Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:36]([N:43]1[C:47](=[O:48])[C:46](=[O:49])[NH:45][C:44]1=[O:50])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C(OC(N=NC(OCC)=O)=O)C>C1COCC1>[CH2:36]([N:43]1[C:47](=[O:48])[C:46](=[O:49])[N:45]([CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:16])[CH:8]=[CH:9][C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)[C:44]1=[O:50])[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: O=C1NC(=O)N(Cc2ccccc2)C1=O
Reactant: O=C(C=Cc1cccnc1)NCCCCO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)C(=O)N(Cc2ccccc2)C1=O

Procedure:
Batch size: 4.4 g (20.0 mmol) N-(4-hydroxybutyl)-3-pyridin-3-yl-acrylamide, 5.2 g (19.8 mmol) triphenylphosphine, 4.1 g (20.1 mmol) 3-benzyl-2,4,5-trioxo-imidazolidine (production according to Ishii et al., J. Med. Chem. 39, 1924 (1996)) and 3.5 g (20.0 mmol) azodicarboxylic acid diethyl ester in 60 ml THF.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[C@@H:11]1([NH:21][CH2:1][C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: N#Cc1ccc(C=O)cc1
Product: N#Cc1ccc(CN[C@H]2CCCc3ccccc32)cc1

Procedure:
4-Formylbenzonitrile and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8]C)[C:3]=1[C:10]1[NH:11][C:12]2[CH:18]=[C:17]([N:19]3[CH2:24][CH2:23][N:22]([C:25](=[O:27])[CH3:26])[CH2:21][CH2:20]3)[CH:16]=[C:15]([CH3:28])[C:13]=2[N:14]=1.O.[ClH:30]>O1CCOCC1>[C:25]([N:22]1[CH2:23][CH2:24][N:19]([C:17]2[CH:16]=[C:15]([CH3:28])[C:13]3[N:14]=[C:10]([C:3]4[C:4](=[O:8])[NH:5][CH:6]=[CH:7][C:2]=4[Cl:30])[NH:11][C:12]=3[CH:18]=2)[CH2:20][CH2:21]1)(=[O:27])[CH3:26]
Reactant: Cl
Reactant: COc1nccc(I)c1-c1nc2c(C)cc(N3CCN(C(C)=O)CC3)cc2[nH]1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1CCN(c2cc(C)c3nc(-c4c(Cl)cc[nH]c4=O)[nH]c3c2)CC1
Temperature: 25 °C
Reaction time: 14 h
Yield: 100 %

Procedure:
To a solution of 1-{4-[2-(4-Iodo-2-methoxy-pyridin-3-yl)-7-methyl-3H-benzimidazol-5-yl]-piperazin-1-yl}-ethanone (5.2 g, 10.6 mmol) in 4 M HCl in dioxane (60 mL) was added water (5 mL). The reaction mixture was stirred at room temperature for 14 h. Concentration of the reaction mixture gave the title compound (4.02 g, 100%) which was used for the next step without purification. LCMS (M+H)+ m/z 486 (t=1.55 min.).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=[C:6]([CH3:19])[CH:5]=1.[CH2:20]([CH:22]1[O:24][CH2:23]1)Cl>CS(C)=O.O>[CH3:19][C:6]1[CH:5]=[C:4]([O:3][CH2:20][CH:22]2[CH2:23][O:24]2)[C:13]2[C:12]3[CH2:14][CH2:15][CH2:16][CH2:17][C:11]=3[C:10](=[O:18])[O:9][C:8]=2[CH:7]=1
Reactant: Cc1cc(O)c2c3c(c(=O)oc2c1)CCCC3
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(OCC2CO2)c2c3c(c(=O)oc2c1)CCCC3
Reaction time: 0.08 h

Procedure:
To a stirred solution of NaOH (4.0 g, 0.1 m) in dimethylsulfoxide (DMSO) (250 ml) and water (250 ml), was added 7,8,9,10-tetrahydro-1-hydroxy-3-methyl-6-oxo-6H-dibenzo[b,d]pyran (20.0 g, 0.87 m) and the mixture stirred for 5 minutes, then treated with epichlorohydrin (50 ml). After 5 hours the mixture was cooled in an ice bath for 30 minutes and the precipitated solid collection by filtration, washed with water and dried to give 7,8,9,10-tetrahydro-3-methyl-1-(oxiranylmethoxy)-6-oxo-6H-dibenzo[b,d]pyran as a white solid, mp. 164°-165° C. An analytical sample recrystallized from methanol melted at 165°-166° C.
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([F:9])[C:5]([NH2:6])=[C:4]([Cl:10])[C:3]=1[F:11].[O:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH:13]1[N:18]1[C:22](B2OC(C)(C)C(C)(C)O2)=[CH:21][CH:20]=[N:19]1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:4]1[C:3]([F:11])=[C:2]([C:22]2[N:18]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17][O:12]3)[N:19]=[CH:20][CH:21]=2)[CH:8]=[C:7]([F:9])[C:5]=1[NH2:6]
Reactant: CC1(C)OB(c2ccnn2C2CCCCO2)OC1(C)C
Reactant: Nc1c(F)cc(Br)c(F)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Nc1c(F)cc(-c2ccnn2C2CCCCO2)c(F)c1Cl
Temperature: 80 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
4-Bromo-2-chloro-3,6-difluoroaniline (12.37 mmol, 3 g) and 1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (12.37 mmol, 3.44 g) were dissolved in DME. Bis(triphenylphosphine)palladium(II) chloride (0.619 mmol, 0.434 g) and sodium carbonate, 2 M solution (12.37 mmol, 1.311 g) were added. The reaction mixture was refluxed at 80° C. for 4 h and the stirring was continued at 50° C. overnight. The solvent was evaporated and the residue was extracted three times with EtOAc. The combined organics were washed with water and brine. The organics were dried, filtered and evaporated. The crude product was purified by flash chromatography. 1.935 g of the title compound was obtained. 1H-NMR (400 MHz, MeOH-d4): δ 1.49-1.79 (m, 2H), 1.80-1.88 (m, 1H), 1.93-2.19 (m, 2H), 2.33-2.47 (m, 1H), 3.47-3.77 (m, 1H), 3.96-4.07 (m, 1H), 5.09-5.43 (m, 1H), 6.30-6.39 (m, 1H), 7.04-7.13 (m, 1H), 7.50-7.63 (m, 1H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11].[CH2:17]([O:19][P:20]([CH2:25][C:26](Cl)=[O:27])(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]>C1(C)C=CC=CC=1>[CH2:22]([O:21][P:20]([CH2:25][C:26](=[O:27])[NH:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[CH:10]=[O:11])(=[O:24])[O:19][CH2:17][CH3:18])[CH3:23]
Reactant: Nc1cc(Cl)ccc1C=O
Reactant: CCOP(=O)(CC(=O)Cl)OCC
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CCOP(=O)(CC(=O)Nc1cc(Cl)ccc1C=O)OCC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Pyridine (3.7 ml, 45.7 mmol) is added to a solution of 2-amino-4-chloro-benzaldehyde (6.18 g, 39.7 mmol) in 170 ml of anhydrous toluene, followed dropwise by a solution of chlorocarbonylmethylphosphonic acid diethyl ester (9.8 g, 45.7 mmol) in 15 ml of anhydrous toluene whilst maintaining the reaction mixture at a temperature of less than 30° C. When the addition is complete, the mixture is stirred for 1 hour at room temperature. The reaction mixture is washed several times with water and then with a 1N HCl solution, and then again with water. Finally the mixture is washed with an aqueous saturated NaCl solution. The organic phase is dried over MgSO4, and filtration is carried out, followed by evaporation to obtain the expected crude product in the form of an orange oil. The crude product is used in the following step.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][OH:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].O[C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:16]1[CH:17]=[N:18][C:19]2[C:24]([CH:25]=1)=[CH:23][CH:22]=[CH:21][CH:20]=2)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7]
Reactant: Oc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1CO
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1cnc2ccccc2c1

Procedure:
A 2.77 g sample of (R)-1-t-butoxycarbonyl-2-pyrrolidinemethanol and 3 g of 3-hydroxyquinoline were reacted with triphenylphosphine and DEAD in 100 mL of THF according to the procedure of Example 14a, to give 2.5 g of the title compound. MS (DCI/NH3) m/e 329 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ: 8.67 (d, J=3 Hz 1H), 8.4 (d, J=7 Hz, 1H), 7.72 (dd, J=7, 1 Hz 1H), 7.56-7.40 (m, 3H), 4.24-3.94 (m, 3 H), 3.42 (bs 2H), 2.11-1.94 (m 3H), 1.92-1.48 (m 1H), (s 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N:3]=1.C(OO)(=[O:12])C.[OH-].[K+]>C(O)(=O)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][CH3:9])[N+:3]=1[O-:12]
Reactant: CC(=O)OO
Reactant: CCc1cccc(Br)n1
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CCc1cccc(Br)[n+]1[O-]
Temperature: 50 °C
Reaction time: 5 h
Yield: 100 %

Procedure:
To a solution of 2-bromo-6-ethyl-pyridine (15.4 g, 82.8 mmol) (S. G. Davies and M. R. Shipton, J. Chem. Soc., Perkin Trans. 1, 1991, 3, 501) in acetic acid (15 ml) was added peracetic acid (26 ml of a 39% solution) maintaining T<50° C. After complete addition the mixture was stirred at 50° C. for 5 hr and then cooled to room temperature (rt). Crushed ice (40 g) was added and the pH was adjusted to pH 12 with 40% aqueous KOH solution. After extraction with CHCl3 (6×60 ml) the combined organic phases were dried (Na2CO3) and evaporated to give 20.0 g (>100%) of the title compound, MS: m/e=201 (M+) as a yellow oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[NH:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH:30](N1C2C=CC=CC=2N=N1)=[O:31]>C1COCC1>[Si:1]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[N:11]1[CH:30]=[O:31])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3)C(=O)O1
Reactant: O=Cn1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3C=O)C(=O)O1
Reaction time: 1 h
Yield: 88.9 %

Procedure:
A stirred mixture of the product from Step 9 (0.39 g, 0.93 mmol) and THF (15 ml), under nitrogen is treated with N-formylbenzotriazole (0.164 g, 1.12 mmol) and kept at ambient temperature for 1 h. It is then concentrated in vacuo. Chromatography of the residue on silica gel with mixtures of acetone-methylene chloride containing 20-40% acetone gave 0.37 g of the titled product: 1H NMR (300 MHz, CDCl3) δ0.00 (m, 6H), 0.73, 0.86 (s, s, 9H), 2.02 (s, 3H), 2.70, 3.23 (m, m, 2H), 3.68 (m, 5H), 4.03 (m, 1H), 4.43, 4.80 (m, m, 1H), 4.75 (m, 1H), 6.14 (m, 1H), 7.08, 7.20, 7.47, 7.61, 8.04 (m, 3H), 8.52, 8.86 (s, s, 1H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[Cl:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[Cl:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(Cl)c4Cl)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cccc(Cl)c3Cl)c2O1

Procedure:
The title compound was prepared (0.051 g, 40%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,3-dichlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.165 g, 0.341 mmol) and methylamine (0.106 g, 3.41 mmol). mp 219-221° C.
Reaction SMILES: F[C:2](F)(F)C(O)=O.[O:8]=[C:9]([N:28]1[CH2:33][CH2:32][C:31]([CH2:34][C:35]2[S:36][CH:37]=[CH:38][N:39]=2)=[CH:30][CH2:29]1)/[CH:10]=[CH:11]/[C:12]1[CH:13]=[C:14]2[C:24](=[N:25][CH:26]=1)[NH:23][C:22](=[O:27])[C:16]1([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH2:15]2.C=O.C(N(CC)CC)C.[BH4-].[Na+]>CO>[CH3:2][N:19]1[CH2:20][CH2:21][C:16]2([CH2:15][C:14]3[C:24](=[N:25][CH:26]=[C:12](/[CH:11]=[CH:10]/[C:9](=[O:8])[N:28]4[CH2:33][CH2:32][C:31]([CH2:34][C:35]5[S:36][CH:37]=[CH:38][N:39]=5)=[CH:30][CH2:29]4)[CH:13]=3)[NH:23][C:22]2=[O:27])[CH2:17][CH2:18]1
Reactant: O=C(/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2)N1CC=C(Cc2nccs2)CC1
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1CCC2(CC1)Cc1cc(/C=C/C(=O)N3CC=C(Cc4nccs4)CC3)cnc1NC2=O
Temperature: 27.5 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a stirred solution of (E)-β-methyl-6-(3-oxo-3-(4-(thiazol-2-ylmethyl)-5,6-dihydropyridin-1(2H)-yl)prop-1-en-1-yl)-1H-spiro[[1,8]naphthyridine-3,4′-piperidin]-2(4H)-one (Compound 34) (200 mg, 0.35 mmol) in methanol (3 mL) was added 37% formaldehyde solution (0.086 mL, 1.07 mmol), followed by triethylamine (0.15 mL, 1.07 mmol) at 20-35° C. and the mixture was continued stirring at 20-35° C. for 30 minutes. Then NaBH4 (20 mg, 0.53 mmol) was added slowly portionwise at 0° C. and the reaction mixture was allowed to stir at 20-35° C. for 16 h. The reaction mixture was rotary evaporated under vacuum to get residue which was purified by preparative HPLC to get the desired compound as an off-white solid (25 mg, 15%); 1H NMR (400 MHz, DMSO-d6) δ 10.66 (s, 1H), 8.34 (s, 1H), 8.15 (s, 1H), 7.71 (d, J=2.9 Hz, 1H), 7.61 (d, J=2.5 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.30-7.14 (m, 1H), 5.68-5.64 (m, 1H), 4.26-4.22 (m, 1H), 4.06-4.02 (m, 1H), 3.80-3.72 (m, 3H), 3.68-3.62 (m, 1H), 2.90 (s, 2H), 2.62-2.54 (m, 2H), 2.28-2.04 (m, 4H), 2.19 (s, 3H), 1.90-1.78 (m, 2H), 1.42-1.28 (m, 2H); LC-MS: 464.3 (M+1)+. Preparative HPLC conditions: Column-Phenomenex Luna C18 (2) (250×21.1 mm, 5μ), Mobile Phase: (A) 0.1% TFA(Aq); (B) ACN; Flow rate: 15 ml/min.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:8]=[C:9]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:10]3[C:16](=[O:18])[CH:17]=2)=[N:3][CH:2]=1.[CH3:19][Si]([N-][Si](C)(C)C)(C)C.[Li+].CI>O1CCCC1>[CH3:19][CH:15]1[CH2:14][CH2:13][CH2:12][CH2:11][N:10]2[C:16](=[O:18])[CH:17]=[C:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][N:3]=3)[N:8]=[C:9]12
Reactant: O=c1cc(-c2ccncn2)nc2n1CCCCC2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC1CCCCn2c1nc(-c1ccncn1)cc2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
To a solution of 26.1 g (107.73 mmol) of 2-pyrimidin-4-yl-7,8,9,10-tetrahydro-6H-pyrimido[1,2-a]azepin-4-one in dry tetrahydrofuran (450 mL) under argon at −78° C. was added 82.5 mL (82.5 mmol) of lithium bis(trimethylsilyl)amide (1M in tetrahydrofuran). The solution was stirred at −78° C. for 10 min and 25.7 mL of methyl iodide (412.7 mmol) was added. The reaction was stirred at −78° C. for 1 h and then at 0° C. for 2 h. The mixture was quenched with the addition of a saturated solution of ammonium chloride and extracted with ethyl acetate. The organic phase was dried over sodium sulfate and concentrated. The residue was chromatographed on silica gel eluting with a mixture of dichloromethane/methanol in the proportions 99/1 to afford 11.0 g (40%) of the desired compound as a white solid.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[F-:7].[Cs+].Cl[C:10]1[C:11]([F:20])=[N:12][CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1>CS(C)=O>[F:20][C:11]1[C:10]([F:7])=[CH:15][C:14]([C:16]([F:19])([F:18])[F:17])=[CH:13][N:12]=1
Reactant: Fc1ncc(C(F)(F)F)cc1Cl
Reactant: [F-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CS(C)=O
Product: Fc1cc(C(F)(F)F)cnc1F
Temperature: 65 °C

Procedure:
A 100 ml 4-neck round bottom flask, containing a magnetic stir bar and fitted with a thermometer, nitrogen inlet and distillation condenser, was charged with 75 ml of DMSO, 0.5 g of anhydrous K2CO3 and 22.8 g (0.15 mole) of CsF. The reaction mixture was heated to 115° C. at 57 mm Hg so that about 20 ml of DMSO was distilled to dry the reaction mixture. The light yellow reaction mixture was cooled to 65° C. and 20 g (0.1 mole) of 3-chloro-2-fluoro-5-(trifluoromethyl)pyridine was added through a pressure equalizing addition funnel which replaced the distillation condenser. After a dry ice condenser was attached to the flask the reaction temperature was maintained at 105°-115° C. for 46.5 hours with constant agitation. The reaction mixture was black with dark solids on the sides of the flask. A short path distillation condenser was attached to the flask and 13 g of crude product was collected in a receiver, which was cooled in a dry ice/acetone bath (pressure=210 mm Hg; temperature (overhead)=85°-130° C.; temperature (pot)=125°-160° C.). This crude product was extracted with water to remove any residual DMSO and dried over 4 Å molecular sieves (11.5 g crude product; 11 g crude product after drying). The product was then transferred to a 25 ml round bottom flask and distilled at 102° C. (uncorrected)/760 mm Hg through a Vigreaux® column resulting in 9.3 g of substantially pure 2,3-di-fluoro-5-(trifluoromethyl)pyridine. The isolated yield of desired product was calculated to be 48.4% of theoretical. The structure of the product was confirmed by its nuclear magnetic resonance (NMR) spectra. Elemental analysis results for the product were: Theoretical: C, 39.36; H, 1.09; N, 7.65; Cl, 0. Found: C, 38.44; H, 1.01; N, 7.79; Cl, 0.25.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1I)[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[K+].[K+].CC1(C)COB([C:26]2[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=2)OC1>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:26]1[N:30]([CH3:31])[N:29]=[CH:28][CH:27]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(I)c(Br)c1
Reactant: Cn1nccc1B1OCC(C)(C)CO1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)c1ccc(-c2ccnn2C)c(Br)c1
Temperature: 80 °C

Procedure:
To a solution of methyl 3-bromo-4-iodobenzoate (409 mg, 1.2 mmol) in dioxane/H2O (4:1, 10 mL) was added K2CO3 (497 mg, 3.6 mmol), tetrakistriphenylphosphine Pd(0) (69 mg, 0.06 mmol) and 5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1-methyl-1H-pyrazole (349 mg, 3.6 mmol). The reaction mixture was heated to 80° C. in a sealed tube for 12 h and was then partitioned between 6N NaOH and DCM. The pH of the aqueous phase was adjusted to ˜3 with 3M HCl and washed several times with DCM. The combined organic fractions were dried (Na2SO4), concentrated under vacuum and used directly without further purification (307 mg, 87%): LC-MS (ES) m/z=296 (M+H)+.
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[N:17]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:18](=[O:26])[CH2:19][C:20]1[O:24][N:23]=[C:22]([CH3:25])[CH:21]=1)C1C=CC=CC=1.[H-].[Na+].CCOC(C)=O>CN(C=O)C>[CH2:27]([N:17]1[C:11]2[C:10](=[CH:15][C:14]([Cl:16])=[CH:13][CH:12]=2)[C:9]([OH:8])=[C:19]([C:20]2[O:24][N:23]=[C:22]([CH3:25])[CH:21]=2)[C:18]1=[O:26])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Cc1cc(CC(=O)N(Cc2ccccc2)c2ccc(Cl)cc2C(=O)OCc2ccccc2)on1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1cc(-c2c(O)c3cc(Cl)ccc3n(Cc3ccccc3)c2=O)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 2-{benzyl-[2-(3-methyl-isoxazol-5-yl)-acetyl]-amino}-5-chloro-benzoic acid benzyl ester (3.30 g, 7.58 mmol) in 25 ml of DMF at 0° C. was added NaH (340 mg). The mixture was stirred at rt for 1 h under Ar. Treated with 200 ml of EtOAc, the mixture was extracted with H2O (4×50 ml). The combined aqueous layers were neutralized to pH=6 with 1N HCl and extracted with EtOAc (4×50 ml). The combined org. layers were washed with H2O (2×50 ml), brine (50 ml) and dried (Na2SO4). Removal of the solvent under reduced pressure gave. 2.35 g (92%) of product as a white solid: 1H-NMR (CD3OD, 400 MHz) δ 9.49 (s, 1H), 8.21 (d, 1H, J=2.6 Hz), 7.48 (dd, 1H, J=9.0, 2.6 Hz), 7.17-7.36 (m, 7H), 5.60 (s, 2H), 2.43 (s, 3H), 2.54 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C20H15ClN203, 367.1 (M+H), found 367.0.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br.Br[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC#N>[CH3:1][C:2]1[C:3]([C@H:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]2[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCc1ccccn1
Reactant: Cc1cccnc1[C@@H]1CCC[C@H](c2ncccc2C)N1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: Cc1cccnc1[C@H]1CCC[C@@H](c2ncccc2C)N1Cc1ccccn1
Reaction time: 15.5 h
Yield: 57 %

Procedure:
A solution of (2′R,6′S)-3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (166 mg, 0.621 mmol), 2-(bromomethyl)pyridine hyrdobromide (189 mg, 0.745 mmol), DIPEA (265 μL, 1.52 mmol) and KI (10 mg, 0.060 mmol) in CH3CN (6 mL) was warmed to 50° C. and stirred for 15.5 h according to General Procedure A. Purification by flash chromatography on silica gel using CH2Cl2/MeOH/NH4OH (94:5:1) afforded COMPOUND 73 (127 mg, 57%) as an orange solid. 1H NMR (CDCl3) δ 1.75-1.85 (m, 3H), 1.93-2.02 (m, 1H), 2.09-2.21 (m, 2H), 2.42 (s, 6H), 3.80 (bs, 2H), 6.81-6.85 (m, 2H), 6.96 (dd, 2H, J=7.7, 3.9 Hz), 7.23-7.30 (m, 3H), 8.18 (d, 1H, J=4.8 Hz), 8.40 (d, 2H, J=4.4 Hz); ES-MS m/z 359 (M+H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH2:15])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([C:30]3[O:31][C:32]([C:35]([F:38])([F:37])[F:36])=[N:33][N:34]=3)[CH:28]=2)[N:23]=[CH:22][N:21]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([NH:15][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([C:30]5[O:31][C:32]([C:35]([F:38])([F:36])[F:37])=[N:33][N:34]=5)[CH:28]=4)[N:23]=[CH:22][N:21]=3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: FC(F)(F)c1nnc(-c2ccc3ncnc(Cl)c3c2)o1
Reactant: Nc1ccc2c(cnn2Cc2cccc(F)c2)c1
Product: Fc1cccc(Cn2ncc3cc(Nc4ncnc5ccc(-c6nnc(C(F)(F)F)o6)cc45)ccc32)c1

Procedure:
The title compound was prepared according to Procedure A from 1-(3-fluoro-benzyl)-1H-indazol-5-ylamine and 4-chloro-6-(5-trifluoromethyl-1,3,4-oxadiazol-2-yl)-quinazoline; δH [2H6]DMSO 11.84(1H,bs), 9.54(1H,s), 8.89(1H,s), 8.77(1H,dd), 8.25(1H,s), 8.11(2H,m), 7.87(1H,d), 7.69(1H,dd), 7.39(1H,m), 7.10 (3H,m), 5.73(2H,s); m/z (M+1+) 506.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:18]3[C:19]4[C:11]([CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+].[N+](C1C=CC=CC=1)([O-])=O>[Cu].C1(C)C=CC=CC=1>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([N:7]([C:8]2[C:18]3[C:19]4[C:11]([CH2:12][CH2:13][C:14]=4[CH:15]=[CH:16][CH:17]=3)=[CH:10][CH:9]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(Nc2ccc3c4c(cccc24)CC3)cc1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: Cc1ccc(N(c2ccccc2)c2ccc3c4c(cccc24)CC3)cc1
Yield: 83.8 %

Procedure:
4.66 g (0.018 mol) of the above prepared 5-[N-(4-tolyl)amino]acenaphthene was mixed with 4.99 g (0.022 mol) of iodo benzene, 0.13 g (0.002 mol) of copper powder, 2.76 g (0.02 mol) of anhydrous potassium carbonate and 5 ml of nitrobenzene, and the resultant mixture was stirred at 200° C. for 25 hours. The reaction was determined to be finished when disappearance of 5-[N-(4-tolyl)amino]acenaphthene was identified. 100 ml of toluene was added thereto to dissolve the reaction product, and the mixture was filtrated and concentrated. The concentrated material thus obtained was purified by column chromatography (carrier: silica gel, eluent: toluene/hexane=1/4) to obtain 5.06 g (yield: 83.8%, melting point: 147.0°-148.0° C.) of 5-[N-(4-tolyl)-N-phenylamino]acenaphthene.