Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:8][CH2:9][C:10](O)=[O:11])(OC(C)(C)C)=O.CN(C=O)C.Cl.[NH2:19][CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:46])=[C:25]([N:27]2[C:32]([CH3:33])=[CH:31][C:30]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=3[F:43])=[C:29]([Cl:44])[C:28]2=[O:45])[CH:26]=1.Cl>CO>[ClH:44].[Cl:44][C:29]1[C:28](=[O:45])[N:27]([C:25]2[CH:26]=[C:21]([CH:22]=[CH:23][C:24]=2[F:46])[CH2:20][NH:19][C:10](=[O:11])[CH2:9][NH2:8])[C:32]([CH3:33])=[CH:31][C:30]=1[O:34][CH2:35][C:36]1[CH:41]=[CH:40][C:39]([F:42])=[CH:38][C:37]=1[F:43]
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CN)ccc1F
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(CNC(=O)CN)ccc1F
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 130.1 %

Procedure:
A 25 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with boc-glycine (105 mg, 0.6 mmol) and 8 mL of DMF. The mixture was cooled to 0° C. and isboutylchloroformate (77.5 μL, 0.6 mmol) was added and stirred for 20 min. 1-[5-(aminomethyl)-2-fluorophenyl]-3-chloro-4-[(2,4 difluorobenzyl)oxy]-6-methylpyridin-2(1H)-one hydrochloride (250 mg, 0.6 mmol) was added and stirred for 3 h. After completion of the reaction by LC-MS, concentrated HCl (2 mL) and 2 mL of methanol was added to remove the boc group. The reaction was stirred for 24 h, neutralized with 2M NaOH and extracted with ethyl acetate. The organic phase was dried with Na2SO4 and concentrated in vacuo to obtain (196 mg, 66%) of the desired product as a the HCl salt. 1H NMR (400 MHz, (CD3OD) δ 7.6 (q, J=8 and 6.5 Hz, 1H), 7.5 (m, 1H), 7.3 (m, 2H), 7.0 (m, 2H), 6.63 (s, 1H), 5.35 (s, 2H), 4.4 (q, J=15 and 13.6 Hz, 2H), 3.7 (s, 2H), 2.05 (s, 3H) ppm. ES-HRMS m/z 466.1157 (M+H calcd for C22H20ClF3N3O3 requires 466.1140).
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH2:7]([OH:17])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(=O)C.[Na+]>C(OCC)(=O)C.CCCCCC>[OH:6][CH2:1][CH2:2][CH2:3][C:4]([O:17][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[O:5]
Reactant: CCCCCCCCCCO
Reactant: O=C1CCCO1
Agent: CC(=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCCCCCCCOC(=O)CCCO
Temperature: 150 °C
Yield: 17.7 %

Procedure:
To a mixture of 10 ml of gamma-butyrolactone and 40 ml of 1-decanol was added a crystal of p-toluenesulfonic acid. The reaction mixture was heated at 150° C. for 72 hours with stirring, cooled to room temperature, and then treated with 10 mg of sodium acetate. Flash chromatography (silica; 4:1 hexane:ethyl acetate eluent) afforded 5.6 g (17.7%) of 4-hydroxybutanoic acid, n-decyl ester as an oil.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4].[NH2:26][CH2:27][C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>CCO>[CH2:32]([O:31][C:29](=[O:30])[C:28]([CH3:35])([CH3:34])[CH2:27][NH:26][C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)[CH:9]=2)=[O:4])[CH3:33]
Reactant: CCOC(=O)C(C)(C)CN
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O
Solvent: CCO
Product: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc(Cl)cc3)ccc2c1O

Procedure:
7-(4-Chloro-phenoxy)-1-cyano-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester (21 mg, 0.06 mmol) and ethyl 3-amino-2,2-dimethylpropanoate (34 mg, 0.24 mmol) in EtOH (3 mL) were heated at 150° C. in a microwave for 1.5 hours. The solvent was removed in vacuo and the residue oil was purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 20 mg. 1H NMR (CDCl3, 200 MHz): δ=8.41 (d, 1H, J=9.0 Hz), 8.32 (t, 1H, J=6.6 Hz), 7.60-7.39 (m, 4H), 7.12-7.06 (m, 2H), 4.24 (q, 2H, J=7.0 Hz), 3.61 (d, 2H, J=6.6 Hz), 1.37 (t, 3H, J=7.0 Hz), 1.30 (s, 6H).
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][CH:5]([CH2:11][C:12]#[N:13])[CH2:6][C:7](OC)=[O:8].[H-].[H-].[H-].[H-].[Li+].[Al+3].O>C1COCC1>[OH:2][CH2:3][CH2:4][CH:5]([CH2:6][CH2:7][OH:8])[CH2:11][C:12]#[N:13]
Reactant: COC(=O)CC(CC#N)CC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CCC(CCO)CCO
Reaction time: 0.5 h
Yield: 86 %

Procedure:
Under nitrogen atmosphere, 3-cyanomethyl-pentanedioic acid dimethyl ester (212 g) was added to a suspension of LiAlH4 (50.0 g) in THF (1.8 L) at −20° C. After stirring for 30 min., H2O (200 mL) was slowly added to the reaction mixture. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 5-hydroxy-3-(2-hydroxy-ethyl)-pentanenitrile (131 g). 1H NMR (200 MHz, CDCl3) δ ppm 1.38-1.91 (m, 4 H) 1.98-2.36 (m, 1 H) 2.50 (d, J=5.71 Hz, 2 H) 3.51-3.90 (m, 4 H).
Reaction SMILES: [C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[CH3:30][Mg]Br.C(OCC)C>O1CCCC1>[OH:3][C:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8]([NH:10][C:11]2[CH:27]=[CH:26][CH:25]=[CH:24][C:12]=2[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[O:14])=[O:9])=[CH:6][CH:5]=1)([CH3:30])[CH3:2]
Reactant: C[Mg]Br
Reactant: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)=O)cc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(NC(=O)c2ccccc2NC(=O)c2ccc(C(C)(C)O)cc2)cc1
Reaction time: 1 h
Yield: 14 %

Procedure:
To a solution of 2-(4-acetylbenzoylamino)-N-(4-methoxyphenyl)benzamide (161 mg, 0.410 mmol) in tetrahydrofuran (10 mL) cooled to 0° C. was added 3 M methyl magnesium bromide in diethyl ether (0.2 mL, 0.6 mmol). After 1 h, the reaction mixture was quenched with saturated aqueous ammonium chloride solution (2 mL), diluted with ether, and washed with water. The organic layer was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was chromatographed (silica gel, 15% ethyl acetate/85% hexanes to 35% ethyl acetate/65% hexanes) to give 24 mg (14%) of the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.[N+:13]([C:16]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:17]=1[S:26](Cl)(=[O:28])=[O:27])([O-:15])=[O:14].N1C=CC=CC=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:1][C:2]1[CH:11]=[CH:10][C:9]([NH:12][S:26]([C:17]2[CH:18]=[CH:19][C:20]([C:22]([F:24])([F:25])[F:23])=[CH:21][C:16]=2[N+:13]([O-:15])=[O:14])(=[O:27])=[O:28])=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2
Reactant: Nc1ccc(F)c2cccnc12
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1S(=O)(=O)Nc1ccc(F)c2cccnc12
Yield: 58.5 %

Procedure:
In a similar fashion using route 14 general procedure 27, 5-fluoro-quinolin-8-ylamine (Intermediate 50) (280 mg, 1.73 mmol), 2-nitro-4-trifluoromethylbenzenesulfonyl chloride (0.6 g, 2.07 mmol), DMAP (cat), pyridine (0.42 ml, 5.19 mmol) and DCM (5 ml) gave the title compound (420 mg, 59%) after purification by column chromatography with DCM/MeOH (98:2) as the eluent.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][OH:29])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:33])[CH3:32])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:41][CH:42]1[O:46][C:43]1([CH3:45])[CH3:44]>O1CCCC1.C(OCC)(=O)C>[Si:1]([O:8][C@@H:9]1[C@@:26]2([CH3:27])[C:13](=[CH:14][CH:15]=[C:16]3[C@@H:25]2[CH2:24][CH2:23][C@@:21]2([CH3:22])[C@H:17]3[CH2:18][CH:19]=[C:20]2[CH2:28][O:29][CH2:41][CH:42]2[O:46][C:43]2([CH3:45])[CH3:44])[CH2:12][C@@H:11]([O:30][Si:31]([C:34]([CH3:37])([CH3:36])[CH3:35])([CH3:32])[CH3:33])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC2=CC=C3[C@H](CC[C@]4(C)C(CO)=CC[C@@H]34)[C@@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)C1
Reactant: CC1(C)OC1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(C)OC1COCC1=CC[C@H]2C3=CC=C4C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)[C@]4(C)[C@H]3CC[C@]12C
Yield: 81.1 %

Procedure:
A solution of 1α,3β-bis(tert-butyldimethylsilyloxy)-17-(hydroxymethyl)androsta-5,7,16-triene (51.6 mg, 0.0947 mmol), sodium hydride (95%, 21.1 mg, 0.879 mmol) and 1-bromo-2,3-epoxy-3-methylbutane (91.2 mg, 0.553 mmol) in tetrahydrofuran (1 ml) was stirred at room temperature for 20 min. and refluxed under heating for 20 min. The reaction solution was diluted with ethyl acetate and washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, evaporated under reduced pressure to remove the solvent, and the thus obtained residue was purified by preparative thin layer chromatography (1 sheet (0.5 mm thickness), hexane:ethyl acetate=10:1, developed twice) to give the titled compound (48.3 mg, 81%) as a pale yellow oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([OH:21])[CH2:20][CH2:19][CH2:18][S:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:23](F)(F)C(O)=O>CO>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([O:21][CH3:23])[CH2:20][CH2:19][CH2:18][S:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(C2(O)CCCSC2)cc1OC1CCCC1
Solvent: CO
Product: COc1ccc(C2(OC)CCCSC2)cc1OC1CCCC1
Reaction time: 8 h

Procedure:
A solution of 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-hydroxy-3,4,5,6-tetrahydro-2H-thiopyran (2 g; which is prepared as described in Example 7) methanol (175 mL) is treated with trifluoroacetic acid (0.5 mL) and the mixture is allowed to stand at room temperature overnight. The mixture is concentrated in vacuo, and it is then treated with diethyl ether (175 mL) and washed with saturated aqueous sodium bicarbonate solution (25 mL) and water (25 mL) and dried over magnesium sulphate. The solvent is removed and the resulting oily residue is subjected to flash chromatography on silica gel, using a mixture of pentane and ethyl acetate (9:1 v/v) as eluent, to give 3-(3-cyclopentyloxy-4-methoxyphenyl)-3-methoxy-3,4,5,6-tetrahydro-2H-thiopyran (1.16 g), in the form of a colorless oil.
Reaction SMILES: Br[CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18].[CH2:19]([O:21][P:22]([O:26]CC)[O:23][CH2:24][CH3:25])[CH3:20]>>[CH2:19]([O:21][P:22]([CH2:2][C:3]1[S:7][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[N:5][C:4]=1[CH3:18])(=[O:26])[O:23][CH2:24][CH3:25])[CH3:20]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1CBr
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1C)OCC
Temperature: 150 °C

Procedure:
A mixture of 5-(bromomethyl)-4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole (intermediate 3, 1.48 g) and triethylphosphite (1.5 ml) was heated under nitrogen at 150° C. for 1 hour. The mixture was allowed to cool and excess triethylphosphite was removed under reduced pressure. This gave the title compound as a yellow solid.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([CH:13]=C2C3C(=CC=CC=3)CC2C2C=CC=CC=2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1([CH:35]2[CH2:44][C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[C:37](=O)[CH2:36]2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([N:8]1[C:12]([CH:13]=[C:37]2[C:38]3[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=3)[CH2:44][CH:35]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:36]2)=[CH:11][N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C(=C1c2ccccc2CC1c1ccccc1)c1cncn1Cc1ccccc1
Reactant: O=C1CC(c2ccccc2)Cc2ccccc21
Product: C(=C1CC(c2ccccc2)Cc2ccccc21)c1cncn1Cc1ccccc1

Procedure:
1-Benzyl-5-(3-phenyl-3,4-dihydro-2H-naphthalen-1-ylidenemethyl)-1H-imidazole was prepared as 1-benzyl-5-(2-phenylindan-1-ylidenemethyl)-1H-imidazole above except that 3-phenyl-3,4-dihydro-2H-naphthalen-1-one (prepared according to J. Vebrel and R. Carrie Bull. Soc. Chem. Fr. (1982) 116) was used as a starting material. The crude product as its hydrochloride salt was used in the next step without purification.
Reaction SMILES: [Mg].[CH2:2]([O:4][C:5]1[CH:10]=[CH:9][C:8](Br)=[CH:7][CH:6]=1)[CH3:3].[Cl:12][Si:13](Cl)([CH3:15])[CH3:14]>O1CCCC1>[Cl:12][Si:13]([C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:2][CH3:3])=[CH:6][CH:7]=1)([CH3:15])[CH3:14]
Reactant: CCOc1ccc(Br)cc1
Reactant: C[Si](C)(Cl)Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: CCOc1ccc([Si](C)(C)Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred suspension of 3.5 g (0.14 mole) of magnesium powder in 100 mL of dry tetrahydrofuran was added dropwise 17.5 g (0.14 mole) of p-bromophenyl ethyl ether during a one hour period. The mixture was warmed for one hour and then cooled to room temperature. The reaction mixture was added dropwise to a solution of dichlorodimethylsilane in 100 mL of dry tetrahydrofuran which was cooled to -78° C. Upon completion of addition the reaction mixture was allowed to warm to room temperature. Stirring was continued overnight. After dilution with hexane, the reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure, leaving a liquid residue. Distillation of this residue yielded 18 g of chloro(4-ethoxyphenyl)dimethylsilane as a clear, colorless oil, b.p. 79-81° C./0.09 mm of Hg.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:12][C:13](=[O:15])[CH3:14].C(O)(=O)C.[Br:20]Br.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Br:20][C:6]1[CH:5]=[CH:4][C:3]([NH:12][C:13](=[O:15])[CH3:14])=[C:2]([CH3:1])[C:7]=1[C:8]([F:10])([F:11])[F:9]
Reactant: BrBr
Reactant: CC(=O)Nc1cccc(C(F)(F)F)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(Br)c(C(F)(F)F)c1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of N-[2-methyl-3-(trifluoromethyl)phenyl]acetamide (6.2 g) and acetic acid (40 ml) was added an acetic acid solution (10 ml) of bromine (1.8 ml) under water-cooling. The reaction liquid was stirred at room temperature overnight and then at 50° C. for 2 hours. In addition, to the reaction liquid was added bromine (1.5 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 1 day. In addition, to the reaction liquid was added bromine (2.0 ml) under water-cooling, followed by stirring at 50° C. for 4 days. The reaction liquid was poured into ice water (about 200 g), ethyl acetate was added thereto, followed by neutralization with potassium carbonate. A liquid-separation operation was carried out, and the organic layer was washed with an aqueous sodium thiosulfate solution and saturated brine in this order, dried over anhydrous sodium sulfate, and then evaporated under reduced pressure to obtain N-[4-bromo-2-methyl-3-(trifluoromethyl)phenyl]acetamide (9.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](N(OC)C)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:17][Mg]Br>CCOCC.[Cl-].[Na+].O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][C:11](=[O:12])[CH3:17])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: C[Mg]Br
Reactant: CON(C)C(=O)CCc1ccc(Cl)c(Cl)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: CC(=O)CCc1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 61.8 %

Procedure:
At 0° C. to a solution of 3-(3,4-dichlorophenyl)-N-methoxy-N-methylpropanamide (569 mg, 2.17 mmol) in ether (10 mL) was added drop wise methyl magnesium bromide (2.17 mL, 6.51 mmol) and the solution was stirred at 0° C. for 1 h. The reaction mixture was allowed to warm up to rt and stirred for 18 h. The reaction mixture was cooled to 0° C. and brine was added to quench the reaction. The aqueous layer was extracted with DCM three times. The combined organic layers were dried over MgSO4, filtered and concentrated. The residue was purified by ISCO chromatography (EtOAc/Hexanes 0-50% over 20 min, column 40 g, flow rate 40 mL/min) to give Intermediate 15B (292 mg, 1.34 mmol, 62.0% yield) as a yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.15 (3H, s), 2.75 (2H, t, J=6.9 Hz), 2.80-2.90 (2H, m), 7.02 (1H, dd, J=8.2, 2.2 Hz), 7.28 (1H, d, J=2.2 Hz), 7.33 (1H, d, J=8.2 Hz).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:28])[CH3:27])[N:11]=2)=[CH:18][CH:17]=1
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Reactant: CC1(C)OB(c2ccncc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4ccncc4)cc2-3)cc1
Temperature: 100 °C
Yield: 65 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (0.76 g, 1.5 mmol), 4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridine (0.3 g, 2.3 mmol), Na2CO3 (2 M, 3.7 mL), and Pd(PPh3)2Cl2 (14.6 mg, 0.012 mmol) in toluene/ethanol (1:1, 10 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (20% EtOAc in hexane) to give 6-(4-Methoxy-phenyl)-2-pyridin-4-yl-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene as brown solid in 65% yield.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C-:12]#[N:13].[Na+].ClC(Cl)C>CN(C)C=O>[Cl:8][C:7]1[CH:6]=[CH:5][CH:4]=[C:3]([N+:9]([O-:11])=[O:10])[C:2]=1[C:12]#[N:13]
Reactant: O=[N+]([O-])c1cccc(Cl)c1Cl
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cccc1[N+](=O)[O-]
Yield: 78.3 %

Procedure:
2,3-dichloronitrobenzene (19.2 g), cuprous chloride (2.4 g), anhydrous cupric sulfate (1.0 g), sodium cyanide (purity of 90%, 5.4 g) and dimethylformamide (3.0 g) were heated together to 190° C. and made to react for 3.5 hours at the temperature. After the reaction was over, 100 ml of dichloroethane were added to the reaction mixture and the mixture was filtered. After separating the filtrate, 100 ml of an aqueous 5% solution of ammonia were added to the filtrate and after well shaking the mixture, it was separated into layers. After distilling off dichloroethane from the organic layer and washing the residue with ethanol, 14.3 g of 2-chloro-6-nitrobenzonitrile was obtained as a pale yellow crystal. The yield was 78% theoretical.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:11]=2[CH2:12][C:13](=[O:19])[NH:14]3)=[CH:6][CH:5]=1.[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[C:37](C)=[C:36]([CH:39]=O)[NH:35][C:34]=2[CH3:41])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)C.N1CCCCC1>[N:22]1([CH2:27][CH2:28][CH2:29][NH:30][C:31]([C:33]2[CH:37]=[C:36]([CH3:39])[NH:35][C:34]=2[CH:41]=[C:12]2[C:11]3[C:15](=[CH:16][CH:17]=[CH:18][C:10]=3[C:7]3[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:20])[F:21])=[CH:9][CH:8]=3)[NH:14][C:13]2=[O:19])=[O:32])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C1Cc2c(cccc2-c2ccc(OC(F)(F)F)cc2)N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)NCCCN1CCCC1
Solvent: CCO
Solvent: C1CCNCC1
Product: Cc1cc(C(=O)NCCCN2CCCC2)c(C=C2C(=O)Nc3cccc(-c4ccc(OC(F)(F)F)cc4)c32)[nH]1
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.9 %

Procedure:
To a solution of 4-(4-trifluoromethoxy-phenyl)-1,3-dihydro-indol-2-one (69.3 mg, 0.25 mmol) and 5-formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide (69.8 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-methyl-2-[2-oxo-4-(4-trifluoromethoxy-phenyl) 1,2-dihydro-indol-3-ylidenemethyl]-1H-pyrrole-3-carboxylic acid (3-pyrrolidin-1-yl-propyl)-amide as a yellow solid (96.8 mg, 72%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=3)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(OCC)(=O)C.C(O)C.[Pt](=O)=O>[C:1]1([C:7]2[NH:8][C:9]([C:18]3[CH:19]=[CH:20][C:21]([NH2:24])=[CH:22][CH:23]=3)=[CH:10][C:11]=2[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1ccc(-c2cc(-c3ccncc3)c(-c3ccccc3)[nH]2)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-c2cc(-c3ccncc3)c(-c3ccccc3)[nH]2)cc1
Reaction time: 2 h

Procedure:
To a suspension of 55 mg (0.161 mmol) 2-phenyl-3-(4-pyridyl)-5-[(4-nitro)phenyl]-1H-pyrrole (prepared according to Example 33) in 1.5 ml ethyl acetate and 1.5 ml ethanol was added 10 mg platinum (IV) oxide. The mixture was stirred under H2 for 2 hours. The contents of flask were centrifuged, and the catalyst washed with ethyl acetate three times. The solvents were evaporated in vacuo to afford the desired product as a pale orange solid, homogeneous by TLC (5% MeOH/CH2Cl2). FAB ms: Calc.: 312 for C21H17N3 ; Obs.: 313 (M+ +1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11])=[N:6][CH:7]=1.[OH:14][C:15]([CH3:48])([CH3:47])[CH2:16][C@@:17]1([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[O:22][C:21](=[O:23])[N:20]([C@H:24]([C:26]2[CH:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH3:25])[CH2:19][CH2:18]1.C([O-])(O)=O.[Na+]>COCCOC.CCO.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>[OH:12][C:10]([CH3:13])([CH3:11])[CH2:9][O:8][C:5]1[N:6]=[CH:7][C:2]([C:29]2[CH:28]=[CH:27][C:26]([C@@H:24]([N:20]3[CH2:19][CH2:18][C@:17]([CH2:16][C:15]([OH:14])([CH3:47])[CH3:48])([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[O:22][C:21]3=[O:23])[CH3:25])=[CH:31][CH:30]=2)=[CH:3][CH:4]=1
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Reactant: CC(C)(O)COc1ccc(Br)cn1
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: [Na+]
Solvent: COCCOC
Solvent: CCO
Product: C[C@@H](c1ccc(-c2ccc(OCC(C)(C)O)nc2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 12 %

Procedure:
To a solution of 1-(5-bromopyridin-2-yloxy)-2-methylpropan-2-ol (30 mg, 0.122 mmol) in DME (6 mL) was added Pd(PPh3)4 (10 mg) under nitrogen. The mixture was stirred for 1 h at rt. A solution of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one (58.4 mg, 0.122 mmol) in EtOH (2 mL) and satd aq NaHCO3 (2 mL) were added. The mixture was stirred at 100° C. for 2 h, quenched with water, and extracted with EtOAc (3×10 mL). The combined organic layer was dried over anhydrous Na2SO4, concentrated, and purified by preparative TLC (1:1 PE/EtOAc) and HPLC to afford the title compound (7.6 mg, 12.1%). 1H NMR (CDCl3): δ 8.23 (d, 1H), 7.72 (q, 1H), 7.74-6.68 (m, 10H), 5.70 (m, 1H), 4.24 (s, 2H), 3.43 (s, 1H), 2.85 (m, 1H), 2.40 (m, 1H), 2.27-2.14 (m, 5H), 1.54 (d, 3H), 1.33-1.29 (d, 3H), 1.18-1.12 (d, 3H).