Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[Cl:9][CH2:10][CH:11]([OH:26])[CH2:12][N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>[Na].C(O)C>[ClH:9].[OH:26][CH:11]([CH2:10][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:12][N:13]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[CH:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: Sc1ccccc1
Reactant: OC(CCl)CN(C1CCCCC1)C1CCCCC1
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: OC(CSc1ccccc1)CN(C1CCCCC1)C1CCCCC1
Yield: 63 %

Procedure:
One mol of thiphenol is dissolved in a solution of 46 g of sodium of ethanol. To the resulting solution there is progressively added 1 mol of an ethanolic solution of (3-chloro-2-hydroxy propyl) dicyclohexylamine hydrochloride. This mixture is then heated for two hours at reflux. After cooling the same, the reaction mixture is filtered and the filtrate evaporated to dryness. The resulting oily residue is taken up in sulfuric ether, through which there is then bubbled gaseous HCl. A white precipitate rapidly forms which is then filtered therefrom and recrystallized in ethanol for a 63 percent yield of white crystals melting at 181° C.
Reaction SMILES: [OH:1][C:2]([C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][CH:39]=1)[C:36]([CH3:40])=[C:35]([C:41]([O:43][CH3:44])=[O:42])[CH:34]=[CH:33]2)([C:6]1[N:7]=[CH:8][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1)[CH:3]([CH3:5])[CH3:4].[Br:45]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:45][CH2:40][C:36]1[C:37]2[C:32](=[CH:31][C:30]([C:2]([OH:1])([C:6]3[N:7]=[CH:8][N:9]([C:11]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH:10]=3)[CH:3]([CH3:5])[CH3:4])=[CH:39][CH:38]=2)[CH:33]=[CH:34][C:35]=1[C:41]([O:43][CH3:44])=[O:42]
Reactant: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc2cc(C(O)(c3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)C(C)C)ccc2c1CBr

Procedure:
Methyl 6-[1-hydroxy-2-methyl-1-(1-trityl-1H-imidazol-4-yl)propyl)-1-methyl-2-naphthoate (34.61 g) was suspended in carbon tetrachloride (0.8 L) and N-bromosuccinimide (12.28 g) and 2,2′-azobisisobutyronitrile (0.99 g) were added. The reaction mixture was heated under reflux for 21 hrs., and the solvent was evaporated. The residue was diluted with saturated aqueous sodium hydrogen carbonate and extracted twice with ethyl acetate-THF (1:1). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was purified by column chromatography (carrier;silica gel, developing solvent; ethyl acetate) to give a mixture of the title compound and the starting material (title compound:starting material=about 7:1, 23.10 g) as brown crystals.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(N(CC)C(C)C)(C)C>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[O:9][N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)no4)c3)c2cc1OC
Temperature: 50 °C
Yield: 57.6 %

Procedure:
A mixture of phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate (0.158 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) was heated at 50° C. for 5 hours. It was quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 40-95% EtOAc/hexane as eluants to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy]phenyl)urea as solid (0.115 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.56 (m, 3H), 7.39 (s, 1H), 7.27 (s and d, 2H), 6.24 (s, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.30 (s, 3H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: O[CH2:2][C:3]1([CH3:17])[CH2:5][CH:4]1[C:6]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:7]=1[OH:16].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[CH3:2][C:3]12[CH2:5][CH:4]1[C:6]1[C:11]([O:12][CH2:13][O:14][CH3:15])=[CH:10][CH:9]=[CH:8][C:7]=1[O:16][CH2:17]2
Reactant: COCOc1cccc(O)c1C1CC1(C)CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COCOc1cccc2c1C1CC1(C)CO2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 98.7 %

Procedure:
To a solution of 2-[2-(hydroxymethyl)-2-methylcyclopropyl]-3-{[(methyloxy)methyl]oxy}phenol (Intermediate 123, 307 mg) in dry tetrahydrofuran (10 ml) were added triphenylphosphine (338 mg, 1.288 mmol) and bis(1-methylethyl)(E)-1,2-diazenedicarboxylate (261 mg, 1.288 mmol). The reaction turned yellow and was stirred for 20 minutes at room temperature under nitrogen. The solvent was then evaporated under vacuum to give the crude product as pale yellow oil. The residue obtained was purified by silica gel chromatography (Companion system, with a gradient from pure Cyclohexane to cyclohexane/ethyl acetate 10/1) to give the title compound as a white solid (280 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.Br[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15].O1C=CN=C1>C(OCC)(=O)C>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]2[O:7][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)CBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: c1cocn1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1coc(-c2ccc(O)cc2)n1
Temperature: 115 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
A mixture of 25.0 g (182.3 mmol) of 4-hydroxybenzamide and 23.0 mL (182.3 mmol) of ethyl bromopyruvate was stirred and heated at 115° C. for 30 minutes. The mixture cooled to room temperature and sat under N2 atmosphere overnight. Ethyl acetate (100 mL) was added and the mixture stirred for 1 hour. The solid oxazole (36.99 g, 158.6 mmol) was collected by suction filtration in 87% yield: 1H NMR (CDCl3) δ 10.21 (broad s, 1H), 8.82 (s, 1H), 7.83 (d, J=8.7 Hz, 2H), 6.90 (d, J=8.7 Hz, 2H), 4.29 (q, 2H), 1.29 (t, 3H); IR (cm-1) 3400, 3169, 1731, 1612, 1731, 1507, 1444; FDMS 233. Anal. (C12H11NO4) C, H, N.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([NH:6][C:7](=[O:17])[C:8]1[CH:13]=[C:12]([F:14])[C:11]([CH3:15])=[CH:10][C:9]=1[F:16])(=[O:5])=[O:4].[Br:19]N1C(=O)CCC1=O>ClCCCl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:19][CH2:15][C:11]1[C:12]([F:14])=[CH:13][C:8]([C:7]([NH:6][S:3]([N:2]([CH3:1])[CH3:18])(=[O:5])=[O:4])=[O:17])=[C:9]([F:16])[CH:10]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(F)c(C(=O)NS(=O)(=O)N(C)C)cc1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClCCCl
Product: CN(C)S(=O)(=O)NC(=O)c1cc(F)c(CBr)cc1F
Temperature: 25 °C

Procedure:
A mixture of N-[(dimethylamino)sulfonyl]-2,5-difluoro-4-methylbenzamide (Preparation 2, 0.50 g, 1.80 mmol), N-bromosuccinimide (freshly recrystallised and dried, 0.42 g, 2.34 mmol) and azobisisobutyronitrile (14.8 mg, 0.09 mmol) in 1,2-dichloroethane (15 mL) was heated under reflux with stirring whilst being irradiated with light from a 100 watt lamp. After 6 hours more N-bromosuccinimide (300 mg, 1.69 mmol) and azobisisobutyronitrile (10 mg, 0.06 mmol) were added and the mixture heated for a further 4 hours. An additional amount of N-bromosuccinimide (100 mg, 0.56 mmol) was then added and the mixture heated under reflux for a further 4 hours. The reaction mixture was cooled to room temperature and evaporated in vacuo to leave a pale yellow oil (0.54 g). Purification by silica gel column chromatography eluting with ethyl acetate/heptane 0:100-1:4 afforded the title compound (0.176 g, 27%) as a colourless oil which solidified on standing.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[C:5](S(C(F)(F)F)(=O)=O)[CH:6]=[CH:7][CH:8]=2)[N:3]=1.C(Cl)Cl>C1COCC1>[CH2:8]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH2:1])[CH:11]=[CH:10]2)[CH2:9][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: Nc1ccc2cccc(S(=O)(=O)C(F)(F)F)c2n1
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCCCc1cccc2ccc(N)nc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 2-amino-8-trifluoromethanesulfonylquinoline (50.0 mg, 0.171 mmol) in THF (1.0 mL) was degassed by bubbling N2 through the solution under vacuum for 5 min. The solution was added to a glass screw-top tube containing Pd(dppf)2Cl2.CH2Cl2 (13.9 mg, 0.1 equiv). Argon was then bubbled through the mixture for 1 minute, and 1-hexylzinc bromide (1.0 mL, 1 M in THF) was added. The tube was quickly sealed and placed in a heater/shaker at 65° C. for 20 h. The reaction mixture was cooled to room temperature, filtered through a 0.45 μm filter, and concentrated. The residue was dissolved in 1:1 DMSO/MeOH, filtered through a 0.45 μm filter, and purified by reverse phase HPLC. 1H NMR (300 MHz, DMSO-d6) δ 9.10 (br s, 1H), 8.36 (br s, 1H), 8.23 (br s, 1H), 7.77 (d, 1H), 7.63 (d, 1H), 7.43 (br s, 1H), 7.10 (d, 1H), 1.41–1.25 (m, 10H), 0.86 (t, 3H); MS (DCI/NH3) m/z 228 [M]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([C:17]1[CH:26]=[CH:25][C:20]([CH2:21][NH:22][O:23][CH3:24])=[CH:19][CH:18]=1)([O:15][CH3:16])=[O:14]>>[CH3:16][O:15][C:13](=[O:14])[C:17]1[CH:26]=[CH:25][C:20]([CH2:21][N:22]([C:8](=[O:9])[CH:7]=[C:5]2[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]2)[O:23][CH3:24])=[CH:19][CH:18]=1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CONCc1ccc(C(=O)OC)cc1
Product: COC(=O)c1ccc(CN(OC)C(=O)C=C2OC(C)(C)OC2=O)cc1
Yield: 83 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with N-4-carbomethoxybenzyl-O-methyl-hydroxylamine as described in the preparation of Compound 44-C gave the title amide as a white solid (83% yield): mp 120° C. (dichloromethane-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.75 (6H, s, CH3), 3.67 (3H, s, OCH3), 3.91 (3H, s, OCH3), 4.88 (2H, s, NCH2), 6.40 (1H, s, CH), 7.42 (2H, d, aromatics), 8.0 (2H, d, aromatics). Anal. calcd for C17H19NO7: C, 58.45; H, 5.48; N, 4.01. Found: C, 58.54; H, 5.55; N, 3.61.
Reaction SMILES: [O:1]1[CH2:3][C@@H:2]1[CH2:4][OH:5].[CH3:6][O:7][C:8]1[CH:9]=[CH:10][C:11]([N+:15]([O-:17])=[O:16])=[C:12](O)[CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([N+:15]([O-:17])=[O:16])=[C:10]([CH:9]=1)[O:5][CH2:4][C@H:2]1[CH2:3][O:1]1
Reactant: OC[C@H]1CO1
Reactant: COc1ccc([N+](=O)[O-])c(O)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1ccc([N+](=O)[O-])c(OC[C@H]2CO2)c1
Temperature: 25 °C
Yield: 60.7 %

Procedure:
To a mixture of (2S)-oxiran-2-ylmethanol (445 mg, 6.0 mmol), 5-methoxy-2-nitrophenol (1.02 g, 6.0 mmol) and triphenylphosphine (1.57 g, 6.0 mmol) in THF (10 mL) was added DEAD (0.95 mL, 6.0 mmol) in THF (5 mL) dropwise at 0° C. After addition was completed the ice bath was removed and the mixture was stirred at room temperature over night. The volatiles were removed in vacuo and the residue was purified by silica gel flash chromatography (0-40% ethyl acetate in petroleum spirit) to give the sub-title compound (820 mg).
Reaction SMILES: [N:1]#CBr.[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]2C=CC=CC=2)=[CH:7][CH:6]=1>CCOCC>[Br:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12][C:13]#[N:1])=[CH:7][CH:6]=1
Reactant: Brc1ccc(CNc2ccccc2)cc1
Reactant: N#CBr
Solvent: CCOCC
Product: N#CNCc1ccc(Br)cc1
Reaction time: 72 h
Yield: 31.6 %

Procedure:
A mixture of cyanogen bromide (3.18 g, 30 mmol), and (4-bromophenyl) methyl aniline (11.25 g, 61 mmol) in ether (50 mL) was stirred for 3 days under nitrogen. The mixture was filtered, the filtrate evaporated, and the residue flash chromatographed on silica gel using 9/1 Hexane/acetone to give (4-bromophenyl)methylcyanamide (2 g, 16 %).
Reaction SMILES: I[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12]([C:14]3[S:15][C:16]([CH3:19])=[CH:17][CH:18]=3)=[O:13])=[N:7][C:6]=2[C:5]([O:20][CH3:21])=[CH:4][CH:3]=1.[CH3:22][N:23]([CH3:33])[C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][CH:29]=1>>[CH3:22][N:23]([CH3:33])[C:24]1[CH:29]=[C:28]([C:2]2[C:10]3[S:9][C:8]([NH:11][C:12]([C:14]4[S:15][C:16]([CH3:19])=[CH:17][CH:18]=4)=[O:13])=[N:7][C:6]=3[C:5]([O:20][CH3:21])=[CH:4][CH:3]=2)[CH:27]=[CH:26][CH:25]=1
Reactant: CN(C)c1cccc(B(O)O)c1
Reactant: COc1ccc(I)c2sc(NC(=O)c3ccc(C)s3)nc12
Product: COc1ccc(-c2cccc(N(C)C)c2)c2sc(NC(=O)c3ccc(C)s3)nc12
Yield: 71 %

Procedure:
5-Methyl-thiophene-2-carboxylic acid [7-(3-dimethylamino-phenyl)-4-methoxy-benzothiazol-2-yl]-amide is synthesized from 5-methyl-thiophene-2-carboxylic acid (7-iodo-4-methoxy-benzothiazol-2-yl)-amide (100 mg, 0.23 mmol) and 3-dimethylaminophenylboronic acid (58 mg, 0.35 mmol) using the general procedure A as a light yellow solid in 71% yield. MS: m/e=424 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1.ClC1C(=O)C(C#N)=C(C#N)C(=[O:23])C=1Cl>C1COCC1.O>[Br:1][C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[C:7](=[O:23])[CH2:8][CH2:9][CH2:10][C:11]=3[NH:12]2)=[CH:4][CH:3]=1
Reactant: Brc1ccc2c3c([nH]c2c1)CCCC3
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCCc2[nH]c3cc(Br)ccc3c21
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 81 %

Procedure:
A solution 7-bromo-2,3,4,9-tetrahydro-1H-carbazole (2.87 g, 11.5 mmol) in THF (103 mL) and H2O (11.5 mL) was cooled to 0° C. and treated with a solution of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.23 g, 23.1 mmol) in THF (46 mL) at such a rate that the reaction mixture did not exceed 4° C. The resulting solution was allowed to stir for an additional 45 min at 0° C. The solution was concentrated to dryness under reduced pressure. The resulting solids were suspended in EtOAc (100 mL) and saturated NaHCO3 solution (300 mL). The solids were collected by filtration and washed with additional saturated NaHCO3 solution (400 mL) followed by H2O (150 mL). The solid was dried to provide the title compound (2.46 g, 81%) as a light pink solid: 1H NMR (500 MHz, DMSO-d6) δ 11.97 (s, 1H), 7.86 (d, J=8.5 Hz, 1H), 7.58 (d, J=1.5 Hz, 1H), 7.27 (dd, J=8.5, 2.0 Hz, 1H), 2.95 (t, J=6.0 Hz, 2H), 2.42 (t, J=6.0 Hz, 2H), 2.14-2.09 (m, 2H); ESI MS m/z 263 [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH:15]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:19]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([CH2:10][CH2:11][CH3:12])=[CH:8][C:7]([CH2:13][CH2:14][CH2:15][N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:18]=3[CH3:17])[CH2:26][CH2:27]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: CCCc1cc(CCC=O)nn1C(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CCCc1cc(CCCN2CCN(c3ccc(C)cc3C)CC2)nn1C(C)(C)C

Procedure:
96mg (98%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-propyl-1H-pyrazol-3-yl)propanal (50 mg, 0.225 mmol), 1-(2,4-dimethylphenyl)piperazine (43 mg, 0.225 mmol), DIPEA (0.060 mL, 0338 mmol) and NaBH(OAc)3 (143 mg, 0.675 mmol).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=[C:2]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:11]=1
Reactant: Cc1cc(Cl)nc2ccccc12
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(N2CCNCC2)nc2ccccc12
Temperature: 140 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 2-chloro-4-methylquinoline (2 g, 11 mmol) in N,N-dimethylformamide (40 ml) was added piperazine (4.86 g, 56.4 mmol, 5 eq) and potassium carbonate (2.34 g, 16.8 mmol, 1.5 eq). The mixture was stirred overnight at 140° C., quenched by the addition of water (200 ml), and extracted with ethyl acetate (3×100 ml). The organic layers were combined and washed with saturated aqueous sodium chloride (200 ml). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 1-10% methanol in dichloromethane to elute. The product-containing fractions were combined and concentrated to afford 4-methyl-2-(piperazin-1-yl)quinoline as colorless oil (2.2 g, 86%); (ES, m/z) [M+H]+ 228; 1H NMR (300 MHz, CDCl3): δ 7.70-7.78 (m, 2H), 7.50-7.55 (t, J=7.5 Hz, 1H), 7.22-7.27 (t, J=6.9 Hz, 1H), 6.83 (s, 2H), 3.70-3.73 (t, J=4.8 Hz, 1H), 3.00-3.03 (t, J=5.1 Hz, 1H), 2.59 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20](O)=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:42])[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][NH:32][C:33]2[CH:38]=[CH:37][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:35][CH:34]=2)=[CH:27][CH:26]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([N:32]([CH2:31][C:28]1[CH:27]=[CH:26][C:25]([N:24]([CH3:42])[CH3:23])=[CH:30][CH:29]=1)[C:33]1[CH:34]=[CH:35][C:36]([CH:39]([CH3:41])[CH3:40])=[CH:37][CH:38]=1)=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1CCCc2c(OCc3ccccc3)ccc(F)c21
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cc1
Yield: 79.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 5-benzyloxy-8-fluoro-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.5 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.45 g) as starting materials, 5-benzyloxy-N-[(4-dimethylaminophenyl)methyl]-8-fluoro-N-(4-isopropylphenyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was obtained.
Reaction SMILES: S(=O)(=O)(O)O.C([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH:14](C(OCC)=O)[CH:13]2[OH:25])(=O)C>O>[OH:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[C:15](=[O:19])[CH2:14][C:13]2=[O:25]
Reactant: CCOC(=O)C1C(=O)c2ccc(OC(C)=O)cc2C1O
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CC(=O)c2cc(O)ccc21

Procedure:
4 ml of 10N sulphuric acid were added to a suspension of 0.01 mol of 5-acetoxy-2-carbethoxy-3-hydroxy-1-indanone in 80 ml water. The reaction mixture was refluxed for 15 minutes. The insoluble substance was filtered when hot and the yellow precipitate formed after cooling was dried on vacuo pump, washed in ice water and dried.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[NH:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:29])C(=O)C1>>[Br:29][C:11]1[C:10]2[NH:9][C:8]3[C:16](=[CH:17][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:6][CH:7]=3)[C:15]=2[CH:14]=[C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])[CH:12]=1
Reactant: CC(C)(C)c1ccc2[nH]c3ccc(C(C)(C)C)cc3c2c1
Reactant: O=C1CCC(=O)N1Br
Product: CC(C)(C)c1ccc2[nH]c3c(Br)cc(C(C)(C)C)cc3c2c1
Yield: 80 %

Procedure:
The reaction of 3,6-di-tert-butyl-9H-carbazole with NBS produced 1-bromo-3,6-di-tert-butyl-9H-carbazole as a white-glassy solid in 80% yield after purification by flash chromatography on silica gel (FIG. 13).
Reaction SMILES: C([O:8][N:9]1[C@@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[C@H:11]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:10]1=[O:26])C1C=CC=CC=1>CO.[Pd]>[C:22]([O:21][C:19]([NH:18][C@H:11]1[C@H:12]([CH2:13][O:14][C:15](=[O:17])[NH2:16])[N:9]([OH:8])[C:10]1=[O:26])=[O:20])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(OCc2ccccc2)[C@H]1COC(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C(=O)N(O)[C@H]1COC(N)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.9 %

Procedure:
In 50 ml of methanol is dissolved 1.83 g (5 mmole) of trans-1-benzyloxy-3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-2-azetidinone, and 190 mg of 10% palladium-charcoal is added to the solution, followed by stirring under a hydrogen atmosphere at room temperature for 30 minutes. The catalyst is filtered off, and the filtrate is concentrated under reduced pressure to give 1.32 g (96.1%) of trans-3-(tert-butoxycarbonylamino)-4-carbamoyloxymethyl-1-hydroxy-2-azetidinone as a colorless foamy product.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH:8]=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:23]=1)=[O:20]>>[CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([CH2:8][N:31]2[CH2:32][CH2:33][CH:28]([C:24]3[CH:23]=[C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])[CH:27]=[CH:26][CH:25]=3)[CH2:29][CH2:30]2)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: Cc1c(C=O)c(=O)n(-c2ccccc2)n1C
Product: Cc1c(CN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)c(=O)n(-c2ccccc2)n1C

Procedure:
Prepared by Procedure F and Scheme R using 1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carbaldehyde and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 447.2 (M+H)+.
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7]([C:10]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:9])=[O:8]>C(OCC)(=O)C>[C:1]([NH:5][S:7]([C:10]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[CH:16][C:11]=1[C:12]([O:14][CH3:15])=[O:13])(=[O:8])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)Cl
Reactant: CC(C)(C)N
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
206 g of tert-butylamine are added dropwise to a solution of 384 g of methyl 2-chlorosulfonyl-4-nitro-benzoate (Example b) in 1500 ml of ethyl acetate at 0° C. The reaction mixture is then allowed to warm up to room temperature and is stirred at this temperature for 1 hour. After washing with dilute hydrochloric acid and water, the organic phase is dried over MgSO4 and concentrated. The residue is extracted by stirring with diisopropyl ether; Yield of sulfonamide: 377.6 g; m.p.: 122-124° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][C:16]=2[CH3:24])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc([N+](=O)[O-])ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(N)ccc1OC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 1.5 h
Yield: 106.1 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-4-(4-nitro-2-methylphenyloxy)piperidine (9.0 g) in ethanol (100 ml) was added conc. hydrochrolic acid (2.3 ml) and, by using 10% palladium/carbon (containing 48% of water, 1 g) as a catalyst, catalytic reduction was conducted under normal pressure for 1.5 hours. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to obtain 1-tert-butyloxycarbonyl-4-(4-amino-2-methylphenyloxy)piperidine (8.7 g) as a light brown amorphous material.