Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:15]=[C:14](C(=S)CC)[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:10])=[O:9].ClC1C=CC=[C:28]([C:32]([O:34]O)=O)C=1>ClCCl>[F:1][C:2]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:15]=[C:14]([C:32](=[O:34])[CH2:28][S:8]([CH3:11])(=[O:10])=[O:9])[CH:13]=[CH:12][C:6]=1[NH:7][S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCC(=S)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Solvent: ClCCl
Product: CS(=O)(=O)CC(=O)c1ccc(NS(C)(=O)=O)c(Oc2ccc(F)cc2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.5 %

Procedure:
A mixture of 2'-(2,4-difluorophenoxy)-4'-(methylthioacetyl)methanesulfonanilide (1.4 g) and m-chloroperbenzoic acid (1.4 g) in dichloromethane (15 ml) was stirred for 1 hour at room temperature. The mixture was washed with an aqueous solution of sodium bicarbonate and water, dried, and concentrated. The residue was recrystallized from ethyl acetate to give colorless crystals of 2'-(2,4-difluorophenoxy)-4'-(methylsulfonylacetyl)methanesulfonanilide (0.66 g), mp 162° to 163° C.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C@H:10]([SH:25])[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:21])[CH2:3][CH2:2]1.[O:27]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34](Cl)=[O:35])=[CH:28]1>>[CH:1]1([CH2:4][N:5]2[CH2:24][CH2:23][C@:12]34[C:13]5[C:14]6[O:22][C@H:11]3[C@H:10]([S:25][C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]3[CH:30]=[CH:31][O:27][CH:28]=3)[CH2:9][CH2:8][C@@:7]4([OH:26])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[O:20][CH3:21])[CH2:3][CH2:2]1
Reactant: O=C(Cl)/C=C/c1ccoc1
Reactant: COc1ccc2c3c1O[C@H]1[C@H](S)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Product: COc1ccc2c3c1O[C@H]1[C@H](SC(=O)/C=C/c4ccoc4)CC[C@@]4(O)[C@@H](C2)N(CC2CC2)CC[C@]314
Yield: 59 %

Procedure:
The procedure of Example 11 was repeated, except that 17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-3-methoxy-6β-mercaptomorphinan(K. Kanematsu, T. Toshiyasu, M. Yoshida., Chem., Pharm. Bull., 38, 1141, (1990)) was used instead of 17-cyclopropylmethyl-4,5α-epoxy-3,14β-dihydroxy-6α-(N-methylamino)morphinan 4 and trans-3-(3-furyl)acryloyl chloride was used instead of 3,4-dichlorophenylacetyl chloride, thereby preparing 17-cyclopropylmethyl-4,5α-epoxy-14β-hydroxy-3-methoxy-6β-[trans-3-(3-furyl)acryloylthio]morphinan 169 (yield: 59%).
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH2:17]Cl)(OC(C)(C)C)=O.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[NH:25][C:26](=[O:45])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][NH:34][CH:35]2[C:44]3[N:43]=[CH:42][CH:41]=[CH:40][C:39]=3[CH2:38][CH2:37][CH2:36]2)=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.C(OCC)(=O)C>[CH2:37]1[CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[N:43][C:44]=2[CH:35]([N:34]([CH2:17][C:9]2[NH:8][C:12]3[C:11](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:26]([NH:25][C:20]3[N:19]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[O:45])=[CH:28][CH:29]=2)[CH2:36]1
Reactant: CC(C)(C)OC(=O)n1c(CCl)nc2ccccc21
Reactant: O=C(Nc1ccccn1)c1ccc(CNC2CCCc3cccnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccn1)c1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 47.6 %

Procedure:
N-BOC-chloromethylbenzimidazole (115 mg, 0.43 mmol), N-Pyridin-2-yl-4-[(5,6,7,8-tetrahydro-quinolin-8-ylamino)-methyl]-benzamide (AMD9362) (155 mg, 0.43 mmol), and K2CO3 (179 mg, 1.29 mmol) were heated to reflux in CH3CN (3 mL) for 24 hours under N2. The reaction mixture was diluted with 200 mL ethyl acetate, and washed with sat. NaHCO3, brine and dried over Na2SO4. Evaporation of the solvent and purification of the residue by flash chromatography on silica gel, followed by radial chromatography on silica gel (2 mm plate, 3:3:94 CH3OH—NH3 H2O—CH2Cl2), afforded AMD9370 (100 mg, 47%) as white foam. 1H NMR (CDCl3) δ 1.68-1.75 (m, 1H), 1.97-2.08 (m, 2H), 2.26-2.32 (m, 1H), 2.71-2.84 (m, 1H), 2.86-2.91 (m, 1H), 3.84 (s, 2H), 3.95 (d, 1H, J=16.5 Hz), 4.08-4.14 (m, 1H), 4.22 (d, 1H, J=16.0 Hz), 7.03-7.07 (m, 1H), 7.16-7.22 (m, 3H), 7.45 (d, 1H, J=6.9 Hz), 7.52-7.61 (m, 3H), 7.65 (d, 1H, J=7.5 Hz), 7.73 (ddd, 1H, J=1.8, 7.2, 8.7 Hz), 7.80 (d, 2H, J=8.1 Hz), 8.27-8.29 (m, 1H), 8.33 (d 1H, J=8.4 Hz), 8.44 (br, s, 1H), 8.72-8.80 (m, 1H); 13C NMR (CDCl3) δ 21.72, 23.30, 29.56, 49.29, 54.16, 60.83, 111.39, 114.52, 120.17, 122.29, 122.81, 127.72, 129.28, 133.58, 135.17, 137.76, 138.77, 144.61, 147.38, 148.21, 152.00, 156.13, 157.54, 165.99; ES-MS m/z 489.2 (M+H); Anal. Calcd. for (C30 H28N6O)•0.6(H2O)•0.7(CHCl3): C, 63.25; H, 5.17; N, 14.42. Found: C, 63.56; H, 5.25; N, 14.31.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11](OS(C)(=O)=O)[CH2:10][C@H:9]1[C:18]([O:20][CH3:21])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:22]=[N+:23]=[N-:24].[Na+]>CS(C)=O.C(OCC)(=O)C>[N:22]([C@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:18]([O:20][CH3:21])=[O:19])[CH2:10]1)=[N+:23]=[N-:24]
Reactant: COC(=O)[C@@H]1C[C@H](OS(C)(=O)=O)CN1C(=O)OC(C)(C)C
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)[C@@H]1C[C@@H](N=[N+]=[N-])CN1C(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 8 h
Yield: 86.4 %

Procedure:
A mixture of (2S,4S)-1-t-butoxycarbonyl-4-methylsulfonyloxy-2-methoxycarbonylpyrrolidine (27.7 g) and sodium azide (10.6 g) in dimethyl sulfoxide (350 ml) was stirred at 90° C. overnight and the solution was diluted with ethyl acetate (600 ml). The solution was washed successively with water and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-4-azido-1-t-butoxycarbonyl-2-methoxycarbonylpyrrolidine (20.0 g) as a pale brown oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[OH:12])[CH2:7][OH:8])[CH3:2].[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21](O)=[O:22].O>CCCCCC>[CH3:13][CH:14]([CH3:24])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:8][CH2:7][C:6]1[CH:9]=[CH:10][C:11]([OH:12])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)=[O:22]
Reactant: CCOc1cc(CO)ccc1O
Reactant: CC(C)CCCCCCC(=O)O
Solvent: O
Solvent: CCCCCC
Product: CCOc1cc(COC(=O)CCCCCCC(C)C)ccc1O
Temperature: 50 °C
Yield: 89.1 %

Procedure:
3-Ethoxy-4-hydroxybenzyl alcohol (733 mg, 4.35 mmol), 8-methylnonanoic acid (751 mg, 4.35 mmol) and Novozyme 435 (100 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 3-ethoxy-4-hydroxybenzyl 8-methylnonanoate (1.25 g, yield 88.8%) as a colorless oil.
Reaction SMILES: C([NH:4][C:5]1[S:6][C:7]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][N:9]=1)(=O)C.Cl.C(O)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH2:4][C:5]1[S:6][C:7]([S:10]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[O:11])=[CH:8][N:9]=1
Reactant: CC(=O)Nc1ncc(S(=O)c2ccc(N)cc2)s1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(S(=O)c2cnc(N)s2)cc1
Yield: 105.8 %

Procedure:
A mixture of 2-acetylamino-5-(4-aminophenylsulfinyl)thiazole (5.0 g) in a mixture of aqueous 6N-hydrochloric acid (10 ml) and acetic acid (35 ml) was refluxed for 3.5 hours with stirring. The reaction mixture was diluted with water and adjusted to pH 8 using aqueous sodium carbonate under ice cooling. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-amino-5-(4-aminophenylsulfinyl)thiazole (4.5 g, yield: 100%).
Reaction SMILES: O.O.[F-].[K+].[OH:5][C:6]1[CH:7]=[C:8]([CH:11]=[C:12]([N+:15]([O-:17])=[O:16])[C:13]=1[OH:14])[CH:9]=[O:10].Br[CH2:19][CH2:20]Br>CN(C)C=O>[N+:15]([C:12]1[C:13]2[O:14][CH2:19][CH2:20][O:5][C:6]=2[CH:7]=[C:8]([CH:9]=[O:10])[CH:11]=1)([O-:17])=[O:16]
Reactant: BrCCBr
Reactant: O=Cc1cc(O)c(O)c([N+](=O)[O-])c1
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1cc2c(c([N+](=O)[O-])c1)OCCO2
Temperature: 130 °C
Yield: 61.3 %

Procedure:
To a mixture of potassium fluoride dihydrate (2.573 g, 27.3 mmol), and 3,4-dihydroxy-5-nitrobenzaldehyde (500 mg, 2.73 mmol) in N,N-dimethylformamide (20 mL) was added 1,2-dibromoethane (3.8 mL, 43.7 mmol), and the mixture was heated at 130° C. for 17 h. The reaction mixture was quenched with water followed by a standard aqueous/EtOAc workup and purified by column chromatography on silica gel (petroleum ether/ethyl acetate=15:1) to give Intermediate 45 (350 mg, yield 62.1%).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[N:7][C:8]([C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=3[Cl:26])=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[CH:10]=2)[N:5]([CH2:27][CH:28]([CH3:30])[CH3:29])[C:4](=[O:31])[C:3]=1[CH3:32].[H-].[Na+].[C:35](Cl)(=[O:37])[CH3:36]>C1COCC1.CCOC(C)=O>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[C:11]3[C:6](=[N:7][C:8]=2[C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][C:20]=2[Cl:26])[N:5]([CH2:27][CH:28]([CH3:29])[CH3:30])[C:4](=[O:31])[C:3]([CH3:32])=[C:2]3[NH:1][C:35](=[O:37])[CH3:36])=[CH:17][CH:16]=1
Reactant: Cc1c(N)c2cc(-c3ccc(Cl)cc3)c(-c3ccc(Cl)cc3Cl)nc2n(CC(C)C)c1=O
Reactant: CC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)Nc1c(C)c(=O)n(CC(C)C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12

Procedure:
To the product of EXAMPLE 42 (28 mg) in THF (0.5 mL) at 0° C. was added NaH (5 mg, 60% dispersion in mineral oil). The reaction stirred 10 minutes before acetyl chloride (7 μL) was added. Two hours later an additional 20 μL portion of acetyl chloride was added and again after an additional 90 minutes. After an additional hour of reaction time the reaction was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution and dried (Na2SO4). The concentrated residue was purified by preparative TLC on silica gel eluted with 70% EtOAc in hexane affording the title compound. HPLC/MS: 528.0 (M+1), 530.0 (M+3); Rt=4.27 min.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].[Cl:27][CH2:28][CH2:29][CH2:30][CH2:31][C:32]#[CH:33].C(N(CC)CC)C>CN(C)C=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[CH2:1]([C:5]1[N:6]=[C:7]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][C:18]=2[O:25][CH3:26])[C:8]2[NH:13][N:12]=[C:11]([C:33]#[C:32][CH2:31][CH2:30][CH2:29][CH2:28][Cl:27])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(I)c2n1
Reactant: C#CCCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCc1nc(NCc2ccc(OC)cc2OC)c2[nH]nc(C#CCCCCCl)c2n1
Yield: 52.3 %

Procedure:
A solution of 5-butyl-N-(2,4-dimethoxybenzyl)-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7-amine (50 g, 107 mmol), 6-chloro-1-hexyne (18.71 g, 160 mmol), triethylamine (22.37 mL, 160 mmol), bis(triphenylphosphine)palladium(II)dichloride (5.63 g, 8.02 mmol) and copper(I) iodide (3.04 g, 15.94 mmol) in N,N-Dimethylformamide (1000 mL) under nitrogen was heated to 70° C. for 4 hours. The cooled solution was evaporated and the residue was purified by chromatography on a 1.5 kg silica cartridge eluted with 20-80% cyclohexane—EtOAc during 12 column volumes. Appropriate fractions were evaporated to give the title compound as a yellow foam (25.5 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[S:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:32]1([CH2:38][O:39][C:40](Cl)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>ClCCl>[C:32]1([CH2:38][O:39][C:40]([N:22]2[CH2:21][CH2:20][CH:19]([S:18][C:10]3[N:9]([CH2:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=4[N:11]=3)[CH2:24][CH2:23]2)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: Fc1ccc(Cn2c(SC3CCNCC3)nc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(Sc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reaction time: 1 h

Procedure:
To a stirred mixture of 10.2 parts of 1-[(4-fluorophenyl)methyl]-2-[(4-piperidinyl)thio]-1H-benzimidazole, 3.1 parts of N,N-diethylethanamine and 130 parts of dichloromethane was added dropwise a solution of 5.12 parts of (phenylmethyl)carbonochloridate in 65 parts of dichloromethane. Upon completion, stirring was continued for 1 hour at room temperature. The reaction mixture was washed with water. The organic layer was dried, filtered and evaporated, yielding 14.3 parts of (phenylmethyl)4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]thio]-1-piperidinecarboxylate as a residue (75).
Reaction SMILES: [C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C:9](=[CH:21][CH2:22]P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[Li]CCCC.[CH3:44][Si:45]([CH3:68])([CH3:67])[O:46][C:47]([CH3:66])([CH3:65])[C:48]#[C:49][CH2:50][C@H:51]([C:53]1[C@:54]2([CH3:64])[C@@H:59]([CH2:60][CH2:61][CH:62]=1)[C:58](=O)[CH2:57][CH2:56][CH2:55]2)[CH3:52]>C1COCC1>[C:1]([Si:5]([CH3:38])([CH3:37])[O:6][C@H:7]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[CH2:10][C:9](=[CH:21]/[CH:22]=[C:58]2\[CH2:57][CH2:56][CH2:55][C@@:54]3([CH3:64])[C@H:59]\2[CH2:60][CH2:61][CH:62]=[C:53]3[C@H:51]([CH3:52])[CH2:50][C:49]#[C:48][C:47]([CH3:66])([O:46][Si:45]([CH3:44])([CH3:68])[CH3:67])[CH3:65])[CH2:8]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2C(=O)CCC[C@]12C
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1CC(=CCP(=O)(c2ccccc2)c2ccccc2)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: C[C@H](CC#CC(C)(C)O[Si](C)(C)C)C1=CCC[C@H]2/C(=C/C=C3C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O[Si](C)(C)C(C)(C)C)C3)CCC[C@]12C
Reaction time: 0.75 h

Procedure:
511 mg (0.893 mmol) of carefully dried (3R,5R)-[2-[3,5-bis-(t-butyl-dimethyl-silanyloxy)-cyclohexylidene]-ethyl]-diphenyl-phosphine oxide (Tetrahedron Lett. 32, 7663 (1991)) was dissolved in 5 ml of abs. THF and treated at -78° with 0.65 ml of nBuLi (1.55M, hexane). 15 Minutes later, 179 mg (0.496 mmol) of (4aS,8aR)-5-[(R)-5-trimethylsilanyloxy-1,5-dimethyl-hex-3-ynyl]-4a-methyl-1,2,3,4,4a,7,8,8a-octahydro-naphthalen-1-one, dissolved in 0.5 ml of abs. THF, was added to the deep red solution and kept for 1 h at -78° and for 0.75 h at 0°. The reaction mixture was then poured onto crushed ice/KH2PO4, extracted twice with ether, washed with water and brine, dried over sodium sulfate, and the solvents carefully removed i.V. Flash chromatography (SiO2, hexane/AcOEt=9/1) afforded 108 mg of the title compound as colorless oil, besides 122 mg of recovered ketone in the more polar fractions.
Reaction SMILES: [C:1]1([CH3:10])[C:2]([C:7](Cl)=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[C-:12]#[N:13].[Na+]>ClCCl.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:10][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([C:12]#[N:13])=[O:8]
Reactant: Cc1ccccc1C(=O)Cl
Reactant: [C-]#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccccc1C(=O)C#N
Reaction time: 2 h

Procedure:
To a stirred solution of o-toluoyl chloride (38.86 g) in dichloromethane (250 ml) at room temperature was added water (20.0 ml) followed immediately by tetrabutylammonium bromide (0.15 g) and sodium cyanide (13.0 g). The reaction mixture was stirred vigorously for 11/2 hours, then filtered. The filtrate was washed with water (2×100 ml) then dried (MgSO4) and evaporated under reduced pressure to give a golden oil. Distillation under vacuum gave 2-methylbenzoyl cyanide, as a colourless oil, bp 47°-50°/0.05 mm. To 85% w/w sulphuric acid (140 ml) at room temperature was added sodium bromide (20 g) followed immediately by the dropwise addition of 2-methylbenzoyl cyanide (34.8 g). The reaction mixture was then heated gently until the exothermic reaction started and then maintained at 70° C. for 10 minutes by cooling. Methanol (400 ml) was added and the mixture heated under reflux for 1 hour, cooled and diluted with ice/water (500 ml). Extraction with diethyl ether gave a golden oil which was distilled under vacuum to give methyl oxo(o-tolyl)acetate, as B colourless oil, bp 75°-85°/0.4 mm.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6](=O)[CH2:5]1)(=[O:3])[CH3:2].[CH3:14][C:15]1([CH3:23])[CH2:20][C:19](=[O:21])[CH2:18][C:17](=[O:22])[CH2:16]1.C(N(CC)CC)C>C(O)(=O)C>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH:18]2[C:19](=[O:21])[CH2:20][C:15]([CH3:23])([CH3:14])[CH2:16][C:17]2=[O:22])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: CC(=O)N1CC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)n1cc(C2C(=O)CC(C)(C)CC2=O)c2ccccc21
Yield: 76 %

Procedure:
1-Acetyl-1,2-dihydroindol-3-one of Example 1d (131.3 g, 0.75 mol) and 5,5-dimethyl-cyclohexane-1,3-dione (105 g, 0.75 mol) were added to a mixture of acetic acid (700 mL) and triethylamine (105 mL, 0.75 mol) at room temperature under stirring. The reaction mixture was refluxed for 6 h. About ⅓ volume of solvents was removed in vacuum, and the mixture was cooled and diluted with water (50 mL). The precipitate was filtered off, washed with ethanol-water, 1:1 and dried to afford 169.4 g (76%) of colorless crystals; m.p. 225-227° C.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH2:15]>COC(C)(C)C.C(O)(C)C>[CH3:10][N:11]([CH3:16])[CH2:12][CH2:13][CH2:14][NH:15][C:8]([NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[S:9]
Reactant: CN(C)CCCN
Reactant: S=C=Nc1ccccc1
Solvent: CC(C)O
Solvent: COC(C)(C)C
Product: CN(C)CCCNC(=S)Nc1ccccc1
Reaction time: 2 h
Yield: 70.1 %

Procedure:
Phenyl isothiocyanate (5.283 g, 39.1 mmole) in 30 mL t-butyl methyl ether was added to a solution of 3-(dimethylamino)propylamine (3.993 g, 39.1 mmole) in 10 mL isopropanol. After stirring 2 hr at room temp., the solid which separated was filtered out and washed with t-butyl methyl ether to afford 6.51 g of 1-[3-(dimethylamino)propyl]-3-phenylthiourea (mp 112–114° C.), part of which (2.374 g, 10 mmole) was dissolved in ethanol (20 mL) containing conc. HCl (1.67 mL, 20 mmole) and added to 2-methylnaphthoquinone dissolved in warm ethanol (35 mL). After 4 days in a stoppered flask at room temp., the mixture was concentrated, and dissolved in ethyl acetate. The solid which separated after 16 hr was filtered out, but became sticky on the filter and was discarded. The filtrate was stored another 12 days at room temp. The powder which separated was filtered out to give 600 mg of pinkish-buff powder. Of this, 325 mg was recrystallized from 10 mL methanol+60 mL ethyl acetate containing a few drops of water to give 260 mg of the title compound, mp 238–240° C.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:9](O)=[O:10])[N:5]([CH3:8])[C:6]=1[Br:7].C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:28][C:29]1[NH:33][N:32]=[N:31][N:30]=1>>[Br:1][C:2]1[C:3]([O:12][CH:13]([CH3:15])[CH3:14])=[C:4]([C:9]([NH:28][C:29]2[NH:33][N:32]=[N:31][N:30]=2)=[O:10])[N:5]([CH3:8])[C:6]=1[Br:7]
Reactant: CC(C)Oc1c(Br)c(Br)n(C)c1C(=O)O
Reactant: Nc1nnn[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)Oc1c(Br)c(Br)n(C)c1C(=O)Nc1nnn[nH]1
Yield: 51.5 %

Procedure:
Prepared by the method described in Example 115 from 4,5-dibromo-3-(1-methylethoxy)-1-methyl-1H-pyrrole-2-carboxylic acid (3.5 g, 0.01 moles), 1,1'-carbonyldiimidazole (1.7 g, 0.01 moles), and 5-aminotetrazole (0.87 g, 0.01 moles). Recrystallization from ethyl acetate gave the product (2.1 g); mp 218°-220° C. (dec).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18](Cl)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH:26]([C:30]#[N:31])[CH2:25]1.C(N(C(C)C)CC)(C)C>CC(O)C>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[C:18]([NH:23][C@@H:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([C:30]#[N:31])[CH2:25]4)=[C:13]3[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1Cl
Reactant: N#CC1CCCC(N)C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: N#C[C@H]1CCC[C@@H](Nc2c([N+](=O)[O-])cnc3c2ccn3S(=O)(=O)c2ccccc2)C1
Yield: 23.5 %

Procedure:
A mixture of 1-benzenesulfonyl-4-chloro-5-nitro-1H-pyrrolo[2,3-b]pyridine (1.01 g, 3.00 mmol), 3-amino-cyclohexanecarbonitrile (3.30 mmol assumed) and diisopropylethylamine (2.60 mL, 15.0 mmol) in propan-2-ol (30 mL) were heated to reflux for 2 hours. The cooled reaction mixture was filtered and the yellow solid further purified by column chromatography on silica gel (gradient: 0 to 10% ethyl acetate in toluene) to afford 300 mg (23%) of cis 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)cyclohexanecarbonitrile. 1H NMR (400 MHz, DMSO) δ: 8.90 (s, 1H), 8.80 (d, 1H), 8.13 (m, 2H), 7.84 (d, 1H), 7.76 (m, 1H), 7.66 (m 2H), 7.09 (d, 1H), 4.11 (m, 1H), 3.10 (m, 1H), 2.28 (m, 1H), 1.98 (m, 2H), 1.79 (m, 2H), 1.50 (m, 3H). The filtrate was concentrated and purified by column chromatography on silica gel (gradient: 0 to 10% ethyl acetate in toluene) to afford 220 mg (17%) of trans 3-(1-benzenesulfonyl-5-nitro-1H-pyrrolo[2,3-b]pyridine-4-ylamino)cyclohexanecarbonitrile. LCMS (Method I, ESI): RT=3.76 min, m+H=426.1; 1H NMR (400 MHz, DMSO) δ: 8.92 (s, 1H), 8.13 (dd, 2H), 7.88 (d, 1H), 7.77 (t, 1H), 7.65 (t, 2H), 6.99 (d, 1H), 4.27 (m, 1H), 3.26 (m, 1H), 2.18 (m, 1H), 1.99 (m, 1H), 1.91 (m, 1H), 1.83-1.58 (m, 5H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Ni].CCO>[N:13]1([CH2:12][CH2:11][NH:10][C:7]2[CH:6]=[CH:5][C:4]([NH2:1])=[CH:9][CH:8]=2)[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: O=[N+]([O-])c1ccc(NCCN2CCCC2)cc1
Agent: [Ni]
Agent: NN
Solvent: CCO
Solvent: O
Product: Nc1ccc(NCCN2CCCC2)cc1
Temperature: 65 °C
Reaction time: 1 h
Yield: 71.3 %

Procedure:
A 25 mL round bottom flask was charged with (4-Nitro-phenyl)-(2-pyrrolidin-1-yl-ethyl)-amine (0.352 g, 1.50 mmol) and EtOH (5 mL). Hydrazine Hydrate (0.326 mL, 10.5 mmol) was then added to the solution. Excess RaNi was then added in dropwise until gas evolution ceased. The suspension was then allowed to stir for an additional 1 h at 65° C. The suspension was cooled to room temperature and then was filtered over celite. The celite was washed with MeOH (˜20 mL) and the combined organic solutions were then concentrated in vacuo affording pure N-(2-Pyrrolidin-1-yl-ethyl)-benzene-1,4-diamine as a light purple oil (0.219 g, 1.07 mmol, 71% yield).