Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.Cl.[NH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH:7]1[CH2:12][C:13]([OH:15])=[O:14].[CH3:16]O>>[ClH:3].[CH3:16][O:14][C:13](=[O:15])[CH2:12][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][NH:6]1
Reactant: O=C(O)CC1CCCCN1
Reactant: CO
Reactant: O=S(Cl)Cl
Agent: Cl
Product: COC(=O)CC1CCCCN1
Temperature: 25 °C

Procedure:
Thionyl chloride (1.8 ml, 25.2 mmol) was added dropwise to a solution, cooled to 0° C., of piperidin-2-ylacetic acid hydrochloride (1.5 g, 8.4 mmol) in methanol (35 ml), and the mixture was heated for 16 h at gentle boiling and then cooled to room temperature. The solvent was removed azeotropically in vacuo with benzene. Yield: 1.3 g (100%)
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:20])[CH2:9]2)(=[O:4])=[O:3].Cl.Cl[CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][N:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[C:10](=[O:20])[CH2:9]3)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:26][CH2:27]1
Reactant: COC(=O)CN1C(=O)Cc2cc(NS(C)(=O)=O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)Cc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Temperature: 65 °C
Yield: 15.1 %

Procedure:
A mixture of methyl 2-(5-(methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.500 g, 1.607 mmol) (prepared in an analogous manner as described in Example 20, Scheme 20, Steps 1, 2, 3, 4), 4-(2-chloroethyl)morpholine hydrochloride (0.393 g, 2.112 mmol), and K2CO3 (0.524 g, 3.788 mmol) in DMF (25 ml) was heated at 65° C. for 2 hours. The mixture was partitioned between ethyl acetate and aqueous 5% NaHCO3; the organic phase was washed several times with brine and dried over sodium sulfate. The solvent was removed under vacuum and the dark crude was purified by flash chromatography on silica gel column (DCM:MeOH=99:1 to 97:3) affording methyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-2-oxoindolin-1-yl)acetate (0.100 g, 0.243 mmol, 14.5% yield, MS/ESI+ 412.0 [MH]+).
Reaction SMILES: [CH3:1][CH:2]([C:7]([O:9][CH3:10])=[O:8])[C:3]([O:5][CH3:6])=[O:4].[H-].[Na+].I[CH2:14][C@@H:15]1[CH2:19][N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[C:17](=[O:28])[CH2:16]1.O>CS(C)=O>[CH3:6][O:5][C:3](=[O:4])[C:2]([CH3:1])([CH2:14][C@H:15]1[CH2:16][C:17](=[O:28])[N:18]([C@H:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:21])[CH2:19]1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(C)C(=O)OC
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](CI)CC1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)C(C)(C[C@H]1CC(=O)N([C@@H](C)c2ccccc2)C1)C(=O)OC
Yield: 67.1 %

Procedure:
To dimethyl methylmalonate (1.06 g, 7.29 mmol) in DMSO (7 mL) at room temperature was added NaH (291 mg of a 60% dispersion in oil). After the effervescence had ceased the lactam 85 (2 g, 7.29 mol) in DMSO (5 mL) was added. After 1 hour water was added and the aqueous solution extracted with ether. The combined organic extracts were dried (MgSO4) and concentrated. Flash chromatography (1:1 hexane/acetone) of the residue gave the product as an oil (1.7 g, 81%). MS m/z 348 (M+H, 100%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].O1CCCC1.CN(C)C=O.[H-].[Na+].[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Cl)=[CH:23][CH:22]=1>O>[CH3:19][O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][N:1]2[CH2:5][CH2:4][CH2:3][C:2]2=[O:6])=[CH:23][CH:22]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=C1CCCN1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(CN2CCCC2=O)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.4 %

Procedure:
To a solution of pyrrolidin-2-one (15 g) in a mixed solvent of tetrahydrofuran/N,N-dimethylformamide (1/1, 100 mL) was added sodium hydride (60% in mineral oil, 8.5 g) at 0° C. under nitrogen atmosphere, and the mixture was stirred for 30 min. p-Methoxybenzyl chloride (33 g) was added thereto at the same temperature, and the mixture was stirred at room temperature for 5 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (28 g).
Reaction SMILES: [OH:1][CH2:2][CH:3]([CH2:18][OH:19])[CH:4]1[C:13]2[C:8](=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=2)[CH2:7][CH2:6][NH:5]1.C(N(CC)CC)C.[C:27](Cl)(Cl)=[S:28]>C(Cl)(Cl)Cl>[OH:1][CH2:2][CH:3]1[CH:4]2[C:13]3[C:8]([CH2:7][CH2:6][N:5]2[C:27](=[S:28])[O:19][CH2:18]1)=[CH:9][C:10]([O:16][CH3:17])=[C:11]([O:14][CH3:15])[CH:12]=3
Reactant: S=C(Cl)Cl
Reactant: COc1cc2c(cc1OC)C(C(CO)CO)NCC2
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc2c(cc1OC)C1C(CO)COC(=S)N1CC2
Yield: 19 %

Procedure:
To a solution of 2.67 g (0.01 mole) of 1-[bis(hydroxymethyl)-methyl]-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline in 150 ml of absolute chloroform a solution of 2.0 g (0.02 mole) of triethyl amine in 10 ml of absolute chloroform is added, and to the mixture 1.15 g (0.01 mole) of thiophosgene are added dropwise with stirring, under cooling with ice. The reaction mixture is stirred for 10 minutes, then it is washed to neutral with 15 ml of a 5% hydrochloric acid solution and subsequently water. The chloroformic phase is dried over sodium sulfate and evaporated to dryness. The residue is taken up in 15 to 20 ml of ethanol, and ether is added to the mixture until slight turbidity. The desired compound is obtained in crystalline form.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[NH:5][C:4](=[O:11])[CH:3]=1.Br[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:16][C:15]=1[F:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:28][C:15]1[CH:16]=[C:17]([C:20]2[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:18]=[CH:19][C:14]=1[CH2:13][N:5]1[C:4](=[O:11])[CH:3]=[C:2]([CH3:1])[N:7]=[C:6]1[CH2:8][CH2:9][CH3:10]
Reactant: N#Cc1ccccc1-c1ccc(CBr)c(F)c1
Reactant: CCCc1nc(C)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1F
Temperature: 50 °C
Reaction time: 12 h
Yield: 29.5 %

Procedure:
To a solution of 6-methyl-2-propylpyrimidin-4(3H)-one (2.0 g) and 4′-(bromomethyl)-3′-fluorobiphenyl-2-carbonitrile (4.4 g) in acetonitrile (50 mL) was added potassium carbonate (3.6 g), and the mixture was stirred at 50° C. for 12 hr. The insoluble material was filtered off, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to give the title compound (1.4 g, 29%) as a colorless viscous substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]=[N:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[C:4]([O:18][Si](C(C)(C)C)(C)C)[C:3]=1[S:26]([N:29]([CH3:31])[CH3:30])(=[O:28])=[O:27].[N:32]#[C:33]N.C([N:38](CC)C(C)C)(C)C.[F-].[Cs+]>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C:33]#[N:32])[C:9]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Br:17])=[NH:38])=[C:4]([OH:18])[C:3]=1[S:26]([N:29]([CH3:30])[CH3:31])(=[O:28])=[O:27]
Reactant: CCN(C(C)C)C(C)C
Reactant: N#CN
Reactant: CN(C)S(=O)(=O)c1c(Cl)ccc(N=C=Nc2ccccc2Br)c1O[Si](C)(C)C(C)(C)C
Agent: [Cs+]
Agent: [F-]
Solvent: CC#N
Product: CN(C)S(=O)(=O)c1c(Cl)ccc(N(C#N)C(=N)Nc2ccccc2Br)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.2 %

Procedure:
To a solution of N-[4-chloro-2-tert-butyldimethylsilyloxy-3-(N″,N″-dimethylaminosulfonyl)phenyl]-N′-(2-bromophenyl)carbodiimide (266 mg, 0.49 mmol) in acetonitrile (5 mL) at room temperature, cyanamide (83 mg, 1.96 mmol) and N,N-diisopropylethylamine (76 mg, 0.59 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. The residue was diluted with a mixture of THF (3 mL) and methanol (1 mL). Cesium fluoride (90 mg, 0.59 mmol) was added at 0° C. The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by Gilson HPLC to give the desired product (70 mg, 30%). EI-MS m/z 473.75(M+).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][CH2:8][C:7](=[O:10])[N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:4].O.[F:19][C:20]1[CH:21]=[C:22]([Mg]Br)[CH:23]=[CH:24][C:25]=1[F:26]>O1CCCC1>[C:14]([O:13][C:11]([NH:6][C@@H:5]([CH2:9][CH2:8][C:7]([C:23]1[CH:22]=[CH:21][C:20]([F:19])=[C:25]([F:26])[CH:24]=1)=[O:10])[C:3]([O:2][CH3:1])=[O:4])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: Fc1ccc([Mg]Br)cc1F
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H](CCC(=O)c1ccc(F)c(F)c1)NC(=O)OC(C)(C)C
Reaction time: 2 h

Procedure:
To a solution of (S)-5-oxopyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.5 g) in tetrahydrofuran (100 mL), 3,4-difluorophenylmagnesium bromide (0.5 M solution in tetrahydrofuran; 50 mL) was added dropwise at −40° C. over 10 minutes, and the reaction solution was stirred at −40° C. to 0° C. for two hours. Water was added to the solution in small portions, followed by extraction with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (heptane-ethyl acetate system) to obtain 8.0 g of the title compound. The property values of the compound are as follows.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].C(N(CC)CC)C.C(Cl)Cl.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>>[CH3:27][S:28]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8](=[O:16])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])(=[O:30])=[O:29]
Reactant: CCCCCCCC(=O)NCCCCCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCCCC(=O)NCCCCCOS(C)(=O)=O
Yield: 81.6 %

Procedure:
To a solution of 2.00 g (7.77 mmol) of N-(5-hydroxypentyl)caprylamide and 1.30 ml (9.32 mmol) of triethylamine in50 ml of methylene chloride was added 0.72 ml (9.32 mmol) of methanesulfonyl chloride under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution and water and dried. The solvent was distilled off. The residue was washed with hexane to obtain 1.95 g of the desired compound (74.8%, colorless powder), mp: 67.0°-68.0° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH3:20])[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10]1.C1C(=O)N([Br:34])C(=O)C1>>[Br:34][CH2:20][C:13]1[NH:12][C:11]([C:21]2[S:22][C:23]([F:26])=[CH:24][N:25]=2)=[N:10][CH:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[Cl:1])[C:14]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(C)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Reactant: O=C1CCC(=O)N1Br
Product: CCOC(=O)C1=C(CBr)NC(c2ncc(F)s2)=NC1c1ccc(F)cc1Cl
Yield: 66.5 %

Procedure:
Ethyl 4-(2-chloro-4-fluorophenyl)-2-(5-fluorothiazol-2-yl)-6-methyl-1,4-dihydropyrimidine-5-carboxylate (0.17 g, 0.41 mmol) was reacted with NBS (0.07 g, 0.41 mmol) according to the procedure as described in Example 1, Step B to give the title compound as a yellow solid (0.13 g, 65%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14]Cl)[CH2:10][CH2:11][C:5]=2[CH:4]=1.[NH2:22][C:23]1[C:28]([Cl:29])=[CH:27][C:26]([NH:30][CH2:31][CH2:32][NH2:33])=[CH:25][C:24]=1[Cl:34]>>[CH3:1][O:2][C:3]1[C:19]([O:20][CH3:21])=[CH:18][C:6]2[C:7](=[O:17])[C:8](=[O:16])[N:9]([CH2:12][CH2:13][CH2:14][NH:33][CH2:32][CH2:31][NH:30][C:26]3[CH:25]=[C:24]([Cl:34])[C:23]([NH2:22])=[C:28]([Cl:29])[CH:27]=3)[CH2:10][CH2:11][C:5]=2[CH:4]=1
Reactant: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCCl)CC2
Reactant: NCCNc1cc(Cl)c(N)c(Cl)c1
Product: COc1cc2c(cc1OC)C(=O)C(=O)N(CCCNCCNc1cc(Cl)c(N)c(Cl)c1)CC2

Procedure:
The title compound is prepared from 3-(7,8-dimethoxy-1,3,4,5-tetrahydro-2H-3-benzazepin-1,2-dion-3-yl)-propyl chloride and 2-(4-amino-3,5-dichlorophenylamino)-ethylamine analogously to Example 6.
Reaction SMILES: [O:1]1[C:5]2[CH2:6][N:7]([C:10](=[O:27])[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH:14]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=[CH:2]1.[CH3:28][NH:29][CH3:30].[CH2:31]=O>C(O)(=O)C>[CH3:28][N:29]([CH2:31][C:2]1[O:1][C:5]2[CH2:6][N:7]([C:10](=[O:27])[CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][CH2:20][C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH:14]=3)[CH2:8][CH2:9][C:4]=2[CH:3]=1)[CH3:30]
Reactant: CNC
Reactant: C=O
Reactant: O=C(CCc1cccc(CCc2ccccc2)c1)N1CCc2ccoc2C1
Solvent: CC(=O)O
Product: CN(C)Cc1cc2c(o1)CN(C(=O)CCc1cccc(CCc3ccccc3)c1)CC2
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.338 g (0.940 mmol) of 1-(5,7-dihydro-4H-furo[2,3-c]pyridin-6-yl)-3-(3-phenethylphenyl) propan-1-one in 20 ml of acetic acid, 0.10 g (1.1 mmol) of 50% aqueous dimethylamine and 0.09 g (1.1 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 15 minutes. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=4/1) to yield the desired product.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:5]=1[CH2:6][CH:7]([CH2:11][CH3:12])[C:8](O)=[O:9].S(Cl)([Cl:23])=O>O>[Br:3][C:4]1[CH:16]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:14]=[CH:13][C:5]=1[CH2:6][CH:7]([CH2:11][CH3:12])[C:8]([Cl:23])=[O:9]
Reactant: O=S(Cl)Cl
Reactant: CCC(Cc1ccc(C(C)(C)C)cc1Br)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCC(Cc1ccc(C(C)(C)C)cc1Br)C(=O)Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
To a mixture of sodium ethoxide obtained from 13.7 g (0.60 mol) of sodium metal and 375 ml of dry ethanol and 193 g (0.50 mol) of diethyl (2-bromo-4-tert-butylbenzyl)malonate 65.5 g (0.60 mol) of ethyl bromide was added dropwise by vigorous stirring. This mixture was refluxed for 4 hours, then cooled, and a solution of 100 g of KOH in 270 ml of water was added. The obtained mixture was refluxed for 5 hours, then ethanol was distilled off. A mixture of the obtained solution and 1.5 liters of cold water was acidified by 1 M HCl to pH 1. The precipitate was decanted and then dissolved in 500 ml of ether. This solution was evaporated to dryness, and the residue was decarboxilated for ca. 2 hours at 180° C. To the obtained 2-(2-bromo-4-tert-butylbenzyl)butanoic acid 128 ml (209 g, 1.76 mol) of thionyl chloride was added. The resulting mixture was stirred for 12 hours at room temperature. An excess of thionyl chloride was distilled off. Fractional rectification of the residue gave 116 g (70%) of yellowish liquid, b.p. 137° C.-142° C./1 mm Hg. Anal. calc. for C15H20BrClO: C, 54.32; H, 6.08. Found: C, 54.43; H, 6.20. 1H NMR (CDCl3): δ 7.54 (d, J=1.9 Hz, 1H, 3-H in C6H3), 7.25 (dd, J=8.0 Hz, J=1.9 Hz, 1H, 5-H in C6H3), 7.16 (d, J=8.0 Hz, 1H, 6-H in C6H3), 3.24-3.06 (m, 2H, CH2CHCH2Me), 2.93 (dd, J=13.6 Hz, J=6.1 Hz, 1H, CHCH2Me), 1.89-1.69 (m, 2H, CH2Me), 1.28 (s, 9H, tBu), 1.02 (t, J=7.5 Hz, CH2Me). 13C{1H} NMR (CDCl3): δ 176.4, 152.1, 133.9, 130.9, 130.1, 124.7, 124.4, 58.3, 37.1, 34.5, 31.1, 24.9, 11.0.
Reaction SMILES: [CH3:1][N:2]([CH3:5])[C:3]#[N:4].C#C.[CH:8]1[CH:13]=CC=[CH:10][CH:9]=1>[CH-]1C=CC=C1.[CH-]1C=CC=C1.[Co+2]>[CH3:1][N:2]([C:3]1[CH:10]=[CH:9][CH:8]=[CH:13][N:4]=1)[CH3:5]
Reactant: CN(C)C#N
Reactant: c1ccccc1
Agent: [Co+2]
Agent: C#C
Agent: c1cc[cH-]c1
Product: CN(C)c1ccccn1
Temperature: 70 °C

Procedure:
3.1 gm. of cobaltocene (0.016 mole) under nitrogen was dissolved in 44.0 gm. of benzol. The solution mixed with 164 gm. of anhydrous N,N-dimethylcyanamide (2.3 moles). The reaction mixture was saturated with 12 atm. of acetylene at 20° C. in a 1-liter autoclave (with stirring). The reaction mixture was heated to 70° C. Then at the beginning of the exothermal reaction, the heating was carefully increased so that a temperature of 160° C. prevailed in the autoclave. After a drop in pressure in the autoclave to below 12 atm., acetylene was repressed on. After 10 hours of reaction time, the autoclave was cooled down and expansion allowed. As a result of fractional distillation, 238 gm. of 2-(N,N-dimethylamino)-pyridine (boiling point: 92° C., 21 torr) was obtained, after benzol and a small quantity of N,N-dimethylcyanamide had been obtained. The 2-(N,N-dimethylamino)-pyridine had a purity of 99.8 percent--this corresponded to a yield of 84.5 percent.
Reaction SMILES: [C:1]1([C:11]([N:13]2[CH2:17][CH:16]([CH2:18][OH:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[OH2:34]>C(Cl)(Cl)(Cl)Cl.CC#N>[C:1]1([C:11]([N:13]2[CH2:17][CH:16]([C:18]([OH:34])=[O:19])[CH:15]([CH2:20][N:21]3[CH2:26][CH2:25][CH:24]([C:27]4[CH:28]=[CH:29][C:30]([F:33])=[CH:31][CH:32]=4)[CH2:23][CH2:22]3)[CH2:14]2)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(c1cccc2ccccc12)N1CC(CO)C(CN2CCC(c3ccc(F)cc3)CC2)C1
Reactant: O
Solvent: CC#N
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(O)C1CN(C(=O)c2cccc3ccccc23)CC1CN1CCC(c2ccc(F)cc2)CC1

Procedure:
A mixture of 0.126 g (0.28 mmol) of 1-(1-naphthoyl)-3-(RS)-(4-(4-fluorophenyl)piperidinylmethyl)-4-(SR)-hydroxymethyl pyrrolidine, 0.18 g (0.85 mmol) of NaIO4, and 0.0029 g (0.014 mmol) of RuCl3.3 H2O in 2 mL of CCl4, 3 mL of H2O and 2 mL of CH3CN was stirred at rt for 1 H. The reaction mixture was partitioned between CH2Cl2 and H2O. The organic fraction was dried over Na2SO4, filtered and the filtrate was concentrated to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:18]([N+:19]([O-])=O)=[CH:17][CH:16]=[C:15]4[C:11]=3/[C:12](=[CH:23]/[C:24]3[NH:25][CH:26]=[CH:27][C:28]=3[O:29][CH3:30])/[C:13](=[O:22])[NH:14]4)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.O.[Cl-].[NH4+]>CO.C1COCC1.[Zn]>[NH2:19][C:18]1[C:10]([C:6]2[CH:5]=[C:4]3[C:9](=[CH:8][CH:7]=2)[NH:1][CH:2]=[CH:3]3)=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:22])/[C:12]/2=[CH:23]\[C:24]1[NH:25][CH:26]=[CH:27][C:28]=1[O:29][CH3:30]
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc([N+](=O)[O-])c(-c3ccc4[nH]ccc4c3)c21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2ccc(N)c(-c3ccc4[nH]ccc4c3)c21

Procedure:
To a solution of (Z)-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-5-nitro-2H-indol-2-one (33 mg, 0.08 mmol) (from Step A above) in 1 mL of a 10% water in methanol solution and 0.5 mL THF was added zinc dust (145 mg, 2.21 mmol) followed by ammonium chloride (14 mg, 0.26 mmol). The reaction was heated at gentle reflux for 4 hours, at which time the reaction mixture was filtered through a pad of Celite® and rinsed thoroughly with ethyl acetate. The resulting solution was diluted with 5 mL water and the product was extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated. The resulting powder was recrystallized from EtOAc/hex to give (Z)-5-amino-1,3-dihydro-4-(5-indolyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one as a red powder. (Yield 24 mg, 80%).
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11][C:4]2([NH:8][C:7](=[O:9])[NH:6][C:5]2=[O:10])[CH2:3]1.[OH-:18].[K+].Br[CH2:21][CH:22]([OH:25])[CH2:23]Br>CN(C)C=O>[OH:25][CH:22]([CH2:23][N:6]1[C:5](=[O:18])[C:4]2([CH2:3][C:2]([CH3:1])([CH3:17])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9])[CH2:21][N:6]1[C:5](=[O:10])[C:4]2([CH2:3][C:2]([CH3:17])([CH3:1])[N:13]([CH3:14])[C:12]([CH3:16])([CH3:15])[CH2:11]2)[NH:8][C:7]1=[O:9]
Reactant: [OH-]
Reactant: CN1C(C)(C)CC2(CC1(C)C)NC(=O)NC2=O
Reactant: OC(CBr)CBr
Agent: [K+]
Solvent: CN(C)C=O
Product: CN1C(C)(C)CC2(CC1(C)C)NC(=O)N(CC(O)CN1C(=O)NC3(CC(C)(C)N(C)C(C)(C)C3)C1=O)C2=O
Reaction time: 0.5 h

Procedure:
22.0 g of 7,7,8,9,9-pentamethyl-1,3,8-triazaspiro[4.5]decane-2,4-dione and 5.1 g of potassium hydroxide were added to 200 ml of N,N-dimethylformamide, and the mixture was heated, with stirring, for 30 minutes at 50°-60° C. At the end of this time, 9.0 g of 1,3-dibromo-2-propanol were added dropwise to the mixture and the whole mixture was heated, with stirring, for 6 hours at 100°-110° C. After completion of the reaction, the reaction mixture was condensed by evaporation and the residue was washed with a 1% w/w aqueous solution of potassium hydroxide and then recrystallised from a 2:1 by volume mixture of benzene and ethanol, giving the desired Compound No. 164 in the form of white crystals, melting point 255°-256° C.
Reaction SMILES: [CH3:1][O-:2].[Na+].[CH3:4][C:5]1([CH3:18])[C@@H:7]([CH:8](Br)[C:9](=O)[CH2:10]Br)[C@H:6]1[C:14]([O:16][CH3:17])=[O:15].C[OH:20]>>[CH3:4][C:5]1([CH3:18])[C@@H:7](/[CH:8]=[CH:9]\[C:10]([O:2][CH3:1])=[O:20])[C@H:6]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: COC(=O)[C@@H]1[C@H](C(Br)C(=O)CBr)C1(C)C
Reactant: CO
Reactant: C[O-]
Agent: [Na+]
Product: COC(=O)/C=C\[C@H]1[C@@H](C(=O)OC)C1(C)C
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
0.16 g of sodium methylate and 1.6 ml of methanol were mixed together under an inert gas atmosphere and after the mixture was cooled to about 0° C., 0.5 g of methyl (1R,cis) 2,2-dimethyl-3-(1,3-dibromo-2-oxopropyl)-cyclopropane-1-carboxylate in solution in 2.5 ml of methanol were slowly added. The mixture was stirred at about -5° C. for 90 minutes and then the solvent was evaporated under reduced pressure at about 30° C. and 10 ml of methylene chloride were added. The solution was washed with water, dried and concentrated to dryness to obtain 0.324 g of crude product which was chromatographed on silica, eluting with a cyclohexane - ethyl acetate mixture (6-4) to obtain 0.262 g of the expected product.