Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][NH:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.Cl[C:29]1[N:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:31][N:30]=1>CC(O)C>[CH:1]([CH:4]1[C:9]2=[CH:10][C:11]3[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[CH:15][C:16]=3[N:8]2[CH2:7][CH2:6][N:5]1[C:29]1[N:34]=[C:33]([C:35]([F:37])([F:38])[F:36])[C:32]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:31][N:30]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Reactant: CSc1ccc2cc3n(c2c1)CCNC3C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CCOC(=O)c1cnc(N2CCn3c(cc4ccc(SC)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
To a solution of 1-isopropyl-7-(methylthio)-1,2,3,4-tetrahydropyrazino[1,2-a]indole (100 mg, 0.38 mmol) and DIPEA (248.3 mg, 1.921 mmol) in i-PrOH (3 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (196 mg, 0.77 mmol). The reaction mixture was stirred at rt overnight. The mixture was concentrated and purified by preparative TLC on silica gel eluting with PE/EtOAc 1:1 to afford ethyl 2-(1-isopropyl-7-(methylthio)-3,4-dihydropyrazino[1,2-a]indol-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (60 mg, 32.6% yield) as a colorless oil. LC-MS MS (ESI) m/z 478.7 [M+H]+.
Reaction SMILES: Cl.C([N:4]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:5][C:6]([OH:8])=[O:7])C.[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1.N1C=CC=[CH:27][CH:26]=1>CC#N>[F:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:4]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:5][C:6]([O:8][CH2:26][CH3:27])=[O:7])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: c1ccncc1
Reactant: CCN(CC(=O)O)c1ccccc1
Agent: Cl
Solvent: CC#N
Product: CCOC(=O)CN(C(=O)c1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 63 %

Procedure:
To a solution of ethyl phenylglycine, hydrochloride (prepared above) in CH3CN (60 mL) were added 4-fluorobenzoyl chloride (25.4 g, 0.16 mol) and pyridine. The resulting mixture was stirred at room temperature for about 5.5 h, then was partitioned between aqueous NaHCO3 and EtOAc. The organic extract was washed successively with 10% aqueous NaOH, 3N HCl and saturated aqueous NaCl. The solvent was removed in vacuo, and the residue was crystallized from CH2Cl2 /hexanes to afford the title compound (19 g, 63%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH3:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([N:1]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH:3]=[N:2]2)=[CH:14][CH:13]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: c1ccc2[nH]ncc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(-n2ncc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.7 %

Procedure:
A mixture of 1H-Indazole (0.50 g, 4.23 mmol), 4-methoxyphenylboronic acid (1.30 g, 8.5 mmol), triethylamine (0.86 g, 8.5 mmol) and cupric acetate ((0.77 g, 4.23 mmol) in CH2Cl2 (50 mL) was stirred at room temperature for 48 h. The reaction mixture was diluted with water and passed through a pad of Celite. The filtrate was extracted with EtOAc, washed with brine, and dried over Na2SO4. After being concentrated, the crude material was purified by a chromatography on silica gel to yield the title compound (0.32 g, 30%).
Reaction SMILES: CS(C)=O.[CH2:5]([O:12][C:13]1[C:20]([CH3:21])=[CH:19][C:16]([CH2:17]O)=[CH:15][C:14]=1[CH3:22])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH:23](=[N:30][C:31]1[N:32]=[CH:33][NH:34][C:35]=1[C:36]([NH2:38])=[O:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>Cl[Si](C)(C)C.CN(C)C=O.O>[CH:23](=[N:30][C:31]1[N:32]=[CH:33][N:34]([CH2:17][C:16]2[CH:19]=[C:20]([CH3:21])[C:13]([O:12][CH2:5][C:6]3[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=3)=[C:14]([CH3:22])[CH:15]=2)[C:35]=1[C:36]([NH2:38])=[O:37])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NC(=O)c1[nH]cnc1N=Cc1ccccc1
Reactant: Cc1cc(CO)cc(C)c1OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Cn2cnc(N=Cc3ccccc3)c2C(N)=O)cc(C)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.48 ml of dimethylsulfoxide was added to a solution of 1.49 g (6.15 mmol) of 4-benzyloxy-3,5-dimethylbenzyl alcohol in 40 ml of chlorotrimethylsilane, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under vacuum. The concentrate was dissolved in ethyl acetate, washed with distilled water and saturation brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the dry product under vacuum was dissolved in 30 ml of N,N-dimethylformamide. This solution was mixed with a suspension of 0.88 g (4.1 mmol) of 4-benzylideneamino-5-imidazolecarboxamide and 2.27 g (16.4 mmol) of potassium carbonate in 30 ml of N,N-dimethylformamide. After the addition of 1.64 ml of distilled water, the mixture was heated for 10 minutes and stirred overnight. The reaction solution was concentrated under vacuum and distilled water was added to the concentrate to precipitate a crude product. The precipitate was collected by filtration using a funnel glass filter. The solid obtained was washed with distilled water and toluene, and dried under vacuum to obtain 4-benzylidene amino-1-(4-benzyloxy-3,5-dimethylbenzyl)-5-imidazole carboxamide. The resulting compound was suspended in 25 ml of 1,4-dioxane and 25 ml of 1N aqueous solution of hydrochloric acid was added, followed by stirring overnight. The reaction solution was washed with ether, added 25 ml of methanol, and neutralized with 4N aqueous solution of sodium hydroxide. The organic solvent was evaporated under vacuum and the residue was allowed to stand overnight in a refrigerator. The precipitated solid was collected by filtration, washed with distilled water, and dried to obtain 1.10 g of 4-amino-1-(4-benzyloxy-3,5-dimethylbenzyl)-5-imidazole carboxamide (yield 86%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[SH:20][C:21]1[N:25]([CH3:26])[CH:24]=[N:23][N:22]=1>>[CH3:26][N:25]1[CH:24]=[N:23][N:22]=[C:21]1[S:20][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: Cn1cnnc1S
Reactant: Nc1ccccn1
Reactant: Clc1ncnc2ccc(I)cc12
Product: Cn1cnnc1Sc1ccc2ncnc(Nc3ccccn3)c2c1

Procedure:
The compound of Example 20 was manufactured by the same method as in Example 1, by a similar method thereto or by a combination of such a method with a conventional method using 4-chloro-6-iodo-quinazoline, 2-aminopyridine and 3-mercapto-4-methyl-1,2,4-triazole.
Reaction SMILES: Br[CH:2]([CH2:4]CCCCC)[CH3:3].C[CH:11]([CH2:23][CH2:24]C)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21].C=O.[CH2:28](Br)CC>>[CH2:3]([CH:19]([CH2:18][CH2:17][CH2:16][CH:15]([CH3:28])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:23][CH3:24])[C:20]([OH:22])=[O:21])[CH2:2][CH3:4]
Reactant: CCCCCCC(C)Br
Reactant: CCCC(C)CCCCCCCCC(=O)O
Reactant: CCCBr
Agent: C=O
Product: CCCCCCC(C)CCCC(CCC)C(=O)O

Procedure:
The procedure used is that of GENERAL PROCEDURE III except that 2-bromooctane is used as compound (1) in step (a), formaldehyde is used in place of ethylene oxide in step (b), y=1, and propyl bromide is used in place of methyl iodide in step (h).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Br[C:40]1[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[C:41]([CH3:46])=[N:42][CH:43]=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3]
Reactant: Cc1ncccc1Br
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: COCCOC
Solvent: O
Product: Cc1ncccc1-c1ccc(C2(c3nnc4n3CCSC(C)(CO[Si](C)(C)C(C)(C)C)C4)CC2)cc1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-bromo-2-methylpyridine (344 mg, 2 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was cooled to room temperature and purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (388 mg, 72%) as a brown solid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH2:16])=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2].[C:26]1([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:31]=[CH:30][C:29]([C:32](Cl)=[O:33])=[CH:28][CH:27]=1.N1C=CC=CC=1>O1CCCC1>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([NH:16][C:32](=[O:33])[C:29]3[CH:30]=[CH:31][C:26]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[CH:27][CH:28]=3)=[CH:11][C:12]=2[O:14][CH3:15])[C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)([CH3:17])[CH2:6][C:5]1([CH3:25])[CH3:24])(=[O:3])[CH3:2]
Reactant: COc1cc(N)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COc1cc(NC(=O)c2ccc(-c3ccccc3)cc2)cc2c1N(C(C)=O)C(C)(C)CC2(C)c1ccccc1

Procedure:
Acylation of 1-acetyl-6-amino-8-methoxy-4-phenyl-1,2,3,4-tetrahydro-2,2,4-trimethylquinoline (20 mg) with 4-biphenylcarbonyl chloride (100 mg) and pyridine (100 μl) in tetrahydrofuran (5 ml) was performed according to the method described in example 6.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([CH3:9])[CH:8]=1)[NH2:5].Cl[C:11]1[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=1.CS(O)(=O)=O.[OH-].[Na+]>C1(C)C=CC=CC=1.O.CCCCCCC>[Br:1][C:2]1[CH:3]=[C:4]([NH:5][C:11]2[N:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:14]=[CH:13][N:12]=2)[CH:6]=[C:7]([CH3:9])[CH:8]=1
Reactant: FC(F)(F)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCCCCCC
Product: Cc1cc(Br)cc(Nc2nccc(C(F)(F)F)n2)c1
Temperature: 105 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of 3-bromo-5-methylaniline (45.77 g, 246 mmol) in toluene (500 ml) were sequentially added 2-chloro-4-(trifluoromethyl)pyrimidine (53.9 g, 295 mmol) and methanesulfonic acid (28.4 g, 295 mmol). The resulting solution was heated to 105° C. overnight. The resulting mixture was cooled, diluted with water (500 mL) and adjusted to pH 14 via addition of a concentrated aqueous sodium hydroxide solution (26.6 g of a solution containing 320 mmol of sodium hydroxide). The resulting solution was extracted with MTBE (500 mL), the layers separated, and the organic layer subsequently washed with water (300 ml) then 50% saturated brine solution (200 mL). The organic layer was concentrated in vacuo to 200 ml resulting in product crystallization. To the slurry was added heptane (660 mL) over 40 minutes followed by a 2 hr aging at 20° C. The solid was isolated via filtration, washed with heptane (200 mL) and dried in a vacuum oven at 40° C. overnight to provide the title compound (69.5 g, 209 mmol) as a light yellow solid. MS ESI: [M+H]+ m/z 334.0. 1H NMR (400 MHz, CDCl3): δ 8.68 (d, J=4.9 Hz, 1H); 7.79 (s, 1H); 7.30 (s, 2H); 7.10-7.06 (m, 2H); 2.36 (s, 3H).
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[N:42]=[C:41]([CH:43]3[CH2:46][C:45](=O)[CH2:44]3)[N:40](C)[C:39]=2[CH:49]=1>C1COCC1>[Br:34][C:35]1[CH:36]=[CH:37][C:38]2[N:42]=[C:41]([CH:43]3[CH2:44][C:45](=[CH:2][O:3][CH3:4])[CH2:46]3)[NH:40][C:39]=2[CH:49]=1
Reactant: Cn1c(C2CC(=O)C2)nc2ccc(Br)cc21
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC=C1CC(c2nc3ccc(Br)cc3[nH]2)C1
Reaction time: 0.5 h
Yield: 30 %

Procedure:
To a stirred solution of (methoxymethyl)triphenylphosphonium chloride (4.98 g) in THF (20 ml) was added lithium hexamethyldisilazide (1.0 M solution in hexane, 29 ml) at −15° C., and the resulting mixture was stirred at the same temperature for 30 min. A solution of 3-(6-bromo-1-methyl-1H-benzimidazol-2-yl)cyclobutanone (2.7 g) in THF (5 ml) was added to the reaction mixture, and the resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution, concentrated in vacuo and diluted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, concentrated in vacuo and purified by column chromatography (hexane/EtOAc) to afford the title compound (850 mg) as a yellow solid.
Reaction SMILES: C(N(CC)CC)C.[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](Cl)=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1.Cl.[F:24][C:25]([CH3:29])([CH3:28])[CH2:26][NH2:27].O>CN(C=O)C>[Br:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([NH:27][CH2:26][C:25]([F:24])([CH3:29])[CH3:28])=[C:14]([N+:19]([O-:21])=[O:20])[CH:15]=[N:16]2)=[N:11][CH:10]=1
Reactant: CC(C)(F)CN
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(F)CNc1c([N+](=O)[O-])cnc2cc(Br)cnc12
Temperature: 25 °C
Reaction time: 14.5 h
Yield: 100.1 %

Procedure:
Triethylamine (17.3 g, 171 mmol) was added to a suspension of 7-bromo-4-chloro-3-nitro[1,5]naphthyridine (52.2 mmol) in DMF (50 mL), and then a solution of 2-fluoro-2-methylpropan-1-amine hydrochloride (5.46 g, 42.8 mmol) in DMF (25 mL) was added dropwise over a period of ten minutes. The reaction mixture was stirred at room temperature for 14.5 hours, and water (500 mL) was added. The resulting mixture was stirred for one hour. A solid was present and was isolated by filtration, washed with water, and dried overnight in a vacuum oven at 65° C. to provide 14.7 g of 7-bromo-N-(2-fluoro-2-methylpropyl)-3-nitro[1,5]naphthyridin-4-amine as a reddish-brown solid.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10](F)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2].[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.COB(OC)OC.C(#N)C>O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:16])=[C:10]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:11]=2[O:13][CH3:14])[C:6](=[O:17])[C:5]([C:18]([OH:20])=[O:19])=[CH:4]1)[CH3:2]
Reactant: C1CCNCC1
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(F)c(OC)c21
Agent: COB(OC)OC
Solvent: O
Solvent: CC#N
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCCCC3)c(OC)c21
Temperature: 25 °C
Yield: 63.2 %

Procedure:
A mixture of 2.83 g of 1-ethyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (10 mmol), 1.70 g of piperidine (20 mmol), 1.04 g of trimethoxyborane (10 mmol) and 15 ml of acetonitrile was refluxed with heating for 4.5 hours. The reaction solution was cooled to room temperature, 30 ml of water was added therein, a pH was adjusted to 8 with 6N--HCl, and separated crystals were filtered and dried to obtain 2.20 g of the objective compound.
Reaction SMILES: [C:1]([CH2:3][C@@:4]12[C@@H:20]([C:21](=[O:23])[CH3:22])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C@:8]3([CH3:25])[C:13]([CH2:14][CH2:15]1)=[CH:12][C:11](=[O:24])[CH2:10][CH2:9]3)[CH2:6][CH2:5]2)#[CH:2].[BH4-].[Na+].C(O)(=O)C>CO>[C:1]([CH2:3][C@@:4]12[C@@H:20]([CH:21]([OH:23])[CH3:22])[CH2:19][CH2:18][C@H:17]1[C@H:16]1[C@@H:7]([C@:8]3([CH3:25])[C:13]([CH2:14][CH2:15]1)=[CH:12][C:11](=[O:24])[CH2:10][CH2:9]3)[CH2:6][CH2:5]2)#[CH:2]
Reactant: C#CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: C#CC[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@@H]1CC[C@@H]2C(C)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 4.2 g of 18-ethynylpregn-4-ene-3,20-dione in 125 ml of methanol is cooled to 0° C. and 950 mg of sodium borohydride is added. The resulting mixture is stirred at 0° C. for 1 hour and then allowed to warm to room temperature over an additional hour. Acetic acid is then added and the solution is concentrated. The resulting residue is suspended in ethyl acetate, washed with water, aqueous sodium bicarbonate and brine and dried, and the solvent is evaporated. The residue is dissolved in 400 ml of chloroform, 42 g of activated manganese dioxide is added, and the resulting suspension is stirred for 24 hours. The inorganic solid is then removed by filtration through Celite and the filter cake is washed thoroughly with hot chloroform. The filtrate is then concentrated and the residue is purified by recrystallization from acetone/hexane to give 18-ethynyl-20-hydroxypregn-4-en-3-one.
Reaction SMILES: [NH2:1][NH2:2].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12].[C:13]([O-:32])(=O)CCCCCCCCCCCCCCCCC.[Mg+2].C([O-])(=O)CCCCCCCCCCCCCCCCC>>[N:3]1([C:13]([NH:1][NH2:2])=[O:32])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCCCCCCCCCCCCCCCCC(=O)[O-]
Reactant: NN
Agent: [Mg+2]
Product: NNC(=O)N1C(=O)Cc2ccccc21

Procedure:
An oxindole hydrazine derivative of formula (I) is admixed as a dry powder with a dry gelatin binder in an approximate 1:2 weight ratio. A minor amount of magnesium stearate is added as a lubricant. The mixture is formed into 240-270 mg tablets (80-90 mg of active oxindole hydrazide compound per tablet) in a tablet press.
Reaction SMILES: [Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12](Cl)(=[O:14])=[O:13])=[CH:3][Cl:4].O.[NH3:17]>C(Cl)Cl>[Cl:1][C:2]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[S:12]([NH2:17])(=[O:14])=[O:13])=[CH:3][Cl:4]
Reactant: N
Reactant: O=S(=O)(Cl)c1ccccc1OC(Cl)=CCl
Solvent: O
Solvent: ClCCl
Product: NS(=O)(=O)c1ccccc1OC(Cl)=CCl
Reaction time: 6 h

Procedure:
A solution of 17.5 g of 2-(1,2-dichlorovinyloxy)phenylsulfonyl-chloride in 150 ml of methylene chloride is added slowly to a mixture of 30 ml of methylene chloride, 50 ml of water and 50 ml of 30% aqueous ammonia. The reaction mixture is stirred for 6 hours at a temperature of 20°-25° C. The organic phase is washed with water, dried over sodium sulfate and evaporated to a volume of 40 ml. The crystallised 2-(1,2-dichlorovinyloxy)phenylsulfonamide is separated and dried. Yield: 12.5 g, m.p. 147°-149° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:20])[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[C:27]1(C)C=CC=C[CH:28]=1>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>[Cl:20][C:4]1[C:5]([CH2:8][N:9]2[C:17](=[O:18])[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]2=[O:19])=[N:6][CH:7]=[C:2]([CH:27]=[CH2:28])[CH:3]=1
Reactant: Cc1ccccc1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ncc(Br)cc1Cl
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+]
Product: C=Cc1cnc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Yield: 65 %

Procedure:
To a stirred solution of 2-((5-bromo-3-chloropyridin-2-yl)methyl)isoindoline-1,3-dione (0.23 g, 0.65 mmol) in toluene (10 mL) were added Pd(PPh3)4 (3.7 mg, 0.003 mmol), K2CO3 (0.269 g, 1.95 mmol) and vinyl boronic anhydride pyridine complex (0.78 g, 3.28 mmol), and the reaction mixture was heated at reflux for 16 h. The reaction mixture was filtered, and the filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. Purification by flash column chromatography (20-30% EtOAc in hexane) afforded the title compound as an off-white solid (0.2 g, 65%): 1H NMR (400 MHz, CDCl3) δ 8.30 (s, 1H), 7.91 (m, 2H), 7.77 (m, 3H), 7.72 (m, 1H), 6.63 (m, 1H), 5.79 (d, J=16.0 Hz, 1H), 5.39 (d, J=16.0 Hz, 1H), 5.12 (s, 2H); ESIMS m/z 299.20 ([M+H]+).
Reaction SMILES: [I:1]Cl.C[Si](C)(C)[C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][C:24]([C:31]7[CH:43]=[CH:42][C:41]8[C:40]9[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=9)[C:34]([CH2:47][CH2:48][CH3:49])([CH2:44][CH2:45][CH3:46])[C:33]=8[CH:32]=7)=[CH:25][CH:26]=6)[C:21]([CH2:53][CH2:54][CH3:55])([CH2:50][CH2:51][CH3:52])[C:20]=5[CH:19]=4)=[CH:12][CH:13]=3)[C:8]([CH2:61][CH:62]([CH3:65])[CH2:63][CH3:64])([CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])[C:7]=2[CH:6]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>C(Cl)(Cl)(Cl)Cl>[I:1][C:5]1[CH:17]=[CH:16][C:15]2[C:14]3[C:9](=[CH:10][C:11]([C:18]4[CH:30]=[CH:29][C:28]5[C:27]6[C:22](=[CH:23][C:24]([C:31]7[CH:43]=[CH:42][C:41]8[C:40]9[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=9)[C:34]([CH2:47][CH2:48][CH3:49])([CH2:44][CH2:45][CH3:46])[C:33]=8[CH:32]=7)=[CH:25][CH:26]=6)[C:21]([CH2:53][CH2:54][CH3:55])([CH2:50][CH2:51][CH3:52])[C:20]=5[CH:19]=4)=[CH:12][CH:13]=3)[C:8]([CH2:61][CH:62]([CH3:65])[CH2:63][CH3:64])([CH2:56][CH:57]([CH3:60])[CH2:58][CH3:59])[C:7]=2[CH:6]=1
Reactant: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCC)(CCC)c3cc(-c5ccc6c(c5)C(CC(C)CC)(CC(C)CC)c5cc([Si](C)(C)C)ccc5-6)ccc3-4)cc21
Reactant: ClI
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: ClC(Cl)(Cl)Cl
Product: CCCC1(CCC)c2ccccc2-c2ccc(-c3ccc4c(c3)C(CCC)(CCC)c3cc(-c5ccc6c(c5)C(CC(C)CC)(CC(C)CC)c5cc(I)ccc5-6)ccc3-4)cc21
Reaction time: 0.5 h
Yield: 90.7 %

Procedure:
ICl (1.0 M in methylene chloride, 2.80 ml, 2.80 mmol) is added dropwise to a solution of 2-trimethylsilyl-9,9-bis(2-methylbutyl)-9′,9′,9″,9″-tetrakis(n-propyl)-7,2′;7′,2″-terfluorene (13a) (2.45 g, 2.80 mmol) in CCl4 (15 ml) at 0° C. After stirring for 30 min, the reaction mixture is poured into a Na2CO3 aqueous solution (5 wt %) with vigorous stirring until discoloration for extraction with methylene chloride. The organic extracts are washed with brine before dried over MgSO4. Upon evaporating off the solvent, the residue is washed with ethanol to yield 2-iodo-9,9-bis(2-methylbutyl)-9′,9′,9″,9″-tetrakis(n-propyl)-7,2′;7′,2″-terfluorene (14a) (2.36 g, 91%) as a light yellow solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH2:17]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27](O)=O)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]1[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=1[C:27]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: O=C(O)c1ccccc1OCc1ccccc1
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccccc2OCc2ccccc2)o1
Yield: 29 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-benzyloxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate:dichloromethane=70:10:20 to 40:40:20, 109 mg, 29%) which was obtained as a white solid. MS: m/e=410.1 [M+H]+.