Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][N:8]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24](=[O:27])[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].[Cl-].[NH4+]>C(OCC)C>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][C:24]([OH:27])([C:9]2[C:10]([Cl:13])=[CH:11][CH:12]=[C:7]([Cl:6])[N:8]=2)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Clc1ccc(Cl)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
n-Butyl lithium (1.7M, 1 mL) was added dropwise to a solution of 2,5-dichloro-pyridine (2.0 g, 13.57 mmol) in diethyl ether (20 mL), under nitrogen at −78° C. and stirred for 1 hour. 4-Oxo-piperidine-1-carboxylic acid tert-butyl ester (2.69 g, 13.57 mmol) in diethyl ether (5 mL) was added dropwise at −78° C. and the reaction mixture stirred for 0.5 hours before warming to room temperature. A solution of saturated aqueous ammonium chloride was added and the mixture extracted into ethyl acetate. The organics washed with brine, dried over sodium sulphate, filtered and the solvent removed by evaporation under vacuum. The residue was purified by flash chromatography on silica eluting with 5-20% ethyl acetate/cyclohexane. The fractions containing the desired product were concentrated under vacuum to give the title compound (1.44 g).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+].[ClH:31]>C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.CCOC(C)=O.CO.CCOC(C)=O>[ClH:31].[C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][N:12]([CH2:16][CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:11][CH2:10]2)=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: BrCCCc1ccccc1
Reactant: O=C(c1ccccc1)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CO
Product: O=C(c1ccccc1)C1CCN(CCCc2ccccc2)CC1

Procedure:
A solution of phenyl (4-piperidinyl)methanone (18.1 g, 0.096 mol) was dissolved in toluene (200 ml) containing 1-bromo-3-phenylpropane (21.9 g, 0.11 mol, 16.7 ml), K2CO3 (30.4 g, 0.22 mol) and KI (0.2 g ) and was refluxed for 64 h. The reaction mixture was filtered and concentrated to give a light yellow oil. This material was dissolved in toluene/EtOAc (1:1) and treated with HCl 0.096 mol) dissolved in CH3OH/EtOAc (2:5, 35 ml) to give a precipitate which was filtered off and recrystallized twice from EtOH/Et2O (150 ml) to give phenyl[1-(3-phenylpropyl)-4-piperidinyl]-methanone hydrochloride, mp 199°-200° C.
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]#[N:8])=[CH:5][CH:6]=1.[CH3:9][O:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[Na+].[Na+].Cl>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.C(COC)OC>[C:7]([C:4]1[S:3][C:2]([C:14]2[CH:15]=[CH:16][C:11]([O:10][CH3:9])=[CH:12][CH:13]=2)=[CH:6][CH:5]=1)#[N:8]
Reactant: COc1ccc(B(O)O)cc1
Reactant: N#Cc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C#N)s2)cc1
Yield: 80.2 %

Procedure:
A solution of 2-bromo-5-cyanothiophene (4.9 g), 4-methoxyphenyl boronic acid (4.7 g), 2M aqueous sodium carbonate solution (80 cm3), tetrakis(triphenylphosphine)palladium (0) (0.4 g) and dimethoxyethane (80 cm3) was heated under reflux for 6 h under an atmosphere of nitrogen. 20% Hydrochloric acid (200 cm3) was added and the resultant mixture extracted with diethyl ether (5×100 cm3). The combined organic layers were washed with 20% hydrochloric acid (1×100 cm3), brine (2×100 cm3) and then dried (MgSO4), filtered and evaporated down. The residue was purified by column chromatography on silica gel using a 9:1 hexane/ethyl acetate mixture as eluent and recrystallisation from ethanol to yield 4.5 g of 2-cyano-5-(4-methoxyphenyl)thiophene, K 58-60° C., I.
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:39]=[CH:38][C:15]2[N:16]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([O:29]CC)=[O:28])[C:17]([C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])=[N:18][C:14]=2[CH:13]=1>C(O)C.[OH-].[Na+]>[F:25][C:19]([F:24])([C:17]1[N:16]([CH:26]([CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[C:27]([OH:29])=[O:28])[C:15]2[CH:38]=[CH:39][C:12]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]3[N:1]=[N:2][NH:3][N:4]=3)=[CH:13][C:14]=2[N:18]=1)[C:20]([F:21])([F:23])[F:22]
Reactant: CCCCCCC(C(=O)OCC)n1c(C(F)(F)C(F)(F)F)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCC(C(=O)O)n1c(C(F)(F)C(F)(F)F)nc2cc(-c3ccccc3-c3nn[nH]n3)ccc21
Yield: 0.1 %

Procedure:
Ethyl 2-[5-[2-(2H-tetrazol-5-yl) phenyl]-2-pentafluoroethyl-1H-benzimidazol-1-yl]octanoate (0.25 moles, 0.14 g) was dissolved in 25 ml ethanol and 1 ml 5N NaOH. The solution heated on a steam bath for 1 hour. The solvent was removed in vacuo. The residue was dissolved in water. The pH was adjusted to 3.0 using 5N HCl. The precipitate was collected and dried to yield 0.12 g of 2-[2-pentafluoroethyl-5-[2-(2H-tetrazol-5-yl)phenyl]-1H-benzimidazol-1-yl]octanoic acid. (MS)
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:31])=[N:22][CH:23]=[C:24]([C:26]2[CH:27]=[N:28][NH:29][CH:30]=2)[CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[O:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[C:20]1[C:21]([NH2:31])=[N:22][CH:23]=[C:24]([C:26]2[CH:30]=[N:29][N:28]([CH2:3][CH2:4][N:5]3[CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[CH:27]=2)[CH:25]=1
Reactant: ClCCN1CCOCC1
Reactant: Nc1ncc(-c2cn[nH]c2)cc1-c1nc2ccccc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ncc(-c2cnn(CCN3CCOCC3)c2)cc1-c1nc2ccccc2o1
Temperature: 120 °C
Reaction time: 7 h

Procedure:
4-(2-Chloroethyl)morpholine hydrochloride (101 mg) was added to a stirred solution 3-(1,3-benzoxazol-2-yl)-5-(1H-pyrazol-4-yl)pyridin-2-amine (150 mg, 0.54 mol) and potassium carbonate (164 mg, 1.19 mol) dissolved in DMA (1 ml) over a period of 5 minutes. The resulting solution was stirred at 120° C. for 7 hours. The mixture was filtered. The reaction mixture was purified by preparative HPLC using a Waters X-Terra reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 1% acetic acid) and acetonitrile as eluent. The fractions containing the desired compound were evaporated to dryness to afford 3-(1,3-benzoxazol-2-yl)-5-[1-(2-morpholinoethyl)pyrazol-4-yl]pyridin-2-amine (134 mg. NMR Spectrum: (CDCl3) 2.27-2.58 (m, 4H), 2.88 (t, 2H), 3.68-3.77 (m, 4H), 4.30 (t, 2H), 6.90 (bs, 2H), 7.34-7.41 (m, 2H), 7.58-7.63 (m, 1H), 7.73 (s, 1H), 7.74-7.77 (m, 1H), 7.79 (s, 1H), 8.38 (d, 1H), 8.39 (d, 1H); Mass spectrum: M+H+ 391.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH2:5][OH:6].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[Cl:10])[CH:5]=[O:6]
Reactant: OCc1ccc(Cl)c(Br)c1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=Cc1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
To a solution of 3-bromo-4-chlorobenzyl alcohol (2.73 g, 12.34 mmol) in dichloromethane (75 mL) was added, at room temperature, pyridinium chlorochromate (2.66 g, 12.34 mmol). The reaction mixture was stirred at room temperature for 1 hr then filtered over celite. The solvent was removed under reduced pressure and the residue chromatographed on silica gel (10% ethyl acetate in hexane) to afford 2.52 g of 3-bromo-4-chloro-benzaldehyde (93% yield). 1H NMR (300 MHz; CDCl3) 1H NMR (300 MHz; CDCl3) 7.65 (d, J=8.1 Hz, 1H); 7.78 (dd, J1=8.4 Hz, J2=2.1 Hz, 1H); 8.12 (d, J=2.1 Hz, 1H).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1.C(O)(=[O:18])C>>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][C:5]2[CH:6]=[CH:7][C:2](=[O:18])[NH:3][N:4]=2)=[CH:10][CH:11]=1
Reactant: CC(=O)O
Reactant: Clc1ccc(Oc2ccc(Cl)nn2)cc1
Product: O=c1ccc(Oc2ccc(Cl)cc2)n[nH]1
Yield: 80 %

Procedure:
A solution of 10 g 3-chloro-6-(4-chlorophenoxy)-pyridazine in 100 ml acetic acid is maintained at reflux temperature for a few hours. The precipitate which appears on cooling is isolated and then recrystallised from butanol. There is thus obtained, at 80% yield, 6-(4-chlorophenoxy)-3-pyridazinone which melts at 202° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([NH:6][S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8])[CH2:4][CH3:5].[Br:19][CH2:20][CH2:21][CH2:22]Br.CCCCCC.CCOC(C)=O>CN(C=O)C>[Br:19][CH2:20][CH2:21][CH2:22][N:6]([CH2:3][CH2:4][CH3:5])[S:7]([C:10]1[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=1[CH3:18])(=[O:9])=[O:8]
Reactant: BrCCCBr
Reactant: CCCNS(=O)(=O)c1c(C)cc(C)cc1C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCCN(CCCBr)S(=O)(=O)c1c(C)cc(C)cc1C
Yield: 71.8 %

Procedure:
NaH (60%, 0.34 g, 8.4 mmol), 65 (1.7 g, 7.0 mmol), and 1,3-dibromopropane (17.0 g, 84 mmol) in DMF (30 mL) were combined and worked up by the method of 43. Column chromatography (6:1 hexane/EtOAc) produced 1.82 g (80%) of 66 as an oil: NMR δ 0.79 (s, 3 H), 1.48-1.56 (m, 2 H), 2.04-2.10 (m, 2 H), 2.30 (s, 3 H), 2.60 (s, 6 H), 3.09-3.14 (m, 2 H), 3.29-3.36 (m, 4 H). Anal. (C15H24BrNO2S) C, H, N.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:19])=[CH:4][C:5]([Cl:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.O.C1(C)C(C)=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:35][S:36](Cl)(=[O:38])=[O:37].Cl>[Cl-].C([N+](CCC)(CCC)CCC)CC>[Cl:19][C:3]1[CH:4]=[C:5]([Cl:18])[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:15])[F:16])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]=1[NH:1][S:36]([CH3:35])(=[O:38])=[O:37]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nn(-c2cc(N)c(Cl)cc2Cl)c(=O)n1C(F)F
Agent: CCC[N+](CCC)(CCC)CCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1C
Solvent: O
Product: Cc1nn(-c2cc(NS(C)(=O)=O)c(Cl)cc2Cl)c(=O)n1C(F)F
Reaction time: 0.75 h

Procedure:
The solid 1-(5-amino-2,4-dichlorophenyl)-4,5-dihydro-4-difluoromethyl-3-methyl-1,2,4-triazol-5(1H)-one (1.0 equiv.) was suspended in 20 equivalent of water and the reaction mixture chilled to 10 C. Vigorous stirring was commenced and 0.05 equiv of tetra-n-propylammonium chloride in 0.05 equiv of xylene was added. Using a meter, the pH of the suspension was brought to 7.8 by adding adequate quantity of 1 molar sodium carbonate aqueous solution. Simultaneous addition of 1.2 equiv methanesulfonyl chloride was started into the reaction while keeping the flow of the aqueous sodium carbonate on such that the pH of 7.8 was maintained throughout. After 45 minutes the reaction was complete and the suspension was replaced by a clear solution. Concentrated hydrochloric acid was added slowly to bring the pH of the reaction to 2.0 wherein a precipitate was formed. The precipitate was collected by filtration, washed with water and dried to give the N-[2,4-dichloro-5-[4-(difluoromethyl)-4,5-dihydro-3-methyl-5-oxo-1H-1,2,4-triazol-1-yl] phenyl]methanesulfonamide as a white solid (0.92 equiv and 97% purity).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[CH:5][CH:4]=1.[CH2:16]([Li])CCC.CI.O>C1COCC1>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]([O:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)=[C:5]([CH3:16])[CH:4]=1
Reactant: [Li]CCCC
Reactant: COc1ccc(OC2CCCCO2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CI
Product: COc1ccc(OC2CCCCO2)c(C)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Dissolve 2-(4-methoxyphenoxy)tetrahydro-2H-pyran (20 g, 96 mmol, Preparation 27) in 200 mL anhydrous THF at 0° C. under nitrogen atmosphere. Add n-butyl lithium (n-BuLi) (78 mL, 1.6 M in hexanes, 125 mmol) dropwise via an additional funnel. Stir the resulting mixture at 0° C. for 3 hours. Add CH3I (7.8 mL, 125 mmol) in one batch. After 10 minutes add water. Rotary evaporate off volatiles, extract residue with Et2O and dry to give 21.3 g (100%) of 2-(4-methoxy-2-methyl-phenoxy)tetrahydro-2H-pyran as a yellow oil (21.3 g, 100%). 1H NMR (400 MHz, CDCl3) δ 7.03 (d, J=8.8 Hz, 1H), 6.75 (d, J=3.0 Hz, 1H), 6.68 (dd, J=8.8, 3.1 Hz, 1H), 5.30 (t, J=3.3 Hz, 1H), 3.96 (ddd, J=12.0, 9.2, 3.1 Hz, 1H), 3.78 (s, 3H), 3.67-3.56 (m, 1H), 2.28 (s, 3H), 2.10-1.96 (m, 1H), 1.94-1.83 (m, 2H), 1.67 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 154.14, 149.33, 128.78, 116.55, 115.79, 111.08, 97.20, 62.15, 55.56, 30.73, 25.38, 19.14, 16.55.
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][CH:3]1[CH2:18][CH3:19].[Cl:20]Cl>C(O)(=O)C.Cl>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH2:18][CH3:19])[Cl:20]
Reactant: CCC1Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Reactant: ClCl
Agent: Cl
Solvent: CC(=O)O
Product: CCC1(Cl)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Temperature: 0 °C
Yield: 98 %

Procedure:
To a suspension of (1-oxo-2-ethyl-6,7-dichloro-5-indanyloxy)acetic acid (6.06 g., 0.02 mole) in glacial acetic acid (100 ml.) and concentrated hydrochloric acid (2 drops) is added, with stirring, a solution of glacial acetic acid (50 ml.) and chlorine (1.56 g., 0.22 mole) over a period of 10 minutes. During the addition the reaction vessel is heated on a steam bath. After the addition is complete, the mixture is stirred without heating for 30 minutes and then poured into ice water (600 ml.). The white solid that separates is collected by filtration, washed with water and dried to afford 6.6 g. (98% yield) of (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetic acid, m.p. 185°-187° C. After recrystallization from acetic acid (25 ml.) the yield of (1-oxo-2-ethyl-2,6,7-trichloro-5-indanyloxy)acetic acid is 5.7 g., m.p. 186°-188° C.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH:18]([NH2:21])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:31])[CH3:30].O>C(Cl)Cl.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH2:10][CH2:11][O:12][CH2:13][CH2:14][CH2:15][N:16]3[CH2:20][CH2:19][CH:18]([NH:21][C:29](=[O:31])[CH3:30])[CH2:17]3)=[CH:9][C:4]=2[CH:3]=[CH:2]1
Reactant: NC1CCN(CCCOCCc2ccc3sccc3c2)C1
Reactant: CC(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCN(CCCOCCc2ccc3sccc3c2)C1
Temperature: -60 °C
Reaction time: 1 h

Procedure:
In 5 mL of methylene chloride was dissolved 0.50 g of 1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinamine, and the solution was cooled to −60° C., after which 0.27 mL of triethylamine and 0.14 mL of acetyl chloride were added to the solution and the resulting mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction mixture and the organic layer was separated. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent. The residue was purified by a column chromatography (eluent; chloroform: methanol=50:1 to 10:1) to obtain 0.55 g of N-(1-{3-[2-(1-benzothiophen-5-yl)ethoxy]propyl}-3-pyrrolidinyl)acetamide as a yellow oil.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:31]=[CH:30][C:11]([NH:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:20])[CH2:15][CH2:14]2)=[CH:10][CH:9]=1.C([Si]([O:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH2:57][CH:58]2[CH2:60][O:59]2)=[CH:52][CH:51]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[CH2:22]([NH:21][C:19]([N:16]1[CH2:15][CH2:14][CH:13]([NH:12][C:11]2[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][NH:4][CH2:60][C@H:58]([OH:59])[CH2:57][O:56][C:53]3[CH:54]=[CH:55][C:50]([OH:49])=[CH:51][CH:52]=3)=[CH:31][CH:30]=2)[CH2:18][CH2:17]1)=[O:20])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCN)cc2)CC1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O=CO
Product: CCCCCCCCNC(=O)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 41.2 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-octyl-1-piperidinecarboxamide formate (0.40 g, 0.916 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.37 g, 0.916 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.30 g, 0.377 mmol).
Reaction SMILES: [O:1]1[C@@:5]2([CH:10]3[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]3)[CH2:6]2)[CH2:4][NH:3][C:2]1=[O:13].Br[C:15]1[S:16][C:17]([N:20]2[CH:24]=[CH:23][CH:22]=[N:21]2)=[CH:18][CH:19]=1>[Cu]I>[N:21]1[N:20]([C:17]2[S:16][C:15]([N:3]3[CH2:4][C@:5]4([CH:10]5[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]5)[CH2:6]4)[O:1][C:2]3=[O:13])=[CH:19][CH:18]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: Brc1ccc(-n2cccn2)s1
Reactant: O=C1NC[C@@]2(CN3CCC2CC3)O1
Agent: [Cu]I
Product: O=C1O[C@]2(CN3CCC2CC3)CN1c1ccc(-n2cccn2)s1

Procedure:
The compound was prepared by a method analog to that described in Preparation 3 from (S)-spiro[1-azabicyclo[2.2.2]octan-3,5′-oxazolidin]-2′-one and 2-bromo-5-(2-pyrazolyl)thiophene using 3.6 equivalents of copper (I) iodide. The title compound was obtained as a pale solid, m/z 343 (MH+).
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].Cl.[NH:7]1[CH2:11][CH2:10][NH:9][CH:8]1[N:12]=[C:13]1[NH:17][C:16]([CH2:18]Cl)=[CH:15][S:14]1>Cl>[NH:7]1[CH2:11][CH2:10][NH:9][CH:8]1[N:12]=[C:13]1[NH:17][C:16]([CH2:18][S:5][CH2:4][CH2:3][NH2:2])=[CH:15][S:14]1
Reactant: NCCS
Reactant: ClCc1csc(=NC2NCCN2)[nH]1
Agent: Cl
Product: NCCSCc1csc(=NC2NCCN2)[nH]1
Yield: 39.9 %

Procedure:
Cysteamine hydrochloride (2.22 g; 19.5 mmoles) and 2-[(2-imidazolidinyl)imino]-4-chloromethylthiazole hydrochloride (4.94 g; 19.51 mmoles) [prepared from 1,3-dichloro-2-propanone and N-(2-imidazolidin-2-yl)thiourea which is itself prepared from 2-(cyanimino)imidazolidine] were dissolved in 20 ml of concentrated hydrochloric acid and heated at an oil bath temperature of 100° for 5.5 hours. The reaction mixture was evaporated under reduced pressure and the residue made basic with 40% NaOH. The aqueous phase was extracted with methyl acetate, dried and evaporated to give 2.02 g of the title compound which was used in the next step without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]1[N:5]=[N:6][C:7]2[C:12]([C:13]=1Cl)=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:15].Cl.[OH:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[C:20]([CH3:25])[CH:19]=1>C(O)(C)C>[ClH:1].[OH:17][C:18]1[CH:24]=[CH:23][C:21]([N:22]2[C:13]3[C:12]4[CH:11]=[CH:10][CH:9]=[C:8]([CH3:15])[C:7]=4[N:6]=[N:5][C:4]=3[CH2:3][CH2:2]2)=[C:20]([CH3:25])[CH:19]=1
Reactant: Cc1cccc2c(Cl)c(CCCl)nnc12
Reactant: Cc1cc(O)ccc1N
Agent: Cl
Solvent: CC(C)O
Product: Cc1cc(O)ccc1N1CCc2nnc3c(C)cccc3c21

Procedure:
3-(2-Chloroethyl)-4-chloro-8-methylcinnoline (2 g, 0.0083 mol) and 4-hydroxy-2-methylaniline hydrochloride (1.32 g, 0.0083 mol) in isopropanol (50 ml) were heated under reflux in a nitrogen atmosphere for 20 hours. The solid obtained was collected by filtration and dried. Recrystallization from isopropanol/ethanolic HCl gave the title compound as a partial hydrate, 0.64 g, m.p. 292-294°.
Reaction SMILES: [C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:21]=[CH:20][C:16]([C:17]([O-:19])=[O:18])=[CH:15][CH:14]=2)=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C(O)(=O)C>O>[C:1]1([CH2:7][C:8]2[CH:25]=[CH:24][CH:23]=[CH:22][C:9]=2[C:10]([NH:12][C:13]2[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:20][CH:21]=2)=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C([O-])c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=C(O)c1ccc(NC(=O)c2ccccc2Cc2ccccc2)cc1
Yield: 100 %

Procedure:
A mixture of 4.0 g sodium 4-[[2-(phenylmethyl)benzoyl]amino]benzoate is suspended in water and the pH adjusted to 5 with acetic acid. The solid is collected by filtration and dried at 80° C. in vacuo to give 3.75 g of the desired product, 246°-247° C. M+ =332.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[Cl:5][C:6]1[CH:7]=[C:8](/[C:13](/[C:30]([F:33])([F:32])[F:31])=[CH:14]\[C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)=[C:21]([CH:24]=2)[C:22]#[N:23])=[O:16])[CH:9]=[C:10]([Cl:12])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>C1(C)C=CC=CC=1>[Cl:5][C:6]1[CH:7]=[C:8]([C@:13]([CH2:4][N+:1]([O-:3])=[O:2])([C:30]([F:31])([F:33])[F:32])[CH2:14][C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:25]3[CH:29]=[N:28][CH:27]=[N:26]3)=[C:21]([CH:24]=2)[C:22]#[N:23])=[O:16])[CH:9]=[C:10]([Cl:12])[CH:11]=1
Reactant: N#Cc1cc(C(=O)/C=C(\c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: C[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1cc(C(=O)C[C@](C[N+](=O)[O-])(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
A solution of anthracenylmethyl quininium chloride (19 mg), nitromethane (0.025 ml) and 5-[(E)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-but-2-enoyl]-2-(1,2,4-triazol-1-yl)benzonitrile (100 mg) in toluene (2 mL) under argon, was heated for 2 hours at 50° C. then potassium carbonate (64 mg) was added. The reaction was heated for 24 hours at 50° C. then more nitromethane (0.02 mL) was added. The reaction was heated again at 50° C. for 3 hours then was allowed to stand at room temperature for 18 hours. Water was then added and the resulting mixture was extracted with dichloromethane and the combined organic fractions were dried over sodium sulfate. The crude product was purified by flash chromatography (0% to 50% ethyl acetate in cyclohexane) to afford 5-[(3R)-3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-(nitromethyl)butanoyl]-2-(1,2,4-triazol-1-yl)benzonitrile (69 mg). Chiral HPLC analysis (CHIRALPAK AS-RH, acetonitrile:Methanol:water=40:5:55, 1 ml/min, retention time 11.88 minutes (minor enantiomer), 13.88 minutes (major enantiomer) indicated that the reaction proceeded with 50% enantioselectivity in favor of the R enantiomer.
Reaction SMILES: [CH3:1][C:2]([CH3:39])([CH3:38])[CH2:3][CH2:4][C:5]1([NH:34]C(=O)C)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33].Cl>O1CCOCC1>[NH2:34][C:5]1([CH2:4][CH2:3][C:2]([CH3:39])([CH3:38])[CH3:1])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]([OH:15])=[C:7]([C:16]2[NH:21][C:20]3[CH:22]=[CH:23][C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])=[CH:25][C:19]=3[S:18](=[O:32])(=[O:31])[N:17]=2)[C:6]1=[O:33]
Reactant: CC(=O)NC1(CCC(C)(C)C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)CCC1(N)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Temperature: 100 °C
Yield: 46.1 %

Procedure:
To a solution of the product from Example 65 (62 mg, 0.11 mmol) in 1,4-dioxane (1 mL) was added 4N HCl (aq., 2 mL), and the resulting mixture was heated at 100° C. for 2 days. The cooled mixture was concentrated in vacuo, and was suspended in H2O to precipitate unreacted starting material. The filtrate was concentrated in vacuo to give the title compound as an off-white solid (27 mg, 44%). 1H NMR (300 MHz, DMSO-d6) δ ppm 14.44 (br s, 1H), 9.95 (s, 1H), 8.62 (br s, 2H), 8.13 (d, J=7.7 Hz, 1H), 7.59-7.74 (m, 2H), 7.48-7.59 (m, 2H), 7.42-7.48 (m, 1H), 7.33-7.39 (m, 1H), 3.01 (s, 3H), 1.94-2.12 (m, 1H), 1.76-1.94 (m, 1H), 1.01-1.18 (m, 1H), 0.70-0.80 (m, 1H), 0.69 (s, 9H).