Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH3:13])([CH3:12])[CH2:4][C:3]1=[O:14].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20]>C(=S)=S>[C:19]([C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[N:2]([CH3:1])[C:3](=[O:14])[CH2:4][C:5]2([CH3:12])[CH3:13])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CN1C(=O)CC(C)(C)c2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CC(=O)c1ccc2c(c1)C(C)(C)CC(=O)N2C
Temperature: 0 °C
Yield: 74.2 %

Procedure:
21.5 g of 3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone were dissolved in 43 g of carbon disulphide and the solution was treated with 85 g of aluminum chloride. 17.8 g of acetyl chloride were slowly added dropwise thereto while cooling with ice and stirring vigorously. The mixture was subsequently heated at reflux for 1.5 hours, cooled and treated cautiously with ice-water. The resulting mixture was extracted three times with ethyl acetate and the ethyl acetate extracts were washed with water, dried and evaporated. The thus-obtained brownish oil was filtered over silica gel [eluting agent: hexane/ethyl acetate (2:1)] and then recrystallized from hexane/ethyl acetate. There were obtained 19.5 g of 6-acetyl-3,4-dihydro-1,4,4-trimethyl-2(1H)-quinolinone in the form of colourless crystals of melting point 75°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]=[C:7](NC(=O)[C@@H](NC(=O)C(NC(OC(C)(C)C)=O)C2C=CC(OCCOC)=CC=2)CC2C=CC=CC=2)[S:8][CH:9]=1)=[O:4].FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]([C:5]1[N:6]=[CH:7][S:8][CH:9]=1)=[O:4]
Reactant: COCCOc1ccc(C(NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)Nc2nc(C(=O)OC)cs2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cscn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2-((S)-2-{2-tert-Butoxycarbonylamino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester (a mixture of two epimers, R/S=85:15) (0.21 g, 0.343 mmol) was dissolved into dry dichloromethane (20 mL) and trifluoroacetic acid (2 mL, 26 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness. The residue was cooled in an ice bath, then neutralized with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulfate, and concentrated to give crude 2-((S)-2A2-amino-2-[4-(2-methoxy-ethoxy)-phenyl]-acetylamino}-3-phenyl-propionylamino)-thiazole-4-carboxylic acid methyl ester as a white foam (a mixture of two epimers, R/S=85:15) (0.16 g, 91%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])[CH2:29]P(OCC)(OCC)=O)[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1(C)C=CC=CC=1.[CH3:61][N:62]1[CH2:66][CH2:65][CH2:64][C@@H:63]1[CH:67]=O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([NH:16][C:17]2[C:26]3[C:21](=[CH:22][C:23]([O:39][CH2:40][CH3:41])=[C:24]([NH:27][C:28](=[O:38])/[CH:29]=[CH:67]/[C@H:63]4[CH2:64][CH2:65][CH2:66][N:62]4[CH3:61])[CH:25]=3)[N:20]=[CH:19][C:18]=2[C:42]#[N:43])[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1
Reactant: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)CP(=O)(OCC)OCC
Reactant: CN1CCC[C@@H]1C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOc1cc2ncc(C#N)c(Nc3ccc(OCc4ccccn4)c(Cl)c3)c2cc1NC(=O)/C=C/[C@H]1CCCN1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 19.7 %

Procedure:
N-[4-[[3-Chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-2-diethoxyphosphoryl-acetamide 1d (250 mg, 0.40 mmol) was dissolved in 10 mL of dry tetrahydrofuran in a dry ice bath, followed by dropwise addition of a solution of lithium bis(trimethylsilyl)amide (1 M) in toluene (440 μL, 0.44 mmol). The reaction mixture was stirred for 30 minutes, added dropwise with a solution of (2R)-1-methylpyrrolidine-2-carbaldehyde 5c (90 mg, 0.80 mmol) in 5 mL of tetrahydrofuran, and stirred for 30 minutes, then warmed up to room temperature and stirred for 12 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography with elution system A to obtain the title compound (E)-N-[4-[[3-chloro-4-(2-pyridylmethoxy)phenyl]amino]-3-cyano-7-ethoxy-6-quinolyl]-3-[(2R)-1-methylpyrrolidin-2-yl]prop-2-enamide 5 (46 mg, yield 19.7%) as a yellow solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:11][CH2:10][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[NH:19][C:18]([C:23]([N:25]3[CH2:30][CH2:29][C:28]([F:32])([F:31])[CH2:27][CH2:26]3)=[O:24])=[CH:17]4)=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH:1]1([N:6]2[CH2:7][CH2:8][N:9]([C:12]([C:14]3[CH:15]=[C:16]4[C:20](=[CH:21][CH:22]=3)[N:19]([C:37]3[CH:38]=[CH:39][C:34]([CH3:33])=[CH:35][CH:36]=3)[C:18]([C:23]([N:25]3[CH2:26][CH2:27][C:28]([F:31])([F:32])[CH2:29][CH2:30]3)=[O:24])=[CH:17]4)=[O:13])[CH2:10][CH2:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1ccc2[nH]c(C(=O)N3CCC(F)(F)CC3)cc2c1)N1CCN(C2CCCC2)CC1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(C(=O)N4CCN(C5CCCC5)CC4)ccc32)cc1
Yield: 89 %

Procedure:
The title compound was synthesized in analogy to example 66, from [5-(4-cyclopentyl-piperazine-1-carbonyl)-1H-indol-2-yl]-(4,4-difluoro-piperidin-1-yl)-methanone (example 8), 4-methylphenylboronic acid, copper(II) acetate and pyridine in dichloromethane, to give the desired product as a white foam (89%).
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([NH:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:7][CH2:6][N:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4]1.Cl[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>CC1C=CC=CC=1>[C:11]1([CH2:10][N:9]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C@H:8]2[CH2:7][CH2:6][N:5]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:4][C@H:3]2[O:2][CH3:1])[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CCOC(=O)N1CC[C@H](NCc2ccccc2)[C@H](OC)C1
Reactant: ClCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)[C@H](OC)C1
Reaction time: 240 h
Yield: 64 %

Procedure:
A mixture of 183.4 parts of ethyl cis-3-methoxy-4-[(phenylmethyl)amino]-1-piperidinecarboxylate, 144 parts of (chloromethyl)benzene, 85 parts of sodium carbonate and 720 parts of methylbenzene was stirred for 10 days at reflux temperature. The reaction mixture was filtered and the filtrate was washed three times with 400 parts of water, dried, filtered and evaporated. Petroleumether was added. The whole was cooled whereupon the product solidified. It was filtered off and crystallized from petroleumether. The product was filtered off and dried in vacuo at 40° C., yielding 155 parts (64%) of ethyl cis-4-[bis(phenylmethyl)amino]-3-methoxy-1-piperidinecarboxylate; mp. 95.2° C. (int. 46).
Reaction SMILES: Cl[C:2]1[C:3](Cl)=[C:4](Cl)[C:5](Cl)=[C:6]2[C:11](=[O:12])[O:10][C:8](=[O:9])[C:7]=12.[CH3:16][C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2>C(Cl)CCl>[C:16]1([C:17]2[NH:18][C:19]3[C:24]([C:25]=2[C:8]([C:7]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[C:11]([OH:10])=[O:12])=[O:9])=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=C1OC(=O)c2c(Cl)c(Cl)c(Cl)c(Cl)c21
Solvent: ClCCCl
Product: O=C(O)c1ccccc1C(=O)c1c(-c2ccccc2)[nH]c2ccccc12

Procedure:
Employing a procedure similar to that described in part A of Example 10 above, 7.15 g (0.025 mole) of tetrachlorophthalic anhydride and 3.65 g (0.028 mole) of 2-methylindole were interacted in 100 ml of ethylene dichloride to obtain 2-[(2-methyl-3-indolyl)carbonyl]-4,5,6,7-tetrachlorobenzoic acid (Formula VIII: R0 =R1 =R2 =R3 =Cl; R5 =CH3 ; R6 =Y1 =H), an orange solid melting at 200°-201° C.
Reaction SMILES: C([O:8][C:9]1[C:29]([O:30][CH3:31])=[CH:28][C:12]([CH2:13][N:14]([N:23]2[CH:27]=[N:26][N:25]=[CH:24]2)[C:15]2[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=2)=[CH:11][C:10]=1[Cl:32])C1C=CC=CC=1>[Pd].C(O)C.C1COCC1>[Cl:32][C:10]1[CH:11]=[C:12]([CH:28]=[C:29]([O:30][CH3:31])[C:9]=1[OH:8])[CH2:13][N:14]([N:23]1[CH:27]=[N:26][N:25]=[CH:24]1)[C:15]1[CH:16]=[CH:17][C:18]([C:19]#[N:20])=[CH:21][CH:22]=1
Reactant: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1cc(CN(c2ccc(C#N)cc2)n2cnnc2)cc(Cl)c1O
Reaction time: 24 h

Procedure:
Palladium on charcoal (100 mg, 5% Pd) was added to a solution of 4-[(4-benzyloxy-3-chloro-5-methoxy-benzyl)-[1,2,4]triazol-4-yl-amino]-benzonitrile (CAB02177, 1.34 g, 3.0 mmol) in ethanol (60 mL) and THF (40 mL). The mixture was stirred under hydrogen atmosphere (balloon) for 24 h (TLC monitored), then filtered through celite and concentrated under reduced pressure. The residue was dried under high vacuum. Yield: 1.06 g (99%), white powder. 1H-NMR (400 MHz, d6-DMSO) δ=3.77 (s, 3H, —OCH3), 4.92 (s, 2H), 6.79 (d, J=9.0 Hz, 2H), 6.81 (d, J=1.8 Hz, 1H), 6.85 (d, J=1.8 Hz, 1H), 7.77 (d, J=9.0 Hz, 2H), 8.79 (s, 2H), 9.49 (s, 1H, —OH). LRMS (FAB+): 356.0 (100, [M+H]+). HRMS (FAB+): 356.09234 C17H15N15O2Cl requires 356.091428.
Reaction SMILES: C([O:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([C:18](=[O:34])[C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)=[C:16]([C:35]3[CH:40]=[CH:39][C:38]([O:41][C:42]([O:44]CC)=O)=[CH:37][CH:36]=3)[S:15][C:14]=2[CH:47]=1)(=O)C1C=CC=CC=1.C([O-])(=O)[C:49]1[C:50](=[CH:54][CH:55]=[CH:56][CH:57]=1)[C:51]([O-])=O>>[OH:9][C:10]1[CH:11]=[CH:12][C:13]2[C:17]([C:18](=[O:34])[C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:23][CH:24]=3)=[C:16]([C:35]3[CH:36]=[CH:37][C:38]([O:41][C:42]([CH:49]4[CH2:57][CH2:56][CH2:55][CH2:54][CH2:50][CH2:51]4)=[O:44])=[CH:39][CH:40]=3)[S:15][C:14]=2[CH:47]=1
Reactant: O=C([O-])c1ccccc1C(=O)[O-]
Reactant: CCOC(=O)Oc1ccc(-c2sc3cc(OC(=O)c4ccccc4)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Product: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(OC(=O)C3CCCCCC3)cc2)sc2cc(O)ccc12

Procedure:
6-benzoyloxy-2-(4-ethoxycarbonyloxyphenyl)-3-[4-(2-piperidinoethoxy)benzoyl]benzo[b]thiophene, phthalate
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[CH:16]2.O[CH:26]([C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[CH:27]1[CH2:29][CH:28]1[C:30]#[N:31]>ClCCl>[F:12][C:13]1[CH:14]=[C:15]2[C:19](=[C:20]([CH2:22][S:23][CH3:24])[CH:21]=1)[NH:18][CH:17]=[C:16]2[CH:26]([C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[CH:27]1[CH2:29][CH:28]1[C:30]#[N:31]
Reactant: Cc1ccc(C(O)C2CC2C#N)cc1
Reactant: CSCc1cc(F)cc2cc[nH]c12
Agent: [Cl-]
Agent: [In+3]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cc(F)cc2c(C(c3ccc(C)cc3)C3CC3C#N)c[nH]c12

Procedure:
130 mg (0.59 mmol) of indium(III) chloride and 0.05 ml (0.64 mmol) of trifluoroacetic acid were added to 104 mg (0.53 mmol) of the compound from Example 11A and 100 mg (0.53 mmol) of the compound from Example 158A in 6 ml of dichloromethane, and the mixture was stirred under reflux for 1 h. It was diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 39.6 mg (20% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[N:25]1([C:22]2[N:20]3[CH:21]=[C:16]([O:12][C@H:5]4[C:6]5[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=5)[C@@H:2]([NH2:1])[CH2:3][CH2:4]4)[CH:17]=[CH:18][C:19]3=[N:24][N:23]=2)[CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: Fc1ccc2nnc(N3CCCC3)n2c1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc3nnc(N4CCCC4)n3c2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 13.7 %

Procedure:
Intermediate A (222 mg, 1.36 mmol) was added to a mixture of NaH (60% in mineral oil, 163 mg, 4.08 mmol) in DMF (15 mL) at RT and stirred for 30 min. Intermediate 75a (280 mg, 1.36 mmol) was then added and the resulting mixture heated to 60° C. for 1 h. After cooling, the reaction was quenched with sat. aq. NH4Cl solution. The mixture was diluted with water and extracted with EtOAc. The combined organic extracts were washed with sat. aq. NaHCO3 solution and brine, and concentrated in vacuo. The resulting residue was purified by FCC, using 0 to 15% [2M NH3 in MeOH] in DCM, to afford the title compound as a brown solid (65.0 mg, 14%). LCMS (Method 3): Rt 1.89 min, m/z 350 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([OH:6])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[CH2:28]([O:35][NH2:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(N(CC)CC)C>C1COCC1>[NH2:1][C:2]1[C:10]([F:11])=[C:9]([F:12])[C:8]([F:13])=[C:7]([F:14])[C:3]=1[C:4]([NH:36][O:35][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:6]
Reactant: NOCc1ccccc1
Reactant: Nc1c(F)c(F)c(F)c(F)c1C(=O)O
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Nc1c(F)c(F)c(F)c(F)c1C(=O)NOCc1ccccc1
Yield: 106.1 %

Procedure:
Following the procedure for Example A, 2-amino-3,4,5,6-tetrafluorobenzoic acid (3.0 g, 14.4 mmol) was reacted with carbonyldiimidazole (2.8 g, 17.2 mmol), O-benzylhydroxylamine hydrochloride (3.44 g, 21.5 mmol), and triethylamine (3.0 mL, 21.5 mmol) in THF (50 mL) to provide 4.8 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:20][C:21]1[C:25]([S:26](Cl)(=[O:28])=[O:27])=[C:24]([CH3:30])[O:23][N:22]=1>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Cl:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[C:14]([Cl:15])=[CH:13][C:12]([C:16]([F:19])([F:18])[F:17])=[CH:11][N:10]=2)=[CH:3][C:2]=1[NH:1][S:26]([C:25]1[C:21]([CH3:20])=[N:22][O:23][C:24]=1[CH3:30])(=[O:28])=[O:27]
Reactant: Cc1noc(C)c1S(=O)(=O)Cl
Reactant: Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1S(=O)(=O)Nc1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Yield: 50.1 %

Procedure:
A solution of 2.5 g of 2-(3-amino-4-chlorophenyl)-3-chloro-5-trifluoromethylpyridine and 2.3 g of 3,5-dimethylisoxazole-4-sulfonyl chloride in a mixture of 100 ml of toluene and 100 ml of pyridine was refluxed for 16 hours. The mixture was concentrated and the residue was taken up in 50 ml of ethyl acetate. The solution was washed with 50 ml each of 10% strength hydrochloric acid and 10% strength aqueous sodium bicarbonate solution and was dried over sodium sulfate and concentrated. Chromatography on silica gel with cyclohexane/ethyl acetate (6:1) resulted in 1.9 g of colorless crystals; melting point: 161°-162° C.
Reaction SMILES: [F:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][N:13]=3)[CH2:8][CH2:7][C:6]=2[CH:5]=[C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[N:3]=1.[H-].[Na+].[CH2:30](Br)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37].O>CN(C=O)C>[CH2:30]([O:18][C:15]1[CH:16]=[CH:17][C:12]([CH:9]2[CH2:10][C:11]3[C:2]([F:1])=[N:3][C:4]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[CH:5][C:6]=3[CH2:7][CH2:8]2)=[N:13][CH:14]=1)[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCCCCCCCOc1cc2c(c(F)n1)CC(c1ccc(O)cn1)CC2
Reactant: CCCCCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCCCCOc1ccc(C2CCc3cc(OCCCCCCCC)nc(F)c3C2)nc1
Reaction time: 0.5 h
Yield: 75.5 %

Procedure:
10 mmol of 1-fluoro-7-(5-hydroxypyridin-2-yl)-3-octyloxy-5,6,7,8-tetrahydroisoquinoline are dissolved in 50 ml of DMF, and 11 mmol of sodium hydride are added. After the mixture has been stirred for 30 minutes, 11 mmol of 1-octyl bromide are added dropwise, and the mixture is stirred at 60° C. for a further 140 minutes and poured into water. The mixture is extracted with dichloromethane, the combined organic phases are dried, the solvent is removed in vacuo and the residue is chromatographed on silica gel, giving 7.55 mmol of 7-[5-(octyloxy)pyridin-2-yl]-1-fluoro-3-octyloxy-5,6,7,8-tetrahydroisoquinoline.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:17]([OH:19])=O)[CH:16]=2)[CH:4]=1)[CH3:2].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>>[CH2:20]([NH:24][C:17]([C:15]1[CH:16]=[C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])[CH:12]=[N:13][CH:14]=1)=[O:19])[CH2:21][CH2:22][CH3:23]
Reactant: CCCCN
Reactant: CCc1cc(-c2cncc(C(=O)O)c2)c(C)[nH]c1=O
Product: CCCCNC(=O)c1cncc(-c2cc(CC)c(=O)[nH]c2C)c1

Procedure:
Method 1, Example 205 is substantially repeated except for utilizing 5′-ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[3,3′]bipyridinyl-5-carboxylic acid and n-butyl amine to afford the title compound. MS: m/e=314 (M+H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:45]=[CH:44][C:42]([CH3:43])=[CH:41][CH:40]=5)(=[O:38])=[O:37])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22][C:21](=O)[CH2:20]1)[CH3:18].C([O-])(O)=O.[Na+]>C1COCC1.CCOC(C)=O>[CH2:17]([C@H:19]1[C@@H:23]([C:24]2[N:28]3[C:29]4[CH:35]=[CH:34][N:33]([S:36]([C:39]5[CH:40]=[CH:41][C:42]([CH3:43])=[CH:44][CH:45]=5)(=[O:37])=[O:38])[C:30]=4[N:31]=[CH:32][C:27]3=[N:26][N:25]=2)[CH2:22]/[C:21](=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])/[CH2:20]1)[CH3:18]
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: CC[C@@H]1CC(=O)C[C@@H]1c1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)n12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C1\C[C@@H](CC)[C@@H](c2nnc3cnc4c(ccn4S(=O)(=O)c4ccc(C)cc4)n23)C1
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a slurry of NaH (0.034 g, 0.85 mmol) in THF (5 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (0.177 mL, 0.886 mmol) at rt. After about 30 min, a solution of (3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentanone (0.300 g, 0.708 mmol, Preparation #25) in THF (1 mL) was added. After about 4 h, EtOAc (20 mL) and saturated aqueous NaHCO3 (20 mL) were added. The organic layer was separated, concd in vacuo, and purified by chromatography on silica gel (40 g) eluting with EtOAc/heptane/DCM (2:1:1) to provide (E)-ethyl 2-((3R,4S)-3-ethyl-4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclopentylidene)acetate (0.260 g, 74%). LC/MS (Table 1, Method a) Rt=2.54 min; MS m/z: 494 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[NH:5][CH:4]([C:13]2[CH:14]=[C:15]([NH2:19])[CH:16]=[CH:17][CH:18]=2)[CH2:3]1.N1C=CC=CC=1.[F:27][C:28]1[CH:29]=[C:30]([S:34](Cl)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>ClCCl>[F:27][C:28]1[CH:29]=[C:30]([S:34]([NH:19][C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([CH:4]3[CH2:3][C:2]([CH3:20])([CH3:1])[C:11]4[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=4)[NH:5]3)[CH:14]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(N)c1)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc2c(c1)C(C)(C)CC(c1cccc(NS(=O)(=O)c3cccc(F)c3)c1)N2
Yield: 37.7 %

Procedure:
To a stirred mixture of 3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenylamine (135 mg, 0.5 mmol) in dichloromethane (3 mL) was added pyridine (60 mg, 0.75 mmol) in dichloromethane (2 mL) and 3-fluoro-benzenesulfonyl chloride (108 mg, 0.56 mmol) under nitrogen. The resultant mixture was stirred for 4 h. The reaction mixture was diluted with dichloromethane, washed with water (twice), saturated brine, and dried over magnesium sulfate. Magnesium sulfate was removed by filtration, and after evaporation, the residue was purified on chromatography column (silica gel, petroleum ether: Ethyl acetate=12:1) to afford 80 mg of 3-fluoro-N-[3-(4,4,6-trimethyl-1,2,3,4-tetrahydro-quinolin-2-yl)-phenyl]-benzenesulfonamide as yellow solid (Yield: 38%). MS (ESI+APCI) M+1=425.2.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=[C:18]([C:21]4[CH:25]=[C:24]([CH2:26][N:27]([CH3:32])[CH:28]([CH3:31])CC)[S:23][CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[CH2:36]([O:38]CCN)[CH3:37].CC(N)CC>>[CH2:36]([O:38][CH2:31][CH2:28][N:27]([CH2:26][C:24]1[S:23][CH:22]=[C:21]([C:18]2[CH:19]=[C:20]3[C:15](=[C:16]([C:33]([NH2:35])=[O:34])[CH:17]=2)[NH:14][CH:13]=[C:12]3[CH:9]2[CH2:8][CH2:7][N:6]([S:3]([CH2:1][CH3:2])(=[O:4])=[O:5])[CH2:11][CH2:10]2)[CH:25]=1)[CH3:32])[CH3:37]
Reactant: CCC(C)N(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Reactant: CCOCCN
Agent: CCC(C)N
Product: CCOCCN(C)Cc1cc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)cs1
Yield: 11.5 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[methyl(1-methylpropyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide, substituting 2-(ethyloxy)ethanamine (1 mmol) for added 2-butanamine to afford 6.1 mg of the title compound (11.5%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[O:30])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1.C(OCC)(=O)C>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=2)([OH:30])[CH2:26][CH2:25]1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: FC(F)(F)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: OC1(c2ccc(C(F)(F)F)cc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 46 %

Procedure:
4-Bromobenzotrifluoride (1 g, 4.44 mmol) was dissolved in THF (15 ml), to which n-butyllithium (1.5 M) hexane solution (3.1 ml, 4.67 mmol) was added dropwise at −70° C. Then a solution of 1-benzyl-4-piperidone in THF (15 ml) was added dropwise to the mixture, and the resulting mixture was stirred for 2 hours and then at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate, washed with water and brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/acetone=2/1) to afford 1-benzyl-4-(4-trifluoromethylphenyl)piperidin-4-ol (692 mg, yield 46%) as a colorless crystalline powder.