Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH3:12]>C(O)(C)C>[NH2:12][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: N
Solvent: CC(C)O
Product: Nc1nc(Cl)ccc1[N+](=O)[O-]
Reaction time: 24 h

Procedure:
There were led into a solution of 21.3kg of 2,6-dichloro-3-nitropyridine (90%, water wet) in 100 liters of isopropanol with stirring at 20°-30° C. 6.8 kg (400 moles) of ammonia gas (there can also be dropped in liquid ammonia). Then stirring was carried out for 24 hours at room temperature. The 2-amino-3-nitro-6-chloro-pyridine formed was further reacted in suspension after the testing for unreacted 2,6-dichloro-3-nitro-pyridine by means of thin layer chromatography or gas chromatography is negative.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].CN(C)C=O.Br[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=1>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[CH:42]=[CH:41][C:40]([CH3:43])=[CH:39][CH:38]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1ccc(CBr)cc1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2ccc(C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 61.2 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), sodium hydride (0.17 g) and N,N-dimethylformamide (15 mL) was stirred at room temperature for 10 min, 1-(bromomethyl)-4-methylbenzene (0.62 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogen sulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.79 g, 61%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]=[C:15]2[CH:23]([F:25])[F:24])[N:3]=1.[OH:26][CH2:27][CH2:28][CH2:29][NH:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>CN(C=O)C.CCN(C(C)C)C(C)C>[F:24][CH:23]([F:25])[C:15]1[N:14]([C:4]2[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][O:11][CH2:10][CH2:9]3)[N:7]=[C:2]([N:30]([CH2:29][CH2:28][CH2:27][OH:26])[CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:42])[CH3:43])=[O:38])[CH2:33][CH2:32]3)[N:3]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N:16]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NCCCO)CC1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(N(CCCO)c2nc(N3CCOCC3)nc(-n3c(C(F)F)nc4ccccc43)n2)CC1
Yield: 83 %

Procedure:
Reaction of 1-[4-chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (WO 2006/095906) with tert-butyl 4-[(3-hydroxypropyl)amino]-1-piperidinecarboxylate in DMF and DIPEA as in Example 21 gave tert-butyl 4-[[4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)amino]-1-piperidinecarboxylate in 83% yield: mp (CH2Cl2/hexanes) 188-190° C.; 1H NMR (DMSO-d6) (rotamers) δ 8.45 and 8.35 (2d, J=7.9, 8.3 Hz, 1H), 7.83 and 7.75 (2t, JHF=52.9 Hz, 1H), 7.85 (2d, J=8.0 Hz, 1H), 7.54-7.41 (m, 2H), 4.72-4.65 and 4.56-4.51 (2m, 1H), 4.58 and 4.48 (2t, J=4.8, 5.0 Hz, 1H), 4.15-4.07 (m, 2H), 3.83-3.78 (m, 4H), 3.70 (m, 4H), 3.62-3.47 (m, 4H), 2.81 (m, 2H), 1.78-1.65 (m, 6H), 1.42 (s, 9H); Anal Calcd. for C28H38F2N8O4: C, 57.1; H, 6.5; N, 19.0. Found: C, 57.4; H, 6.3; N, 19.1%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][CH2:12][C:13](=O)[CH3:14])[C:6]=1[F:16])[CH3:2].Cl.[Cl:19][C:20]1[CH:21]=[C:22]([NH:26]N)[CH:23]=[CH:24][CH:25]=1>>[CH2:1]([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:23]3[C:22](=[CH:21][C:20]([Cl:19])=[CH:25][CH:24]=3)[NH:26][C:13]=2[CH3:14])[C:6]=1[F:16])[CH3:2]
Reactant: CCOC(=O)c1cccc(SCC(C)=O)c1F
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1F

Procedure:
Prepared according to the procedure described in Example 2, Step 1, using the following starting materials: 2-fluoro-3-(2-oxo-propylsulfanyl)-benzoic acid ethyl ester and 3-chlorophenylhydrazine hydrochloride.
Reaction SMILES: [CH2:1]([Zn]CC)C.C1(C)C=CC=CC=1.ClCI.[CH3:16]/[C:17](=[CH:20]\[CH:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH3:22])/[CH2:18][OH:19].S(=O)(=O)(O)O>>[CH3:16][C@@:17]1([CH2:18][OH:19])[CH2:1][C@H:20]1[C@H:21]([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH3:22]
Reactant: CC[Zn]CC
Reactant: C/C(=C\C(C)c1ccccc1)CO
Agent: ClCI
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: C[C@@H](c1ccccc1)[C@@H]1C[C@@]1(C)CO
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 42 %

Procedure:
Under a nitrogen atmosphere, a diethylzinc solution in toluene (concentration: 15% by weight, 37.9 g, 46.0 mmol) was placed into a 200-ml flask equipped with a stirring apparatus, a dropping funnel, and a thermometer, and cooled to −20° C. Chloroiodomethane (16.22 g, 92.0 mmol) was placed into the dropping funnel, and added dropwise with the temperature kept between −15 to −20° C. After completion of the dropwise addition, the mixture was stirred at −10 to −15° C. for 30 minutes, and then cooled to −25° C. (E)-2-Methyl-4-phenylpent-2-ene-1-ol (4.11 g, 23.3 mmol) was added dropwise over a period of 60 minutes in the range from −20 to −25° C. After completion of the dropwise addition, the stirring was continued at −15 to −25° C. for 60 minutes. Next, a 20% aqueous sulfuric acid solution (17.0 ml) was added. After stirring for 10 minutes, the aqueous layer was separated. The organic layer was washed twice with water (20 ml), and the solvent was recovered under reduced pressure to obtain a condensed residue. This residue was purified by silica gel column chromatography (hexane:ethyl acetate=8:2). [(1R*,2S*)-1-Methyl-2-((R*)-1-phenylethyl)cyclopropyl]methanol (1.85 g, 9.74 mmol, 42% yield) was obtained as the main isomer, and [(1R*,2S*)-1-methyl-2-((S*)-1-phenylethyl)cyclopropyl]methanol (0.55 g, 2.9 mmol, 12% yield) was obtained as a minor isomer. The relative configurations of the main isomer and the minor isomer were determined by NOESY measurement.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C:8]([C:9](=[O:23])[N:10]([CH:20]2[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])=[CH:26][CH:25]=2)[CH2:6][CH2:5][N:4]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O.C(Cl)Cl>>[NH2:1][CH2:2][C@@H:3]1[C:8]([C:9]([N:10]([CH:20]2[CH2:22][CH2:21]2)[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])=[O:23])=[C:7]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][O:33][C:34]3[C:39]([Cl:40])=[CH:38][CH:37]=[CH:36][C:35]=3[Cl:41])=[CH:26][CH:25]=2)[CH2:6][CH2:5][NH:4]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C(C(=O)N(Cc2cccc(Cl)c2Cl)C2CC2)[C@H]1CN
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H]1NCCC(c2ccc(OCCOc3c(Cl)cccc3Cl)cc2)=C1C(=O)N(Cc1cccc(Cl)c1Cl)C1CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25 %

Procedure:
Into a 10 mL round bottom flask was added 19D (50 mg, 79 μmol) and 25% TFA/DCM (5 mL). The mixture was stirred at room temperature for 3 hours. Solvent was removed under vacuum and the residue was purified by preparatory LCMS to yield Compound 14 (25-80%). 1H NMR (400 MHz, DMSO-d6) δ ppm 0.23-0.91 (m, 4H) 2.33 (m, 2H) 2.99 (br. s., 1H) 3.30-3.59 (m, 4H) 4.07-4.68 (m, 7H) 6.85-7.07 (m, 2H) 7.14-7.31 (m, 4H) 7.40-7.59 (m, 4H). ESI-MS:m/z 636.2 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[CH3:30][O:31][C:32]1[N:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>CCCCCC.C(OCC)(=O)C>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:6]3[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:3]([CH3:29])=[C:2]([C:35]4[CH:36]=[N:37][C:32]([O:31][CH3:30])=[CH:33][CH:34]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(-c2c(C)c(NC(=O)CC(C)(C)C)c(C)c3c2OCC3c2ccc(C(C)C)cc2)cn1
Yield: 48 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and (6-methoxypyridin-3-yl)boronic acid, the title compound was synthesized in the same manner as in Example 101. Yield: 48%. Melting point: 120-123° C. (hexane-ethyl acetate).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:6][CH3:7])[CH2:4][NH2:5].C(O)[CH2:9][CH2:10][CH2:11][CH3:12]>>[CH2:1]([O:2][CH:3]([O:6][CH2:7][CH2:12][CH2:11][CH2:10][CH3:9])[CH2:4][NH2:5])[CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: COC(CN)OC
Reactant: CCCCCO
Product: CCCCCOC(CN)OCCCCC

Procedure:
Aminoacetaldehyde di-n-pentyl acetal was prepared by transacetalization of aminoacetaldehyde dimethyl acetal with pentanol following the general procedure of Juret and Chin in J. Am. Chem. Soc. 83, 1560 (1961).
Reaction SMILES: Cl[C:2]1[N:6]([C@H:7]2[O:15][CH2:14][C@@H:12]([OH:13])[C@H:10]([OH:11])[C@@H:8]2[OH:9])[C:5]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=2[N:3]=1.[CH:22]1([NH2:29])[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C>[CH:22]1([NH:29][C:2]2[N:6]([C@H:7]3[O:15][CH2:14][C@@H:12]([OH:13])[C@H:10]([OH:11])[C@@H:8]3[OH:9])[C:5]3[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:4]=3[N:3]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: NC1CCCCCC1
Reactant: O[C@@H]1[C@H](O)[C@@H](n2c(Cl)nc3cc(Cl)c(Cl)cc32)OC[C@H]1O
Solvent: CCO
Product: O[C@@H]1[C@H](O)[C@@H](n2c(NC3CCCCCC3)nc3cc(Cl)c(Cl)cc32)OC[C@H]1O
Reaction time: 48 h

Procedure:
Compound 4 (200 mg, 0.57 mmol) was dissolved in ethanol (4 mL). Cycloheptylamine (3.9 mL, 28 mmol) was added, the flask was sealed and the reaction mixture stirred at 60 ûC. for 2 days. The mixture was decanted and evaporated to dryness at 65 ûC. under high vacuum. The residue was dissolved in ethyl acetate (20 mL), and crystals of cycloheptylammonium chloride were removed by filtration. The organic extract was dried over sodium sulfate, filtered and the filtrate was evaporated under reduced pressure. The residue was subjected to silica gel chromatography [2×15 cm, eluent:gradient of methanol (0-6%) in dichloromethane]. Fractions that contained the major spot [Rf (system 3): 0.30] were evaporated and the resulting solid was suspended in boiling dichloromethane. Methanol was added until complete dissolution of the solid. Compound 7 crystallized from this solution (150 mg, 61%).
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([O:20]C)=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[N:12]=1.[OH-].[Na+]>CO>[CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]1[C:11]1[C:16]([CH:17]([CH2:22][CH2:23][CH3:24])[C:18]([OH:20])=[O:19])=[C:15]([CH3:25])[N:14]=[C:13]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[N:12]=1
Reactant: CCCC(C(=O)OC)c1c(C)nc(-c2ccccc2)nc1N1CCc2ccccc2C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(-c2ccccc2)nc1N1CCc2ccccc2C1
Yield: 68.6 %

Procedure:
This compound was prepared according to general method D from methyl 2-(4-(3,4-dihydroisoquinolin-2(1H)-yl)-6-methyl-2-phenylpyrimidin-5-yl)pentanoate (0.110 g; 0.265 mmol), sodium hydroxide 10N (0.265 mL; 2.65 mmol) in methanol (2.6 mL) to afford 0.073 g (69%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15]([C:17]([OH:19])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:21][NH:22][O:23][CH3:24].C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.CCN=C=NCCCN(C)C>C(Cl)Cl>[CH3:24][O:23][N:22]([CH3:21])[C:17]([C:15]1[S:14][C:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C:10]=2[CH:16]=1)=[O:19]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCc2sc(C(=O)O)cc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)c1cc2c(s1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
5-(tert-Butoxycarbonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (968 mg, 3.42 mmol) and N,O-dimethylhydroxylamine hydrochloride (333 mg, 3.42 mmol) were dissolved in MC (50 ml) and the solution was cooled to 0° C. HOAt (46.5 mg, 0.34 mmol), diisopropylethylamine (0.66 ml, 3.76 mmol) and EDCI (720 mg, 3.76 mmol) were added to this mixture and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride (50 ml) and washed with 0.5 M KHSO4 solution (100 ml), NaHCO3 solution and NaCl solution. The combined organic phases were dried with Na2SO4, filtered and concentrated in vacuo. The product obtained in this way (1.13 g) was employed in the next stage without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:14]=[C:15]([OH:23])[C:16]3[CH:17]=[CH:18][CH:19]=[N:20][C:21]=3[CH:22]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].CO.[C:26]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C=CC(COC(/N=N/C(OCC2C=CC=CC=2)=O)=O)=CC=1>C(Cl)Cl>[CH3:26][O:23][C:15]1[CH:14]=[C:13]([C:5]2[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:22]=[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]=[N:20]2
Reactant: COc1cc(-c2cc(O)c3cccnc3c2)cc(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: O=C(/N=N/C(=O)OCc1ccccc1)OCc1ccccc1
Solvent: ClCCl
Solvent: CO
Product: COc1cc(-c2cc(OC)c3cccnc3c2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 72 h
Yield: 11.5 %

Procedure:
100 mg of 7-(3,4,5-Trimethoxyphenyl)quinolin-5-ol, 42 μL of MeOH and 480 mg of triphenylphosphine was dissolved in 5 mL of DCM. 435 mg of DBAD was added and the mixture stirred for 3 days at room temperature. The mixture was diluted with DCM and extracted with 1N NaOH and water. The organic phase was concentrated in vacuo and purified with HPLC (XbridgeC18, MeOH/water, TFA) to yield after lyophilisation 12 mg of Example 3 as solid.
Reaction SMILES: Br[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>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.O>[Cl:13][C:14]1[CH:19]=[C:18]([CH:17]=[CH:16][CH:15]=1)[C:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH:3]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=c1c(Br)coc2ccccc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(-c2cccc(Cl)c2)coc2ccccc12
Yield: 50.1 %

Procedure:
Prepared according to general procedure using 3-bromochromone (338 mg, 1.5 mmol), 3-chlorophenylboronic acid (256 mg, 1.65 mmol), K2CO3 (622 mg, 4.5 mmol), PdCl2(PPh3)2 (45 mg, 0.045 mmol), THF (3 mL) and water (1.5 mL). Purified by flash column chromatography (SiO2, 10% EtOAc/Hex) to afford 38 (193 mg, 50%) as a white solid. Analytical data for isoflavone 38: 1H NMR (500 MHz, CDCl3) δ 8.33 (d, J=9.5 Hz, 1H), 8.06 (s, 1H), 7.73 (app t, J=8.5 Hz, 1H), 7.60 (s, 1H), 7.59-7.45 (m, 3H), 7.39 (d, J=7 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 176.1, 156.4, 153.6, 134.6, 134.1, 133.9, 130.0, 129.2, 128.6, 127.4, 126.7, 125.7, 124.7, 124.5, 118.4; LCMS: Mass calculated for C15H9ClO2, [M+H]+, 257. Found 257.
Reaction SMILES: Br[C:2]1[C:3](=[O:19])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[F:46][C:47]1[CH:48]=[C:49](B(O)O)[CH:50]=[CH:51][C:52]=1[CH3:53]>>[F:46][C:47]1[CH:48]=[C:49]([C:2]2[C:3](=[O:19])[C:4]3[C:9]([C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][C:7]([O:17][CH3:18])=[CH:6][CH:5]=3)[CH:50]=[CH:51][C:52]=1[CH3:53]
Reactant: COc1ccc2c(c1)C(c1ccccc1)=C(Br)C2=O
Reactant: Cc1ccc(B(O)O)cc1F
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc2c(c1)C(c1ccccc1)=C(c1ccc(C)c(F)c1)C2=O
Reaction time: 0.17 h
Yield: 65 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-5-methoxy-3-phenyl-1H-inden-1-one obtained in Step 4 of Example 129 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 3-fluoro-4-methylphenylboronic acid instead of 3-pyridinylboronic acid, and being stirred for 10 min to obtain the title compound (65%).
Reaction SMILES: [CH2:1]([O:19][C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[S:31][C:32]1[S:33][C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[N:36]=1>>[CH2:1]([O:19][C:20]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:36]2[C:35]3[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=3[S:33][C:32]2=[S:31])=[CH:24][CH:23]=1)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CSc1nc2ccccc2s1
Reactant: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(CBr)cc1
Product: CCCCCCCCCCCCCCCCCCOC(=O)c1ccc(Cn2c(=S)sc3ccccc32)cc1

Procedure:
4-Octadecyloxycarbonylbenzyl bromide (4.7 g, Step 2) and 2-methylmercaptobenzothiazole (2.5 g) were heated together for 35 minutes/190°-195° C. The mixture was cooled and triturated with ligroin to produce a solid which was recrystallized from pyridine/methanol to form the product; yield 4.5 g (81%), m.p. 105°-107° C.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl>[O:3]=[CH:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7]1
Reactant: CCOC(=O)CC1CCN(C(=O)OC(C)(C)C)C1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(CC=O)C1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A flask was charged with tert-butyl 3-(2-ethoxy-2-oxoethyl)pyrrolidine-1-carboxylate (160 g, 623 mmol) and dichloromethane (2,500 ml) and cooled to −78° C. A solution of diisobutylaluminum hydride (800 ml, 1.10 equiv) was added dropwise, such that the internal temperature was maintained at −78° C. After 1 h at 78° C., the reaction mixture was quenched by the addition of 30 ml of methanol. After warming to ambient temperature, the mixture was filtered and the filter cake was washed with dichloromethane (3×1,000 mL). The filtrate was dried over sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford tert-butyl 3-(2-oxoethyl)pyrrolidine-1-carboxylate as light yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([OH:32])([C:28]([F:31])([F:30])[F:29])[CH2:25][CH:26]=[CH2:27])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[O:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1>CCOC(C)=O.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][N:19]4[CH:23]=[C:22]([C:24]([OH:32])([C:28]([F:30])([F:31])[F:29])[CH2:25][CH2:26][CH3:27])[N:21]=[N:20]4)=[CH:15][CH:16]=3)[O:11][C:10](=[O:33])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C=CCC(O)(c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1)C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCC(O)(c1cn(Cc2ccc3c(-c4cccc(F)c4)cc(=O)oc3c2)nn1)C(F)(F)F
Yield: 88.8 %

Procedure:
A solution of 4-(3-fluorophenyl)-7-({4-[1-hydroxy-1-(trifluoromethyl)but-3-en-1-yl]-1H-1,2,3-triazol-1-yl}methyl)-2H-chromen-2-one from Step 5 (56 mg, 0.122 mmol) in EtOAc (2 mL) was stirred under H2 (1 atm), in the presence of 10% Pd/C (12 mg), for 17 h. After H2 was evacuated and the system purged with nitrogen, the reaction mixture was filtered through celite. The cake was rinsed with EtOAc and the filtrate concentrated. The residue was subjected to chromatography on silica gel (EtOAc/toluene 25:75) affording the title compound (50 mg). MS (−ESI): 460 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][C:23]=1[Cl:24])[C:5]([N:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH3:8])=[O:6].[F-].[K+].[Cl:27][C:28]1[CH:33]=[C:32]([Cl:34])[C:31](B(O)O)=[CH:30][N:29]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[Cl:24][C:23]1[CH:22]=[CH:21][C:4]([C:5]([N:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH3:8])=[O:6])=[CH:3][C:2]=1[C:31]1[CH:30]=[N:29][C:28]([Cl:27])=[CH:33][C:32]=1[Cl:34]
Reactant: CN(C)CCOc1ccccc1N(C)C(=O)c1ccc(Cl)c(Br)c1
Reactant: OB(O)c1cnc(Cl)cc1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [F-]
Solvent: C1COCCO1
Product: CN(C)CCOc1ccccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(Cl)cc2Cl)c1
Temperature: 110 °C

Procedure:
A mixture of dioxane (1.0 mL) containing 3-bromo-4-chloro-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl-benzamide (44.0 mg, 0.11 mmol), Pd2(dba)3 (10 mg, 0.01 mmol), P(t-Bu)3HBF4 (7 mg, 0.022 mmol), KF (22 mg, 0.38 mmol) and 2,4 dichloropyridine-5-boronic acid (21 mg, 0.11 mmol) was degassed by bubbling N2 for 5 minutes and then sealed and heated at 110° C. overnight. The mixture was filtered and purified by preparative LCMS to yield 4-chloro-3-(4,6-dichloro-pyridin-3-yl)-N-[2-(2-dimethylamino-ethoxy)-phenyl]-N-methyl benzamide 7-1. MS [M+H]+: 478.0; tR=5.26 min. (method 2)
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH:15]=[CH2:16])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH:31]=[O:32].C(N(CC)CC)C>C(O)C.[Cl-].C([N+]1C(C)=C(CCO)SC=1)C1C=CC=CC=1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([CH2:18][CH:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[C:14](=[O:17])[CH2:15][CH2:16][C:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=3)=[O:32])=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: C=CC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: O=Cc1ccccn1
Agent: Cc1c(CCO)sc[n+]1Cc1ccccc1
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(CCC(=O)C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1)c1ccccn1
Temperature: 25 °C
Yield: 56 %

Procedure:
To a solution of 4-[4-(cyclopropylsulfonyl)phenyl]-5-(tetrahydro-2H-pyran-4-yl)pent-1-en-3-one (300 mg) in ethanol (5 mL) were added pyridine-2-carbaldehyde (100 μL), 3-benzyl-5-(2-hydroxyethyl)-4-methyl-1,3-thiazol-3-ium chloride (25 mg) and triethylamine (52 μL), and the mixture was stirred with heating under reflux for 2 hr. After cooling to room temperature, the reaction mixture was diluted with ethyl acetate and washed with water. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (220 mg, yield 56%) was obtained as a brown oil from a fraction eluted with ethyl acetate-hexane (4:1, volume ratio). MS: 456 (MH+).