Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Br[C:37]1[N:44]=[CH:43][CH:42]=[CH:41][C:38]=1[C:39]#[N:40]>>[OH:1][C:2]([CH3:34])([CH3:35])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:14]=[CH:15][C:16]([C:37]3[N:44]=[CH:43][CH:42]=[CH:41][C:38]=3[C:39]#[N:40])=[CH:17][CH:18]=2)[CH3:12])[CH2:6][CH2:5]1
Reactant: N#Cc1cccnc1Br
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: C[C@@H](c1ccc(-c2ncccc2C#N)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O

Procedure:
The title compound was prepared from (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 2-bromonicotinonitrile following a procedure analogous to that described in Example 583. LC-MS Method 2 tR=1.23 min, m/z=398.1; 1H NMR (CD3OD) 0.93 (s, 3H), 1.26 (s, 3H), 1.57 (d, 3H), 2.17 (s, 2H), 2.28 (m, 1H), 2.50 (m, 2H), 3.09 (m, 1H), 5.58 (m, 1H), 7.08 (d, 2H), 7.22-7.41 (m, 5H), 7.50 (m, 1H), 7.62 (d, 2H), 8.23 (d, 1H), 8.81 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH2:13][C:12]3([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[C:11]2=[O:20])=[CH:6][CH:5]=1.O=C(Cl)[O:25][C:26](Cl)(Cl)Cl.[CH2:31]([NH2:39])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:31]([NH:39][C:26]([N:17]1[CH2:16][CH2:15][C:12]2([C:11](=[O:20])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:21])[F:22])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)[CH2:19][CH2:18]1)=[O:25])[CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: NCCc1ccccc1
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Product: O=C(NCCc1ccccc1)N1CCC2(CC1)CCN(c1ccc(OC(F)(F)F)cc1)C2=O

Procedure:
This material was prepared in analogy to example 251 step B) from 2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one, diphosgene and phenethylamine. MS (ESI): 462.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].Br[C:18]1[S:22][C:21]([C:23]([O:25][CH3:26])=[O:24])=[C:20]([C:27]2[C:36]3[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=3[C:30]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:29][CH:28]=2)[C:19]=1[CH3:41]>C1(C)C=CC=CC=1.C(O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[S:22][C:21]([C:23]([O:25][CH2:26][CH3:11])=[O:24])=[C:20]([C:27]3[C:36]4[CH2:35][CH2:34][CH2:33][CH2:32][C:31]=4[C:30]([S:37](=[O:40])(=[O:39])[NH2:38])=[CH:29][CH:28]=3)[C:19]=2[CH3:41])=[CH:4][CH:3]=1
Reactant: COC(=O)c1sc(Br)c(C)c1-c1ccc(S(N)(=O)=O)c2c1CCCC2
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(Cl)cc2)c(C)c1-c1ccc(S(N)(=O)=O)c2c1CCCC2
Temperature: 25 °C
Yield: 34.4 %

Procedure:
(4-chlorophenyl)boronic acid [0.027 g, 0.17 mmol] and potassium carbonate (0.043 g, 0.31 mmol) were added to a solution of methyl 5-bromo-4-methyl-3-(4-sulfamoyl-5,6,7,8-tetrahydronaphthalen-1-yl)thiophene-2-carboxylate (59d, 0.07 g, 0.16 mmol) in a mixture of 1 ml toluene and 4 ml ethanol at 25° C. A nitrogen gas was bubbled through reaction mixture for 15 minutes. To the reaction mixture was then added tetrakis(triphenylphosphine)palladium(0) (0.009 g, 0.008 mmol) under nitrogen atmosphere and the reaction mixture was heated at a temperature of about 95° C. to about 100° C. for 3 hr under stirring. The progress of the reaction was monitored by TLC. The reaction mixture was then cooled to 25° C. and filtered through celite, the celite cake washed with 10 ml ethyl acetate. The combined filtrate so obtained was then concentrated under reduced pressure to obtain a crude product, which was then purified by flash column chromatography using 30% ethyl acetate in hexanes as an eluent to obtain the title compound (0.027 g, 35.0%).
Reaction SMILES: N[C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@H:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C([N:26](CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([CH2:18][C@H:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@:3]([NH2:26])([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4])=[O:20])[CH3:23]
Reactant: CCOC(=O)CBr
Reactant: N[C@H](c1ccccc1)[C@@H](O)c1ccccc1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C[C@H](c1ccccc1)[C@](N)(O)c1ccccc1
Temperature: 25 °C

Procedure:
(1S,2R)-2-amino-1,2-diphenylethanol (3.15 g) was dissolved in dichloromethane (45 ml) and stirred at room temperature. Ethyl bromoacetate (3.0 g), dissolved in dichloromethane (15 ml), was added to the solution. The mixture was stirred at room temperature for 7 days, and then triethylamine (2.31 ml) was added and stirred at room temperature for an additional day. After the spot of the starting material in TLC disappeared, dichloromethane was evaporated under reduced pressure. Benzene (100 ml) was added to the remaining residue, and the triethylamine hydrobromide salt was washed out with water. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solution was filtered and evaporated. The residue (3.41 g, 77%) was recrystallized from hexane (ca. 300 ml). The crystals deposited were collected and dried under reduced pressure. Yield 3.25 g (73%); mp 126.5-127 ° C.; [α]D22 -2.5° (c 1.01, EtoH). IR and 1H-NMR spectra, and Rf value of the product are completely identical with those of (1R,2S)-form mentioned in Example 1.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].CCN(CC)CC.[Br:14][C:15]1[CH:16]=[C:17]([S:21](Cl)(=[O:23])=[O:22])[CH:18]=[N:19][CH:20]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[OH:4][CH2:3][C:2]([NH:1][S:21]([C:17]1[CH:18]=[N:19][CH:20]=[C:15]([Br:14])[CH:16]=1)(=[O:23])=[O:22])([CH3:6])[CH3:5]
Reactant: CC(C)(N)CO
Reactant: O=S(=O)(Cl)c1cncc(Br)c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(CO)NS(=O)(=O)c1cncc(Br)c1
Temperature: 23 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
To a solution of commercially available 2-amino-2-methyl-1-propanol (478 mg, 5 mmol) and Et3N (0.75 mL, 5 mmol) in THF (50 mL) at 0° C. was added portionwise added 5-bromo-pyridine-3-sulfonyl chloride [CAS-No. 65001-21-0] (according to J. Org. Chem. 1989, 54(2), 389) (1.28 g, 5 mmol) and the mixture was stirred at 23° C. for 1 h. The reaction is worked up by neutralization with 5% citric acid, extracted with EtOAc, washed with sat. NaHCO3-sol. and brine, dried over Na2SO4, filtered and concentrated to give a light brown solid, which was purified by trituration with heptane/diethyl ether gave the title compound as a white solid (1.25 g, 82%). MS (ISP) 309.2 [(M+H)+], 311.1 [(M+2+H)+]; mp 112° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[CH2:9][NH:8][CH2:7][CH2:6]2.[N:15]1[C:22](Cl)=[N:21][C:19](Cl)=[N:18][C:16]=1[Cl:17].[C:24](=[O:27])([O-])[O-].[Na+].[Na+]>O1CCOCC1>[Cl:17][C:16]1[N:15]=[C:22]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[N:21]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:27][CH3:24])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:9]2)[N:18]=1
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: O=C([O-])[O-]
Reactant: COc1cc2c(cc1OC)CNCC2
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc2c(cc1OC)CN(c1nc(Cl)nc(N3CCc4cc(OC)c(OC)cc4C3)n1)CC2

Procedure:
A vigorously stirred dispersion of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (9.57 g, 40.4 mM) and cyanuric chloride (3.75 g, 20.2 mM) in dioxane (80 mL) was treated with sodium carbonate solution (0° C., 1M, 80 mL) at 0° C. for 0.5 hr then 4 hr at ambient temperature. Extraction with chloroform (4×70 mL), washing with saturated sodium chloride solution (80 mL), filtration through a cotton plug and concentration afforded an oil. Evaporation from benzene (2×40 mL) left a white foam which was triturated with hot methanol to provide a white crystalline solid, 9.35 g, (94%), mp=149°-151° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:20])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1.C1C=C(Cl)C=C(C(OO)=[O:30])C=1.C([O-])([O-])=O.[Na+].[Na+].[OH2:39]>C(Cl)(Cl)Cl>[CH3:1][S:2]([CH2:3][C@@H:4]1[N:9]2[C:10]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[N:13]=[C:12]([NH2:20])[C:11]=3[N:21]=[C:8]2[CH2:7][O:6][CH2:5]1)(=[O:30])=[O:39]
Reactant: CSC[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CS(=O)(=O)C[C@H]1COCc2nc3c(N)nc4ccccc4c3n21
Temperature: 0 °C

Procedure:
A solution of (11R)-11-[(methylthio)methyl]-10,11-dihydro-8H-[1,4]oxazino[4′,3′:1,2]imidazo[4,5-c]quinolin-6-amine (640 mg, 2.1 mmol) dissolved in 10 mL of CHCl3 was cooled to 0° C. and treated with MCPBA (50% purity, 1.2 g, 4.3 mmol). The reaction mixture was warmed to ambient temperature over 1 hour. The resulting light brown reaction mixture was treated with 2 N aqueous Na2CO3 solution, diluted with water, and extracted with CHCl3. The organic layer was dried over Na2SO4, filtered and then concentrated under reduced pressure to give a brown oil. Chromatography (SiO2, 0-30% CMA/CHCl3) gave the desired product as an oil. The oil was slurried in acetonitrile to produce a solid which was isolated by filtration to give 250 mg of the title compound as a white solid, mp 158-161° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:50]=[CH:49][C:18]([CH2:19][N:20]2[CH:24]=[C:23]([CH:25]=O)[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:17][CH:16]=1.C(OP([CH2:59][C:60]([O:62][CH2:63][CH3:64])=[O:61])(OCC)=O)C.[H-].[Na+]>CN(C)C=O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]2[CH:24]=[C:23](/[CH:25]=[CH:59]/[C:60]([O:62][CH2:63][CH3:64])=[O:61])[C:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH2:36][C:37]4[N:38]=[C:39]([C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[O:40][C:41]=4[CH3:42])=[CH:31][CH:30]=3)=[N:21]2)=[CH:49][CH:50]=1
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(Cc3ccc(OCc4nc(-c5ccccc5)oc4C)cc3)cc2C=O)cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.9 %

Procedure:
To a mixture of 1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-carbaldehyde (25.20 g), ethyl diethylphosphonoacetate (9.50 g), and N,N-dimethylformamide (200 ml), sodium hydride (60%, oily, 1.68 g) was added at 0° C., and the mixture was stirred at room temperature for 2 hours. The reaction mixture was added to ice water, and the obtained crystals were collected by filtration, and ethyl(E)-3-[1-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyl]-3-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)benzyloxy]-1H-pyrazol-4-yl]propenoate (25.58 g, yield: 92%) was obtained. This was recrystallized from tetrahydrofuran-hexane. Melting point: 148–149° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5]/[C:4](=[C:12]2/[C:13]([CH3:18])=[N:14][NH:15][C:16]/2=[O:17])/[CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([SH:26])=[CH:22][CH:21]=1>>[NH2:19][C:20]1[CH:25]=[CH:24][C:23]([S:26][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5]/[C:4](=[C:12]3/[C:13]([CH3:18])=[N:14][NH:15][C:16]/3=[O:17])/[CH:3]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(S)cc1
Reactant: CC1=NNC(=O)/C1=C1/C=C(Cl)c2ccccc2N1
Product: CC1=NNC(=O)/C1=C1/C=C(Sc2ccc(N)cc2)c2ccccc2N1

Procedure:
The title compound was prepared from (Z)-4-(4-chloroquinolin-2(1H)-ylidene)-3-methyl-1H-pyrazol-5(4H)-one and 4-aminothiophenol using the procedure described in Example 6. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 1.97 (s, 3H) 6.77-6.79 (m, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.64 (t, J=7.45 Hz, 1H) 7.88 (t, J=7.83 Hz, 1H) 7.96 (d, J=8.59 Hz, 1H) 8.14 (d, J=8.08 Hz, 1H); ESI-MS: m/z calc'd for C19H16N4OS 348.10. found 349.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5](O)=[O:6].S(Cl)(Cl)=O.[NH4+:16].[OH-].[Na+].[Cl-]>C1COCC1>[F:1][C:2]([F:11])([F:10])[C:3]([CH3:9])([CH3:8])[CH2:4][C:5]([NH2:16])=[O:6]
Reactant: CC(C)(CC(=O)O)C(F)(F)F
Reactant: [NH4+]
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(C)(CC(N)=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.2 %

Procedure:
A solution of 4,4,4-trifluoro-3,3-dimethylbutanoic acid [See: US2010/0240663](0.6 g, 3.53 mmol) in thionyl chloride (6 mL, 82 mmol) was heated at 60° C. for 2 h, cooled to RT and concentrated to dryness. The residue was dissolved in DCM (2 mL), added drop-wise to a mixture of THF (8 mL) and NH4OH (˜15M, 8 mL, ˜120 mmol) and stirred at RT overnight. Solid NaCl was added until saturated, the mixture extracted with 4:1 DCM/THF (3×) and the combined organics were washed with satd. NaHCO3, then brine, dried over Na2SO4 and concentrated to dryness to afford 4,4,4-trifluoro-3,3-dimethylbutanamide (240 mg, 40%). 1H NMR (400 MHz, DMSO-d6): δ 7.46 (s, 1H), 6.93 (s, 1H), 2.20 (s, 2H), 1.18 (s, 6H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]([NH2:13])[CH3:12])=[CH:2]1.C(N(CC)CC)C.[C:21](Cl)(Cl)=[S:22].[CH3:25][N:26]([CH3:40])[C:27]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH:30]([NH2:33])[CH2:29][CH2:28]1>C(Cl)(Cl)Cl>[CH3:25][N:26]([CH3:40])[C:27]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:32][CH2:31][CH:30]([NH:33][C:21]([NH:13][CH:11]([CH3:12])[CH2:10][C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[S:22])[CH2:29][CH2:28]1
Reactant: CC(N)Cc1c[nH]c2ccccc12
Reactant: S=C(Cl)Cl
Reactant: CN(C)C1(c2ccccc2)CCC(N)CC1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(Cc1c[nH]c2ccccc12)NC(=S)NC1CCC(c2ccccc2)(N(C)C)CC1
Reaction time: 16 h

Procedure:
2-(1H-indol-3-yl)-1-methyl-ethylamine (349 mg, 2 mmole) was dissolved in dry chloroform (10 ml) and combined with triethylamine (555 μl, 4 mmole). Thiophosgene (153 μl, 2 mmole) was added to this mixture. After a reaction time of 16 h, the diastereoisomer mixture of N,N-dimethyl-1-phenyl-cyclohexane-1,4-diamine was added and stirring was continued for a further 16 h at RT. Working up was performed by extracting the batch with saturated NaHCO3 solution (3×20 ml). The organic phase was dried with Na2SO4 and evaporated. The product was a mixture of two diastereoisomers and could be purified by column chromatography [silica gel 60 (50 g); methanol (500 ml)]. The more polar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-thiourea was obtained as a colorless solid in a yield of 256 mg (29%). The more nonpolar diastereoisomer of 1-(4-dimethylamino-4-phenyl-cyclohexyl)-3-[2-(1H-indol-3-yl)-1-methyl-ethyl]-thiourea was obtained as a colorless solid in a yield of 324 mg (37%).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][O:3][CH2:4][CH2:5][OH:6].[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15](Cl)=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]>>[N+:8]([C:11]1[CH:19]=[CH:18][C:14]([C:15]([C:1]([OH:7])([C:15](=[O:16])[C:14]2[CH:13]=[CH:12][C:11]([N+:8]([O-:10])=[O:9])=[CH:19][CH:18]=2)[CH2:2][O:3][CH2:4][CH2:5][OH:6])=[O:16])=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: OCCOCCO
Product: O=C(c1ccc([N+](=O)[O-])cc1)C(O)(COCCO)C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 83.3 %

Procedure:
Diethylene glycol (31.8 g, 0.3 mole) and p-nitrobenzoyl chloride (116 g, 0.62 mole) were reacted under the conditions described in Example 1, Part A. The product was crystallized from ethyl acetate to give bis-(4-nitrobenzoyl)-diethylene glycol (101 g) as a pale yellow solid, m.p. 100°-102° C. The product was homogeneous by TLC.
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N:17]=[C:18]=[O:19]>>[OH:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH:4][C:18]([NH:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[Br:10])=[O:19]
Reactant: Nc1ccc(F)cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc(F)cc1O)Nc1ccccc1Br

Procedure:
The urea was prepared from 2-hydroxy 4-fluoro aniline (254 mg, 2 mmol) and 2-bromo phenyl isocyanate by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane (173 mg, 26%). EI-MS m/z 325 (M+H)+
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][CH2:4][CH2:3]1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[N+:12]([C:8]1[CH:7]=[C:6]2[C:11]([CH:2]([CH3:1])[CH2:3][CH2:4][NH:5]2)=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: O=[N+]([O-])O
Reactant: CC1CCNc2ccccc21
Agent: O=S(=O)(O)O
Product: CC1CCNc2cc([N+](=O)[O-])ccc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 55.6 %

Procedure:
1,2,3,4-Tetrahydro-4-methylquinoline (55 mg, 0.337 mmol) was dissolved in sulfuric acid (0.5 mL) and the temperature was lowered to 0° C. To this solution 90% fuming nitric acid (15 mL, 0.337 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with sat. NaHCO3 (1×3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 8:2) which afforded 36 mg (52%) of 7-nitro-1,2,3,4-tetrahydro-4-methylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-4-methylquinoline: 1H NMR (400 MHz, CDCl3) 7.41 (dd, J=8.3, 2.2, 1H), 7.27 (d, J=2.3, 1H), 7.11 (d, J=8.32, 1H), 4.21 (s, 1H), 3.35 (m, 2H), 2.95 (m, 1H), 1.96 (m, 1H), 1.72 (m, 1H), 1.3 (d, J=7.0, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:29])=[O:28])[C:17]([NH:19][O:20]C3CCCCO3)=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[CH:3]=1.Cl>ClCCl.O1CCOCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]([CH2:14][CH2:15][C@@:16]([CH3:31])([S:27]([CH3:30])(=[O:28])=[O:29])[C:17]([NH:19][OH:20])=[O:18])[C:10](=[O:32])[CH:9]=2)=[C:4]([F:33])[CH:3]=1
Reactant: C[C@@](CCn1ccc(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Solvent: ClCCl
Product: C[C@@](CCn1ccc(-c2ccc(Cl)cc2F)cc1=O)(C(=O)NO)S(C)(=O)=O
Yield: 104.1 %

Procedure:
(2R)-4-[4-(4-chloro-2-fluorophenyl)-2-oxopyridin-1(2H)-yl]-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (1188 mg impure material, 1 mmol) was dissolved in 3 mL of dichloromethane. To this solution was added 1 mL of 4M HCl in dioxane and 1 mL of water. The reaction was monitored for completion by LCMS. Upon completion, the reaction mixture was concentrated and redissolved in a minimal amount of dimethylsulfoxide and water and loaded onto a 5 g c18 guard-column. This material was purified on a 75 g c18 column with 10-40% acetonitrile in water with 0.1% trifluoroacetic acid. The desired material was concentrated yielding 434 mg (88%) of a light yellow solid. LCMS m/z 417.5 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.58 (s, 3H) 2.10-2.23 (m, 1H) 2.37-2.47 (m, 1H) 3.11 (s, 3H) 3.69-3.82 (m, 1H) 4.04-4.19 (m, 1H) 6.44-6.52 (m, 1H) 6.58 (s, 1H) 7.42 (dd, J=8.29, 1.85 Hz, 1H) 7.56-7.67 (m, 2H) 7.77 (d, J=7.02 Hz, 1H) 11.12 (br. s., 1H)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2].C(N(C(C)C)CC)(C)C.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:33](=[O:40])[C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])[CH3:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)c1cncc2c(COc3cccc(N)c3)csc12
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4)c3)csc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(3-amino-phenoxymethyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (25.6 mg, 0.078 mmol) (from Example 3 supra) in THF (2 mL) were added diisopropylethyl-amine (22 mg, 0.170 mmol) (Aldrich) and then benzoyl chloride (12.5 mg, 0.085 mmol) (Aldrich). The reaction was stirred at room temperature for 30 minutes before it was concentrated to remove the solvent. The residue was diluted with EtOAc (40 mL), washed with aqueous 1N NaOH (10 mL), brine (2×10 mL), dried (Na2SO4) and concentrated. The residue was purified by column chromatography (hexanes/EtOAc, 60/40) to give 3-(3-benzoylamino-phenoxy-methyl)-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester as a white solid. (Yield 26.0 mg, 77%).
Reaction SMILES: [C:1]1([C:7]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li][CH2:16]CCC.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH:9]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH2:16])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1
Reactant: [Li]CCCC
Reactant: O=C(c1ccccc1)C1CCCCC1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1ccccc1)C1CCCCC1
Temperature: 2 °C
Reaction time: 1 h

Procedure:
α-Cyclohexylstyrene was prepared from cyclohexyl phenyl ketone using standard Wittig chemistry (Gupta, P.; Fernandes, R. A.; Kumar, P. Tet. Lett. 2003, 44, 4231–4232.) Methyltriphenylphosphonium bromide (29.57 g, 82.77 mmol) was slurried in 600 mL THF in the glovebox. The mixture was cooled to 2° C., and nBuLi (1.6 M in hexanes, 52 mL) was added over 15 min. After 1 h, solid cyclohexyl phenyl ketone (15.18 g, 80.63 mmol) was added, and the solution was allowed to slowly warm to room temperature overnight. Water (200 mL) was added. The solution was extracted with Et2O (3×150 mL). The combined organic extracts were washed with brine, dried (MgSO4) and evaporated under vacuum to give a tan liquid. Ph3PO crystallized upon standing and was removed by filtration and washed with hexane (200 mL). The hexane solution was filtered through a 2 in column of neutral alumina, washing with an additional 200 mL of hexane. The filtrate was evaporated to a colorless liquid which was distilled (46–49° C./0.1 mm Hg) to give 13.72 g of colorless liquid (89% yield).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:15][C:16]([NH:18][CH3:19])=[O:17].C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:15][C:16]([NH:18][CH3:19])=[O:17])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)CCl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC(=O)CN1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 18 h
Yield: 82.7 %

Procedure:
A mixture of 1-benzyl-piperazine (1.0 g, 5.67 mmol), 2-chloro-N-methylacetamide (671.2 mg, 6.24 mmol, 1.1 eq.), and potassium carbonate (941 mg, 6.81 mmol, 1.2 eq.) in anhydrous THF (23 mL) was stirred at 60° C. under N2 for 18 h. The mixture was cooled to rt and poured into EtOAc. The organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by MPLC (Biotage®, gradient elution 1:4:5 v/v MeOH:Acetone:DCM) to give 1.16 g (83%) of the product as a white solid. 1H-NMR (300 MHz, DMSO-d6) 7.62 to 7.56 (broad d, 1H), 7.33 to 7.20 (m, 5H), 3.45 (s, 2H), 2.85 (s, 2H), 2.58 (d, 3H), 2.44 to 2.33 (broad s, 8H); ES-MS m/z 248.2 [M+H]+, RT (min) 0.33.