Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.[C:12]([N:19]1[CH:23]=[CH:22][N:21]=[CH:20]1)(N1C=CN=C1)=O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1C1CNCCN1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:19]1[CH2:23][CH2:22][N:21]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[O:25][CH3:24])[CH2:20][CH2:12]1)=[O:11]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cc1ccccc1Br
Reactant: COc1ccccc1C1CNCCN1
Solvent: ClC(Cl)Cl
Product: COc1ccccc1N1CCN(C(=O)Cc2ccccc2Br)CC1
Yield: 54.6 %

Procedure:
A stirred solution of 2-bromophenylacetic acid (28.4 g, 132 mmol) in chloroform (200 ml) was treated dropwise over 10 rain with 1,1'-carbonyldiimidazole (21.4 g, 132 mmol) in chloroform (120 ml) under argon, after 1 h treated with 2-(methoxyphenyl)piperazine (24.4 g, 127 mmol) in chloroform (100 ml), after 18 h washed with 0.5 N-HC1 (2×200 ml), 0.5 N-NaOH (2×200 ml), and brine (200 ml), dried (MgSO4), and evaporated in vacuo. The oil was crystallised by trituration with cyclohexane (100 ml) to give the product (27.0 g), m.p. 95°-97°.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[CH:12]([CH:14]=[CH2:15])=[O:13].O>C1COCC1.C(N(CC)CC)C>[F:11][C:2]([F:1])([F:10])[C:3]1[CH:4]=[CH:5][C:6]([S:9][CH2:15][CH2:14][CH:12]=[O:13])=[CH:7][CH:8]=1
Reactant: C=CC=O
Reactant: FC(F)(F)c1ccc(S)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=CCCSc1ccc(C(F)(F)F)cc1
Yield: 99.6 %

Procedure:
Ten grams of 4-trifluoromethylthiophenol was dissolved in 15 ml of THF, and after adding 4.0 g of 95% acrolein under ice-cooling, 0.1 g of triethylamine was added while thoroughly stirring the reaction solution. After stirring for 1.5 hours under ice-cooling, the reaction solution was poured into water and extracted with ether. The ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to obtain 13.1 g of 3-(4-trifluoromethylphenylthio)propionaldehyde.
Reaction SMILES: C([O-])(=O)C.[Na+].[N-:6]=[N+:7]=[N-:8].[Na+].[CH3:10][C:11]([O:14][C:15]([NH:17][C@@H:18]1[C@@H:23](OS(C)(=O)=O)[CH2:22][CH2:21][O:20][CH2:19]1)=[O:16])([CH3:13])[CH3:12].O>CN(C=O)C.C(OCC)(=O)C>[N:6]([C@@H:23]1[CH2:22][CH2:21][O:20][CH2:19][C@@H:18]1[NH:17][C:15](=[O:16])[O:14][C:11]([CH3:12])([CH3:10])[CH3:13])=[N+:7]=[N-:8]
Reactant: CC(C)(C)OC(=O)N[C@H]1COCC[C@@H]1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1COCC[C@H]1N=[N+]=[N-]
Temperature: 95 °C
Yield: 80.4 %

Procedure:
Sodium acetate (129 g), sodium azide (102 g) and 1,5-anhydro-2,4-dideoxy-2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)-3-O-(methylsulfonyl)-L-threo-pentitol (232 g) were mixed in DMF (1 l) and stirred and heated at 95° C. for 6 h. Water (2 l) was added and the mixture thoroughly mixed, ethyl acetate 1.5 l) was added and the mixture stirred for 5 min. The phases were separated, the aqueous extracted with ethyl acetate (1 l), the combined organics washed with water (2×2 l), dried and reduced to dryness in vacuo to give 1,1-dimethylethyl [(3R,4R)-4-azidotetrahydro-2H-pyran-3-yl]carbamate (153 g).
Reaction SMILES: [F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17](Cl)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1.CCN(C(C)C)C(C)C.[CH2:35]([N:37]([CH2:43][CH3:44])[CH:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)[CH3:36]>>[F:1][C:2]1([F:25])[CH2:7][CH2:6][CH2:5][C:4]([CH2:9][NH:10][C:11]([C:13]2[C:14]3[CH:15]=[CH:16][C:17]([N:40]4[CH2:41][CH2:42][CH:38]([N:37]([CH2:43][CH3:44])[CH2:35][CH3:36])[CH2:39]4)=[N:18][C:19]=3[CH:20]=[CH:21][C:22]=2[Cl:23])=[O:12])([OH:8])[CH2:3]1
Reactant: CCN(CC)C1CCNC1
Reactant: O=C(NCC1(O)CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)C1CCN(c2ccc3c(C(=O)NCC4(O)CCCC(F)(F)C4)c(Cl)ccc3n2)C1

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-1-hydroxycyclohexylmethyl)-amide, DIPEA and 3-diethylaminopyrrolidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.75 (1H), 7.85 (m, 1H), 7.58 (2H), 7.05 (1H), 4.56 (s, 1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 3H), 3.34 (m, 2H), 3.26 (m, 1H), 2.63 (m, 4H), 2.06 (m, 2H), 1.85 (m, 2H), 1.74-1.76 (m, 2H), 1.27-1.32 (m, 2H), 0.98 (m, 5H). m/z: 496 [M+H]
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[NH:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH:3][C:2]([N:25]1[CH2:29][CH2:28][CH2:27][CH2:26]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: C1CCNC1
Product: Cc1nc2ccc(N3CCCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Yield: 56 %

Procedure:
The title compound was prepared from 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] and pyrrolidine according to the procedure of example 25. Yield: 56%; MS: m/z=385 (M+H).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:9][SH:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1>O1CCCC1.O>[CH2:9]([S:10][C:12]1[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: SCc1ccccc1
Reactant: Cc1cccnc1Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cccnc1SCc1ccccc1
Reaction time: 0.25 h
Yield: 222.1 %

Procedure:
To a suspension of sodium hydride (60% in oil, 1.44 g) in tetrahydrofuran (45 mL) was added dropwise phenylmethanethiol (465 mg) at room temperature and the mixture was stirred for 15 min. 2-Bromo-3-methylpyridine (2.0 g) was added to the reaction mixture, and the mixture was stirred at 60° C. for 1.5 hr. The reaction mixture was diluted with water, and concentrated under reduced pressure. The residual aqueous layer was extracted twice with ethyl acetate. Combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-hexane-ethyl acetate=97:3) to give the title compound as a gray oil (yield 1.79 g, 72%).
Reaction SMILES: [CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:19][C:20]4[CH:25]=[CH:24][C:23]([CH2:26][N:27]5[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]5)=[CH:22][CH:21]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:33][I:34]>CN(C=O)C>[I-:34].[CH:1]1([C:7]2[CH:16]=[C:15]3[C:10]([CH2:11][CH2:12][C:13]([C:17]([NH:19][C:20]4[CH:21]=[CH:22][C:23]([CH2:26][N+:27]5([CH3:33])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]5)=[CH:24][CH:25]=4)=[O:18])=[CH:14]3)=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CI
Reactant: O=C(Nc1ccc(CN2CCCCC2)cc1)C1=Cc2cc(C3CCCCC3)ccc2CC1
Solvent: CN(C)C=O
Product: C[N+]1(Cc2ccc(NC(=O)C3=Cc4cc(C5CCCCC5)ccc4CC3)cc2)CCCCC1
Product: [I-]
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In DMF (2 ml) was dissolved 7-cyclohexyl-N-[4—(piperidinomethyl)phenyl]-3,4-dihydronaphthalene-2-carboxamide (120 mg), and to the mixture was added methyl iodide (45 μl). The mixture was stirred at room temperature for 24 hours and concentrated under reduced pressure. The residue was recrystallized from ethyl acetate to give 1-[4—(7-cyclohexyl-3,4-dihydro-naphthalene-2-carboxamido) benzyl]-1-methylpiperidinium iodide (Compound 2) (148 mg) as colorless crystals.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:12])=[O:11])=[CH:6][N:5]=1)[NH2:3].C(O)(C(F)(F)F)=O.[F:21][C:22]([F:35])([F:34])[C:23](=O)[CH2:24][C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=O>C(O)C(F)(F)F>[CH2:4]([NH:5][CH2:6][CH3:7])[CH3:9].[CH:27]1([C:25]2[N:2]([C:4]3[CH:9]=[CH:8][C:7]([S:10]([CH3:13])(=[O:11])=[O:12])=[CH:6][N:5]=3)[N:3]=[C:23]([C:22]([F:21])([F:34])[F:35])[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)c1ccc(NN)nc1
Reactant: O=C(CC(=O)C(F)(F)F)C1CCCCC1
Agent: Cl
Solvent: OCC(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCNCC
Product: CS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2C2CCCCC2)nc1
Yield: 86 %

Procedure:
2-Hydrazino-5-(methylsulfonyl)pyridine hydrochloride (425.2 mg, 1.9 mmol) and TFA (0.44 mL, 5.7 mmol) were mixed in trifluoroethanol (15 mL) and heated at reflux temperature for 15 minutes 4,4,4-trifluoro-1-cyclohexyl-1,3-butanedione (422 mg, 1.9 mmol) in trifluoroethanol (5 ml) was added. The resulting reaction mixture was heated at reflux temperature for 3 hours. The solvent was then removed in vacuo, and the residue was partitioned between EtOAc and water. The organic layer was washed with brine and concentrated in vacuo. The product was purified by flash chromatography using 7:2:0.5 of hexane:diethylamine:methanol to give the title compound (305 mg, 43%).
Reaction SMILES: [CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:17][CH:16]=3)=[N:12][CH:13]=[C:8]2[CH2:7][NH:6][C:5]1=[O:26])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CC(C)([O-])C.[K+]>O1CCCC1>[CH:1]([N:4]1[C:9]2=[N:10][C:11]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([N:21]4[CH:25]=[CH:24][CH:23]=[N:22]4)=[CH:19][CH:20]=3)=[N:12][CH:13]=[C:8]2[CH:7]=[N:6][C:5]1=[O:26])([CH3:3])[CH3:2]
Reactant: CC(C)N1C(=O)NCc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)n1c(=O)ncc2cnc(Nc3ccc(-n4cccn4)cc3)nc21
Reaction time: 48 h
Yield: 77.4 %

Procedure:
Prepared from 150 mg (0.32 mmol) of 1-isopropyl-7-[4-(pyrazol-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one, trifluoroacetic acid and 218 mg (1.94 mmol) of potassium tert-butoxide in 10 mL of tetrahydrofuran. The reaction mixture is stirred for 48 hours, 50 mg (0.44 mmol) of potassium tert-butoxide is added, and the reaction is continued for 72 hours. After the workup, the semi-solid is triturated in diethyl ether, and the powder is collected and dried to give 86 mg (73%) of the title compound: mp 243-247° C. (dec).
Reaction SMILES: C[N:2](C)[CH:3]=[CH:4][C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[N:8]=1)=O.[C:24]1([NH:30]N)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CO>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH2:20])=[O:19])=[CH:16][CH:15]=2)[N:8]=[C:7]1[C:5]1[N:30]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:2]=[CH:3][CH:4]=1
Reactant: CN(C)C=CC(=O)c1nn(-c2ccc(C(N)=O)cc2)ccc1=O
Reactant: NNc1ccccc1
Solvent: CO
Product: NC(=O)c1ccc(-n2ccc(=O)c(-c3ccnn3-c3ccccc3)n2)cc1
Yield: 6 %

Procedure:
To a solution of 4-{3-[3-(dimethylamino)prop-2-enoyl]-4-oxopyridazin-1(4H)-yl}benzamide (crude 682 mg, 2.19 mmol) in 20 mL of methanol was added phenylhydrazine (946 mg, 8.76 mmol). The mixture was refluxed for 4 h and concentrated. The residue was dissolved in dichloromethane (20 mL), washed with 1N HCl aqueous solution and brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by prep-HPLC to give 4-[4-oxo-3-(1-phenyl-1H-pyrazol-5-yl)pyridazin-1(4H)-yl]benzamide (50 mg, 6% for two steps) as a yellow solid.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3[N:17]=[CH:18][N:19]=[C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:15]=3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.C([O:38][C@@H:39]([CH3:43])[C:40](Cl)=[O:41])(=O)C>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[C:15]3[NH:14][C:13]([CH3:34])=[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@@H:3]([NH:2][C:40](=[O:41])[C@@H:39]([OH:38])[CH3:43])[CH2:4][CH2:5]4)=[O:11])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](N)CC4)c(C)[nH]c23)c1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Agent: Cl
Product: COc1ccc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@H]4CC[C@@H](NC(=O)[C@H](C)O)CC4)c(C)[nH]c23)c1

Procedure:
Starting from N-(cis-4-aminocyclohexyl)-4-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f25) and commercially available (2S)-1-chloro-1-oxopropan-2-yl acetate the title compound is obtained as colorless solid.
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])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].C(N(CC)CC)C.[C:32](Cl)(Cl)=[S:33].[NH2:36][CH2:37][CH2:38][CH2:39][N:40]1[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]1[CH3:46]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:32]([NH:36][CH2:37][CH2:38][CH2:39][N:40]2[CH2:45][CH2:44][CH2:43][CH2:42][CH:41]2[CH3:46])=[S:33])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CC1CCCCN1CCCN
Reactant: S=C(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=S)NCCCN4CCCCC4C)c(C)c3C)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 47.5 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (51 mg) was dissolved in N,N-dimethylformamide (2 ml) and triethylamine (1 ml) to prepare a solution. Thiophosgene (51 mg) was then added to the solution, and the mixture was stirred at room temperature for 6 hr. Next, 1-(3-aminopropyl)-2-methylpiperidine (50 mg) was added thereto, and the mixture was further stirred at room temperature for 15 hr. Ethyl acetate was added to the reaction solution, followed by washing with water and saturated brine in that order. The organic layer was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by HPLC using chloroform/methanol for development to give the title compound (39 mg, yield 47%).
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]([F:28])([F:27])[C:9]1[CH:26]=[CH:25][C:12]([O:13][CH:14]2[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17][NH:16][CH2:15]2)=[CH:11][CH:10]=1.C(N(CC)CC)C.[C:36]1([CH2:42][C:43](Cl)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)(Cl)Cl>[C:36]1([CH2:42][C:43]([N:16]2[CH2:15][CH:14]([O:13][C:12]3[CH:25]=[CH:26][C:9]([C:8]([F:7])([F:27])[F:28])=[CH:10][CH:11]=3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[CH2:18][CH2:17]2)=[O:44])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: FC(F)(F)c1ccc(OC2CNCCc3ccccc32)cc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C(O)C(=O)O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C(Cc1ccccc1)N1CCc2ccccc2C(Oc2ccc(C(F)(F)F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cooled solution of 2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine of Example 1 (5.8 g. 0.019 mole) and triethylamine (2.3 g, 0.023 mole) in chloroform (75 ml) was slowly dropped phenylacetyl chloride (3.5 g. 0.023 mole) in chloroform (10 ml). After stirring at ambient temperature overnight the reaction mixture was concentrated to an oil. The oil was dissolved in ether, then washed with water, dilute HCl (10%), again with water and dried (saturated NaCl, anhydrous MgSO4). The solution was filtered, concentrated to an oil which was extracted with boiling hexanes and then concentrated to an oil (6.8 g, 84%). A sample was distilled to yield an oil of 3-phenylacetyl-2,3,4,5-tetrahydro-1-(p-trifluoromethylphenoxy)-3-benzazepine, 240°-250° C./0.1 mm.
Reaction SMILES: I.[NH2:2][C:3]1[C:4]([C:11]([NH:13][C:14](=[NH:17])SC)=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1.C([N:20](CC)CC)C.Cl.N[CH2:27][CH2:28][CH2:29][CH2:30][C:31]1[CH:42]=[CH:41][C:34]([C:35]([NH:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][CH:32]=1>C1COCC1.CO>[ClH:10].[NH2:2][C:3]1[C:4]([C:11]([N:13]([CH2:27][CH2:28][CH2:29][CH2:30][C:31]2[CH:42]=[CH:41][C:34]([C:35]([NH:37][CH2:38][CH2:39][OH:40])=[O:36])=[CH:33][CH:32]=2)[C:14]([NH2:17])=[NH:20])=[O:12])=[N:5][C:6]([Cl:10])=[C:7]([NH2:9])[N:8]=1
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Reactant: NCCCCc1ccc(C(=O)NCCO)cc1
Reactant: CCN(CC)CC
Agent: Cl
Agent: I
Solvent: C1CCOC1
Solvent: CO
Product: N=C(N)N(CCCCc1ccc(C(=O)NCCO)cc1)C(=O)c1nc(Cl)c(N)nc1N
Reaction time: 4 h
Yield: 28.2 %

Procedure:
1-(3,5-Diamino-6-chloropyrazinoyl)-2-methylisothiourea hydriodide (0.48 g, 1.24 mmol) and triethylamine (0.7 mL, 4.74 mmol) were sequentially added into a solution of 28 (0.28 g, 1.19 mmol) in a mixture of THF/MeOH (4 mL, 1/1). The reaction mixture was stirred in the boiling solvent for 4 h, then at room temperature overnight. The solvent was evaporated. The free base of the target compound 29 (0.36 g, 62%) was purified by Flash™ (BIOTAGE, Inc) (90 g silica gel cartridge 40M, 12:1:0.1 chloroform/ethanol/concentrated ammonium hydroxide) as a yellow solid. 100 mg of the yellow solid was treated with 2 mL of 3% HCl. The precipitate was collected by filtration, washed with water (2×5 mL) and dried under vacuum to give 85 mg (79%) of 29 as a yellow powder. 1H NMR (300 MHz, DMSO-d6) δ 1.60 (m, 4H), 2.68 (m, 2H), 3.28 (m, 4H), 3.49 (m, 2H), 4.80 (m, 1H), 7.28 (d, 2H), 7.44 (br s, 2H), 7.82 (d, 2H), 8.45 (m, 1H). m/z (APCI)=449 [C19H25ClN8O3+H]+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7](Cl)=[O:8])=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19].CCN(C(C)C)C(C)C.O>C1COCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:7]([C:5]2[S:6][C:2]([Br:1])=[CH:3][CH:4]=2)=[O:8])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C(Cl)c1ccc(Br)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1ccc(Br)s1

Procedure:
The product from Example 241a (2.178 g, 10.25 mmol) was reacted with 4-fluoro-3-nitro-phenylamine (1.60 g, 10.25 mmol) dissolved in THF (25 mL) and Hunig's base (2.484 g, 19.22 mmol). Reaction mixture was stirred at room temperature for 1 hr at which time water was added and the title compound was collected by filtration (2.00 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:9][CH:10]([C:12]2[CH:17]=[C:16]([Cl:18])[CH:15]=[CH:14][C:13]=2[Cl:19])[CH3:11])[C:5]([NH2:8])=[N:6][CH:7]=1.Br[C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.[CH3:30][PH:31](=[O:33])[CH3:32]>>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([Cl:18])=[CH:17][C:12]=1[CH:10]([O:9][C:4]1[C:5]([NH2:8])=[N:6][CH:7]=[C:2]([C:21]2[CH:26]=[CH:25][C:24]([P:31]([CH3:32])([CH3:30])=[O:33])=[CH:23][CH:22]=2)[CH:3]=1)[CH3:11]
Reactant: CC(Oc1cc(Br)cnc1N)c1cc(Cl)ccc1Cl
Reactant: OB(O)c1ccc(Br)cc1
Reactant: C[PH](C)=O
Product: CC(Oc1cc(-c2ccc(P(C)(C)=O)cc2)cnc1N)c1cc(Cl)ccc1Cl

Procedure:
The title compound was prepared from 5-bromo-3-[1-(2,5-dichloro-phenyl)-ethoxy]-pyridin-2-ylamine, 4-bromophenyl boronic acid, and dimethylphosphine oxide following the same procedures as Example 1 Step 1 and Step 3; ESMS: m/z 435 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[C:17]([C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=4)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=3)=[CH:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:31][CH3:32].C(=O)([O-])[O-].[K+].[K+].[NH2:39][CH2:40][CH2:41][OH:42]>CN(C)C=O>[CH3:32][O:31][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:5]=1[O:4][CH2:3][CH2:2][NH:39][CH2:40][CH2:41][OH:42])[N:12]=[CH:11][CH:10]=[C:9]2[O:15][C:16]1[C:17]([C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][N:25]=2)=[N:18][C:19]([CH3:23])=[C:20]([CH3:22])[CH:21]=1
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCCl
Reactant: NCCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccc(C)cn3)ccnc2cc1OCCNCCO
Temperature: 70 °C
Reaction time: 8 h
Yield: 71 %

Procedure:
3-[7-(2-Chloro-ethoxy)-6-methoxy-quinolin-4-yloxy]-5,6,5′-trimethyl-[2,2′]bipyridine (compound 466) (33 mg) was dissolved in N,N-dimethylformamide (2 ml) to prepare a solution. Potassium carbonate (101 mg) and 2-aminoethanol (0.13 ml) were added to the solution, and the mixture was stirred at 70° C. overnight. The solvent was removed by distillation under the reduced pressure, water was then added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (25 mg, yield 71%).
Reaction SMILES: C([Li])(C)(C)C.[CH3:6][O:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10](I)[N:9]=1.[N:15]12[CH2:22][CH2:21][CH:18]([CH2:19][CH2:20]1)[CH2:17][C:16]2=O.[OH2:24]>CCCCC.CCOCC>[CH3:6][O:7][C:8]1[CH:13]=[N:12][CH:11]=[C:10]([C:17]2([OH:24])[CH:18]3[CH2:21][CH2:22][N:15]([CH2:20][CH2:19]3)[CH2:16]2)[N:9]=1
Reactant: O
Reactant: O=C1CC2CCN1CC2
Reactant: COc1cncc(I)n1
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCCCC
Product: COc1cncc(C2(O)CN3CCC2CC3)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
t-Butyllithium (20 ml of a 1.7M solution in pentane, 35.3 mmol) was added dropwise to a rapidly stirred solution of 2-methoxy-6-iodopyrazine (4.17 g, 17.6 mmol) in ether (80 ml), at -40° C. After 0.25 h a solution of quinuclidinone (2.21 g, 17.6 mmol) in ether (60 ml) was added dropwise and the reaction mixture warmed to room temperature and stirred for 2 h. Water (35 ml) was added and extracted with ethylacetate (4×100 ml). The combined extracts were dried (Na2SO4), the solvent removed under vacuum and, the residue chromatographed through alumina, eluting with dichloromethane/methanol (93:7) to give 3-[2-(6-methoxypyrazin)yl]-1-azabicyclo [2.2.2]octan-3-ol (1.65 g); δ (360 MHz, CDCl3) 1.37-1.51 (3H,m, --CH2 and CH of CH2); 1.70-1.90(1H, brs, OH); 1.94-1.96-(1H,m,CH); 2.20-2.32(1H,m,CH of CH2); 2.80-3.10(5H,m,2×CH2 and CH of CH2) 3.74(1H,dd, J=2 and 14.6 Hz, CH of CH2); 3.99(3H,s,Me); 8.15(1H,s,pyrazine-H); 8.39(1H,s,pyrazine-H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][NH:9][C:10]2=[O:13])=[CH:5][CH:4]=1.I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][N:9]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][C:20]=3[CH3:21])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)NCC2
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccc2c(c1)C(=O)N(c1cnccc1C)CC2
Yield: 56.2 %

Procedure:
Using analogous reaction conditions as described in Example 1, 7-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-35b: 1 g, 5.64 mmol) was reacted with 3-iodo-4-methyl-pyridine (1.237 g, 5.64 mmol), 1,4-dioxane (300 mL), copper iodide (107.4 mg, 0.564 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (240.2 mg, 1.69 mmol) and potassium phosphate (2.98 g, 141 mmol) to afford the crude product. Purification by column chromatography on silica gel (40% ethylacetate in hexane) afforded 850 mg of the product (56% yield).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([NH:16][OH:17])([CH3:15])([CH3:14])[CH3:13]>C1C=CC=CC=1>[C:12]([N+:16]([O-:17])=[CH:9][CH2:8][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:11])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)NO
Reactant: CC(CC=O)c1ccccc1
Solvent: c1ccccc1
Product: CC(CC=[N+]([O-])C(C)(C)C)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.8 %

Procedure:
To a mixture of 3-phenylbutyraldehyde (10.0 g, 67.5 mmol, 1.0 equiv) and benzene (150 ml) and silica gel (5 g) was added N-tert-butylhydroxylamine (7.22 g, 81.0 mmol, 1.2 equiv) and the mixture stirred at rt for 18 h. The mixture was filtered and the filtrate was concentrated under vacuum to give N-tert-butyl-C-(2-phenylpropyl)nitrone (13.74 g, 92.80%) as a light yellow oil. 1H NMR (CDCl3) δ 7.33–7.19 (m, 5H), 6.65 (t, 1H), 3.18–3.04 (m, 1H), 2.90–2.65 (m, 2H), 1.40 (s, 9H), 1.34–1.32 (d, 3H).