mmol), benzyl alcohol (7.2 mL, 64.0 mmol) and p-toluenesulfonic acid monohydrate (1.8 g, 9.5 mmol) in benzene (30 mL) was heated at reflux in Dean Stark apparatus during 5 hrs, after which time additional benzene (100 mL) was distilled from reaction mixture. The residue was triturated with diethyl ether, the solid was filtered and dried to give title product (2.93 g).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-:13].[Al+3].[Cl-].[Cl-].[CH:17]1[C:22]([Cl:23])=[CH:21][CH:20]=[C:19](Cl)[CH:18]=1>>[Cl:13][C:20]1[CH:21]=[C:22]([Cl:23])[CH:17]=[CH:18][C:19]=1[C:8]([CH:7]1[CH2:11][CH2:12][N:4]([C:1](=[O:3])[CH3:2])[CH2:5][CH2:6]1)=[O:9]
Reactant: [Cl-]
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Reactant: Clc1ccc(Cl)cc1
Agent: [Al+3]
Product: CC(=O)N1CCC(C(=O)c2ccc(Cl)cc2Cl)CC1
Temperature: 90 °C
Yield: 50 %

Procedure:
Acetylisonipecotoyl chloride (8 g, 42 mmol) was solved in dichlorobenzene and aluminium chloride (11.2 gr, 894 mmol) was added portionwise. The mixture was refluxed at 90° C. for 4 h after complexion of the reaction. Ice/water was added to the mixture that was extracted with dichloromethane. After chromatography from heptane to EtOAc the product was obtained as a yellow oil (6.3 g, 50%). MS (m/e): 300.2 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[CH:31]1([C:34]2[CH:35]=[CH:36][C:37]([F:41])=[C:38]([CH:40]=2)[NH2:39])[CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([NH:39][C:38]3[CH:40]=[C:34]([CH:31]4[CH2:32][CH2:33]4)[CH:35]=[CH:36][C:37]=3[F:41])=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: Nc1cc(C2CC2)ccc1F
Reactant: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)O)c3c(c2[nH]1)CC(C)(C)O3
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(Cl)c1Nc1nc2cc(C(=O)Nc3cc(C4CC4)ccc3F)c3c(c2[nH]1)CC(C)(C)O3
Yield: 22.3 %

Procedure:
The title compound was prepared by following the procedure as described for Example-108 using 2-[(2-chloro-6-methylphenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-35, 0.150 g, 0.400 mmol), thionyl chloride (2.0 mL), 5-cyclopropyl-2-fluoroaniline (Intermediate-47, 0.090 g, 0.600 mmol), THF (5.0 mL) and DIPEA (2 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.045 g of the desired product. 1HNMR (DMSO-d6): δ 0.62-0.63 (m, 2H), 0.93-0.96 (m, 2H), 1.54 (s, 6H), 1.93 (m, 1H), 3.13 (s, 2H), 6.80 (s, 1H), 7.14-7.50 (m, 5H), 8.24 (d, J=7.8 Hz, 1H), 10.07 (s, 1H), 11.20 (s, 2H); MS [M+H]+: 505.23.
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12](=[O:14])[CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)Cl.CO>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([Br:15])=[CH:10][N:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1ccnc(Cc2ccccc2)[nH]1
Reactant: BrBr
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=c1[nH]c(Cc2ccccc2)ncc1Br
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of 2-benzylpyrimidin-4(3H)-one (0.531 g, 2.85 mmol) in CHCl3 (15 mL) and methanol (3 mL) was added bromine (0.146 mL, 2.85 mmol). The reaction mixture was stirred at room temperature for 3 hours and then quenched with 10% sodium bisulfite solution. The reaction mixture was partitioned between EtOAc and H2O. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a crude yellow solid. Purification of the crude product was achieved by trituration with dichloromethane. The resulting solid was filtered, washed with dichloromethane, collected and dried under vacuum to yield the desired product (0.302 g, 40%) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ 13.23 (br s, 1H), 8.25 (s, 1H), 7.35-7.28 (m, 4H), 7.27-7.22 (m, 1H), 3.87 (s, 2H). LRMS (ESI pos) m/e 265, 267 (M+1, Br pattern).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[N:10]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][C:18]=2[S:20](Cl)(=[O:22])=[O:21])[CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:9])[C:5]([CH3:7])([NH:8][S:20]([C:18]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:19]=1[N:10]=[CH:11][CH:12]=[CH:13]2)(=[O:21])=[O:22])[CH3:6]
Reactant: COC(=O)C(C)(C)N
Reactant: O=S(=O)(Cl)c1cccc2cccnc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)C(C)(C)NS(=O)(=O)c1cccc2cccnc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 100.6 %

Procedure:
methyl-2-amino-2-methylpropanoate hydrochloride (5 g, 32.6 mmol) was dissolved in CH2Cl2 (110 ml), added with quinoline-8-sulfonyl chloride (8.18 g, 35.9 mmol) and triethylamine (18 ml, 130.6 mmol), and stirred at room temperature for 12 hours. The resultant solution was added with H2O, extracted with CH2Cl2 (×2), dried with MgSO4, and filtered. Through vacuum distillation, the solvent was removed. The resultant mixture was purified with column chromatography so as to obtain methyl-2-methyl-2-(quinoline-8-sulfonamido)propanoate (8.74 g, 32.8 mmol, 95%).
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH2:21][C:22]1[CH:23]=[C:24]([O:32][CH3:33])[C:25]([O:30][CH3:31])=[C:26]([O:28][CH3:29])[CH:27]=1>C1COCC1>[Br-:20].[CH3:33][O:32][C:24]1[CH:23]=[C:22]([CH:27]=[C:26]([O:28][CH3:29])[C:25]=1[O:30][CH3:31])[CH2:21][P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc(OC)c1OC
Product: [Br-]
Reaction time: 6 h
Yield: 96.4 %

Procedure:
Triphenylphosphine (3.41 g, 13 mmol) was added to a solution of 5-(bromomethyl)-1,2,3-trimethoxybenzene (2.61 g, 10 mmol) in dry THF (30 mL). The mixture was refluxed with stirring for 6 h. The resulting white solid was filtered and washed with ether/hexane to afford the product 3,4,5-trimethoxybenzyltriphenylphosphonium bromide in 96.4% yield. 1H NMR (500 MHz, CDCl3) δ 7.77-7.73, 7.65-7.61 (m, 15H), 6.44 (d, 2H, J=1.5 Hz), 5.37 (d, 2H, J=14 Hz), 3.76 (s, 3H), 3.51 (d, 6H); MS (ESI) m/z 443.1 (M−Br]+. At −78° C., n-BuLi (0.42 mL, 2.5 N in hexane) was added to a solution of 3,4,5-trimethoxybenzyltriphenylphosphonium bromide (500 mg, 0.96 mmol) in 10 mL THF. After stirring at RT for 2 h, aldehyde 42b (109 mg, 0.58 mmol) in 3 mL THF was charged and stirred for 30 min. The reaction mixture was treated with saturated NH4Cl solution. After a conventional workup, column chromatography (silica gel, petroleum ether/ethyl acetate) gave compounds 3a (57 mg) and 3b (99 mg). 1H NMR (500 MHz, CDCl3) δ 7.90-7.89 (m, 2H), 7.42-7.40 (m, 3H), 7.07 (s, 1H), 6.71 (s, 2H), 6.66 (s, 1H), 3.87 (s, 6H), 3.75 (s, 3H); MS (ESI) m/z 376.1 (M+Na)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].F[C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=1.CC(C)([O-])C.[K+].O>CS(C)=O>[F:17][C:16]([F:19])([F:18])[C:13]1[CH:14]=[CH:15][C:10]([O:1][C:2]2[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=2)[NH2:5])=[CH:11][CH:12]=1
Reactant: Nc1cccc(O)c1
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Nc1cccc(Oc2ccc(C(F)(F)F)cc2)c1
Temperature: 95 °C
Yield: 57.2 %

Procedure:
To a stirred solution of 3-hydroxyaniline (6.55 g) and 4-fluorobenzotrifluoride (9.85 g) in DMSO (50 mL) was added in one portion potassium tert-butoxide (7.86 g). The resulting dark solution was heated for 4 hours at 95° C., cooled to room temperature, then poured into water (600 mL). The mixture was extracted with ether (3×125 mL). The organic phase was washed with 2N sodium hydroxide (2×75 mL) and water (100 mL), dried (MgSO4) and the solvent evaporated to give a dark oil. This oil was distilled to give the title aniline as a colorless oil (8.7 g), b.p. 110-112° C. at 0.15 mm.
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:30]2[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[ClH:39].C(OCC)(=O)C>C(O)=O>[ClH:39].[CH2:36]([C:33]1[CH:34]=[N:35][C:30]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:38])=[O:5])[S:12][CH:13]=2)=[N:31][CH:32]=1)[CH3:37]
Reactant: CCCNc1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Agent: Cl
Solvent: O=CO
Solvent: CCOC(C)=O
Product: CCCNc1ccc(CN(CCc2csc(SC(C)(C)C(=O)O)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(propylamino)benzyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (68 mg) synthesized in Example 441-1 was dissolved in formic acid (2.5 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the residue was dried by heating at 60° C. to give the title compound (77 mg) as a white amorphous solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][NH:19][C:20]4[O:21][C:22]([C:25]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:26][CH3:27])=[N:23][N:24]=4)=[CH:15][CH:16]=3)[O:11][C:10](=[O:33])[CH:9]=2)=[CH:4][CH:3]=1.CI.[C:36]([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]([C:20]4[O:21][C:22]([C:25]([OH:32])([C:28]([F:30])([F:31])[F:29])[CH2:26][CH3:27])=[N:23][N:24]=4)[CH3:36])=[CH:15][CH:16]=3)[O:11][C:10](=[O:33])[CH:9]=2)=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CCC(O)(c1nnc(NCc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1)C(F)(F)F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: O
Product: CCC(O)(c1nnc(N(C)Cc2ccc3c(-c4ccc(F)cc4)cc(=O)oc3c2)o1)C(F)(F)F
Temperature: 25 °C

Procedure:
The (−) isomer of 4-(4-fluorophenyl)-7-[({5-[1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-chromen-2-one (0.100 g, 0.22 mmol), methyl iodide (2 mL) and K2CO3 (0.061 g 0.44 mmol) were heated at 50° C. until the disappearance of starting material. The mixture was cooled to rt and diluted with EtOAc-water. The organic layer was separated, dried and the solvent removed. Purification on silica gel (toluene-acetone, 8:2) gave the title compound. 1H NMR (400 MHz, acetone-d6): δ 7.68 (m, 2H), 7.51 (d, 1H), 7.48 (s, 1H), 7.39 (m, 3H), 6.49 (s, 1H), 6.12 (s, 1H), 4.8 (q, 2H), 3.17 (s, 3H), 2.26 (m, 1H), 2.09 (m, 1H), 1.02 (t, 3H).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][O:6][C@@H:7]([CH:12]1[CH2:14][CH2:13]1)[CH2:8]/[CH:9]=[CH:10]/[CH3:11])C.C(OC[C@H](OCC=[N:34][OH:35])CC=C)C1C=CC=CC=1.C(OC(OCC)CO[C@H](CC=C)COCC1C=CC=CC=1)C.C(OC[C@@H]1OCC2=NOC[C@@H]2C1)C1C=CC=CC=1>>[CH:12]1([C@H:7]([O:6][CH2:5][CH:4]=[N:34][OH:35])[CH2:8]/[CH:9]=[CH:10]/[CH3:11])[CH2:14][CH2:13]1
Reactant: C/C=C/C[C@@H](OCC(OCC)OCC)C1CC1
Reactant: C=CC[C@H](COCc1ccccc1)OCC=NO
Agent: C=CC[C@H](COCc1ccccc1)OCC(OCC)OCC
Agent: c1ccc(COC[C@H]2C[C@H]3CON=C3CO2)cc1
Product: C/C=C/C[C@@H](OCC=NO)C1CC1

Procedure:
[(1R,3E)-1-(2,2-Diethoxyethoxyl)pent-3-en-1-yl]cyclopropane (C25) was converted to the product using the method described for synthesis of 2-{[(2R)-1-(benzyloxy)pent-4-en-2-yl]oxy}-N-hydroxyethanimine (C3) in the section “Alternate conversion of C2 to C4.” In this case, purification was carried out using silica gel chromatography (Gradient: 0% to 80% ethyl acetate in heptane) to provide the product as a colorless oil. By 1H NMR, this was assigned as a roughly 1:1 mixture of oxime isomers. Yield: 200 mg, 1.09 mmol, 48%. 1H NMR (400 MHz, CDCl3), characteristic peaks: δ [7.50 (dd, J=5.8, 5.6 Hz) and 6.93 (dd, J=3.6, 3.6 Hz), total 1H], 7.46 and 7.21 (2 br s, total 1H), 5.45-5.63 (m, 2H), {[4.50 (dd, half of ABX pattern, J=16.3, 3.6 Hz) and 4.40 (dd, half of ABX pattern, J=16.3, 3.7 Hz)] and [4.25 (dd, half of ABX pattern, J=12.8, 5.6 Hz) and 4.15 (dd, half of ABX pattern, J=12.9, 5.8 Hz)], total 2H}, 2.59-2.68 (m, 1H), 1.66-1.72 (m, 3H), 0.45-0.54 (m, 1H), 0.29-0.43 (m, 1H), 0.18-0.24 and 0.06-0.14 (2 m, total 1H).
Reaction SMILES: O=[CH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:17])=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)=[O:7].[C:19]([CH:24]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:21][CH2:22][CH3:23])=[O:20]>C1COCC1>[CH2:22]([O:21][C:19](=[O:20])[CH:24]=[CH:2][CH2:3][CH2:4][NH:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([C:16]=1[I:17])=[CH:14][C:13]([F:18])=[CH:12][CH:11]=2)=[O:7])[CH3:23]
Reactant: O=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C=CCCNC(=O)c1[nH]c2ccc(F)cc2c1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-fluoro-3-iodo-1H-indole-2-carboxylic acid (3-oxo-propyl)-amide, prepared as in reference 13, (5.86 g, 16.3 mmol) in THF (200 mL) is added (carbethoxymethylene)triphenylphosphorane (18 g, 51.7 mmol) at 0° C. The reaction is stirred at room temperature overnight. It is washed with saturated NH4Cl (200 mL) and extracted with Et2O (200 mL×2). The combined organic layers are washed with brine and dried. It is concentrated and purified by silica gel column chromatography and eluted with EtOAc-Hexanes to give 5-[(5-fluoro-3-iodo-1H-indole-2-carbonyl)-amino]-pent-2-enoic acid ethyl ester as the trans isomer; 1H NMR (DMSO-d6) δ 1.25 (t, 3H, J=6.8 Hz), 2.52 (t, 2H, J=6.8 Hz), 3.48 (q, 2H, J=5.6 Hz), 4.10 (q, 2H, 6.8 Hz), 5.96 (d, 1H, J=15.6 Hz), 6.96 (dt, 1H, J1=5.8 Hz, J2=15.6 Hz), 7.06-7.18 (m, 2H), 7.46 (dd, 1H, J1=4.0 Hz, J2=8.8 Hz), 8.11 (t, 1H, J=6.4 Hz), 12.10 (s, 1H); m/z [M++1] 431.0.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH:6]=[CH:7][C:8](=[O:13])[C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][CH:3]=1.[C:16]1([SH:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(N(CC)CC)C.C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]([S:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:7][C:8](=[O:13])[C:9]([CH3:10])([CH3:11])[CH3:12])=[CH:14][CH:15]=1
Reactant: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1
Reactant: Sc1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)CC(Sc1ccccc1)c1ccc(Cl)cc1
Reaction time: 4 h

Procedure:
To a mixture of 4-chlorobenzalpinacolone (22.3 g), triethylamine (5 drops) and ethanol (250 ml) was added thiophenol (12 g) and the mixture was kept to 70° C. for 4 hours. After ice-cooling, the resulted precipitates were collected by filtration, washed with cold ethanol and dried to give white crystals of the captioned compound (29 g; 84%). m.p. 127°-128° C.