Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH:6]([NH:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1)#N.S(=O)(=O)(O)[OH:20].[CH3:24][OH:25]>>[CH3:24][O:25][C:1]([C:3]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH:6]([NH:9][CH2:10][CH2:11][NH2:12])[CH2:5][CH2:4]1)=[O:20]
Reactant: CO
Reactant: O=S(=O)(O)O
Reactant: N#CC1(c2ccccc2)CCC(NCCN)CC1
Product: COC(=O)C1(c2ccccc2)CCC(NCCN)CC1
Temperature: 82.5 °C
Yield: 76 %

Procedure:
A mixture of 2-[4-cyano-4-phenylcyclohexylamino]ethylamine (2.34 g, 10 mmol) and concentrated sulfuric acid (20 mL) was heated at 80-85 ° C. for 10 h. It was cooled to room temperature, mixed with anhydrous methanol (200 mL), and refluxed for 20 h. Solvent was evaporated and the residue was poured onto ice (200 g) and basified to pH 11 by addition 6N NaOH. It was extracted with dichloromethane (4×125 mL), dried (potassium carbonate) and solvent evaporated to leave the product as an oil (2.1 g, 76%). This product was a pure mixture of cis and trans isomers. It was used in the next step without any further purification.
Reaction SMILES: CS([O:5][CH2:6][C@@H:7]([O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH3:8])(=O)=O.CC(C)([O-])C.[K+].[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[N:45]=[CH:44][C:43](O)=[CH:42][CH:41]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1.Cl>O.CS(C)=O>[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH:28][C:29]2[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([O:39][C:40]4[CH:41]=[CH:42][C:43]([O:5][CH2:6][C@H:7]([O:9][CH:10]5[CH2:15][CH2:14][CH2:13][CH2:12][O:11]5)[CH3:8])=[CH:44][N:45]=4)[CH:37]=3)[N:32]=[CH:31][N:30]=2)=[N:24]1
Reactant: C[C@@H](COS(C)(=O)=O)OC1CCCCO1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@H](COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1)OC1CCCCO1
Temperature: 100 °C
Reaction time: 24 h
Yield: 75.1 %

Procedure:
(2S)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate (214 mg, 0.90 mmol) and potassium tert-butoxide (200 mg, 1.8 mmol) were added to a dimethyl sulfoxide solution (5 ml) of 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol (300 mg, 0.90 mmol) obtained in Example 6-3), and the reaction solution was stirred for 24 hours at 100° C. The reaction solution was cooled to room temperature, then water and aqueous 1 N hydrochloric acid solution (0.9 ml, 0.9 mmol) were added, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=99:1) to obtain N-(1-methyl-1H-pyrazol-3-yl)-6-[(5-[(2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl]oxyl pyridin-2-yl)oxy]quinazoline-4-amine (322 mg, yield: 75%) as a pale brown solid.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][NH2:26])[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C)[CH:31]=[O:32].C(N(CC)CC)C.C(ON1C(=O)CCC1=O)(=O)[C:42]1[CH:47]=[CH:46][CH:45]=[N:44][CH:43]=1>C(#N)C.O>[C:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:10]=[C:9]([O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([CH3:28])([CH3:27])[CH2:25][N:26]([C:42]3[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=3)[CH:31]=[O:32])[CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(ON1C(=O)CCC1=O)c1cccnc1
Reactant: CC(C)(CN)CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1
Reactant: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Solvent: CC#N
Product: CC(C)(CCCCOc1cc(-c2ccccc2)cc(-c2ccccc2)n1)CN(C=O)c1cccnc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 6-(4,6-diphenyl(2-pyridyloxy))-2,2-dimethylhexylamine (0.14 g, 0.373 mmol), N,N-dimethylformamide (4 mL), and triethylamine (0.3 mL) was stirred at room temperature for 10 min. Succinimidyl nicotinate (0.1 g, 0.447 mmol) was added, and the mixture was stirred for 18 h. The mixture was concentrated under high vacuum, and the residue was purified using reverse-phase HPLC (water-acetonitrile containing 0.1 TFA) to afford 0.114 mg (64%) of a white powdered solid. 1H NMR (CDCl3): 8.12-6.80 (m, 16H), 4.54 (t, 2H), 3.43 (t, 2H), 1.90 (m, 6H), 1.05 (s, 6H); ESMS: Calculated for C31H33N3O2, 479.2573 Found 480.2 [M+H]+1; Rt=17.096 min (100% pure, Vydac C18 column; gradient 20 to 100% acetonitrile/water+0.1% TFA over 30 min).
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]([N:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)=[O:17])[S:15][C:8]=23)=[C:4]([F:25])[CH:3]=1.[C:26]1([CH2:32][C:33]([N:35]=[C:36]=[O:37])=[O:34])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[ClH:38]>CO>[ClH:38].[F:25][C:4]1[CH:3]=[C:2]([NH:1][C:36]([NH:35][C:33](=[O:34])[CH2:32][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:37])[CH:24]=[CH:23][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]2[CH:13]=[C:14]([C:16]([N:18]3[CH2:19][CH2:20][CH2:21][CH2:22]3)=[O:17])[S:15][C:8]=12
Reactant: O=C=NC(=O)Cc1ccccc1
Reactant: Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Agent: Cl
Solvent: CO
Product: O=C(Cc1ccccc1)NC(=O)Nc1ccc(Oc2ccnc3cc(C(=O)N4CCCC4)sc23)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33 %

Procedure:
A mixture of 194 (93 mg, 0.26 mmol, scheme 40) and 2-phenylacetyl isocyanate (83 mg, 0.62 mmol) [J. Hill, et al. JACS, 62; 1940; 1595] was stirred for 1 h at room temperature, loaded directly onto a flash chromatography column and eluted with EtOAc. A white solid was obtained, which was suspended in MeOH and treated with HCl (1 mL, 1.0M in Et2O) to form a clear solution. The solution was concentrated to form a precipitate which was collected by filtration, to afford the title compound 305a (48 mg, 33% yield) as a white solid. 1H NMR (d-DMSO) δ (ppm): 11.05(s, 1H), 10.62(s, 1H), 8.57(d, 1H), 8.02(s, 1H), 7.81(d, 1H), 7.48-7.43(m, 2H), 7.33-7.25(m, 5H), 6.74(d, 1H), 3.85(t, 2H), 3.78(s, 2H), 3.51(t, 2H), 1.98-1.86(m, 2H). MS (m/z): 519.2(M+H) (found).
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][C:15](Br)=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([NH:22][CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:44][C:45]1[CH:53]=[CH:52][C:48]([C:49](Cl)=[O:50])=[CH:47][CH:46]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[CH:18]([N:22]([CH2:23][CH2:24][CH2:25][N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36])[C:49](=[O:50])[C:48]1[CH:52]=[CH:53][C:45]([Cl:44])=[CH:46][CH:47]=1)[CH:19]([CH3:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CC(C)C(NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Br)ccc2n1Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)C(c1nc2ccccc2n1Cc1ccccc1)N(CCCN1C(=O)c2ccccc2C1=O)C(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.7 %

Procedure:
To a solution of 2-{3-[1-(1-Benzyl-5-bromo-1H-benzimidazol-2-yl)-2-methyl-propylamino]-propyl}-isoindole-1,3-dione (260 mg, 0.56 mmol) and triethylamine (0.47 ml, 3.36 mmol) in DCM (3 ml) at 0° C., was added 4-chlorobenzoylchloride (0.36 ml, 2.8 mmol, 5 eq). The reaction mixture was stirred at 0° C. for 30 minutes. Ethyl acetate and saturated sodium bicarbonate were added. The mixture was extracted with ethyl acetate. The organic layers was combined, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo. The crude material was purified by flash chromatography to give N-[1-(1-Benzyl-1H-benzimidazol-2-yl)-2-methyl-propyl]-N-[3-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-propyl]-4-chloro benzamide (182 mg, yield 54%)
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19]>>[Br-:16].[CH2:21]([O:20][C:18]([CH2:17][N+:9]1[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:8]=1)=[O:19])[CH3:22]
Reactant: CCOC(=O)CBr
Reactant: c1ccc(-n2cnc3ccccc32)cc1
Product: CCOC(=O)C[n+]1cn(-c2ccccc2)c2ccccc21
Product: [Br-]
Yield: 56 %

Procedure:
Using the procedure of Step B of Example 1, 1-phenylbenzimidazole [prepared from N-phenyl-o-phenylenediamine with 4HCl and formic acid] and ethyl bromoacetate were reacted to obtain a 56% of 1-ethoxycarbonylmethyl-3-phenyl-benzimidazolium bromide which after crystallization from a mixture of ethyl acetate and methanol melted at 180°-181° C.
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:9][C:10]1[CH:20]=[CH:19][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:12][CH:11]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH:1]1([CH2:7][NH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:19][CH:20]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: BrCC1CCCCC1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCC2CCCCC2)cc1

Procedure:
A solution of 6 g. of cyclohexylmethyl bromide and 11.19 g. of ethyl p-aminobenzoate in 30 ml. of hexamethylphosphoramide is heated in an oil bath for 20 hours. The solution is poured into ice-cold water and extracted several times with diethyl ether. The combined ether extracts are washed with water, dried with anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure to furnish ethyl p-cyclohexylmethylaminobenzoate as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH:13]([CH2:14][N:15]([C@@H:23]([C:25]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=[CH:27][CH:26]=3)[CH3:24])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:12][CH2:11][NH:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[NH:46][C:47](OC1C=CC([N+]([O-])=O)=CC=1)=[O:48])[C:39]([O:41][CH3:42])=[O:40].C(N(CC)CC)C.C(=O)([O-])O.[Na+]>C1COCC1>[C:18]([O:17][C:16]([N:15]([CH2:14][CH:13]1[CH2:12][CH2:11][N:10]([C:47]([NH:46][C:45]2[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][C:36]=2[Cl:35])=[O:48])[CH2:9][CH:8]1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[C@@H:23]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[CH3:24])=[O:22])([CH3:19])([CH3:21])[CH3:20]
Reactant: COC(=O)c1ccc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)c(Cl)c1
Reactant: C[C@H](c1cccc2ccccc12)N(CC1CCNCC1c1cccc(F)c1)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(NC(=O)N2CCC(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C(c3cccc(F)c3)C2)c(Cl)c1
Reaction time: 8 h

Procedure:
To a solution of 231 mg of tert-butyl {[3-(3-fluorophenyl)piperidin-4-yl]methyl}[(1R)-1-(1-naphthyl)ethyl]carbamate and 210 mg of methyl 3-chloro-4-{[(4-nitrophenoxy)carbonyl]amino}benzoate in 4.0 mL of THF was added 0.139 mL of triethylamine at room temperature, followed by stirring overnight. To the reaction mixture was added a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with water and saturated brine in this order, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 394 mg of a pale yellow foamy substance of methyl 4-({[4-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-3-(3-fluorophenyl)piperidin-1-yl]carbonyl}amino)-3-chlorobenzoate as a crude product. ESI+: 674
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][C:20]([OH:22])=O)=[CH:14][CH:13]=2)[CH:8]=[CH:7][N:6]=1)=[O:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.O>[NH:23]([C:20](=[O:22])[CH2:19][CH2:18][C:15]1[CH:14]=[CH:13][C:12]([O:11][C:9]2[CH:8]=[CH:7][N:6]=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[CH:10]=2)=[CH:17][CH:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Nc1ccccc1
Reactant: CNC(=O)c1cc(Oc2ccc(CCC(=O)O)cc2)ccn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(Oc2ccc(CCC(=O)Nc3ccccc3)cc2)ccn1
Temperature: 25 °C
Yield: 36.3 %

Procedure:
A mixture of 3-(4-(2-(methylcarbamoyl)pyridin-4-yloxy)phenyl)-propanoic acid (100 mg, 0.33 mmol), aniline (0.033 mL, 0.36 mmol), and TBTU (117 mg, 0.36 mmol) in DCM (5 mL) was stirred at rt. To this slurry was added DIPEA (0.20 mL, 1.16 mmol). The mixture was allowed to stir at rt overnight and then diluted with water. The aqueous phase was separated and extracted with DCM. The organic solutions were combined, washed with brine, dried over MgSO4, filtered, and concentrated. The resulting solid was treated with MeOH and filtered to give 45 mg of a white solid. 1H NMR (400 MHz, d6-DMSO) δ: 9.90 (br s, 1H), 8.71-8.78 (m, 1H), 8.48 (d, J=5.6 Hz, 1H), 7.55-7.60 (m, 2H), 7.36-7.40 (m, 2H), 7.36 (d, J=2.4 Hz, 1H), 7.25-7.31 (m, 2H), 7.12-7.16 (m, 2H), 7.11 (dd, J=5.2, 2.4 Hz, 1H), 6.99-7.04 (m, 1H), 2.93-2.98 (m, 2H), 2.77 (d, J=4.8 Hz, 3H), and 2.64-2.69 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl.CCO.Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=1>CCO>[C:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:1]2[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]2)=[CH:14][CH:15]=1)#[N:20]
Reactant: C1CNCCN1
Reactant: N#Cc1ccc(CBr)cc1
Agent: Cl
Solvent: CCO
Product: N#Cc1ccc(CN2CCNCC2)cc1

Procedure:
To a solution of piperazine (5.17 g, 60 mmol, 2 equiv) in EtOH (40 mL) was added 1 M HCl-EtOH (60 mL) dropwise over 1 h and the suspension was heated to 70° C. for 1 h. α-Bromo-p-tolunitrile (5.88 g, 30 mmol, 1 equiv) was added and the reaction was heated to reflux for 16 h. After cooling the solvent was removed by rotary evaporation and the residue was partitioned between CH2Cl2 (70 mL) and 2N aqueous KOH (70 mL) and the combined organic phase was washed with saturated aqueous NaCl (100 mL) and dried (MgSO4). Chromatography (SiO2, 20% CH3OH-5% Et3N-CH2Cl2) afforded the monoalkylated material (2.6 g, 6.0 g theoretical, 43%) as an amber oil.
Reaction SMILES: [N+:1]([CH3:4])([O-])=O.[NH:5]1[CH2:10][CH2:9]CCC1.C(O)(=O)C.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:9][CH:10]1[NH:5][CH2:16][CH2:17][C:18]2[N:1]=[CH:4][CH:15]=[CH:20][C:19]1=2
Reactant: C1CCNCC1
Reactant: c1ccccc1
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Product: CC1NCCc2ncccc21

Procedure:
To a solution of aldehyde A (1 mol) in benzene (approx. 20 ml per 1 g of the starting compound) nitromethane (1.2 mol), piperidine (0.1 mol) and acetic acid (0.1 mol) are added. The reaction mixture is refluxed for 2.5 h with azeotrope removing of water. Then, the solvent is evaporated in vacuo. The residue is triturated with cold methanol, filtered, washed with cold methanol that resulted in product crystals in good to moderate yields.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][C:9]=2[CH:15](O)[CH3:16].[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[SH:24].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.O>[CH3:18][N:19]1[CH:23]=[CH:22][N:21]=[C:20]1[S:24][CH:15]([C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[NH:7][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)=[CH:14]2)[CH3:16]
Reactant: CC(O)c1cccc2cc(-c3nccs3)[nH]c12
Reactant: Cn1ccnc1S
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: O
Solvent: C1CCOC1
Product: CC(Sc1nccn1C)c1cccc2cc(-c3nccs3)[nH]c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.7 %

Procedure:
A solution of 1-[2-(1,3-thiazol-2-yl)-1H-indol-7-yl]ethanol (0.089 g), 1-methyl-1H-imidazole-2-thiol (0.046 g) and tributylphosphine (0.458 g) in tetrahydrofuran (7 mL) was stirred, 1,1′-(azodicarbonyl)dipiperidine (0.584 g) was added, and the mixture was stirred at room temperature for 1 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=30:70-70:30) to give the title compound (0.110 g, yield 89%) as colorless crystals.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.Cl[P:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CCCCCC.O1CCCC1>[C:22]1([P:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]2[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=2)[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Brc1ccc(Br)cc1
Reactant: ClP(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Brc1ccc(P(c2ccccc2)c2ccccc2)cc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 29.5 %

Procedure:
To 1.0 mole of n-butyllithium in hexane at -78° C. under an inert atmosphere is added dropwise and with efficient stirring 236 g of p-dibromobenzene in dry tetrahydrofuran (total volume 500 ml). The resulting solution is stirred at -78° C. for 1 hour, then treated dropwise at this temperature with 220.5 g of chlorodiphenylphosphine. When this addition is complete, the mixture is allowed to warm to room temperature, then solvent is removed under vacuum. The residue is triturated with two 400-ml portions of methanol, then distilled through a Vigreux column. The cut with bp 165°-170° C. (0.15 mm) is recrystallized from ethanol to give 100.5 g of p-diphenylphosphinobromobenzene, mp 78°-80° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH:22]1[CH2:27][CH2:26][CH:25]([N:28]2[C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[NH:30][C:29]2=[O:37])[CH2:24][CH2:23]1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C(C)=CC=CC=1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH2:13][CH2:12][CH:11]([N:22]3[CH2:23][CH2:24][CH:25]([N:28]4[C:32]5[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=5[NH:30][C:29]4=[O:37])[CH2:26][CH2:27]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: O=c1[nH]c2ccccc2n1C1CCN(C2CCC(c3ccc(F)cc3)(c3ccc(F)cc3)CC2)CC1

Procedure:
A mixture of 10 g of 4,4-bis(p-fluorophenyl)cyclohexanone, 6.6 g of 1-(4-piperidyl)-2-benzimidazolinone, 0.2 g of p-toluenesulfonic acid and 80 ml of xylene is stirred under reflux for 34 hours, the water formed being removed. The xylene is then removed under reduced pressure, and to the residue is added 200 ml of methanol and 10 ml of water. To the resulting mixture is added dropwise 15 g of sodium borohydride at about 20° C with cooling. After the addition is complete, the mixture is stirred under reflux for 3 hours. The reaction mixture is concentrated completely under reduced pressure, water is added to the residue, and the aqueous mixture is extracted with chloroform. The extract is washed with water and dried over sodium sulfate, and the solvent is removed. The residual viscous oil is purified by column chromatography using methylene chloride and then a mixture of methylene chloride and methanol (9:1) as an eluent. Thus is obtained 1-[1-(4,4-bis(p-fluorophenyl)cyclohexyl)-4-piperidyl]- 2-benzimidazolinone as colorless crystals, melting at 235°-238° C.
Reaction SMILES: [C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.N.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)[N:32]=1>CN(C)C=O.O>[C:1]1([C@H:7]([N:9]2[CH2:15][CH2:14][CH:13]([C:16]3[CH:24]=[CH:23][C:19]([C:20]([NH2:32])=[O:21])=[CH:18][CH:17]=3)[O:12][CH2:11][CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Reactant: C[C@H](c1ccccc1)N1CCOC(c2ccc(C(=O)O)cc2)CC1
Agent: N
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: C[C@H](c1ccccc1)N1CCOC(c2ccc(C(N)=O)cc2)CC1
Reaction time: 24 h

Procedure:
To a solution of 4-[4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-7-yl]-benzoic acid (diastereomer type A) (0.96 g, 2.9 mmol) and 7 mol/L methanol solution of ammonia (2 mL, 14 mmol) in N,N-dimethylformamide (10 mL) was added 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (1.25 g, 4.5 mmol) at room temperature and the mixture was stirred for one day. The reaction mixture was poured into water. The resulting white solid material was collected by filtration and dried under reduced pressure at 50° C. for 5 hours to yield 4-[4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-7-yl]-benzamide (diastereomer type A) (0.58 g, 1.78 mmol, 61%).
Reaction SMILES: [C:1]([Cl:4])(Cl)=[O:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([NH2:12])[CH:11]=1.[CH2:20](N(CC)CC)C>O1CCCC1>[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:20][N:12]([C:1]([Cl:4])=[O:2])[C:10]=2[CH:11]=1
Reactant: O=C(Cl)Cl
Reactant: CCN(CC)CC
Reactant: Nc1cc(Cl)ccc1Sc1ccccc1
Solvent: C1CCOC1
Product: O=C(Cl)N1Cc2ccccc2Sc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a cold (ice-H2O bath), stirred solution of phosgene (1.93M in toluene; 8.6 mL) in anhydrous tetrahydrofuran (40 mL) under a nitrogen atmosphere is added, dropwise, a solution of the title product of Example 48 (2.00 g) and triethylamine (1.3 mL) in anhydrous tetrahydrofuran (30 mL). The resulting mixture is stirred at room temperature for 90 minutes, and the solvent is then evaporated in vacuo to provide the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26](=[O:29])[CH2:27]Br)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([C:27]1[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[C:5]([C:6]=1[NH2:7])=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:29])(=[O:18])[CH3:17]
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Reactant: CC(=O)OCc1ccoc1C(=O)CBr
Product: CCOC(=O)n1c(C(=O)c2occc2COC(C)=O)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in Step 2 of Example 1 from 4-chloro-2-(ethoxycarbonylamino)benzonitrile (Example 1, step 1) and 3-acetoxymethyl-2-(bromoacetyl)furan (Example 372, step 1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C@@H:8]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])#[N:2].Cl.[NH2:22][OH:23].CCN(CC)CC>CCO>[OH:23][NH:22][C:1]([C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][CH2:7][C@@H:8]2[NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[NH:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C#N)cccc21
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H]1CCCc2c(C(=N)NO)cccc21
Temperature: 85 °C

Procedure:
Prepared using General Procedure 1. To a stirring solution of (S)-tert-butyl (5-cyano-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-8 (3.10 g, 11.38 mmol) in EtOH (25 mL) was added hydroxylamine hydrochloride (2.77 g, 39.84 mmol) and NEt3 (3.17 mL, 22.77 mmol). After heating at 85° C. for 15 h, the mixture was concentrated, redissolved in DCM, and washed with NaHCO3. The combined organic layers were dried, concentrated and chromatographed (MeOH/DCM) to provide 3.56 g crude (S)-tert-butyl (5-(N-hydroxycarbamimidoyl)-1,2,3,4-tetrahydronaphthalen-1-yl)carbamate INT-10 (58% product by UV area), which was used in the next reaction without further purification. LCMS-ESI (m/z) calculated for C16H23N3O3: 305.37; found 306.2 [M+H]+, tR=2.00 min.