Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].[C:16]1(=[O:26])[O:21][C:19](=[O:20])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.[Cl-].[Al+3].[Cl-].[Cl-].Cl>ClC1C=CC=CC=1>[CH2:1]([N:3]1[C:15]2[CH:14]=[CH:13][C:12]([C:16]([C:17]3[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=3[C:19]([OH:21])=[O:20])=[O:26])=[CH:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: CCn1c2ccccc2c2ccccc21
Reactant: O=C1OC(=O)c2ccccc21
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1
Product: CCn1c2ccccc2c2cc(C(=O)c3ccccc3C(=O)O)ccc21

Procedure:
To a mixture of 8.17 g (0.05 mole) of N-ethylcarbazole and 3.7 g (0.025 mole) of phthalic anhydride in 112 g of chlorobenzene, 6.65 g (0.05 mole) of aluminum chloride was added in small increments at ambient temperature after which the mixture was warmed in the range of 50°-70° C. for two hours. The reaction mixture was poured onto ice and rendered acidic by the addition of 10 percent hydrochloric acid. The chlorobenzene layer was separated and steam-distilled to remove the chlorobenzene. The residue was extracted with 10 percent aqueous sodium hydroxide, filtered to remove the insolubles and then acidified with dilute hydrochloric acid. The solid which separated was collected by filtration, washed with water and dried to obtain 2-[(9-ethyl-3-carbazolyl)carbonyl]benzoic acid (Formula VII: R0 =R1 =R2 =R3 =H; R8 =CH2CH3) melting over the range 120°-130° C.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH:12]1([NH2:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>CN1C(=O)N(C)CC1.CCOC(C)=O.C(=O)([O-])O.[Na+]>[CH:12]1([NH:18][C:2]2[C:3]3[CH:11]=[CH:10][NH:9][C:4]=3[N:5]=[CH:6][C:7]=2[F:8])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Fc1cnc2[nH]ccc2c1Cl
Reactant: NC1CCCCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCN(C)C1=O
Product: Fc1cnc2[nH]ccc2c1NC1CCCCC1
Temperature: 200 °C
Yield: 12.2 %

Procedure:
A mixture of 4-chloro-5-fluoro-1H-pyrrolo[2,3-b]pyridine (30 mg) and cyclohexylamine (87 mg) in DMI (0.4 mL) was heated in the microwave reactor (200° C., 4 hours). The reaction mixture was allowed to cool to ambient temperature and diluted with EtOAc (10 mL) and half-saturated aqueous sodium hydrogencarbonate (10 mL). The aqueous phase was extracted with EtOAc (2×10 mL) and combined organic layers were washed with brine (20 mL), dried over MgSO4, and concentrated. Purification of the crude product by preparative silica gel thin-layer chromatography (EtOAc) gave N-cyclohexyl-5-fluoro-1H-pyrrolo[2,3-b]pyridin-4-amine (5 mg) as a yellow solid.
Reaction SMILES: [CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([OH:17])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:5]2=[O:27])[CH2:3][CH2:2]1.C(#N)C.[S:31](Cl)([C:34]1[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=1)(=[O:33])=[O:32]>C(N(CC)CC)C>[CH:1]1([N:4]2[C:9](=[O:10])[C:8]3[C:11]([O:17][S:31]([C:34]4[CH:40]=[CH:39][C:37]([CH3:38])=[CH:36][CH:35]=4)(=[O:33])=[O:32])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=3[N:6]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)[C:5]2=[O:27])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Cn1c(=O)cc(O)c2c(=O)n(C3CC3)c(=O)n(-c3cccc([N+](=O)[O-])c3)c21
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)Oc2cc(=O)n(C)c3c2c(=O)n(C2CC2)c(=O)n3-c2cccc([N+](=O)[O-])c2)cc1
Temperature: 110 °C
Yield: 82.4 %

Procedure:
To 3-cyclopropyl-5-hydroxy-8-methyl-1-(3-nitrophenyl)-1H,8H-pyrido[2,3-d]pyrimidine-2,4,7-trione 10 (18 g) obtained in Step 5 were added acetonitrile (180 ml), tosyl chloride 11 (11 g) and triethylamine (8 ml), and the mixture was stirred with heating under reflux at 110° C. for 1 hr. The reaction mixture was concentrated under reduced pressure. Water (100 ml) was added to the residue and the mixture was extracted with chloroform (800 ml). The organic layer was washed with brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from chloroform:diethyl ether=1:5 to give toluene-4-sulfonic acid 3-cyclopropyl-8-methyl-1-(3-nitrophenyl)-2,4,7-trioxo-1,2,3,4,7,8-hexahydro-pyrido[2,3-d]pyrimidin-5-yl ester 12 (21 g, 82%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[CH3:22])[NH2:18].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[OH-].[Na+]>CN(C=O)C>[CH3:14][C:15]1[CH:16]=[C:17]([NH:18][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([F:1])[CH:3]=2)[CH:19]=[CH:20][C:21]=1[CH3:22]
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: Cc1ccc(N)cc1C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(NC(=O)c2ccc([N+](=O)[O-])c(F)c2)cc1C

Procedure:
A solution of 3-fluoro-4-nitrobenzoic acid (2 g), 3,4-dimethylaniline (1.25 g), BOP (5.45 g) and DIEA (2.69 mL) in DMF (20 mL) was stirred at room temperature for 20 h. Then 1N NaOH aqueous solution was added (pH˜12). The aqueous layer was extracted with EtOAc. The organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was washed with CH2Cl2/MeOH mixture, and the solid was filtered to give N-(3,4-dimethyl-phenyl)-3-fluoro-4-nitrobenzamide as a yellow solid: MS (m/z) 289 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 10.39 (s, 1H), 8.30 (t, 1H), 8.10 (d, 1H), 7.97 (d, 1H), 7.53 (s, 1H), 7.49 (d, 1H), 7.13 (d, 1H), 2.23 (s, 3H), 2.20 (s, 3H).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34].O>CS(C)=O>[CH2:17]([N:3]1[C:14](=[O:15])[C:13]2[N:11]([CH3:12])[CH:10]=[N:9][C:8]=2[N:6]([CH3:7])[C:4]1=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH:25]=[CH:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]
Reactant: CCCCCCCCC=CCCCCCCCCBr
Reactant: Cn1cnc2c1c(=O)[nH]c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCC=CCCCCCCCCn1c(=O)c2c(ncn2C)n(C)c1=O
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 34.1 %

Procedure:
Sodium hydride (95%, 84 mg, 3.5 mmol) was added to a solution of theobromine (0.595 g, 3.2 mmol) in dimethylsulfoxide (15 ml). After 20 minutes of stirring, 1-bromo-9-octadecene (0.995 g, 3 mmol), prepared above, was added. After 6 hours of stirring at room temperature, the reaction mixture was warmed to 60° C. over 3 hours and then poured into a separatory funnel containing 50 ml of water. The reaction mixture was extracted with five 40 ml aliquots of dichloromethane. The organic extracts were combined, washed with water (50 ml) and brine (50 ml) and dried over anhydrous magnesium sulfate. Removing the solvent under reduced pressure resulted in a crude product further purified by flash chromatography over silica gel using a 30% acetone/petroleum ether eluant, yielding 0.44 g of 1-(9-octadecenyl)-3,7-dimethylxanthine (34% yield).
Reaction SMILES: Br[CH:2]1[C:11](=O)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[O:4][CH2:3]1.[CH2:15]([NH:18][CH2:19][C:20](=[O:22])[CH3:21])[CH2:16][CH3:17]>C1(C)C=CC=CC=1.[N+](C)([O-])=O>[CH3:14][O:13][C:8]1[CH:7]=[CH:6][C:5]2[O:4][CH2:3][CH:2]3[N:18]([CH2:15][CH2:16][CH3:17])[CH2:19][C:20](=[O:22])[CH:21]=[C:11]3[C:10]=2[CH:9]=1
Reactant: COc1ccc2c(c1)C(=O)C(Br)CO2
Reactant: CCCNCC(C)=O
Solvent: C[N+](=O)[O-]
Solvent: Cc1ccccc1
Product: CCCN1CC(=O)C=C2c3cc(OC)ccc3OCC21

Procedure:
A mixture of 3-bromo-6-methoxy-4-chromanone (2.57 g) and 3.3 g of the ethylene ketal of 1-(propylamino)-2-propanone in 500 ml of toluene if refluxed for 17 hours. The resulting product is dissolved in 20 ml of nitromethane and added to 50 ml of 85% polyphosphoric acid. After 48 hours at room temperature the reaction is poured onto ice to afford 2,3,4a,5-tetrahydro-9-methoxy-4-propyl-4H-[1]-benzopyrano[3,4-b]pyridin-2-one.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32](Cl)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].[CH3:43][O:44][C:45]1[CH:50]=[CH:49][C:48]([SH:51])=[CH:47][CH:46]=1>CN(C=O)C.CCOC(C)=O>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[CH:14][C:15]([C:19]4[CH:24]=[CH:23][C:22]([N:25]5[CH2:30][CH2:29][N:28]([CH3:31])[CH2:27][CH2:26]5)=[CH:21][CH:20]=4)=[CH:16][CH:17]=3)[C:12]3[C:32]([S:51][C:48]4[CH:49]=[CH:50][C:45]([O:44][CH3:43])=[CH:46][CH:47]=4)=[CH:33][CH:34]=[N:35][C:11]2=3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1ccc(S)cc1
Reactant: CN1CCN(c2ccc(-c3ccc4c(c3)c3c(Cl)ccnc3n4S(=O)(=O)c3ccccc3)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Sc2ccnc3c2c2cc(-c4ccc(N5CCN(C)CC5)cc4)ccc2n3S(=O)(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a suspension of 9-Benzenesulfonyl-4-chloro-6-[4-(4-methyl-piperazin-1-yl)-phenyl]-9H-pyrido[2,3-b]indole (Building block A) (60 mg) in DMF (1.2 mL), under Argon, K2CO3 (56 mg, 3.5 equiv.) and 4-methoxythiophenol (0.029 mL, 2 equiv.) were added. After stirring for 0.5 h at r.t., the reaction mixture was diluted with AcOEt (20 mL), washed with sat. aqueous NH4Cl (20 mL) and brine (20 mL) The organic layer was dried over MgSO4, filtered and evaporated to dryness. The trituration procedure afforded the desired compound in 72% yield as a beige solid. 1H-NMR (300 MHz, CDCl3) δ=8.55 (d, J=8.8 Hz, 1H), 8.48 (d, J=1.6 Hz, 1H), 8.21 (d, J=5.4 Hz, 1H), 8.18-8.09 (m, 2H), 7.77 (dd, J=8.8, 1.9 Hz, 1H), 7.65 (d, J=8.7 Hz, 2H), 7.57-7.48 (m, 3H), 7.45-7.35 (m, 2H), 7.04 (d, J=7.8 Hz, 2H), 7.01 (d, J=8.7 Hz, 2H), 6.53 (d, J=5.5 Hz, 1H), 3.88 (s, 3H), 3.47-3.33 (m, 4H), 2.90-2.74 (m, 4H), 2.51 (s, 3H). 13C-NMR (75 MHz, CDCl3) δ=161.4 (C), 150.7 (C), 150.6 (C), 147.7 (C), 146.0 (CH), 138.8 (C), 137.7 (2 CH), 137.1 (C), 136.0 (C), 134.0 (CH), 131.9 (C), 129.0 (2 CH), 128.0 (2 CH), 127.6 (2 CH), 126.5 (CH), 123.8 (C), 121.5 (CH), 118.2 (C), 116.3 (2 CH), 115.8 (2 CH), 115.1 (CH), 114.8 (CH), 114.6 (C), 55.5 (CH3), 55.1 (2 CH2), 48.8 (2 CH2), 46.2 (CH3). ESI-MS: m/z 621.2 [M+H]+.
Reaction SMILES: C1(P(=[CH:20][C:21]([O:23][CH3:24])=[O:22])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=1[OH:34])[CH:29]=O>C1(C)C=CC=CC=1.O>[F:25][C:26]1[CH:27]=[C:28](/[CH:29]=[CH:20]/[C:21]([O:23][CH3:24])=[O:22])[CH:31]=[CH:32][C:33]=1[OH:34]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1ccc(O)c(F)c1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/c1ccc(O)c(F)c1
Temperature: 80 °C
Yield: 77.3 %

Procedure:
13.1 g (0.039 mol, 2.2 eq) of methyl (triphenylphosphoranylidene)acetate are added to a solution of 2.5 g (0.0178 mol, 1 eq) of 3-fluoro-4-hydroxybenzaldehyde in 30 ml of toluene. The reaction mixture is heated at 80° C. for 2 hours. The reaction medium is hydrolyzed in water and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over sodium sulfate. The solvent is evaporated off and the oil obtained is chromatographed on silica gel (70/30 heptane/ethyl acetate). 2.7 g of methyl (E)-3-(3-fluoro-4-hydroxyphenyl)acrylate are obtained in solid form. Yield=78%
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]2[CH:8]=[CH:9][NH:10][C:11]=2[CH:12]=[CH:13][CH:14]=1.[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][NH:28][CH2:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:15][C:16]1[CH:17]=[CH:18][CH:19]=[C:20]2[C:24]=1[NH:23][CH:22]=[C:21]2[C:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[CH:8]=[CH:9][NH:10]3)[CH2:29][CH:30]=1
Reactant: Clc1cccc2c(C3=CCNCC3)c[nH]c12
Reactant: ClCCCOc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1cccc2c(C3=CCN(CCCOc4cccc5[nH]ccc45)CC3)c[nH]c12

Procedure:
The title compound was prepared in a fashion similar to that described in Example 99 using 1-chloro-3-(1H-indole-4-oxy)propane (0.446 g, 2.15 mmol) and 7-chloro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (0.500 g, 2.13 mmol) in the presence of 2.0 equivalents of potassium carbonate (0.593 g, 4.3 mmol) in dimethylformamide at 90° C. Yield 0.190 g (22%) of a tan foam. mp 166°-169° C. FDMS m/e=405 (M+ of free base).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([CH:16]=[C:17]([Cl:19])[N:18]=2)[C:12]([O:14][CH3:15])=[O:13])=[CH:5][CH:4]=1.[CH3:20][NH:21][CH3:22]>C1COCC1>[Cl:19][C:17]1[CH:16]=[C:11]([CH:10]=[C:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:21]([CH3:22])[CH3:20])=[CH:4][CH:5]=2)[N:18]=1)[C:12]([O:14][CH3:15])=[O:13]
Reactant: CNC
Reactant: COC(=O)c1cc(Cl)nc(-c2ccc(CBr)cc2)c1
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)nc(-c2ccc(CN(C)C)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-(4-(bromomethyl)phenyl)-6-chloroisonicotinate (0.533 g, 1.56 mmol) in THF, dimethylamine (7.8 mL, 2M solution in THF) was added and reaction mass stirred at rt for overnight. On completion, reaction mass concentrated and crude obtained was purified by column chromatography over silica gel obtaining pure methyl 2-chloro-6-(4-((dimethylamino)methyl)phenyl)isonicotinate (0.48 g, 99%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1)=[N:7][N:6]=[CH:5]2.[CH:19]1([NH:22][C:23](=[O:40])[C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[C:26](B3OC(C)(C)C(C)(C)O3)[CH:25]=2)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.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>[CH:13]1([NH:12][C:8]2[C:9]3[C:4](=[CH:3][C:2]([C:26]4[CH:25]=[C:24]([CH:29]=[CH:28][C:27]=4[CH3:30])[C:23]([NH:22][CH:19]4[CH2:20][CH2:21]4)=[O:40])=[CH:11][CH:10]=3)[CH:5]=[N:6][N:7]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: Brc1ccc2c(NC3CCCCC3)nncc2c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
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: [K+]
Solvent: CCO
Solvent: COCCOC
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(NC3CCCCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
The mixture of 6-bromo-N-cyclohexylphthalazin-1-amine (0.2 g, 0.65 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.2 g, 0.65 mmol), tetrakis(triphenylphosphine)palladium (38 mg, 0.0325 mmol) and 2M potassium carbonate (1 mL, 1.95 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. (Product MS found to be M+1=401). The mixture was transferred directly to a column and purified via flash chromatography (silica gel) eluting with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.17 g) as a yellow solid. Found MS (ES+): 401(M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:19]([OH:21])=[O:20])[N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8]2)[CH2:3]1.O.O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Ce+3].[C:33](O)(=O)[CH3:34]>C(O)C>[OH:1][C@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@@H:4]([CH2:5][C@@H:6]([C:19]([O:21][CH2:33][CH3:34])=[O:20])[N:7]([C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])[CH2:8]2)[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CCC(=O)C[C@@H]2C[C@H]1C(=O)O
Reactant: CC(=O)O
Agent: [Ce+3]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)[C@@H]1C[C@H]2C[C@@H](O)CC[C@H]2CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 35 %

Procedure:
To a −78° C. solution of (3S, 4aS, 8aR) 6-oxo-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid (6.88 g, 21.14 mmol)(see Preparation 2, Steps A and B, below and Scheme III, Step A generally) and cerium trichloride heptahydrate (7.9 g, 21.2 mmol) in absolute ethyl alcohol (90 mL), under nitrogen sodium borohydride (1.24 g, 32.73 mmol) was added in portions. The resulting mixture was slowly warmed up to room temperature over 5 hours. The reaction mixture was cooled down to 0° C. and acetic acid (50% in water, 25 mL) was carefully added. The resulting mixture was stirred for 1 hour at room temperature and the solvent was removed in vacuo. To the resulting material water and ethyl acetate were added and the phases separated. Aqueous layer was extracted with ethyl acetate (3×). The combined organic phases were dried, filtered and concentrated in vacuo. Flash chromatography (silicagel, 70% ethyl acetate/hexane) gave ethyl (3S, 4aS, 6S, 8aR)6-hydroxy-2-tert-butoxycarbonyl-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (2.4 g, 35%) and the title compound (4.15 g, 60%)
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8](Cl)=[O:9])[CH2:3]1.Cl.[CH3:12][NH:13][O:14][CH3:15].N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:15][O:14][N:13]([CH3:12])[C:8]([CH:4]1[CH2:5][CH2:6][CH2:7][CH:2]([CH3:1])[CH2:3]1)=[O:9]
Reactant: CC1CCCC(C(=O)Cl)C1
Reactant: CNOC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)C1CCCC(C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.5 %

Procedure:
To a solution of 3-methylcyclohexanecarbonyl chloride (1.13 g, 7.03 mmol) and N,O-dimethylhydroxylamine hydrochloride (0.755 g, 7.74 mmol) in CHCl3 (70 mL) at 0° C. was added pyridine (1.252 mL, 15.48 mmol) dropwise. The ice bath was removed and the mixture was warmed to RT. After 1 h, the reaction was evaporated to dryness, diluted with 1:1 mixture of ether and CH2Cl2 (40 ml) and then washed with brine. The aqueous layer was washed once more with 1:1 mixture of ether and CH2Cl2. The organic layers were combined, dried with MgSO4, filtered, and concentrated to afford the crude N-methoxy-N,3-dimethylcyclohexanecarboxamide (1.1 g, 84% yield) as clear yellowish oil which was used without further purification. MS (ESI) m/z: 186.1 (M+H)+. 1H NMR (400 MHz, CHLOROFORM-d) δ 3.74-3.65 (m, 3H), 3.20-3.14 (m, 3H), 2.71 (m., 1H), 1.85-1.12 (m, 10H), 0.94-0.88 (m, 3H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26]Br)[N:23]=[CH:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]>>[C:14]([O:18][C:19]([N:21]1[CH:25]=[C:24]([CH2:26][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=2)[C:3]([O:2][CH3:1])=[O:13])[N:23]=[CH:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OC(=O)n1cnc(CBr)c1
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Product: COC(=O)C(Cc1cn(C(=O)OC(C)(C)C)cn1)c1ccc(Cl)c(Cl)c1

Procedure:
4-[2-(3,4-Dichlorophenyl)-2-methoxycarbonyl-ethyl]-imidazole-1-carboxylic acid tert-butyl ester was prepared by the procedures described in Example 78, Step 1, substituting 3-tert-butoxycarbonylamino-propionic acid tert-butyl ester with (3,4-Dichlorophenyl)-acetic acid methyl ester and substituting 4-Bromo-1-bromomethyl-2-fluoro-benzene with 4-Bromomethyl-imidazole-1-carboxylic acid tert-butyl ester (prepared from 4(5)-hydroxymethylimidazole hydrochloride according to the literature: J. Med. Chem. 1997, 40, 2208). 1H NMR (CDCl3, 400 MHz) δ 7.96 (s, 1H), 7.42 (s, 1H), 7.38 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 4.08 (t, J=7.6 Hz, 1H), 3.66 (s, 3H), 3.32 (dd, J=14.4 Hz, J=8.4 Hz, 1H), 2.92 (dd, J=14.4 Hz, J=6.8 Hz, 1H). LCMS (APCI+) m/z 299, 301, 303 [M-Boc+H]+; Rt=3.72 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.[F:16][C:17]([F:32])([F:31])[C:18]1[CH:30]=[CH:29][C:21]([O:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[CH:20][CH:19]=1>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:26]2[CH2:25][CH2:24][CH:23]([O:22][C:21]3[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:31])[F:32])=[CH:30][CH:29]=3)[CH2:28][CH2:27]2)=[O:15])=[CH:6][CH:7]=1
Reactant: FC(F)(F)c1ccc(OC2CCNCC2)cc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(Oc3ccc(C(F)(F)F)cc3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4-[4-(trifluoromethyl)phenoxy]piperidine (16.9 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (11.6 mg). Calcd for C23H21F3N2O3: 430.1504, found 430.1510.
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH2:17][C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Br[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]([F:45])([F:44])[F:43])=[CH:38][CH:37]=1.[Cl-].[NH4+]>CN1CCCN(C)C1=O.O1CCCC1>[F:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][NH:7][C:8]([C:10]2[S:14][C:13]([N:15]3[CH2:19][CH2:18][CH:17]([CH2:35][C:36]4[CH:37]=[CH:38][C:39]([C:42]([F:43])([F:44])[F:45])=[CH:40][CH:41]=4)[C:16]3=[O:20])=[N:12][C:11]=2[CH3:21])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1nc(N2CCCC2=O)sc1C(=O)NCc1ccc(F)cc1
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCN(C)C1=O
Solvent: C1CCOC1
Product: Cc1nc(N2CCC(Cc3ccc(C(F)(F)F)cc3)C2=O)sc1C(=O)NCc1ccc(F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 40.2 %

Procedure:
To a solution of N-(4-fluorobenzyl)-4-methyl-2-(2-oxopyrrolidin-1-yl)thiazole-5-carboxamide (0.13 g, 0.38 mmol) in a mixture of anhydrous tetrahydrofuran and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (8/1, v/v) at −78° C. was added lithium bis(trimethylsilyl)amide in tetrahydrofuran (0.83 mL, 0.83 mmol) dropwise. The reaction mixture was stirred at −78° C. for 5 minutes, followed by the addition of 1-(bromomethyl)-4-(trifluoromethyl)benzene (0.058 mL, 0.38 mmol) dropwise. The reaction mixture was warmed to −30° C. in 30 minutes. Aqueous saturated ammonium chloride solution (10 mL) was added, followed by extraction with dichloromethane (3×10 mL). The combined organic solutions were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate/hexanes (1/1)) to afford the title compound as a white solid (0.075 g, 41%): mp 175-176° C. (hexanes/ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 7.53 (d, J=7.9 Hz, 2H), 7.32-7.24 (m, 4H), 7.01 (t, J=8.9 Hz, 2H), 6.03 (t, J=5.6 Hz, 1H), 4.52 (d, J=5.6 Hz, 2H), 4.17-4.04 (m, 1H), 3.91-3.81 (m, 1H), 3.30 (dd, J=13.8, 4.3 Hz, 1H), 3.06-2.99 (m, 1H), 2.85 (dd, J=13.8, 8.9 Hz, 1H), 2.61 (s, 3H), 2.32-2.21 (m, 1H), 1.93-1.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 174.4, 162.3, 155.3, 152.8, 142.4, 133.8, 129.9, 129.6, 129.3, 125.6, 118.6, 115.7, 115.6, 45.9, 44.2, 43.4, 36.2, 24.4, 17.3; MS (ES+) m/z 492.3 (M+1).