Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C@:11]([OH:36])([CH3:35])[CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[H-].[Na+].C(OCC)(=O)C.O>CN(C=O)C>[CH3:35][C@@:11]1([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][CH2:22][CH:23]=[CH:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[O:20])[CH2:15][CH2:14]2)[O:36][C:2]2=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]2[CH2:10]1
Reactant: C[C@](O)(CN1CCN(C(=O)OCC=Cc2ccc(C(F)(F)F)cc2)CC1)Cn1cc([N+](=O)[O-])nc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]1(CN2CCN(C(=O)OCC=Cc3ccc(C(F)(F)F)cc3)CC2)Cn2cc([N+](=O)[O-])nc2O1
Reaction time: 1.5 h
Yield: 68.8 %

Procedure:
3-(4-Trifluoromethylphenyl)-2-propenyl (S)-4-[3-(2-bromo-4-nitroimidazol-1-yl)-2-hydroxy-2-methylpropyl]piperazine-1-carboxylate (3.5 g, 6.07 mmol) was dissolved in N,N′-dimethylformamide (10.5 ml), and sodium hydride (316 mg, 7.89 mmol) was added while cooling on ice followed by stirring at the same temperature for 1.5 hours. To the reaction solution, ethyl acetate (3.5 ml) and water (24.5 ml) were added followed by stirring for 30 minutes. The precipitated crystals were filtered off, washed with water, and purified by silica gel column chromatography (ethyl acetate). Recrystallization from 2-propanol/water gives a light yellow powder of 3-(4-trifluoromethylphenyl)-2-propenyl (S)-4-(2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b]oxazol-2-ylmethyl)piperazine-1-carboxylate (2.07 g, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[C:4]([CH:26]=[CH2:27])[CH:3]=1.[CH2:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH2:35])[CH2:31]1)[CH3:29]>C(O)CO.O>[CH2:28]([N:30]1[CH2:34][CH2:33][C@@H:32]([NH:35][CH2:27][CH2:26][C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[S:8]([NH:11][C:12]2[C:21]([C:22]([OH:24])=[O:23])=[C:20]3[C:15]([CH:16]4[CH2:25][CH:17]4[CH2:18][O:19]3)=[CH:14][CH:13]=2)(=[O:9])=[O:10])[CH2:31]1)[CH3:29]
Reactant: C=Cc1cc(F)ccc1S(=O)(=O)Nc1ccc2c(c1C(=O)O)OCC1CC21
Reactant: CCN1CC[C@@H](N)C1
Solvent: O
Solvent: OCCO
Product: CCN1CC[C@@H](NCCc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)O)OCC2CC32)C1
Yield: 2.6 %

Procedure:
A solution of (1aRS,7bSR)-5-(4-fluoro-2-vinylbenzenesulfonylamino)-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (Intermediate 74, 0.150 g) and (R)-1-ethylpyrrolidin-3-ylamine (Intermediate 193, 0.25 g) in ethylene glycol (1 ml) was irradiated in the microwave at 200° C. for 30 minutes. After cooling, the mixture was diluted with water and loaded onto a SCX-2 SPE cartridge then washed with water, methanol and 2M ammonia in methanol. The basic fractions were combined and evaporated to dryness. The residue was purified by preparative HPLC (C18) eluting with a mixture of methanol and water, containing 0.1% ammonia, with a gradient of 10-98%. Then further purified by preparative HPLC (C18) eluting with a mixture of acetonitrile and water, containing 0.1% formic acid, with a gradient of 10-60% to give (1aRS,7bSR)-5-{2-[2-((R)-1-ethylpyrrolidin-3-ylamino)ethyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydro-cyclopropa[c]chromene-4-carboxylic acid (0.005 g) as a white solid.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[CH:6][C:7]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:8]([CH:18]=1)[C:9]([NH:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)=[O:10].ClC1C=CC(S(O[CH2:38][C@H:39]2[CH2:43][CH2:42][CH2:41][N:40]2[C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])(=O)=O)=CC=1.O>CS(C)=O>[C:21]1([CH2:20][O:19][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:38][C@H:39]3[CH2:43][CH2:42][CH2:41][N:40]3[C:44]([O:46][C:47]([CH3:48])([CH3:50])[CH3:49])=[O:45])=[CH:18][C:8]=2[C:9]([NH:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[O:10])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COS(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Nc1cccnc1)c1cc(O)ccc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccccc2)c(C(=O)Nc2cccnc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Sodium hydride (44.9 mg, 1.87 mmol) was added to a solution of 5-hydroxy-2-[(phenylmethyl)oxy]-N-3-pyridinylbenzamide (may be prepared as described in Example 29; 500 mg, 1.56 mmol) in dimethylsulfoxide (8 ml) at 0° C., and the mixture was stirred at room temperature for 1 h. 1,1-Dimethylethyl (2R)-2-({[(4-chlorophenyl)sulfonyl]oxy}methyl)-1-pyrrolidinecarboxylate (555 mg, 1.56 mmol) in dimethylsulfoxide (7 ml) was added dropwise, and the mixture was stirred at 75° C. for 18 h. The mixture was poured into water (100 ml) and extracted with ethyl acetate. The organic layer was dried, and concentrated to obtain a crude product, which was purified by chromatography on silica gel (dichloromethane/methanol=50:1) to yield the title compound as a yellow oil. 0.55 g.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6](OC)=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(Cl)Cl>[Cl:1][C:2]1[CH:11]=[CH:10][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: COC(=O)c1ccc(Cl)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1Cl
Temperature: 25 °C

Procedure:
Methyl 4-chloro-3-methoxybenzoate (5 g, 25 mmol, 1 equiv) in 15 mL of THF and 15 mL of DCM was cooled to 0° C. and treated with LiAlH4 (2.8 g, 3 equiv) overnight and was allowed to warm to rt. The reaction was then quenched with saturated sodium sulfate. Removal of the solid by filtration through celite followed by evaporation of the filtrate gave 4-chloro-3-methoxybenzyl alcohol.
Reaction SMILES: Br[C:2]1[N:11]=[C:5]2[CH:6]=[C:7]([Br:10])[CH:8]=[CH:9][N:4]2[N:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>>[Br:10][C:7]1[CH:8]=[CH:9][N:4]2[N:3]=[C:2]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:11]=[C:5]2[CH:6]=1
Reactant: Brc1ccn2nc(Br)nc2c1
Reactant: C1COCCN1
Product: Brc1ccn2nc(N3CCOCC3)nc2c1
Yield: 35.9 %

Procedure:
A mixture of 2,7-dibromo-[1,2,4]triazolo[1,5-a]pyridine (1 g, 3.61 mmol) and morpholine (10.0 g, 10 ml, 115 mmol) was refluxed for 4 hours under argon atmosphere, the formerly green mixture turning to yellow. The reaction mixture is concentrated to dryness, applied on silica and purified by flash chromatography on a 20 g silica column using heptane/ethyl acetate 10-100% as eluent affording 4-(7-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)morpholine (367 mg, 35.9%) as a white solid. mp.: 178-9° C. MS: m/z=285.0, 283.0 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:18])=[N:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[CH3:19][C:20]1[N:21]=[CH:22][NH:23][CH:24]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:18][C:10]1[C:9]([O:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:23]3[CH:24]=[C:20]([CH3:19])[N:21]=[CH:22]3)[CH:7]=2)=[CH:14][CH:13]=[C:12]([N+:15]([O-:17])=[O:16])[N:11]=1
Reactant: Cc1c[nH]cn1
Reactant: Cc1nc([N+](=O)[O-])ccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: Cc1cn(-c2cc(Oc3ccc([N+](=O)[O-])nc3C)ccn2)cn1
Temperature: 25 °C
Yield: 51.9 %

Procedure:
A solution of Pd2(dba)3 (0.172 g, 0.188 mmol) and Me4t-BuXPhos (0.181 g, 0.376 mmol) in toluene (2 mL) and dioxane (4 mL) was heated at 120° C. for 3 min, cooled to RT, added to a degassed suspension of Example A4 (2.500 g, 9.41 mmol), 4-methyl imidazole (1.00 g, 12.18 mmol) and K3PO4 (4.00 g, 18.82 mmol) in toluene (4 mL) and dioxane (8 mL) and heated at 110° C. overnight. The mixture was cooled to RT, the solids were removed via filtration and washed with THF, and the filtrate was concentrated to dryness and purified via silica gel chromatography (EtOAc/DCM) to afford 2-methyl-3-((2-(4-methyl-1H-imidazol-1-yl)pyridin-4-yl)oxy)-6-nitropyridine (1.52 g, 52%). 1H NMR (400 MHz, DMSO-d6): δ 8.41 (m, 2H), 8.25 (d, J=8.7 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.64 (t, J=1.3 Hz, 1H), 7.47 (d, J=2.2 Hz, 1H), 7.04 (dd, J=5.7, 2.2 Hz, 1H), 2.49 (s, 3H), 2.13 (s, 3H); MS (ESI) m/z: 312.1 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[CH:4][CH:3]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:6]=[N:7][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:3][CH:4]=1)[CH2:10]2
Reactant: Clc1ccc(O[C@H]2CN3CCC2CC3)nn1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: N
Product: c1cc2cc(-c3ccc(O[C@H]4CN5CCC4CC5)nn3)ccc2[nH]1

Procedure:
The product of Example 9A (480 mg, 2 mmol) was coupled with 5-indolylboronic acid (Frontier, 403 mg, 2.5 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (240 mg, yield, 38%). 1H NMR (300 MHz, CD3OD) δ 1.49-1.64 (m, 1H), 1.68-1.93 (m, 2H), 2.00-2.15 (m, 1H), 2.28-2.36 (m, 1H), 2.76-3.05 (m, 5H), 3.43-3.55 (m, 1H), 5.26-5.34 (m, 1H), 6.56 (dd, J=3.4, 1.0 Hz, 1H), 7.25 (d, J=9.2 Hz, 1H), 7.31 (d, J=3.1 Hz, 1H), 7.50 (d, J=8.5 Hz, 1H), 7.74 (dd, J=8.5, 1.7 Hz, 1H), 8.08 (d, J=9.5 Hz, 1H), 8.14 (d, J=1.4 Hz, 1H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]#[N:28])[CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1.[N-:29]=[N+:30]=[N-:31].[Na+].[NH4+].[Cl-]>CN(C)C=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[N:17][C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:27]4[NH:31][N:30]=[N:29][N:28]=4)[CH:15]=3)[N:10]=2)=[CH:7][CH:8]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(-c2nc3ccc(C#N)cc3nc2-c2ccc(OC)cc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3ccc(-c4nnn[nH]4)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 22.5 %

Procedure:
A solution of 2,3-bis(4-methoxyphenyl)quinoxaline-6-carbonitrile (200 mg, 0.51 mmol, 1.00 equiv, 93%) in N,N-dimethylformamide (7 mL), NaN3 (500 mg, 7.69 mmol, 15.18 equiv), and NH4Cl (147.9 mg, 2.79 mmol, 5.00 equiv) was stirred for 4 h at 100° C. in an oil bath. The reaction was then quenched by the addition of water. The resulting solution was extracted with 8×50 mL of dichloromethane/MeOH (10:1) and the organic layers combined and dried over anhydrous sodium sulfate. The resulting solution was concentrated in vacuo, and washed with methanol, affording 47 mg (23%) of 2,3-bis(4-methoxyphenyl)-6-(1H-tetrazol-5-yl)quinoxaline as a yellow solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30](Cl)=[O:31]>>[CH3:27][C:28]([CH3:34])([CH3:33])[CH2:29][C:30]([NH:23][C:22]1[CH:24]=[CH:25][CH:26]=[C:20]([CH2:19][CH2:18][N:15]2[CH2:14][CH2:13][N:12]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH:10]=[CH:11][C:2]([CH3:1])=[N:3]4)[CH2:17][CH2:16]2)[CH:21]=1)=[O:31]
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: CC(C)(C)CC(=O)Cl
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)CC(C)(C)C)c4)CC3)cccc2n1
Yield: 62 %

Procedure:
The title compound was prepared in 62% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}aniline (D6) and 3,3-dimethylbutanoyl chloride.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][C:16]([F:21])=[CH:17][C:18]=3[F:20])[N:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C(O[BH3-])(=O)C.[Na+]>>[F:21][C:16]1[CH:15]=[C:14]2[C:19](=[C:18]([F:20])[CH:17]=1)[N:10]([CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]1)[C:11](=[O:22])[CH:12]=[N:13]2
Reactant: NC1CCN(CCn2c(=O)cnc3cc(F)cc(F)c32)CC1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Product: O=C1COc2ccc(CNC3CCN(CCn4c(=O)cnc5cc(F)cc(F)c54)CC3)nc2N1

Procedure:
1-[2-(4-Aminopiperidin-1-yl)ethyl]-6,8-difluoroquinoxalin-2(1H)-one (Intermediate 196, 52 mg) was reacted with 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) and sodium acetoxyborohydride as described for Example 107 yielding 29 mg of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[F:12].C(NCC)C.[CH:18]1([NH2:21])[CH2:20][CH2:19]1>O>[Cl:1][C:2]1[C:3]([F:12])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:7]=1)[NH:21][CH:18]1[CH2:20][CH2:19]1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(F)c(Cl)cc1F
Solvent: CCNCC
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(Cl)cc1NC1CC1
Reaction time: 16 h
Yield: 79.9 %

Procedure:
1-Chloro-2,5-difluoro-4-nitrobenzene (3.69 g, 19 mmol) is treated at 0° with diethylamine (2.3 g, 23 mmol) and cyclopropylamine (1.3 g, 23 mmol). After 1 hour at 0° the suspension obtained is stirred at 25° for 16 hours. The reaction mixture is taken up in water (150 ml) and extracted with ethyl acetate. The organic phase is washed with 10 percent sodium chloride solution and dried over magnesium sulfate. After distillation of the solvent the residue is recrystallized from ethanol (50 ml). There are obtained 3.5 g (79%) of 5-chloro-N-cyclopropyl-4-fluoro-2-nitroaniline with a m.p. of 73.5°-75.5°.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH:7]=[C:8]1[S:12]C(=S)N[C:9]1=[O:14])[CH3:2].[OH-:21].[Na+]>O>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:7]=[C:8]([SH:12])[C:9]([OH:21])=[O:14])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][CH3:20])[CH3:2]
Reactant: [OH-]
Reactant: CCOc1ccc(C=C2SC(=S)NC2=O)cc1OCC
Agent: [Na+]
Solvent: O
Product: CCOc1ccc(C=C(S)C(=O)O)cc1OCC

Procedure:
A solution of 33.0 g. of 5-(3,4-diethoxybenzylidene)rhodanine and 23.4 g. of sodium hydroxide in 148 ml. of water was heated to 70° C. for 30 minutes. The solution was cooled and filtered and the filtrate was acidified by pouring into excess cold 10% hydrochloric acid. The precipitate was collected by filtration affording 25 g. of the desired subtitle intermediate which was used without further purification.
Reaction SMILES: Br[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2.[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)=[O:17].C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[C:3]2[C:8]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=3[CH:15]=1)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:17]
Reactant: Brc1cc2ccccc2c2ccccc12
Reactant: O=Cc1ccccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=Cc1ccccc1-c1cc2ccccc2c2ccccc12
Temperature: 25 °C
Yield: 88.6 %

Procedure:
Under an argon atmosphere, 25.7 g of 9-bromophenanthrene, 16.5 g of 2-formylphenylboronic acid and 2.31 g of tetraxis(triphenylphosphine)palladium(0) were placed in a flask. 340 mL of dimethoxyethane (DME) and 170 mL of a 2M aqueous sodium carbonate solution were added to this flask, and the resultant was refluxed with stirring while heating for 8 hours. After cooling to room temperature, an aqueous phase was removed. An organic phase was washed with water and saturated brine, and then dried with magnesium sulfate. After the magnesium sulfate was filtered out, the organic phase was concentrated. The residue was purified by means of silica gel column chromatography, whereby 25.0 g (yield: 89%) of intended 9-(2-formylphenyl)phenanthrene was obtained.
Reaction SMILES: C([C:3]1[CH:11]=[C:10](/[CH:12]=[CH:13]/[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O)C.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.Cl.[OH:44][CH:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1>CN(C=O)C.O>[OH:44][CH:45]1[CH2:50][CH2:49][N:48]([C:5]([C:4]2[CH:3]=[CH:11][C:10]([CH:12]=[CH:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:9][CH:8]=2)=[O:7])[CH2:47][CH2:46]1
Reactant: OC1CCNCC1
Reactant: CCc1cc(/C=C/c2ccccc2)ccc1C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1ccc(C=Cc2ccccc2)cc1)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (E)-ethyl 4-styrylbenzoic acid (300 mg, 1.3 mmol) and DIPEA (270 uL, 2.1 mmol) in DMF (5 mL) was added EDC (280 mg, 1.5 mmol), HOBt (270 mg, 2.0 mmol) and 4-hydroxypiperidine hydrochloride (258 mg, 1.8 mmol). The reaction was stirred at room temperature for 18 h. The reaction was diluted with water (10 mL) and (4-hydroxypiperidin-1-yl)(4-styrylphenyl)methanone was isolated (390 mg, 98%) as a white solid by vacuum filtration; 1H-nmr (400 MHz, CDCl3) δ 7.58 (d, J=8.0 Hz, 2H), 7.56-7.52 (m, 2H), 7.44-7.34 (m, 5H), 6.95 (d, 1H), 6.89 (d, 1H), 4.21-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.81-3.48 (m, 1H), 3.47-3.16 (m, 2H), 2.08-1.79 (m, 2H), 1.71-1.42 (m, 2H); LCMS (214 nM) 3.32 min (>98%); MS (ESI) m/z=308.1.
Reaction SMILES: [CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12]O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Br)(Br)(Br)[Br:15].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([O:8][CH2:9]/[CH:10]=[CH:11]\[CH2:12][Br:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC/C=C\COCc1ccccc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrC/C=C\COCc1ccccc1
Yield: 102.2 %

Procedure:
To a solution of (Z)-4-benzyloxy-2-buten-1-ol (2.0 g, 11.2 mmol) in methylene chloride (40 ml) were added carbon tetrabromide (4.46 g, 13.4 mmol) and triphenylphosphine (3.51 g, 13.4 mmol) at 0° C. under stirring in a nitrogen gas stream. After stirring at room temperature for 1.5 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (silica gel: 50 g), whereby from hexane/ethyl acetate (4/1) eluate fractions, the title compound (2.76 g, 100%) was obtained as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:13]([C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)=[CH2:14].C(N(CC)CC)C.O>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>[N:18]1[CH:19]=[CH:20][C:15](/[CH:13]=[CH:14]/[C:2]2[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1ccccc1Br
Reactant: C=Cc1ccncc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccccc1/C=C/c1ccncc1
Temperature: 0 °C
Yield: 81.3 %

Procedure:
50 g (0.22 mol) of ethyl 2-bromobenzoate, 30 g (0.29 mol) of 4-vinylpyridine and 75 ml (0.54 mol) of triethylamine were dissolved in 750 ml of dimethylformamide. Then 0.36 g of palladium(II) acetate, 0.96 g of tri(o-tolyl)phosphine and 1 ml of water were added and the mixture was refluxed for 3 h. The reaction mixture was then poured into ice-water and extracted with ethyl acetate. The organic phase was dried and concentrated in vacuo. The residue was recrystallized [lacuna] cyclohexane/petroleum ether, resulting in 45.3 g (83%) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:11][CH:10]=2)=[CH:5][CH:4]=1.IC.I[CH2:30][CH3:31]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[N:15][C:16]=3[NH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]([CH2:30][CH3:31])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: CCI
Reactant: COc1ccc(-c2c[nH]c3ccnc(Nc4ccccc4)c3c2=O)cc1
Solvent: CI
Product: CCn1cc(-c2ccc(OC)cc2)c(=O)c2c(Nc3ccccc3)nccc21

Procedure:
The title compound was prepared as described in Example 2 above except that 3-(4-chlorophenyl)-1,4-dihydro-4-oxo-5-(2-phenethylamino)-1,6-naphthyridine was replaced with 3-(4-methoxyphenyl)-1,4-dihydro-4-oxo-5-phenylamino-1,6-naphthyridine and iodomethane was replaced with iodoethane. MS 372 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([N:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][CH3:21])[CH2:14][CH2:13]2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([N:18]([CH2:19][CH2:20][CH3:21])[CH:15]2[CH2:14][CH2:13][N:12]([C:4]3[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=3)[CH2:17][CH2:16]2)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCCNC1CCN(c2nc(C)c(C(=O)OCC)s2)CC1
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Product: CCCN(C(=O)c1nc(Cl)c(CC)[nH]1)C1CCN(c2nc(C)c(C(=O)OCC)s2)CC1
Yield: 22.3 %

Procedure:
The same operation as in Example (221c) was performed using ethyl 4-methyl-2-[4-(n-propylamino)piperidin-1-yl]-1,3-thiazole-5-carboxylate obtained in Example (241d) (206 mg, 0.66 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained in Example (1d) (115 mg, 0.66 mmol), WSC hydrochloride (380 mg, 1.98 mmol), 1-hydroxybenzotriazole (89 mg, 0.66 mmol) and N-methylmorpholine (0.15 mL, 1.32 mmol), to obtain 69 mg of the title compound as a white solid (22%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[CH:10]=[N:11][C:12](=O)[NH:13][N:14]=2)[CH:4]=1.C(Cl)(Cl)[Cl:19].P(Cl)(Cl)(Cl)=O>CN(C)C=O>[Cl:19][C:12]1[N:13]=[N:14][C:9]([C:5]2[CH:4]=[C:3]([C:2]([F:17])([F:16])[F:1])[CH:8]=[CH:7][CH:6]=2)=[CH:10][N:11]=1
Reactant: ClC(Cl)Cl
Reactant: O=c1ncc(-c2cccc(C(F)(F)F)c2)n[nH]1
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: FC(F)(F)c1cccc(-c2cnc(Cl)nn2)c1

Procedure:
A 37.2 g. portion of 6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazin-3(2H)-one in 250 ml. of chloroform is refluxed overnight and then cooled. A 250 ml. portion of phosphorus oxychloride and 1.7 g. of N,N-dimethylformamide are added and the mixture is refluxed for 4.5 hours and then concentrated to a brown oil. This oil is dissolved in methylene chloride and poured into ice-water. The mixture is filtered through silica gel giving crystals which are recrystallized from hexane, giving 3-chloro-6-(α,α,α-trifluoro-m-tolyl)-1,2,4-triazine as reddish plates.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:6][CH:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1.[F:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[CH:25][C:26]=1[C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][C:26]=1[C:27]1[O:28][C:29]([CH3:32])=[N:30][N:31]=1)[O:1][CH2:2][CH2:3][C@H:4]1[CH2:6][C@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]1
Reactant: Cc1nnc(-c2ccc(O)cc2F)o1
Reactant: CC(C)(C)OC(=O)N1CCC(C2CC2CCO)CC1
Product: Cc1nnc(-c2ccc(OCC[C@H]3C[C@H]3C3CCN(C(=O)OC(C)(C)C)CC3)cc2F)o1

Procedure:
The title compound was synthesized using rac-tert-butyl 4-[2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carboxylate from Example 1 and 3-fluoro-4-(5-methyl-1,3,4-oxadiazol-2-yl)phenol through a Mitsunobu reaction by a procedure analogous to that procedure reported for Example 6, step 3.