Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:39][CH2:40][CH2:41][N:42]1[CH:46]=[CH:45][N:44]=[CH:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([C@H:12]2[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[N:15]([C:22](=[O:30])[C:23]3[CH:24]=[CH:25][C:26]([O:29][CH2:39][CH2:40][CH2:41][N:42]4[CH:46]=[CH:45][N:44]=[CH:43]4)=[CH:27][CH:28]=3)[C@@H:14]([CH3:31])[CH2:13]2)[C:9](=[O:11])[CH3:10])=[CH:6][CH:7]=1
Reactant: BrCCCn1ccnc1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(O)cc2)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCn3ccnc3)cc2)c2ccccc21
Temperature: 80 °C
Yield: 16 %

Procedure:
(2S,4R)-N-(4-Chloro-phenyl)-N-[1-(4-hydroxy-benzoyl)-2-methyl-1,2,3,4-tetrahydro-quinolin-4-yl]-acetamide (0.1 g, 0.23 mmol) was dissolved in DMF (5 mL) at room temperature. K2CO3 (0.317 g, 2.3 mmol) was added. 1-(3-Bromo-propyl)-1H-imidazole (0.174 g, 0.92 mmol) was added and the reaction was allowed to heat to 80° C. overnight. The reaction mixture was concentrated in vacuo. The residue was partitioned between ethyl acetate and water, then extracted three times with ethyl acetate, dried over MgSO4, filtered and concentrated down. The crude residue was purified by silica gel chromatography (60% EtOAc/40% Hexane) to afford the product (0.020 g, 16%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][NH:2]2.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17](Cl)(=[O:19])=[O:18])([O-:10])=[O:9].CCCCCC.CCOC(C)=O>C(Cl)Cl.C(N(CC)CC)C>[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:17]([N:2]1[CH2:3][CH:4]2[CH2:7][CH:1]1[CH:6]=[CH:5]2)(=[O:19])=[O:18])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C1=CC2CC1CN2
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CC2C=CC1C2
Reaction time: 16 h
Yield: 152 %

Procedure:
2-Azabicyclo[2.2.1]hept-5-ene (52.5 g, 54 mmole), prepared as described in (J Am Chem. Soc., (1985) 107, 1768), 2-nitrobenzenesulfonyl chloride (119.6, 54 mmole), and triethylamine (75 mL, 0.54 mmole) were combined in methylene chloride (500 mL) under a nitrogen atmosphere and stirred for 16 hours. The reaction mixture was quenched with water (500 mL) and the phases separated. The organic phase was washed with 2M HCl (5×100 mL), dried (MgSO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (chloroform then hexane:EtOAc 95:5 to 8:2) to provide the title compound (23 g, 23% yield). MS (DCI/NH3) m/e 281 (M+H)+, 298 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[N:24]=[C:25]([CH3:28])[NH:26][CH:27]=1>>[Br:22][C:23]1[N:24]=[C:25]([CH3:28])[N:26]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:27]=1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(Cl)n2)cc1
Reactant: Cc1nc(Br)c[nH]1
Product: Cc1nc(Br)cn1-c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1

Procedure:
The title compound was prepared from 2-chloro-4-trifluoromethyl-6-(4-trifluoromethylphenyl)-pyrimidine (example A.2) (0.65 g, 2.0 mmol) and commercially available 4-bromo-2-methyl-imidazole (0.48 g, 3.0 mmol) according to the general procedure IVa. Obtained as a light brown solid (0.73 g, 81%). MS (ISP) 451.0 [(M+H)+]; mp 174° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([F:10])=[CH:4][CH:3]=1.[CH2:11](P(=O)(OCC)OCC)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)([O-])C.[K+]>O1CCCC1>[Br:1][C:2]1[N:7]=[C:6](/[CH:8]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:5]([F:10])=[CH:4][CH:3]=1
Reactant: O=Cc1nc(Br)ccc1F
Reactant: CCOP(=O)(Cc1ccccc1)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Fc1ccc(Br)nc1/C=C/c1ccccc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 6-bromo-3-fluoropicolinaldehyde (2.147 g, 10.5 mmol) and diethyl benzylphosphonate (2.413 mL, 11.6 mmol) in tetrahydrofuran (80 mL) at 0° C., was added potassium tert-butoxide(1M in tetrahydrofuran, 11.6 mL, 11.6 mmol) dropwise over a couple of minutes. When addition was complete, the reaction was allowed to stir at 0° C. for 45 min and quenched by addition of saturated ammonium chloride. The reaction was diluted with ether, washed with water (4×), then brine, dried over magnesium sulfate, and concentrated. Column chromatography (8%→15% EtOAc/Hex) gave 121 mg (4.1%). 1H NMR (CDCl3) δ: 7.86 (d, J=16.2 Hz, 1H), 7.64 (d, J=7.3 Hz, 2H), 7.39-7.47 (m, 2H), 7.22-7.39 (m, 4H). 19F NMR (CDCl3) δ: −130.05 (br. s., 1F). Mass spec.: 278.0 (MH)+.
Reaction SMILES: Cl[CH:2]([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:6])[CH3:3].[C:20]([OH:23])(=[O:22])[CH3:21]>>[C:20]([O:23][CH:2]([O:4][C:5]([NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1)=[O:6])[CH3:3])(=[O:22])[CH3:21]
Reactant: COc1ccc(CCNC(=O)OC(C)Cl)cc1OC
Reactant: CC(=O)O
Product: COc1ccc(CCNC(=O)OC(C)OC(C)=O)cc1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The chloroethyl carbamate from Example 11 (0.25 g) was dissolved in acetic acid (25 ml) and mercuric acetate (1.0 g) was added to it. The reaction mixture was stirred at room temperature for 3 hours. It was filtered and the filtrate was evaporated in vacuum at room temperature. The residue was dissolved in ether and filtered. Evaporation of ether gave a thick oil weighing 0.21 g as a practically pure compound. An analytical sample was prepared by filtering through silica gel in chloroform. NMR (CDCl3) δ1.45 (3H, d, J=7 Hz, CH3CH), 2.06 (3H, s, OAc), 2.76 (2H, t, J=7 Hz), ArCH2), 3.38 (2H, t, J=7 Hz, NHCH2), 3.9 (6H, s, OMe), 5.06 (1H, broad t, NH) and 6.6-7.0 (4H, CHCH3 and aromatic). IR (film) ν3345, 1742, 1723, 1515, 1262, 1238 cm-1. m/e 311 (M+), 207, 164, 151, etc.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([N+:10]([O-])=O)[CH:3]=1.[C:13](OCC)(=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].N1CCCCC1>[Pd].C(O)C>[CH2:18]([O:17][C:15]([C:14]1[C:13](=[O:20])[NH:10][C:4]2[C:5]([CH:6]=1)=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:16])[CH3:19]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=Cc1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCNCC1
Solvent: CCO
Product: CCOC(=O)c1cc2ccc(Cl)cc2[nH]c1=O
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A mixture of 4-chloro-2-nitrobenzaldehyde (9-1, 495 mg, 2.64 mmol, 1 equiv) and 10% palladium on carbon (0.280 g, 0.264 mmol, 0.100 equiv) in ethanol (20 mL) was stirred under a hydrogen balloon for 1 h at 23° C. The catalyst was filtered onto a pad of celite and washed with ethanol (20 mL). The combined filtrate was concentrated to 20 mL, then diethyl malonate (0.801 mL, 5.28 mmol, 2.00 equiv) and piperidine (0.130 mL, 1.32 mmol, 0.500 equiv) were added. The resulting mixture was heated at reflux for 5 h. The mixture was allowed to cool to 23° C., and the precipitate was filtered and washed with cold ethanol (10 mL) to give 7-chloro-2-oxo-1,2-dihydro-quinoline-3-carboxylic acid ethyl ester (9-2) as a white solid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:42]([NH:52][C@H:53]([C:55](O)=[O:56])[CH3:54])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]>>[C:42]([NH:52][C@H:53]([C:55]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:41])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:56])[CH3:54])([O:44][CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)=[O:43]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Product: CCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-dodecyl-dodecanamide and N-carbobenzoxy-L-alanine.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([C:23](OCC)=[O:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.C(=O)(O)[O-].[Na+]>C(OCC)C>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[CH:15]=[N:16][C:12]=3[CH:11]=[C:10]([CH2:23][OH:24])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cc(-c2cccc(N)c2)c2c(c1)ncn2-c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: Nc1cccc(-c2cc(CO)cc3ncn(-c4ccccc4)c23)c1
Reaction time: 48 h

Procedure:
To a stirred suspension of lithium alumina hydride (0.24 g, 6.16 mmol) in anhydrous diethyl ether (20 ml) was added 7-(3-aminophenyl)-5-ethoxycarbonyl-1-phenylbenzimidazole (1.1 g, 3.08 mmol). Stirring was continued for 48 hours at ambient temperature in a nitrogen atmosphere. Aqueous sodium bicarbonate (2M) was added and the resultant mixture was extracted with ethyl acetate. This extract was dried over magnesium sulphate and concentrated under reduced pressure. The concentrate was eluted through silica gel with a mixture of ethyl acetate and methanol (9:1 v/v). Removal of solvent from the eluate left the title product as a yellow solid (0.38 g, 39%) m/z, 316.1 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:18]=[CH:17]3.CN(C=O)C.[Br:34]N1C(=O)CCC1=O>O>[Br:34][C:15]1[C:4]2[CH:5]=[C:6]3[C:14]([C:2]([CH3:28])([CH3:1])[C:3]=2[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:20]=2)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7]3
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccccc4)C=C32)C=C2N=c3ccccc3=C21
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Reaction time: 9 h
Yield: 94.8 %

Procedure:
The resulting 12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (7.5 g) and DMF (53 ml) were added to a reaction vessel. N-bromosuccinimide (3.72 g) was added under ice-cooled conditions, and the mixture was stirred for 9 hours and then left for one night. Water (260 ml) was added, and the mixture was subjected to filtration to obtain a brownish white powder of 7-bromo-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (8.67 g; yield 94.6%).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:12][CH2:11][NH:10][CH2:9]1)(C)(C)C.C(N(C(C)C)CC)(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([Cl:33])(=[O:32])=[O:31])=[C:26]([O:34][C:35]([F:38])([F:37])[F:36])[CH:25]=1.C([O-])(O)=O.[Na+].Cl>C(Cl)Cl.C(Cl)(Cl)Cl.CCOC(C)=O>[ClH:33].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:10]2[CH2:11][CH2:12][CH:8]([NH2:7])[CH2:9]2)(=[O:32])=[O:31])=[C:26]([O:34][C:35]([F:37])([F:36])[F:38])[CH:25]=1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1OC(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: NC1CCN(S(=O)(=O)c2ccc(Br)cc2OC(F)(F)F)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 80.1 %

Procedure:
To a solution of pyrrolidin-3-yl-carbamic acid tert-butyl ester (1.00 g, 5.37 mmol) in CH2Cl2 (10 mL) was added diisopropylethylamine (1.96 mL, 5.92 mmol). The mixture was cooled at 0° C. and a solution of 4-bromo-2-trifluoromethoxy-benzenesulfonyl chloride (2.01 g, 5.92 mmol) in CH2Cl2 (10 mL) was added below 10° C. The reaction mixture was stirred at 4° C. for 15 min, dissolved in CHCl3 and saturated aqueous NaHCO3. The two phases were separated, the aqueous layer was extracted with CHCl3 (twice). The combined organic layer was dried over MgSO4, filtered, concentrated, and dried under reduced pressure to give a pale brown solid. To a solution of the above solid in CHCl3 (50 mL) was added 4 M hydrogen chloride in EtOAc (50 mL). The mixture was stirred at ambient temperature for 1 hr, filtered, washed with EtOAc, and dried under reduced pressure to give 1-(4-bromo-2-trifluoromethoxy-benzenesulfonyl)-pyrrolidin-3-ylamine hydrochloride (1.83 g, 80%) as a white solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH2:10][CH2:11][N:12]2[C:17](=[O:18])[CH:16]=[CH:15][C:14]([C:19]([OH:21])=O)=[CH:13]2)=[O:8])[CH:2]=1.[CH3:22][N:23](C)C=O.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:22][NH:23][C:19]([C:14]1[CH:15]=[CH:16][C:17](=[O:18])[N:12]([CH2:11][CH2:10][NH:9][C:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:13]=1)=[O:21]
Reactant: O=C(O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Reactant: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(=O)n(CCNC(=O)c2cccnc2)c1
Temperature: -8 °C
Reaction time: 2.25 h

Procedure:
To a 100 ml round bottomed flask fitted with a magnetic stirrer bar and nitrogen inlet was added 1,6-dihydro-l-[2-(3-pyridinylcarbonylamino)ethyl]-6-oxo-3-pyridinecarboxylic acid (0.22 g, 0.77 mmol) methylamine hydrochloride (0.104 g, 1.54 mmol), and dimethylformamide (25.5 ml). The reaction mixture was cooled in a -8° C. ice bath and treated with triethylamine (1.07 ml, 7.7 mmol) and propylphosphonic acid anhydride (0.55 ml, added as a 0.55 ml ethyl acetate solution, Angew. Chemie 1980, 92(2), 129). The flask was allowed to warm slowly to room temperature and stirred for 2.25 hours. The mixture was concentrated, slurried in aqueous sodium bicarbonate, and again concentrated. The residue was slurried in methanol and filtered. Further purification of the solid recovered from filtration via flash column chromotography (silica gel, 15-20% methanol/dichloromethane) gave the product, MP: 208°-210° C.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[CH2:10]([Li])CCC.[CH:15]([S:18][CH:19]([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16].CI.Cl>O1CCCC1>[CH:15]([S:18][C:19]([CH3:10])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C(C)SC(C)C
Reactant: [Li]CCCC
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)SC(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1,1,1,3,3,3-hexamethyldisilazane (10.4 mL, 48 mmol) in tetrahydrofuran is cooled to 0° C., treated with a 2.04 M solution of n-butyllithium in tetrahydrofuran (22.6 mL, 46 mmol), stirred at 0° C. for 30 minutes, treated dropwise with ethyl 2-(isopropylthio)propionate (7.6 g, 42 mmol), stirred at 0° C. for 1 hour, treated with methyl iodide, stirred at room temperature for 22 hours, and poured into an ice-water mixture (100 g) containing 10 mL of 6 N hydrochloric acid. The resultant aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown liquid. Vacuum distillation of the brown liquid gives the title product as a liquid (6.8 g) which is identified by NMR spectral analysis.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:21])[C:18]([OH:20])=O)[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.C(=O)([O-])O.[Na+]>C(#N)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:12][CH2:13][N:14]([C:17](=[O:21])[C:18]([N:22]2[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH3:31])=[O:29])[CH2:24][CH2:23]2)=[O:20])[CH2:15][CH2:16]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1N1CCN(C(=O)C(=O)O)CC1
Reactant: COC(=O)C1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)C1CCN(C(=O)C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)CC1
Yield: 40.4 %

Procedure:
A solution of [4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetic acid (Example 44, 0.300 g, 1.03 mmol), methyl piperidine-4-carboxylate (0.178 g, 1.24 mmol), EDCI (0.238 g, 1.24 mmol) and HOBt (0.168 g, 1.24 mmol) in acetonitrile (10 mL) was stirred at room temperature for 2 days. The reaction mixture was poured into saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with saturated sodium hydrogen carbonate solution and brine, dried over MgSO4, and the solvent was evaporated in vacuum to give the crude product. The product was purified by flash column chromatography (silica gel, n-hexane/ethyl acetate=90:10 to 50:50) to provide methyl 1-{[4-(2-tert-butylphenyl)piperazin-1-yl](oxo)acetyl}piperidine-4-carboxylate (0.173 g, 40%) as a white amorphous.
Reaction SMILES: [NH2:1][C:2]1[C:25]([N+:26]([O-])=O)=[CH:24][C:5]2[C:6](=[O:23])[CH2:7][C:8]3([O:22][C:4]=2[CH:3]=1)[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:10][CH2:9]3.O1C=CC=CC1=O>>[NH2:26][C:25]1[C:2]([NH2:1])=[CH:3][C:4]2[O:22][C:8]3([CH2:13][CH2:12][N:11]([CH2:14][CH2:15][C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:10][CH2:9]3)[CH2:7][C:6](=[O:23])[C:5]=2[CH:24]=1
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)CC1(CCN(CCc3ccccc3)CC1)O2
Agent: O=c1cccco1
Product: Nc1cc2c(cc1N)C(=O)CC1(CCN(CCc3ccccc3)CC1)O2

Procedure:
In the manner of Example 462, 7-amino-3,4-dihydro-6-nitro-1'-(2-phenylethyl)-spiro[(2H)-1-benzopyran-2,4'-piperidine]-4-one (1.22 g, 3.2 mmol) was reduced to give, after chromatography, the pyranone as a yellow foam (790 mg, 70%).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:37])(=[N:24]S(C3C=CC([N+]([O-])=O)=CC=3)(=O)=O)=[O:23])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].C1(S)C=CC=CC=1>C(#N)C.O.C(Cl)Cl>[CH:1]([NH:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][S:22]([CH3:37])(=[NH:24])=[O:23])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][N:6]=1)([CH3:3])[CH3:2]
Reactant: COc1cc2c(NC(C)C)ncnc2cc1OCCCCS(C)(=O)=NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [Cs+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COc1cc2c(NC(C)C)ncnc2cc1OCCCCS(C)(=N)=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 51 %

Procedure:
(RS)-S-(4-{[4-(Isopropylamino)-6-methoxyquinazolin-7-yl]oxy}butyl)-S-methyl-N-[(4-nitrophenyl)sulphonyl]sulphoximide (267 mg, 0.48 mmol) is dissolved in acetonitrile (7 ml), treated with caesium carbonate (266 mg, 0.82 mmol) and thiophenol (86 mg, 0.77 mmol) and stirred at room temperature for 20 hours. The reaction batch is diluted with water and methylene chloride. The organic phase is separated off and dried over sodium sulphate. The desired product is obtained after removal of the solvent and preparative HPLC in 51% yield (126 mg).
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[CH2:4].[F-:14].[K+].[Br-]>O>[F:14][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[CH2:4]
Reactant: [F-]
Reactant: C=C(CCl)c1ccc([N+](=O)[O-])cc1
Agent: [Br-]
Agent: [K+]
Solvent: O
Product: C=C(CF)c1ccc([N+](=O)[O-])cc1
Reaction time: 5 h

Procedure:
Under a N2 blanket is stirred a mixture of 296.5 g (1.5 Mol) 4(1-chloromethyl-ethenyl)-nitrobenzene, 430 g (7.4 Mol) KF, 78 g (0.15 Mol) hexadecyltributylphosphonimine bromide and 800 ml H2O, during 5 hours at 110°-112°.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[C:4]([OH:11])[CH:3]=1.B>C1COCC1>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][OH:7])=[C:4]([OH:11])[CH:3]=1
Reactant: O=C(O)c1ccc(Cl)cc1O
Agent: B
Solvent: C1CCOC1
Product: OCc1ccc(Cl)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.1 %

Procedure:
To a solution of 4-chloro-2-hydroxybenzoic acid (Aldrich; 2.0 g, 11.6 mmol) in THF (50 ml) was added dropwise 1 M borane in THF (20.9 ml, 20.9 mmol). The suspension was allowed to stir for 30 min at ambient temperature. The mixture was refluxed at 80° C. for 2.5 h. The solvent was removed in vacuo. The residue was loaded in dichloromethane and purified on silica (100 g) using 0-100% ethyl acetate/cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give the title compound (1.51 g) as a white solid; LCMS (System 1): (M-H)−=157, tRET=2.44 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH:14]=O)=[N:5][CH:4]=1.[NH:17]1[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:18]1.[O-]S([O-])(=O)=O.[Na+].[Na+].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=[O:16])[N:10]2[CH2:13][CH2:14][N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][NH:24][C:25](=[O:34])[O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:18]2)=[N:5][CH:4]=1
Reactant: O=C(NC[C@@H]1CCCNC1)OCc1ccccc1
Reactant: COc1cnc2ccc(=O)n(CC=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC[C@@H](CNC(=O)OCc4ccccc4)C3)c2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of [7-(methoxy)-2-oxo-1,5-naphthyridin-1(2H)-yl]acetaldehyde (as the methyl hemiacetal) (0.250 g, 1.15 mmol) in 1:1 (MeOH/CHCl3) (25 mL) were added phenylmethyl [(3R)-3-piperidinyl-methyl]carbamate (0.210 g, 0.90 mmol) and Na2SO4 (0.100 g) and the resulting solution stirred at ambient temperature for 18 hours. Na(OAc)3BH (0.57 g, 2.7 mmol) was added and solution stirred an additional 2 hours. The reaction mixture was concentrated onto silica gel and chromatographed on a silica gel column) [0-100% Hexanes/EtOAc] to yield a colorless oil. (0.207 g, 51%) LCMS: m/z 451 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH2:20])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].N1C=CC=CC=1.[CH3:27][O:28][CH2:29][CH2:30][S:31](Cl)(=[O:33])=[O:32]>ClCCl>[CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[C:16]([NH:20][S:31]([CH2:30][CH2:29][O:28][CH3:27])(=[O:33])=[O:32])[CH:17]=[CH:18][CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COCCS(=O)(=O)Cl
Reactant: CCCCCCN1CC2C(C1)C2(C)c1cccc(N)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCN1CC2C(C1)C2(C)c1cccc(NS(=O)(=O)CCOC)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 3-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 12, 0.11 g, 0.40 mmol) in dichloromethane (1.5 ml) was added pyridine (64 mg) in dichloromethane (0.75 ml) and 2-methoxy-1-ethanesulfonyl chloride (J. F. King, J. Y. L. Lam, S. Kronieczny, J. Am. Chem. Soc., 1992, 114 (5), 1743; 0.96 g, 0.60 mmol). The reaction mixture was stirred at room temperature for 16 h and then concentrated in vacuo. The crude residue was purified by chromatography on silica gel eluting with ethyl acetate:2M ammonia in methanol (99:1).