Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[N:27]=[N:26][N:25]=3)=[CH:14][CH:13]=2)[C:7]=1[C:8]([OH:10])=[O:9])[CH3:2].I[CH2:52][CH2:53][CH3:54].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O.C(OCC)(=O)C>[CH2:1]([C:3]1[N:4]=[C:5]([CH2:48][CH2:49][CH3:50])[N:6]([CH2:11][C:12]2[CH:13]=[CH:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]3[N:28]([C:29]([C:42]4[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=4)([C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)[C:30]4[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:27]=[N:26][N:25]=3)=[CH:16][CH:17]=2)[C:7]=1[C:8]([O:10][CH2:52][CH2:53][CH3:54])=[O:9])[CH3:2]
Reactant: CCCc1nc(CC)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCCOC(=O)c1c(CC)nc(CCC)n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reaction time: 24 h

Procedure:
1.32 g of 4-ethyl-2-propyl-1-[[2'-(N-triphenylmethyl(tetrazol-5-yl))biphenyl-4-yl]methyl]imidazole-5-carboxylic acid, 0.39 mL of iodopropane and 0.55 g potassium carbonate were added to 6 mL DMF. The reaction was allowed to stir for 24 hours then diluted with 12 mL water and 90 mL ethyl acetate. The organic layer was separated and washed five times with water, once with brine and dried with MgSO4. Chromatography with a gradient from 5 to 50% ethyl acetate in hexane gave 0.96 g of desired product.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:14][F:15])[O:7][B:6]([OH:8])[C:5]2[CH:9]=[C:10]([CH3:13])[CH:11]=[CH:12][C:4]1=2.C1C(=O)N([Br:23])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:23][CH2:13][C:10]1[CH:11]=[CH:12][C:4]2[C:3]([CH2:14][F:15])([CH2:2][F:1])[O:7][B:6]([OH:8])[C:5]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)B(O)OC2(CF)CF
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: OB1OC(CF)(CF)c2ccc(CBr)cc21
Temperature: 25 °C
Yield: 87.4 %

Procedure:
To a solution of 3,3-bis(fluoromethyl)-6-methylbenzo[c][1,2]oxaborol-1(3H)-ol (0.5 g, 2.36 mmol) in CCl4 (10 mL) under nitrogen was added NBS (420 mg, 2.36 mmol) and BPO (57 mg, 0.236 mmol). The mixture was refluxed for 2 h under the light from a Sun lamp, and then it was cooled to rt, washed with aqueous NaHCO3 and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by column chromatography to provide the product (0.6 g, yield 87.4%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([CH:27]=[CH:28][C:29]=4[CH3:30])[C:24]([OH:26])=O)=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:31][N:32]1[CH:36]=[C:35]([C:37]2([NH2:40])[CH2:39][CH2:38]2)[N:34]=[CH:33]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>ClCCl.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:22]=[C:23]([C:24](=[O:26])[NH:40][C:37]5([C:35]6[N:34]=[CH:33][N:32]([CH3:31])[CH:36]=6)[CH2:39][CH2:38]5)[CH:27]=[CH:28][C:29]=4[CH3:30])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)ccc3C)cc12
Reactant: Cn1cnc(C2(N)CC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5cn(C)cn5)CC4)ccc3C)cc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
3-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-4-methylbenzoic acid (0.15 g, 0.37 mmol, 1 eq), 1-(1-methyl-1H-imidazol-4-yl)cyclopropanamine (0.061 g, 0.44 mmol, 1.2 eq), EDCI.HCl (0.078 g, 0.40 mmol, 1.1 eq), HOBT (0.049 g, 0.37 mmol, 1.0 eq) and TEA (0.15 ml, 1.1 mmol, 3 eq) were dissolved in dichloromethane and the above mixture was stirred at room temperature for 18 h. The mixture was then added with water. The organic layer was separated, washed with water, concentrated and the crude product purified by Prep. HPLC. Yield: 24.69 mg (10%). 1HNMR (400 MHz, DMSO-d6): δ1.04-1.07 (m, 2H), 1.17-120 (m, 2H), 2.29 (s, 3H), 2.82 (d, J=4.4 Hz, 3H), 3.54 (s, 3H), 6.7 (s, 1H), 7.37-7.43 (m, 5H), 7.58 (s, 1H), 7.74-7.77 (d, J=8.8 Hz, 1H), 7.81-7.82 (m, 2H), 7.97-8.01 (m, 2H), 8.46-8.47 (m, 1H), 9.06 (s, 1H) LCMS: (ES+) m/z=523.2 (M+H)+
Reaction SMILES: [CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]([O:19]C)=[C:14]3[C:10]=2[CH2:11][CH2:12][CH2:13]3)=[C:6]([CH2:21][CH3:22])[N:5]([CH2:23][C:24]([OH:26])=[O:25])[N:4]=1)[CH3:2].B(Br)(Br)Br.O>C(Cl)Cl>[CH2:1]([C:3]1[C:7]([CH2:8][C:9]2[CH:17]=[C:16]([CH3:18])[C:15]([OH:19])=[C:14]3[C:10]=2[CH2:11][CH2:12][CH2:13]3)=[C:6]([CH2:21][CH3:22])[N:5]([CH2:23][C:24]([OH:26])=[O:25])[N:4]=1)[CH3:2]
Reactant: CCc1nn(CC(=O)O)c(CC)c1Cc1cc(C)c(OC)c2c1CCC2
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: CCc1nn(CC(=O)O)c(CC)c1Cc1cc(C)c(O)c2c1CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 78.2 %

Procedure:
To a stirred suspension of [3,5-Diethyl-4-(7-methoxy-6-methyl-indan-4-ylmethyl)-pyrazol-1-yl]-acetic acid (6.0 gm, 0.0168 mole) in Methylene chloride (100 ml), a solution of Boron tribromide (4.2 ml, 0.0442 mole) in Methylene chloride (20 ml) was added at 0-5° C. and stirred for 2-3 hrs at 20-30° C. Water (250 ml) was charged into the reaction mixture and stirred for 1 hour. The separated solid was filtered under vacuum, washed with water. The obtained solid was dissolved in Ethyl acetate (2.0 liter) and washed with water (1 liter). Ethyl acetate was distilled under vacuum and further the obtained solid was stirred in Diethyl ether (50 ml), filtered and dried at 55-60° C. under vacuum to yield 4.5 gm of desired product.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[OH:12][C@H:13]1[CH2:17][NH:16][C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]1.C([O-])(O)=O.[Na+].O>CC(C)=O>[OH:12][C@H:13]1[CH2:17][N:16]([C:2]([O:4][CH2:5][C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:3])[C@H:15]([C:18]([OH:20])=[O:19])[CH2:14]1
Reactant: O=C(O)[C@@H]1C[C@@H](O)CN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=C(O)[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 101.8 %

Procedure:
Benzyl chloroformate (8.6 mL, 0.06 mol) was dissolved in acetone (12 mL), and this solution was added dropwise to a stirred solution of trans-4-Hydroxy-L-proline (6.56 g, 0.05 mol) in satd. NaHCO3 (160 mL) and H2O (24 mL). The resulting solution was stirred for 6 h at room temperature. The solution was washed with diethyl ether, and the organic layer was discarded. The aqueous layer was acidified with to pH 3 with 1 M HCl and extracted with ethyl acetate. The organic layer was dried over MgSO4 and concentrated to afford 13.5 g (quantitative yield) of the desired product as an oil.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Cl:20][C:21]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>CN(C=O)C.O>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][N:53]([C:23](=[O:25])[C:22]2[CH:26]=[C:27]([Cl:30])[CH:28]=[CH:29][C:21]=2[Cl:20])[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: O=C(O)c1cc(Cl)ccc1Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 10 °C
Reaction time: 8 h
Yield: 84.8 %

Procedure:
HOBt (213 mg, 1.5 mmol) and DIEA (508 mg, 3.9 mmol) were added to a stirred solution of 2,5-dichlorobenzoicacid (250 mg, 1.3 mmol) in DMF (2.5 mL). The reaction mixture was then cooled to 10° C. and EDCI.HCl (302 mg, 1.5 mmol) followed by piperazine-1-carboxylic acid tert-butyl ester (260 mg, 1.3 mmol) were added. The resulting mixture was stirred at room temperature overnight. The reaction mixture was then diluted with water and the product extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over Na2SO4, and concentrated under reduced pressure to afford the crude residue which was purified by column chromatography using silica gel 60-120 mesh (30% ethyl acetate in hexane) to afford 396 mg (84%) of 4-(2,5-dichloro-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester, LCMS: 360.08 (M+1)+, 98.2%.
Reaction SMILES: C([Li])CCC.[Si:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[CH:19][S:20][C:16]=2[CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[B:23](OC(C)C)([O:28]C(C)C)[O:24]C(C)C.O>CCCCCC.O1CCCC1>[Si:6]([O:13][C:14]1[CH:22]=[CH:21][C:17]2[CH:18]=[C:19]([B:23]([OH:28])[OH:24])[S:20][C:16]=2[CH:15]=1)([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2ccsc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1ccc2cc(B(O)O)sc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62 %

Procedure:
2.5 M n-butyllithium (23 mL, 57.5 mmol) in hexane was slowly added to the 6-(t-butyldimethylsilyloxy)benzothiophene (23, 13.6 g, 51.0 mmol) dissolved in anhydrous tetrahydrofuran (150 mL) at −78° C. under nitrogen atmosphere. 15 minutes later, the mixture was agitated at room temperature for 1 hour. After cooling again to −78° C., triisopropyl borate ((i-PrO)3B; 14.0 mL, 62.0 mmol) was slowly added. Then, after slowly heating to room temperature and agitating for 3 hours, water was added to quench the reaction. After extracting the organic compound with ethyl acetate and removing water using sodium sulfate, column chromatography yielded the target compound 6-(t-butyldimethylsilyloxy)benzothiophene-2-boronic acid (24, 9.75 g, 62%).
Reaction SMILES: [C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([OH:37])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:35])([CH3:34])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([OH:31])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2].Cl[Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43]>ClCCl.C(OCC)(=O)C>[C:1]([O:4][CH:5]1[C:6]([OH:39])([CH3:38])[CH2:7][CH2:8][CH:9]([O:37][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:10][C:11]([O:13][CH:14](/[C:19](/[CH3:36])=[CH:20]/[CH:21]=[CH:22]/[C:23]([CH3:34])([O:35][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:24][CH:25]2[O:33][CH:26]2[CH:27]([CH3:32])[CH:28]([O:31][Si:41]([CH2:46][CH3:47])([CH2:44][CH3:45])[CH2:42][CH3:43])[CH2:29][CH3:30])[CH:15]([CH3:18])[CH:16]=[CH:17]1)=[O:12])(=[O:3])[CH3:2]
Reactant: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)C=CC1C
Reactant: CC[Si](Cl)(CC)CC
Agent: CCC(O)C(C)C1OC1CC(C)(O)/C=C/C=C(\C)C1OC(=O)CC(O)CCC(C)(O)C(OC(C)=O)/C=C/C1C
Agent: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)/C=C/C1C)O[Si](CC)(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCC(O[Si](CC)(CC)CC)C(C)C1OC1CC(C)(/C=C/C=C(\C)C1OC(=O)CC(O[Si](CC)(CC)CC)CCC(C)(O)C(OC(C)=O)C=CC1C)O[Si](CC)(CC)CC
Reaction time: 18 h

Procedure:
To a solution of (8E,12E,14E)-7-acetoxy-6,3,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (100 mg, 0.18 mmol) in dichloromethane (6 mL) were added N,N-dimethylaminopyridine (221 mg, 1.8 mmol) and chlorotriethylsilane (272 mg, 1.8 mmol) at room temperature, and the reaction mixture was stirred at the same temperature for 18 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous solution of ammonium chloride and brine. The organic layer was dried over anhydrous magnesium sulfate, filtrated and concentrated. The resulting residue was purified by silica gel column chromatography (Kanto silica gel 60N, 40-100 μm; ethyl acetate:hexane=20:80) to give the title compound (159 mg, 98%) as a colorless oil.
Reaction SMILES: [Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH:27]=[CH2:28])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:18])([CH3:17])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].S(C)C.[OH-:32].[Na+].OO>C1COCC1.C(OCC)C>[Si:1]([O:8][CH2:9][C@H:10]([CH2:26][CH2:27][CH2:28][OH:32])[CH2:11][C@H:12]1[CH2:16][O:15][C:14]([CH3:17])([CH3:18])[N:13]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C=CC[C@@H](CO[Si](C)(C)C(C)(C)C)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: CSC
Product: CC(C)(C)OC(=O)N1[C@@H](C[C@@H](CCCO)CO[Si](C)(C)C(C)(C)C)COC1(C)C
Reaction time: 5 h
Yield: 72 %

Procedure:
A solution of (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)pent-4-enyl)-2,2-dimethyloxazolidine-3-carboxylate (26 g, 63 mmol) in THF (200 mL) was cooled in an ice-bath, followed by dropwise addition of 10 M BH3.SMe2 (6.3 mL). After stirring for 5 hr, 10% NaOH solution (32 mL) followed by 30% H2O2 (32 mL) were added carefully. The reaction mixture was stirred at rt for 16 hr. The reaction mixture was diluted with diethyl ether (500 mL) and the aqueous layer was extracted with diethyl ether (3×250 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by column chromatography to afford (S)-tert-butyl 4-((R)-2-((tert-butyldimethylsilyloxy)methyl)-5-hydroxypentyl)-2,2-dimethyloxazolidine-3-carboxylate (19.6 g, 72%).
Reaction SMILES: C([O:3][C:4](=[O:12])[CH2:5][C:6]1[N:7]=[C:8]([CH3:11])[S:9][CH:10]=1)C.[OH-].[K+]>O1CCCC1.O>[CH3:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([OH:12])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cc1csc(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(CC(=O)O)cs1
Yield: 78.1 %

Procedure:
Prepare a solution of (2-methylthiazol-4-yl)acetic acid ethyl ester (17 g, 92 mmol) in tetrahydrofuran/water (1:1, 400 mL). Add potassium hydroxide (10.3 g, 184 mmol). Stir the reaction at room temperature for 1 hour. Concentrate the solution in vacuo to remove the tetrahydrofuran then acidify with 1N HCl. Extract the aqueous solution with CHCl3. Wash the resulting organic phase with brine (200 mL), dry (Na2SO4), filter and concentrate in vacuo to afford (2-methylthiazol-4-yl)acetic acid (11.3 g) as a solid. 1H NMR (CDCl3) δ 7.00 (s, 1H), 3.85 (s, 2H), 2.71 (s, 3H).
Reaction SMILES: [O:1]1[CH2:17][CH:2]1[CH2:3][O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1.[CH:18]([NH2:21])([CH3:20])[CH3:19]>C(O)CC>[OH:1][CH:2]([CH2:17][NH:21][CH:18]([CH3:20])[CH3:19])[CH2:3][O:4][C:5]1[C:10]2[CH2:11][CH2:12][CH2:13][C:14](=[O:16])[NH:15][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: O=C1CCCc2c(cccc2OCC2CO2)N1
Reactant: CC(C)N
Solvent: CCCO
Product: CC(C)NCC(O)COc1cccc2c1CCCC(=O)N2
Yield: 40.3 %

Procedure:
3.3 g (0.014 mole) of 6-(2,3-epoxypropoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one are dissolved in 400 ml of n-propanol, 3 g of isopropylamine are added and the mixture is kept on a boiling waterbath for from 4 to 6 hours. The solvent and excess amine are then distilled off on a rotary evaporator and the residue is twice taken up in methanol, the solvent again being distilled off. The residue thus obtained is chromatographed on a silica gel column, using methanol as the mobile phase. 1.65 g (39.9% yield) of 6-(2-hydroxy-3-isopropylaminopropoxy)-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one, of melting point 143°-145° C., are obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:9][CH:8]2[C:10]([OH:12])=O)=[CH:3][CH:2]=1.[CH3:13][NH:14][C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([O:30]CCC)=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3>>[CH3:13][N:14]([C:10]([CH:8]1[CH2:9][CH:7]1[C:4]1[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=1)=[O:12])[C@H:15]1[CH2:34][N:19]2[C:20]3[C:25]([C:26]([CH2:27][C:28]([OH:30])=[O:29])=[C:18]2[CH2:17][CH2:16]1)=[CH:24][CH:23]=[CH:22][CH:21]=3
Reactant: O=C(O)C1CC1c1ccncc1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Product: CN(C(=O)C1CC1c1ccncc1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 2-(pyridin-4-yl)cyclopropanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 404.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:19](=O)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:7]1)=O)C.O.[NH2:28][NH2:29]>CCO>[C:15]([O:14][C:12]([N:8]1[CH2:9][CH2:10][CH2:11][C:6]2([C:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:29][NH:28][C:4]2=[O:3])[CH2:7]1)=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: CCOC(=O)C1(C(=O)c2ccccc2)CCCN(C(=O)OC(C)(C)C)C1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC2(C1)C(=O)NN=C2c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of racemic mixture of 3-benzoyl-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (step 1) (400 mg, 1.1 mmol) in EtOH (4 ml) was added hydrazine hydrate (166 mg, 3.3 mmol). The reaction mixture was stirred at RT for 30 min before heating in the microwave at 120° C. for 3 hours. The reaction mixture was concentrated in vacuo, dissolved in EtOAc (10 ml) and washed with brine (20 ml). The aqueous phase was further washed with EtOAc (10 ml). The organics portions were combined, dried (MgSO4) and concentrated in vacuo. Purification of the crude product by chromatography on silica eluting with 0-60% EtOAc in iso-hexane afforded the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.N1([C:17]([C:19]2[C:20]([CH3:27])=[C:21]([CH:25]=O)[NH:22][C:23]=2[CH3:24])=[O:18])C=CN=C1.[NH2:28][CH2:29][C@@H:30]([OH:38])[CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.C(N(CC)CC)C>C(#N)C.O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:25]\[C:21]1[NH:22][C:23]([CH3:24])=[C:19]([C:17]([NH:28][CH2:29][C@@H:30]([OH:38])[CH2:31][N:32]2[CH2:33][CH2:34][O:35][CH2:36][CH2:37]2)=[O:18])[C:20]=1[CH3:27]
Reactant: NC[C@@H](O)CN1CCOCC1
Reactant: O=C1Cc2cc(F)ccc2N1
Reactant: Cc1[nH]c(C=O)c(C)c1C(=O)n1ccnc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NC[C@@H](O)CN1CCOCC1
Temperature: 60 °C
Yield: 25.2 %

Procedure:
A 0.25 L flask fitted with a thermometer, condenser, magnetic stirring, and nitrogen inlet was charged with 4.92 g 5-Fluorooxindole, 7.0 g 4-(1H-imidazol-1-ylcarbonyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde, 15.5 g (R)-1-Amino-3-(4-morpholinyl)-2-propanol, 9.78 g Triethylamine and 88 ml Tetrahydrofuran. The mixture was heated to 60° C. for 16.5 hours. The reaction was cooled to ambient temperature and filtered. The solids obtained were slurried (3) three successive times in acetonitrile at 11 ml/g, dried in vacuoto produce a yield of 3.6 g (25.25%) of 5-[(Z)-(5-fluoro-2-oxo-1,2-dihydro-3H-indol-3-ylidene)methyl]-N-[(2R)-2-hydroxy-3-morpholin-4-ylpropyl]-2,4-dimethyl-1H-pyrrole-3-carboxamide.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:12][CH:11](NC)[O:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:15]([N:17]([CH2:20]C)CC)[CH3:16].ClCCl.C(Cl)(=[O:27])C>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH2:12][CH:11]([CH2:20][NH:17][C:15](=[O:27])[CH3:16])[O:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: CCN(CC)CC
Reactant: CNC1CC(c2ccc(Br)cc2)=NO1
Reactant: CC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(=O)NCC1CC(c2ccc(Br)cc2)=NO1
Temperature: 0 °C
Reaction time: 3 h
Yield: 59.4 %

Procedure:
[3-(4-Bromo-phenyl)-4,5-dihydro-isoxazol-5-yl]-methylamine (10 g, 39.1 mmol) and triethylamine (8.2 ml, 58.6 mmol) were added to anhydrous dichloromethane (100 ml) and cooled to 0° C. Acetyl chloride (3.0 ml, 43.6 mmol) was then added dropwise and the reaction was stirred for 3 hours followed by addition of ethyl acetate (200 ml). The precipitate was collected, washed with water (2×100 ml), and finally with ethyl ether (2×50 ml) to give the desired product (6.9 g).
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.[NH2:23][NH:24][C:25](=O)[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][C:28]1=[O:32].C[O-].[Na+]>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:25]([CH2:26][N:27]5[CH2:31][CH2:30][CH2:29][C:28]5=[O:32])[NH:24][N:23]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: NNC(=O)CN1CCCC1=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: O=C1CCCN1Cc1nc(-c2ccc3[nH]nc(-c4ccc(F)cc4)c3c2)n[nH]1
Yield: 34 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.300 g, 0.94 mmol) and N-amino-2-(2-oxopyrrolidinyl)acetamide (0.442 g, 2.81 mmol) in 4 mL of anhydrous methanol was prepared. An excess of a commercial solution of sodium methoxide in methanol (0.643 mL, 4.37 M) was added. Upon adding the basic solution, the reaction mixture became clear then cloudy. After an hour, the temperature was raised to reflux temperature and was maintained for 48 hours. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.118 g, 34% yield): 1H NMR (CD3OD) δ 8.68 (s, 1H), 8.07–8.02 (m, 3H), 7.68 (d, 1H), 7.29 (t, 2H), 4.66 (s, 2H), 3.53 (t, 2H), 2.47 (t, 2H), 2.10 (quintet, 2H); ES-MS (m/z) 377 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([NH2:8])=[O:7].[CH3:9][C:10]([CH:13]=O)([CH3:12])[CH3:11].[NH:15]1[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C(C)=CC=CC=1>[N:15]1([CH:13]([NH:8][C:6]([C:2]2[O:1][CH:5]=[CH:4][CH:3]=2)=[O:7])[C:10]([CH3:11])([CH3:12])[CH3:9])[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N:17]=[N:16]1
Reactant: NC(=O)c1ccco1
Reactant: c1ccc2[nH]nnc2c1
Reactant: CC(C)(C)C=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1C
Product: CC(C)(C)C(NC(=O)c1ccco1)n1nnc2ccccc21

Procedure:
Furan-2-carboxamide, pivaldehyde, benzotriazole, and p-toluenesulfonic acid in xylene were processed as described in Example 18B to provide the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[C:21]([O:23]CC)=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC[O:34]CC>>[C:21](=[O:22])([O-:34])[O-:23].[C:1]1([CH2:7][N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH:9]2[CH2:21][OH:22])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCC
Reactant: CCOC(=O)C1CN(Cc2ccccc2)CCN1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=C([O-])[O-]
Product: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
2,3-Dibromopropionic acid, ethyl ester 7, N,N-dibenzylethylenediamine 8 and triethylamine are reacted in toluene at 80°-100° C., giving 1,4-bis(phenylmethyl)-2-piperazinecarboxylic acid, ethyl ester 9. The ester 9 is then reacted with lithium aluminum hydride in ether, under an inert atmosphere at reflux followed by treatment with an alkali base and an alkali carbonate giving 1,4-bis(phenylmethyl)-2-piperazinemethanol 10, which is then reacted with thionyl chloride in carbon tetrachloride at 50°-60° C. followed by treatment with an alkali hydroxide, giving 2-chloromethyl-1,4-bis(phenylmethyl)piperazine 11. The compound 11 is then reacted with an amine R4, where R4 is dimethylamine, N-methylpiperazine, etc., giving a 2-substituted methyl-1,4-bis(phenylmethyl)piperazine 12 which is then catalytically reduced in ethanol and cyclohexane, giving piperazine derivative 13. Derivative 13 is then reacted with 6 in pyridine in a sealed unit under argon at 120°-130° C., giving 14. ##STR8##