Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@:4]1([C:43]2[CH:48]=[C:47]([CH2:49][C:50]3[CH:55]=[CH:54][C:53]([CH2:56][CH3:57])=[CH:52][CH:51]=3)[C:46]([Cl:58])=[CH:45][C:44]=2[O:59]C)[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:5]1)[CH:2]=[CH2:3]>O>[CH2:1]([C@:4]1([C:43]2[CH:48]=[C:47]([CH2:49][C:50]3[CH:51]=[CH:52][C:53]([CH2:56][CH3:57])=[CH:54][CH:55]=3)[C:46]([Cl:58])=[CH:45][C:44]=2[OH:59])[C@H:9]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@@H:8]([O:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C@H:7]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@@H:6]([CH2:34][O:35][CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[O:5]1)[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2OC)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Solvent: O
Product: C=CC[C@@]1(c2cc(Cc3ccc(CC)cc3)c(Cl)cc2O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 97.8 %

Procedure:
34 (500 mg, 98% yield) was prepared from 33 (520 mg) using the same procedure used to prepare 25. 1H NMR (300 MHz, CDCl3) δ 8.95 (s, 1H), 7.20-7.39 (m, 18H), 6.87-7.14 (m, 10H), 5.48-5.62 (m, 1H), 4.75-4.99 (m, 5H), 4.65 (d, J=12 Hz, 1H), 4.38-4.49 (m, 3H), 3.69-4.02 (m, 9H), 3.52-3.58 (m, 1H), 3.03 (dd, J=6.3, 16.2 Hz, 1H), 2.75 (dd, J=6.3, 16.2 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 1.17 (t, J=7.5 Hz, 3H). LC/MS m/z 827 (M+H+water), 832 (M+Na).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH2:12][CH:13]2[CH2:18][CH2:17][CH:16]([C:19](O)=[O:20])[CH2:15][CH2:14]2)[NH:3]1.C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH2:40]>CN(C=O)C>[F:36][C:37]1[CH:44]=[CH:43][CH:42]=[CH:41][C:38]=1[CH2:39][NH:40][C:19]([C@H:16]1[CH2:15][CH2:14][C@@H:13]([CH2:12][C:4]2[NH:3][C:2](=[O:1])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH2:18][CH2:17]1)=[O:20]
Reactant: O=C(O)C1CCC(Cc2nc3ccccc3c(=O)[nH]2)CC1
Reactant: NCc1ccccc1F
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: O=c1[nH]c(C[C@H]2CC[C@@H](C(=O)NCc3ccccc3F)CC2)nc2ccccc12
Reaction time: 1 h

Procedure:
To a solution of 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid (275 mg, 1.05 mmol), EDC (200 mg, 1.05 mmol) and HOAt (142 mg, 1.05 mmol) in anhydrous DMF (4 mL) was added 2-fluorobenzylamine (131 mg, 1.05 mmol), and the resulting reaction mixture was stirred for 1 h. The reaction mixture was partitioned between saturated aqueous NaHCO3 and EtOAc, and the organic layer washed 2× with water. The EtOAc was dried with MgSO4 and concentrated to give a yellow solid. Preparative chromatography eluting with chloroform:methanol gave the cis 4-(4-oxo-3,4-dihydro-quinazolin-2-ylmethyl)-cyclohexanecarboxylic acid 2-fluoro-benzylamide as a white solid: mass spectrum m/z 394 [(M+H)+; calcd for C23H24FN3O2: 393].
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][S:21]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[S:30](Cl)(=[O:32])=[O:31])(=[O:23])=[O:22]>>[C:1]([O:5][C:6]([N:8]([O:9][C:10]([O:12][CH2:13][CH2:14][O:15][CH2:16][CH2:17][O:18][CH3:19])=[O:11])[S:30]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[S:21]([CH3:20])(=[O:23])=[O:22])(=[O:32])=[O:31])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCOCCOC(=O)ONC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Product: COCCOCCOC(=O)ON(C(=O)OC(C)(C)C)S(=O)(=O)c1ccccc1S(C)(=O)=O

Procedure:
1-({[(tert-Butoxy)carbonyl]({[2-(2-methoxyethoxy)ethoxy]carbonyl}oxy)-amino}sulfonyl)-2-methanesulfonylbenzene (101) is prepared from 1-(2-{[({[(tert-butoxy)carbonyl]amino}oxy)carbonyl]oxy}ethoxy)-2-methoxyethane and 2-methylsulfonyl benzene sulfonyl chloride according to Scheme 11. (2.72 g, 70%), 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 8.40 (2H, ddd, 12.7, 7.5, 1.5 Hz), 7.86 (2 H, m), 4.37-4.56 (2H, m), 3.71-3.85 (2H, m), 3.62-3.71 (2H, m), 3.50-3.60 (2H, m), 3.43 (3H, s), 3.39 (3H, s), 1.43 (9H, s).
Reaction SMILES: Cl[S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[OH:18]>C1(C)C(C)=CC=CC=1>[Cl:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[O:18][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3]
Reactant: Oc1ccccc1OCCCl
Reactant: O=C=NS(=O)(=O)Cl
Solvent: Cc1ccccc1C
Product: O=C=NS(=O)(=O)Oc1ccccc1OCCCl
Temperature: 140 °C

Procedure:
3.4 g (0.024 mol) of chlorosulfonyl isocyanate are added dropwise at 25° C. to a solution of 3.45 g (0.02 mol) of 2-(2-chloroethoxy)phenol in 20 ml of xylene. When the dropwise addition is complete, the temperature is increased slowly to 140° C., and the mixture is refluxed for 2 hours. The mixture is cooled and the solvent as well as excess chlorosulfonyl isocyanate are removed on a rotary evaporator. The yellow oil which remains (5.6 g=100% of theory) is employed without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2Cl)=[O:5])[CH3:2].[O-:21][CH2:22][CH3:23].[Na+]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([S:16]([CH3:19])(=[O:18])=[O:17])=[C:9]2[O:21][CH2:22][CH3:23])=[O:5])[CH3:2]
Reactant: CC[O-]
Reactant: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(Cl)c2c1
Agent: [Na+]
Product: CCOC(=O)c1ccc2ncc(S(C)(=O)=O)c(OCC)c2c1

Procedure:
4-Chloro-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester (example 61f, 7.96 g, 25.4 mmol) was dissolved in anhydrous alcohol (500 mL) which containing sodium ethoxide (3.45 g, 50.8 mmol). The mixture was heated at 60 degrees for 6 hours under stirring. After the reaction, the solvent was evaporated under reduced pressure, and then dichloromethane was added. After filtration, the filtrate was concentrated to give 4-ethoxy-3-methanesulfonyl-quinoline-6-carboxylic acid ethyl ester, which was used for next step without further purification. LC-MS m/e 324 (MH+).
Reaction SMILES: [ClH:1].[CH3:2][N:3]1[CH2:8][CH:7]=[CH:6][CH2:5][CH:4]1[C:9]#[N:10].C[OH:12]>>[ClH:1].[CH3:2][N:3]1[CH2:8][CH:7]=[CH:6][CH:5]=[C:4]1[CH:9]=[N:10][OH:12]
Reactant: CN1CC=CCC1C#N
Reactant: CO
Agent: Cl
Product: CN1CC=CC=C1C=NO

Procedure:
To 200 ml. of cooled, but freshly boiled methanol, 17.0 g. (0.084 mol) of the hydrochloride form of the precursor compound (1-methyl-2-cyano-1,2,3,6-tetrahydropyridine hydrochloride) obtained earlier was added. The suspension was mixed under nitrogen for 11/2 hours. During that time, a solution was formed and a new product was precipitated. The product was filtered, washed with ether, and dried in vacuo to yield 11.7 g. (80%) of the objective compound (1-methyl-1,6-dihydropyridine-2-aldoxime hydrochloride), mp 179° C (decomp). The NMR spectrum was consistent with the structure of the compound obtained. The analysis of the compound by I.R. (KBr pellet) showed strong and medium bands at 1655, 1700. U.V. analysis in 0.1 N HCl-251 nm (ε=13,300); pH of 8 - 308 nm; 0.1N NaOH-260 nm (ε=7640) and 340 nm (ε=5440).
Reaction SMILES: COC1C=CC(N2CCN(CCC3C=CC=CC=3)CC2)=CC=1C.[CH:24]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[C:42]([F:44])[C:41]([O:45]C)=[CH:40][C:39]=3[F:47])[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH:24]1([CH2:30][CH2:31][N:32]2[CH2:37][CH2:36][N:35]([C:38]3[C:39]([F:47])=[CH:40][C:41]([OH:45])=[C:42]([F:44])[CH:43]=3)[CH2:34][CH2:33]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: COc1cc(F)c(N2CCN(CCC3CCCCC3)CC2)cc1F
Agent: COc1ccc(N2CCN(CCc3ccccc3)CC2)cc1C
Product: Oc1cc(F)c(N2CCN(CCC3CCCCC3)CC2)cc1F
Yield: 36.3 %

Procedure:
Production Example 10 was repeated except that 1-(4-methoxy-3-methylphenyl)-4-phenethylpiperazine was replaced with 1-(2-cyclohexylethyl)-4-(2,5-difluoro-4-methoxyphenyl)-piperazine (250 mg). The resulting crude product was purified on TLC (developer, chloroform: methanol=13:1) to provide 4-[4-(2-cyclohexylethyl)piperazin-1-yl]-2,5-difluorophenol (87 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([OH:15])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:5]1[S:6][CH:7]=[CH:8][CH:9]=1.[CH3:17][N:18]1[CH2:22]C[C@@H:20](O)[CH2:19]1>C1(C)C=CC=CC=1>[CH3:17][N:18]1[CH2:19][CH2:20][C@@H:1]([O:2][C:3](=[O:16])[C:4]([OH:15])([C:5]2[S:6][CH:7]=[CH:8][CH:9]=2)[C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[CH2:22]1
Reactant: COC(=O)C(O)(c1cccs1)c1cccs1
Reactant: CN1CC[C@@H](O)C1
Solvent: Cc1ccccc1
Product: CN1CC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1 g of 2-Hydroxy-2,2-dithien-2-ylacetic acid methyl ester (0.0039 mol) was dissolved in 30 ml of toluene. To this solution were added 0.394 g (0.0039 mol) of (3R)-1-methylpyrrolidin-3-ol (Intermediate I-19), and 0.078 g (0.00195 mol) of HNa (60% dispersion in mineral oil). The mixture was stirred 30 min at room temperature, refluxed for 1 hour, and then refluxed with continuous removal of distillate with replacement with fresh toluene when necessary for 2 hours. The cooled mixture was extracted with 2N HCl, the aqueous layer was washed with a small volume of ethyl acetate, basified with solid K2CO3 and extracted three times with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and evaporated. The yield was 0.73 g (58%) of the title product (structure confirmed by 1H-NMR). This product was purified by chromatography on silica gel eluting with chloroform/ethanol/NH4OH (200:8:1). Appropriate fractions were combined and evaporated to give the title compound.
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S:33]([O-:36])([O-:35])=[O:34].[Na+:37].[Na+]>C(O)C.O>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[C:8]2[O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][S:33]([O-:36])(=[O:35])=[O:34])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+:37]
Reactant: BrCCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Reactant: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=S(=O)([O-])CCCCCCCOc1nc(-c2ccccc2)c(-c2ccccc2)n1-c1ccccc1
Yield: 14.3 %

Procedure:
A solution of 1,4,5-triphenyl-2-(7-bromoheptyloxy)-imidazole (2.0 g) in ethanol (10 ml) was refluxed with a solution of sodium sulphite (0.55 g) in water (5 ml) for 20 hours. More sodium sulphite (0.2 g) in water (1 ml) was added and refluxed a further 20 hours. The mixture was evaporated to dryness, boiling ethanol added and filtered hot. Chromatography of the filtrate on silica gel (dichloromethane/methanol 5:1) followed by crystallisation from ethanol/isopropanol gave sodium 7-(1,4,5-triphenylimidazol-2-yloxy)heptanesulphonate (0.3 g, 15%) as a colourless solid, m.p. 246°-8° C. Found: C, 64.47; H, 5.85; N, 5.09; S, 5.50%; C28H29N2NaO4S+2% isopropanol +2% water, Requires: C, 64.19; H, 5.96;N, 5.25; S, 6.01%.
Reaction SMILES: [C:1]([O-:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[K+].C1C=CC(NC2C=CC(NC3C=CC=CC=3)=CC=2)=CC=1.Cl[CH2:29][CH2:30][CH2:31][Si:32]([O:37][CH3:38])([O:35][CH3:36])[O:33][CH3:34]>CN(C)C1C=CN=CC=1>[C:1]([O:6][CH2:29][CH2:30][CH2:31][Si:32]([O:37][CH3:38])([O:35][CH3:36])[O:33][CH3:34])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)[O-]
Reactant: CO[Si](CCCCl)(OC)OC
Agent: CN(C)c1ccncc1
Agent: [K+]
Agent: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1
Product: C=C(C)C(=O)OCCC[Si](OC)(OC)OC
Temperature: 135 °C
Yield: 92 %

Procedure:
1.74 g (0.015 mol) of 4-dimethylaminopyridine were dissolved in 201.5 (1.015 mol) of 3-chloropropyltrimethoxysilane, and the solution was heated to 135° C. while stirring, and was maintained at this temperature for 15 minutes. After the solution had been cooled to 60° C., 124.2 g (1 mol) of potassium methacrylate and 0.6 g of N,N'-diphenyl-p-phenylenediamine were added. The mixture was then heated to 135° C. again and maintained at that temperature for 1 hour. Thereafter, it was cooled, and the potassium chloride which had precipitated was filtered off and washed with 80 g of methanol. The methanol was evaporated from the combined filtrates, and the residue was distilled under reduced pressure. 228.1 g of 3- methacryloxypropyltrimethoxysilane having a boiling point of 83° C. (0.4 mbar) were obtained. The yield was 92% of theory, based on the amount of potassium methacrylate used. The purity of the end product was 99.0%. In the gas chromatogram only traces of 4-dimethylaminopyridine were detectable.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[OH:11].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CN(C)C=O.O>[CH2:18]([O:11][C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[Br:1])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(O)c(Br)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCc2ccccc2)c(Br)c1
Reaction time: 8 h

Procedure:
2-Bromo-4-nitrophenol (10 g), potassium carbonate (12.7 g) and benzyl bromide were dissolved in dimethylformamide and the mixture was stirred overnight. The mixture was diluted with water (1 L) and extracted with ethyl acetate (3×50 ml). The organic laver was washed with water, brine, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/EtOAc (95:5) to give the title compound as a pale vellow solid, (11.8 g, 77%). 1H NMR (250 MHz, CDCl3) δ 8.49 (1H, d, J=2.7 Hz), 8.17 (1H, dd, J=9.1, 2.7 Hz), 7.45 (5H, m), 7.00 (1H, d, J=9.1 Hz), and 5.28 (2H, s).
Reaction SMILES: [CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[C:3]1=[O:16].[BH4-].[Na+]>C(O)C>[CH3:1][CH:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[S:6][C:5]2[S:13][CH:14]=[CH:15][C:4]=2[CH:3]1[OH:16]
Reactant: CC1C(=O)c2ccsc2Sc2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC1c2ccccc2Sc2sccc2C1O

Procedure:
24.6 g (0.1 mole) of 5-methyl-benzo[f]thieno[2,3-b]thiepin-4(5H)-one [see British Patent No. 1,334,538 and U.S. Pat. No. 3,682,959) is suspended in 350 ml of abs. ethanol, and to the suspension is added at 8°, with stirring, 3.8 g (0.1 mole) of sodium borohydride. The mixture is then stirred for 15 hours at room temperature. The clear solution is concentrated in vacuo, and the oily residue is taken up in methylene chloride. The solution is washed twice with water, dried over sodium sulphate and concentrated by evaporation, and the residue is dried in vacuo. The 4,5-dihydro-5-methyl-benzo[f]thieno[2,3-b]thiepin-4-ol thus obtained is a white, slightly sticky, solid mass, and is further processed as crude product.
Reaction SMILES: CC1[N:3]=[CH:4][NH:5]C=1CSCCN.[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].CSC(=N)[NH2:20]>O>[S:12]([OH:16])([OH:15])(=[O:14])=[O:13].[NH2:3][C:4]([NH2:5])=[NH:20]
Reactant: Cc1nc[nH]c1CSCCN
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Solvent: O
Product: N=C(N)N

Procedure:
A solution of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (19.0 g.) and S-methylisothiourea sulphate (15.1 g.) in water (100 ml.) was heated under reflux for 3 hours. Concentration, acidification with sulphuric acid and dilution with ethanol afforded 2-[ (4-methyl-5-imidazolyl)methylthio)ethyl]guanidine sulphate (13.0 g.) m.p. 230°-235° (from aqueous methanol).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:10][C:9]=2[C:19]2[C:20]([F:34])=[C:21]([NH:25][S:26]([C:29]3[CH:33]=[CH:32][O:31][CH:30]=3)(=[O:28])=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:5]=[CH:4][N:3]=1.[CH3:35][Zn]C>>[F:34][C:20]1[C:19]([C:9]2[N:10]=[C:11]([CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:35])[N:7]=2)=[CH:24][CH:23]=[CH:22][C:21]=1[NH:25][S:26]([C:29]1[CH:33]=[CH:32][O:31][CH:30]=1)(=[O:28])=[O:27]
Reactant: O=S(=O)(Nc1cccc(-c2nc(C3CCOCC3)sc2-c2ccnc(Cl)n2)c1F)c1ccoc1
Reactant: C[Zn]C
Product: Cc1nccc(-c2sc(C3CCOCC3)nc2-c2cccc(NS(=O)(=O)c3ccoc3)c2F)n1

Procedure:
Following a procedure analogous to the procedure described in Example 25 using N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(tetrahydro-2H-pyran-4-yl)-1,3-thiazol-4-yl]-2-fluorophenyl}-3-furansulfonamide (200 mg, 0.384 mmol)mmol) and dimethylzinc (384 μl, 0.768 mmol) at 80° C. for 3 hours, the title compound was obtained as a solid (60 mg, 31% yield). MS (ESI): 500.8 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH3:20])[O:5][C:6]1[C:7]([NH2:19])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=C1)=[S:22].[NH4+].[OH-].O>C1COCC1>[CH3:1][O:2][CH2:3][CH:4]([CH3:20])[O:5][C:6]1[C:7]([NH:19][C:21]([NH2:23])=[S:22])=[N:8][CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=1
Reactant: COCC(C)Oc1cc(Oc2ccccc2)cnc1N
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCC(C)Oc1cc(Oc2ccccc2)cnc1NC(N)=S
Reaction time: 22 h
Yield: 70 %

Procedure:
3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridine-2-ylamine (0.28 mmol) is dissolved in THF (4 ml) and 1,1′-thiocarbonyldiimidazole (4 eq.) is added. The reaction solution is stirred 22 hours. 32% NH4OH (20 eq.) is added and stirred 2 hours at room temperature. Water (60 ml) is added and extracted with dichloromethane. The combined organic layers are washed with brine and dried over MgSO4. The solvent is removed in vacuo. [3-(2-Methoxy-1-methyl-ethoxy)-5-phenoxy-pyridin-2-yl]thiourea is obtained as yellow oil in a yield of 70%. HPLC (method C): 1.93 min; LC-MS (method A): 1.85 min, 334.15 (MH+).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]([N:31]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:32](=[O:34])[CH3:33])([C:26]([O:28]CC)=O)[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([N:20]1[CH2:25][CH2:24][C:23]2([N:31]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C:32](=[O:34])[CH2:33][C:26]2=[O:28])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C1(N(C(C)=O)c2ccccc2)CCN(Cc2ccccc2)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C1CC(=O)C2(CCN(Cc3ccccc3)CC2)N1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Diisopropylamine (1.54 g, 15 mmol) was dissolved in THF (50 mL) and then the mixture was cooled to −78° C. n-Butyl lithium (6.1 mL, 2.5 M in hexane) was added dropwise at −78° C. After addition, the reaction mixture was stirred for 30 min at −78° C. Ethyl 1-benzyl-4-(N-phenylacetamido)piperidine-4-carboxylate (2.9 g, 7.6 mmol) was added dropwise at −78° C. The mixture was continued to stir for 1 h at −78° C. The reaction was quenched by dropwise addition of water (10 mL) at −78° C. and then allowed to warm to room temperature. The organic layer was separated. The aqueous phase was acidified to pH 6-7 with acetic acid and extracted with EtOAc (3×20 mL). The combined organics were washed with brine, dried over Na2SO4 and evaporated under vacuum to give crude product as a solid, which was washed with ether to give 8-benzyl-1-phenyl-1,8-diazaspiro[4.5]decane-2,4-dione. 1H NMR (300 MHz, MeOD) δ 7.12-7.47 (m, 15H), 4.04 (s, 2H), 3.65-3.66 (m, 2H), 3.51-3.57 (m, 1H), 3.02-3.06 (m, 2H), 2.66-2.73 (m, 2H), 1.93-2.00 (m, 5H), 1.82-1.87 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24]([O:26]C)=O)#[N:2].Cl.[OH-].[NH4+:30]>C1COCC1.C(OCC)(=O)C>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:30])#[N:2]
Reactant: COC(=O)c1cccc2c1c1c(O)cccc1n2Cc1ccccc1C#N
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: N#Cc1ccccc1Cn1c2cccc(O)c2c2c(C(N)=O)cccc21
Yield: 49 %

Procedure:
A solution of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbomethoxy carbazole (295 mg, 0.83 mM) in 5 mL THF and 20 mL concentrated aqueous ammonium hydroxide was sonicated for 22 hours at 40-50° C. The mixture was diluted with ethyl acetate and acidified to pH 1 with 5 N HCl. The aqueous layer was extracted three times with ethyl acetate. The combined organic extracts were washed with H2O and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with gradient hexanes/ethyl acetate) to afford 140 mg (49%) of the 9-[(2-cyanophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole as a tan solid. 1H NMR (DMSO-d6) δ10.5 (s, 1H), 8.8 (br s, 1H), 8.4 (br s, 1H), 7.9 (d, 1H, J=8 Hz), 7.75 (d, 1H, J=8 Hz), 7.5-7.4 (m, 4H), 7.25 (t, 1H, J=8 Hz), 7.0 (d, 1H, J=8 Hz), 6.6 (d, 1H, J=8 Hz), 6.4 (m, 1H), and 5.85 (s, 2H). IR (KBr, cm−1) 3448, 3356, 2225, 1628, and 1600. MS (ES) m/e 340, 342.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1([OH:24])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6]1.[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30](O)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1.ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.C(N(CC)CC)C>[NH2:25][C:26]1[C:34]([Cl:35])=[CH:33][C:29]([C:30]([NH:3][CH2:4][C:5]2([OH:24])[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:7][CH2:6]2)=[O:31])=[C:28]([O:36][CH3:37])[CH:27]=1
Reactant: NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1(O)CCN(CCCCCC(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 79.5 %

Procedure:
To a solution of 4-aminomethyl-4-hydroxy-1-(6-oxo-6-phenylhexyl)-piperidine dihydrochloride (2.9 g) in dimethylformamide (50 ml) were added triethylamine (3.2 ml), 4-amino-5-chloro-2-methoxybenzoic acid (1.55 g) and 1-hydroxybenzotriazole (1.09 g), which was followed by the addition of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.55 g) under ice cooling, and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was added with water and extracted with chloroform. The organic layer was washed successively with 10% aqueous solution of potassium carbonate and brine, and dried. The solvent was evaporated under reduced pressure, and the obtained residue was purified by a silica gel column chromatography (chloroform:methanol=10:1) to give 2.98 g of 4-amino-5-chloro-N-((4-hydroxy-1-(6-oxo-6-phenylhexyl)-piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH2:12][N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:14])([O-])=O.[H][H]>CO.[Pt]=O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][C:11](=[O:22])[CH2:12][N:13]([CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH3:14]
Reactant: [H][H]
Reactant: CN(CC(=O)Nc1ccccc1[N+](=O)[O-])Cc1ccccc1
Agent: O=[Pt]
Solvent: CO
Product: CN(CC(=O)Nc1ccccc1N)Cc1ccccc1
Yield: 46.3 %

Procedure:
A suspension of N-(2-nitrophenyl)-2-(N-benzyl-N-methylamino)acetamide (30 g) and platinum oxide (0.3 g) in methanol (500 ml) was shaken in an atmosphere of hydrogen at laboratory temperature and atmospheric pressure until the uptake of hydrogen was complete. 6.6 Litres of hydrogen were absorbed. The mixture was filtered, and evaporated to dryness to give an oil which was extracted with boiling cyclohexane (1litre). On cooling, N-(2-aminophenyl)-2-(N-benzyl-N-methylamino)acetamide (12.5 g) was obtained as off-white crystals, m.p. 75°-77° C.