Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:13]1[CH2:47][CH2:46][N:16]2[C:17]3[C:22]([C:23]([C:24]4C(=O)OC(=O)[C:28]=4[C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:30]=4)=[C:15]2[CH2:14]1)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)N[Si](C)(C)C.C[OH:58].C[N:60]([CH3:63])[CH:61]=[O:62]>>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:13]1[CH2:47][CH2:46][N:16]2[C:17]3[C:22]([C:23]([C:24]4[C:63](=[O:58])[NH:60][C:61](=[O:62])[C:28]=4[C:29]4[C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]([C:38]5[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=5)[CH:30]=4)=[C:15]2[CH2:14]1)=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)[C@H]1CCn2c(c(C3=C(c4cn(-c5ccccc5)c5ccccc45)C(=O)OC3=O)c3ccccc32)C1
Reactant: CO
Reactant: CN(C)C=O
Agent: C[Si](C)(C)N[Si](C)(C)C
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)[C@H]1CCn2c(c(C3=C(c4cn(-c5ccccc5)c5ccccc45)C(=O)NC3=O)c3ccccc32)C1
Temperature: 50 °C

Procedure:
A solution of 1.6 g (2.54 mmol) of 3[8(S)-[1(S)-tert.butoxy formamido-2-methylpropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)-furan-2,5-dione in 20 ml of dry N,N-dimethylformamide was treated with 5.35 ml (25.4 mmol) of hexamethyldisilazane and 0.41 g (12.8 mmol) of methanol. The solution was heated at 50° C. for 3 hours and then treated with an additional 5.35 ml (24.8 mmol) of hexamethyldisilazane and 0.41 g (12.8 mmol) of methanol. After a total of 6 hours the solvent was evaporated under reduced pressure and the residue was re-evaporated with 20 ml of methanol. Flash chromatography of the residue on silica gel using ethyl acetate/hexane (1:2) for the elution gave 1.35 g of 3[8(S)-[1(S)-tert.butoxyformamido-2-methylpropyl]-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]-4-(1-phenyl-3-indolyl)-1H-pyrrole-2,5-dione as a red solid of melting point 165°-168° C.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][CH:14]([O:18]C(=O)C3C=CC=CC=3)[CH2:13][C:12]=2[CH2:11][CH2:10][C:9]1=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:28]([N:35]1[C:44]2[CH:39]([CH2:40][CH:41]([O:45]C(=O)C3C=CC=CC=3)[CH2:42][CH:43]=2)[CH2:38][CH2:37][C:36]1=O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH2:1]([N:8]1[C:17]2[CH2:16][CH2:15][CH:14]([OH:18])[CH2:13][C:12]=2[CH2:11][CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[CH2:28]([N:35]1[C:44]2[CH:39]([CH2:40][CH:41]([OH:45])[CH2:42][CH:43]=2)[CH2:38][CH2:37][CH2:36]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: O=C(OC1CC=C2C(CCC(=O)N2Cc2ccccc2)C1)c1ccccc1
Reactant: O=C(OC1CCC2=C(CCC(=O)N2Cc2ccccc2)C1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OC1CC=C2C(CCCN2Cc2ccccc2)C1
Product: OC1CCC2=C(CCCN2Cc2ccccc2)C1

Procedure:
Following the above sequence of reactions, a mixture of 1-n-propyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2(1H)-quinolinone and the corresponding 3,4,4a,5,6,7-hexahydro isomer were first reduced with lithium aluminum hydride to yield a mixture of Δ4a and Δ8 1-n-propyl-6-hydroxyoctahydroquinolines which was converted by treatment with ethereal hydrogen chloride to the enamine hydrochloride. Reduction of this intermediate enamine hydrochloride with sodium cyanoborohydride yielded trans-dl-1-n-propyl-6-hydroxydecahydroquinoline (56 g. of starting material yielded 30 g. of product). Also following the above procedure, 1-benzyl-6-benzoyloxy-3,4,5,6,7,8-hexahydro-2-(1H)-quinolinone in admixture with 1-benzyl-6-benzoyloxy-3,4,4a,5,6,7-hexahydro-2(1H)-quinolinone was reduced with lithium aluminum hydride to yield the corresponding 1-benzyl-6-hydroxy-1,2,3,4,5,6,7,8-octahydroquinoline and 1-benzyl-6-hydroxy-1,2,3,4,4a,5,6,7-octahydroquinoline as a mixture, treatment of which with ethereal hydrogen hydrochloride yielded the enamine salt. Reduction of the enamine salt with sodium cyanoborohydride gave 1-benzyl-6-hydroxydecahydroquinoline (65 g. of starting mixture yielded 49.6 g. of final product).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][CH:51]=1)[N:48]=[C:47]([CH3:52])[C:46]([S:53]([CH3:56])(=[O:55])=[O:54])=[C:45]2[C:57]1[CH:62]=[CH:61][C:60]([C:63]([F:66])([F:65])[F:64])=[CH:59][CH:58]=1.[NH:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(O)(C)(C)C.CCCCCCC>[CH3:56][S:53]([C:46]1[C:47]([CH3:52])=[N:48][C:49]2[C:44]([C:45]=1[C:57]1[CH:58]=[CH:59][C:60]([C:63]([F:64])([F:66])[F:65])=[CH:61][CH:62]=1)=[CH:43][C:42]([N:67]1[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1)=[CH:51][CH:50]=2)(=[O:54])=[O:55]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(C(F)(F)F)cc2)c1S(C)(=O)=O
Reactant: C1COCCN1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Product: Cc1nc2ccc(N3CCOCC3)cc2c(-c2ccc(C(F)(F)F)cc2)c1S(C)(=O)=O
Temperature: 110 °C
Yield: 36.4 %

Procedure:
A tube placed under argon was charged with tris(dibenzylideneacetone)dipalladium chloroform complex (51 mg, 0.05 mmol), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (47 mg, 0.10 mmol) and cesium carbonate (1.21 g, 3.71 mmol). 6-Bromo-3-methanesulfonyl-2-methyl-4-(4-trifluoromethyl-phenyl)-quinoline (compound of example 20) (800 mg, 1.95 mmol) in tert.-butanol (20 ml) was added, followed by morpholine (0.259 g, 2.97 mmol). The tube was sealed and heated at 110° C. for 2 h. The reaction mixture was cooled to 20° C., diluted with heptane, filtered through dicalite and purified directly by flash chromatography on silica gel in heptane/ethyl acetate with a gradient 100:0 to 40:60 to give a yellow solid (320 mg, 29%). MS: m/z=451 (M+H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4].Br[CH2:19][C:20]1[CH:25]=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:30][CH3:31]>CN(C)C=O.O>[CH2:3]([O:5][C:6]([C:8]1[N:9]([CH2:19][C:20]2[CH:25]=[C:24]([C:26]([CH3:27])([CH3:29])[CH3:28])[CH:23]=[CH:22][C:21]=2[O:30][CH3:31])[C:10]2[C:15]([CH:16]=1)=[CH:14][C:13]([Cl:17])=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: COc1ccc(C(C)(C)C)cc1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(Cl)ccc2n1Cc1cc(C(C)(C)C)ccc1OC
Yield: 93.9 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 0.154 g, 3.85 mmol) was added to a solution of 5-chloro-1H indole-2-carboxylic acid ethyl ester (0.70 g, 3.14 mmol) in dimethyl formamide (8 ml) with stirring under nitrogen, followed after 1 h by 2-bromomethyl-4-tert-butyl-1-methoxybenzene (1.00 g, 3.89 mmol). After stirring for 17 h, the reaction was diluted with water (15 ml), extracted into ethyl acetate (2×30 ml), washed with water (2×30 ml), dried with magnesium sulfate and evaporated to dryness under reduced pressure. Purification was achieved by chromatography on silica using DCM as eluent to yield 1-(5-tert-butyl-2-methoxybenzyl)-5-chloro-1H-indole-2-carboxylic acid ethyl ester as an off-white solid (1.18 g, 2.95 mmol, 94%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:29][C:30](Br)=[O:31].[CH3:33][O:34][C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37][NH2:38]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:17][CH:18]([CH3:20])[CH3:19])[CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:29][C:30]([NH:38][CH2:37][C:36]1[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=1[O:34][CH3:33])=[O:31]
Reactant: O=C(Br)CBr
Reactant: COc1ccc(CC2NCCc3cc(OC)c(OC(C)C)cc32)cc1OC
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNC(=O)CN1CCc2cc(OC)c(OC(C)C)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-Dimethoxy-benzyl)-6-methoxy-7-isopropoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-methoxy-benzylamine
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4].I[CH2:21][CH2:22][CH3:23]>>[CH2:21]([N:15]1[CH2:14][CH:13]=[C:12]([C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([S:3]([C:2]([F:1])([F:18])[F:19])(=[O:5])=[O:4])[CH:7]=2)[CH2:17][CH2:16]1)[CH2:22][CH3:23]
Reactant: CCCI
Reactant: O=S(=O)(c1cccc(-c2ccncc2)c1)C(F)(F)F
Product: CCCN1CC=C(c2cccc(S(=O)(=O)C(F)(F)F)c2)CC1
Temperature: 100 °C

Procedure:
4-(3-Trifluoromethylsulfonylphenyl)-Pyridine (0.3 g) was dissolved in 1-iodo-propane (2 ml) and heated to 100° C. for 2 h. Then the voilatiles were evaporated and the residue redissolved in abs EtOH (20 ml) and NaBH4 (340 mg) was added portions wise at −20° C. The mixture was then allowed to reach r.t. and stirred over night. To the mixture was added 10% Na2CO3 solution (20 ml). The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried (MgSO4), filtered and evaporated to dryness. The crude product was purified by flash chromatography (MeOH:CH2Cl2 (1:9 (v/v)). Collection of the fractions containing pure product and evaporation of the solvent afforded pure 1-propyl-4-(3-trifluoromethylsulfonylphenyl)-1,2,3,6-tetrahydropyridine (150 mg). MS m/z (rel. intensity, 70 eV) 333 (M+, 21), 305 (16), 304 (bp), 171 (14), 128 (14). Rf 0.55 (MeOH)
Reaction SMILES: [C:1](OCC)(OCC)(OCC)[CH2:2][CH3:3].[NH2:13][C:14]1[C:18]([CH2:19][CH3:20])=[CH:17][NH:16][N:15]=1.CO.Cl.[NH2:24][OH:25]>C(N(CC)CC)C>[CH2:19]([C:18]1[C:14]([NH:13][C:1](=[N:24][OH:25])[CH2:2][CH3:3])=[N:15][NH:16][CH:17]=1)[CH3:20]
Reactant: CCc1c[nH]nc1N
Reactant: CCOC(CC)(OCC)OCC
Reactant: NO
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CCC(=NO)Nc1n[nH]cc1CC
Temperature: 120 °C
Reaction time: 3 h

Procedure:
A 7.9 g portion of triethyl orthopropionate was added to 5.0 g of 3-amino-4-ethyl-1H-pyrazole and the mixture was heated at 120° C. to distill off the thus formed ethanol. After 3 hours of the reaction, the reaction solution was cooled down to room temperature and mixed with 30 ml of methanol, 3.2 g of hydroxylamine hydrochloride and 4.6 g of triethylamine in that order, followed by 3 hours of heating under reflux. After distilling off the solvent under a reduced pressure, the resulting residue was mixed with 150 ml of ethyl acetate and washed twice with water, and the ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under a reduced pressure. Thereafter, the thus obtained residue was subjected to silica gel column chromatography. Elution with methanol-chloroform (1:20, v/v) gave 3.9 g of N-(4-ethyl-1H-pyrazol-3-yl)propionamidoxime.
Reaction SMILES: C([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:18][C:12]=2[O:11][CH2:10][CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O>ClC(Cl)C>[ClH:26].[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[O:19][C:17]1[CH:16]=[CH:15][C:13]2[CH2:14][NH:8][CH2:9][CH2:10][O:11][C:12]=2[N:18]=1
Reactant: Clc1ccccc1Oc1ccc2c(n1)OCCN(Cc1ccccc1)C2
Agent: CC(Cl)OC(=O)Cl
Solvent: CC(Cl)Cl
Product: Cl
Product: Clc1ccccc1Oc1ccc2c(n1)OCCNC2
Temperature: 90 °C
Reaction time: 2 h
Yield: 175.7 %

Procedure:
To a solution of the compound obtained in step 2 (0.28 g) in dichloroethane (3 mL) was added 1-chloroethyl chloroformate (0.074 mL), and the resulting mixture was stirred at 90° C. for 2 hr. The solvent was evaporated under reduced pressure, and methanol (3 mL) was added. The mixture was stirred at 80° C. for 1 hr. Diisopropyl ether (3 mL) was added, and the precipitate was collected by filtration, and recrystallized from ethanol-diisopropyl ether to give the title compound (0.21 g, 89%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](OCC)=O)=[C:4]([N+:14]([O-])=O)[C:3]=1C.[K].[C:19](=O)([O-])O.[Na+].[C:24]([O:27][CH2:28][CH3:29])(=[O:26])C>C(O)(=O)C.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:8]=[C:9]([C:24]([O:27][CH2:28][CH3:29])=[O:26])[NH:14]2)=[CH:6][C:7]=1[CH3:19]
Reactant: CCOC(=O)Cc1ccc(Cl)c(C)c1[N+](=O)[O-]
Reactant: CCOC(C)=O
Reactant: O=C([O-])O
Agent: [Fe]
Agent: [K]
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc2cc(C)c(Cl)cc2[nH]1
Temperature: 90 °C
Reaction time: 1 h
Yield: 14 %

Procedure:
Iron powder (3.34 g, 60 mmol) was added in 1 portion to a stirred solution of ethyl 4-chloro-3-methyl-2-nitrophenylacetate, potassium salt (6.5 g, 20 mmol) in acetic acid (60 mL) at room temperature under Ar. The reaction was then heated to 90° C. and stirred for 1 h. After allowing to cool to room temperature the mixture was cautiously poured into saturated aqueous sodium hydrogen carbonate solution (200 mL) containing solid sodium hydrogen carbonate (10 g) and ethyl acetate (200 mL). The mixture was filtered through celite and the aqueous and organic layers were separated. The aqueous layer was extracted with ethyl acetate (2×200 mL) and the combined organic extracts were washed with brine (1×200 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave a crude solid. The solid was adsorbed onto sodium sulfate (10 g) and purified by flash column chromatography [SiO2; ethyl acetate-heptane (1:5)→(1:0)] to give the product as yellow solid (1.6 g, 14% over 2 steps). IR νmax (Nujol)/cm−1 3319, 2925, 2855, 1683, 1623, 1570, 1530, 1555, 1418, 1368, 1339, 1330, 1280, 1241, 1158, 1120, 1107, 1021, 996, 976, 885, 855, 828, 773, 736, 664, 580, 574, 514 and 489; NMR δH (400 MHz; CDCl3) 8.82 (1H, br. s), 7.52 (1H, s), 7.44 (1H, s), 7.12 (1H, m), 4.39 (2H, q, J 7.1 Hz), 2.45 (3H, s), 1.40 (3H, t, J 7.1 Hz).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[CH3:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH3:13])[C:7]=1[S:14]([C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)(=[O:16])=[O:15].[C:22]1([CH3:28])[CH:27]=CC=CC=1>>[CH2:17]([N:18]([CH2:27][CH2:22][CH3:28])[C:1]([N:19]1[CH:20]=[CH:21][C:17]([S:14]([C:7]2[C:8]([CH3:13])=[CH:9][C:10]([CH3:12])=[CH:11][C:6]=2[CH3:5])(=[O:15])=[O:16])=[N:18]1)=[O:2])[CH2:21][CH3:20]
Reactant: O=C(Cl)Cl
Reactant: Cc1ccccc1
Reactant: Cc1cc(C)c(S(=O)(=O)c2cc[nH]n2)c(C)c1
Product: CCCN(CCC)C(=O)n1ccc(S(=O)(=O)c2c(C)cc(C)cc2C)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 89 %

Procedure:
2 ml of a 1.98M solution of phosgene in toluene were added to a solution of 200 mg of 3-(2,4,6-trimethylphenylsulfonyl)pyrazole [prepared as described in step (2) above] in 1 ml of toluene, and the resulting solution was heated at 60° C. for 1 hour. The mixture was concentrated by evaporation under reduced pressure, and then 97 mg of triethylamine and 89 mg of diisopropylamine were added, in that order, to the oily residue. The reaction mixture was then stirred at ambient temperature for 20 minutes, after which it was diluted with diethyl ether. The ethereal solution was washed with 1N aqueous hydrochloric acid, with an aqueous solution of sodium hydrogencarbonate and with water, in that order, and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through silica gel, eluted with a 6:1 by volume mixture of hexane and ethyl acetate, to afford 268 mg (yield 89%) of the title compound, melting at 64°-65° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:12][CH:11]([NH:13][OH:14])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C[O:16][C:17]1C=C(C=C[CH:24]=1)C=O.FC1C=C[C:29]([O:30]C2C=C(C=CC=2)C=O)=[CH:28]C=1.C(Cl)(=O)C>C(Cl)Cl.C(N(CC)CC)C>[C:17]([O:14][N:13]([CH:11]1[CH2:10][CH:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH2:12]1)[C:29](=[O:30])[CH3:28])(=[O:16])[CH3:24]
Reactant: COc1cccc(C=O)c1
Reactant: COc1cccc(C2CC(NO)C2)c1
Reactant: O=Cc1cccc(Oc2ccc(F)cc2)c1
Solvent: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(C2CC(N(OC(C)=O)C(C)=O)C2)c1
Temperature: 25 °C

Procedure:
To a solution of 3-(3-methoxyphenyl)cyclobutylhydroxylamine (34.8 mmol), prepared according to the procedure described in Example 1 substituting 3-methoxybenzaldehyde for 3-(4-fluorophenoxy)benzaldehyde, in CH2Cl2 (150 mL) at 0° C., was added acetyl chloride (8.20 g, 104.4 mmol) followed by the dropwise addition of triethylamine and a few crystals of N,N-dimethylaminopyridine. The cooling bath was withdrawn and the reaction allowed to warm to ambient temperature. It was then diluted with brine (100 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (2×100 mL). The organics were combined, dried over MgSO4 and concentrated to afford crude N-acetoxy-N-[3-(3-methoxyphenyl)cyclobutyl]-acetamide.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]([CH3:36])([CH3:35])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C@@H:30]([CH3:34])[CH2:31][CH2:32][OH:33])[C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH:13]=1.Cl[C:38]1[CH:39]=[N:40][CH:41]=[N:42][CH:43]=1.C(O[K])(C)(C)C>CS(C)=O>[CH3:36][C:9]([CH3:35])([CH3:8])[C:10]#[C:11][C:12]1[S:16][C:15]([C:17]([OH:19])=[O:18])=[C:14]([N:20]([C:21]([C@H:23]2[CH2:28][CH2:27][C@H:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[C@@H:30]([CH3:34])[CH2:31][CH2:32][O:33][C:38]2[CH:39]=[N:40][CH:41]=[N:42][CH:43]=2)[CH:13]=1
Reactant: C[C@@H](CCO)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Reactant: Clc1cncnc1
Agent: CC(C)(C)O[K]
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](CCOc1cncnc1)N(c1cc(C#CC(C)(C)C)sc1C(=O)O)C(=O)[C@H]1CC[C@H](C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The 5-(3,3-dimethyl-but-1-ynyl)-3-[(3-hydroxy-1-(S)-methyl-propyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid TFA salt (100 mg, 0.239 mmol) and 5-chloro-pyrimidine (137 mg, 1.194 mmol) were dissolved in DMSO (2 mL). To this solution tBuOK (107 mg, 0.956 mmol) was added in one portion at rt. The reaction was allowed to stir at rt for 1 h and then heated to 60° C. for 1.5 h. Additional tBuOK (50 mg) and 5-chloro-pyrimidine (69 mg) were added and the reaction was run at 60° C. for another 1 h. The reaction was then heated to 100° C. for another 1 h. Additional tBuOK (50 mg) and 5-chloro-pyrimidine (69 mg) were added and the reaction was run at 100° C. overnight. The reaction was cooled to rt and quenched with a 20% (v/v) solution of acetic acid in water. The reaction was diluted with MeOH and 5-(3,3-dimethyl-but-1-ynyl)-3-{(trans-4-methyl-cyclohexanecarbonyl)-[1-(S)-methyl-3-(pyrimidin-5-yloxy)-propyl]-amino}-thiophene-2-carboxylic acid (4 mg, 2.7%) was isolated by reverse phase HPLC as the TFA salt.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]3[CH2:22][CH2:21]3)=[CH:16][C:15]=2[CH:23]2[CH2:25][CH2:24]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.O1CCOCC1.C(OCC)C>ClCCl>[CH:23]1([C:15]2[CH:16]=[C:17]([CH:20]3[CH2:22][CH2:21]3)[CH:18]=[CH:19][C:14]=2[N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: c1cc(N2CCNCC2)c(C2CC2)cc1C1CC1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 68.5 %

Procedure:
A mixture of 1-(2,4-dichlorophenyl)piperazine (3 g), di-tert-butyl dicarbonate (3.23 g), triethylamine (5.5 mL) and methanol (30 mL) was stirred at room temperature for 5 hr. Water and ethyl acetate were added for partitioning, the organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). To a solution of 4-(2,4-dichlorophenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) in tetrahydrofuran (15 mL) were added 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (809 mg), palladium acetate (442 mg), tripotassium phosphate (11 g) and cyclopropylboronic acid (2.54 g), and the mixture was refluxed for 7 hr. After cooling, the mixture was extracted with ethyl acetate, washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (hexane:ethyl acetate) to give 4-(2,4-dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g). 4-(2,4-Dicyclopropylphenyl)piperazine-1-carboxylic acid tert-butyl ester (3.3 g) was dissolved in dichloromethane (20 mL), 4N hydrogen chloride/dioxane (10 mL) was added, and the mixture was stirred at room temperature for 3.5 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4-dicyclopropylphenyl)piperazine (1.6 g). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (237 mg) and 1-(2,4-dicyclopropylphenyl)piperazine (300 mg), the title compound (500 mg) was obtained.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]([F:13])([F:12])[F:11].ClC1C=C(C=CC=1)C(OO)=[O:19].[OH-:25].[Na+]>ClCCl>[CH3:1][S:2]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][C:10]([F:11])([F:12])[F:13])(=[O:19])=[O:25]
Reactant: CSc1ccccc1OC(F)(F)F
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: [OH-]
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccccc1OC(F)(F)F
Reaction time: 8 h

Procedure:
1-Methylsulfanyl-2-trifluoromethoxybenzene (15.0 g, 72 mmol) was dissolved in dichloromethane (200 mL) and m-chloroperoxybenzoic acid (39.0 g, 216 mmol) was added in small portions during 30 minutes. The reaction mixture was then allowed to stand overnight. Dichloromethane (200 mL) was added followed by slow addition of sodium hydroxide (2N, 200 mL). The organic phase was separated and extracted with sodium hydroxide (2N, 3×150 mL), dried (MgSO4) and concentrated in vacuo to give 15.8 g of 1-methylsulfonyl-2-trifluoromethoxybenzene.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1.[CH2:11](OC1C=CC(C(=O)CCC)=CC=1)C1C=CC=CC=1.C(OC1C=CC(C(=O)CC)=CC=1)C1C=CC=CC=1>>[CH2:1]([C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH:3]=1)[CH3:11]
Reactant: Cc1c[nH]c2ccccc12
Reactant: CCCC(=O)c1ccc(OCc2ccccc2)cc1
Agent: CCC(=O)c1ccc(OCc2ccccc2)cc1
Product: CCc1c[nH]c2ccccc12

Procedure:
This compound was synthesized in exact analogy to the xample given for 3-methylindole, supra, using methods a and 2–8. the only difference is that the starting material used is 4′-(benzyloxy)-Butyrophenone CAS No. [26945-71-1] instead of 4′-(benzyloxy)-Propiophenone. Data for intermediates is as follows.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1.[H][H]>CCO.C(Cl)Cl.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:15][CH:14]2[CH2:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1
Reactant: [H][H]
Reactant: COCCN1CC2CC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: COCCN1CC2CC(C1)c1cc(N)ccc12
Yield: 142 %

Procedure:
10-(2-Methoxy-ethyl)-4-nitro-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (75 mg, 0.30 mmol) in 8 ml EtOH and 2 ml methylene chloride in a Parr bottle was treated with 50 mg 10% Pd/C and subjected to hydrogen (g) at 40 psi for 2 h. The suspension was filtered and the solvent removed under reduced pressure to yield 10-(2-methoxy-ethyl)-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine (99 mg, 85%). LC/MS (ESI+): 233 (M+H)