Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5](Br)=[C:4]([CH3:17])[N:3]=1.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]2)[C:5](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@H]2CC[C@H](O)CC2)c1Br
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1c(C)nc(N)nc1N[C@H]1CC[C@H](O)CC1
Temperature: 130 °C

Procedure:
A sealed tube containing trans-4-(2-amino-5-bromo-6-methylpyrimidin-4-ylamino)cyclohexanol (655 mg, 2.17 mmol), tri-o-tolylphosphine (298 mg, 0.979 mmol), ethyl acrylate (355 uL, 3.26 mmol) and palladium (II) acetate (73 mg, 0.33 mmol) in triethylamine (20 mL) was evacuated and back-filled with nitrogen (3×). The reaction mixture was heated overnight at 130° C., filtered and concentrated. The residue was purified by flash chromatography eluting with chloroform/7 N ammonia in methanol (0.5-5%) to afford the title compound (364 mg, 52%).
Reaction SMILES: C12BC(CCC1)CCC2.[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH:30]=[CH2:31])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.I[C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1.[OH-].[Na+]>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:10]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][C@@H:18]1[CH2:30][CH2:31][C:52]1[CH:53]=[N:54][CH:55]=[CH:56][CH:57]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: C=C[C@H]1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: Ic1cccnc1
Agent: [Pd]
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Product: c1ccc(CN2CCN(Cc3ccccc3)[C@@H](CCc3cccnc3)C2)cc1
Yield: 40.3 %

Procedure:
Prepared by the method in Example 128, using 9-borabicyclo[3.3.1]nonane (68.4 mL, 34.2 mmol, 0.5 M in THF), (S)-1,4-dibenzyl-2-vinyl-piperazine (2.5 g, 8.55 mmol), triphenylphosphine (718 mg, 2.74 mmol), tetrakis(triphenylphosphine) palladium(0)(395 mg, 0.34 mmol), 3-iodopyridine (2.63 g, 12.8 mmol) and 3M NaOH (7.0 mL, 21.0 mmol) to give title compound (1.28 g, 40%): mp 94–95.5° C.; mass spectrum (ion spray): m/z=372 (M+1). Analysis calculated for C25H29N3: C, 80.82; H, 7.87; N, 11.31. Found: C, 80.54; H, 7.76; N, 11.32.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@@H:12](Cl)[CH:11]=[CH:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C.O>[N:16]([C@H:12]1[CH2:13][CH2:14][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:10]=[CH:11]1)=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@H](Cl)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@H](N=[N+]=[N-])CC1
Yield: 59.8 %

Procedure:
To a stirred solution of cis-1-(tert-butoxycarbonylamino)-4-chloro-2-cyclohexene (1.85 g, 8.00 mmol) in DMF (40 mL) was added sodium azide (1.17 g, 18.0 mmol) and the resultant mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into brine (40 mL) and diluted with ethyl acetate (120 mL) and water (20 mL). The phases were separated and the organic phase was washed with brine (4×25 mL). The organic phase was dried (MgSO4), and concentrated. Purification of the crude material by column chromatography on silica gel (10:1 hexanes-ethyl acetate) provided 1.14 g (60%) of trans-1-azido-4-(tert-butoxycarbonylamino)-2-cyclohexene as a colorless oil.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:67][O:68][C:69]1[C:74]([CH:75]=O)=[CH:73][CH:72]=[CH:71][N:70]=1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:75]([C:74]3[C:69]([O:68][CH3:67])=[N:70][CH:71]=[CH:72][CH:73]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Reactant: COc1ncccc1C=O
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: COc1ncccc1-c1nc2c(N3CCN(Cc4cccnc4)CC3)c(Br)cnc2[nH]1
Reaction time: 16 h
Yield: 44.9 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (75 mg, 0.19 mmol), DMF (0.85 mL), ethanol (0.15 mL), 1M Na2S2O4 (3 eq, 0.57 mmol, 0.57 mL) and 2-methoxy-3-pyridinecarboxaldehyde (1.1 eq, 0.21 mmol, 0.024 mL). After 16 h, concentration in vacuo and preparation by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (41 mg, 50%) as a pale yellow solid; 1H-NMR (500 MHz, DMSO-d6) 2.61 (br s, 2H, piperazine NCH2), 2.72 (s, br, 2H, piperazine NCH2), 2.89 (s, 2H, CH2), 3.59-3.69 (m, 4H, piperazine N(CH2)2), 4.05 (s, 3H, OCH3), 7.19 (dd, J=7.5, 4.9 Hz, 1H, pyridine H-5), 7.38-7.41 (m, 1H, methoxypyridine H-5), 7.77 (dt, J=7.7, 1.8 Hz, pyridine H-4), 8.28 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.33 (dd, J=4.8, 1.8 Hz, 1H, pyridine H-6), 8.48 (d, br, J=3.4 Hz, 1H, methoxypyridine H-6), 8.53 (d, J=6.8 Hz, 1H, methoxypyridine H-4), 8.56 (s, br, 1H, pyridine H-2);
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5])[CH3:2].[H-].[Na+].[Br:22][C:23]1[CH:33]=[CH:32][C:26]2[S:27][C:28]([CH2:30]Br)=[CH:29][C:25]=2[CH:24]=1.[Cl-].[NH4+]>O1CCCC1>[Br:22][C:23]1[CH:33]=[CH:32][C:26]2[S:27][C:28]([CH2:30][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=3)[C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:29][C:25]=2[CH:24]=1
Reactant: BrCc1cc2cc(Br)ccc2s1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(Br)ccc2s1)(C(=O)OCC)c1ccc(OC)cc1
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
14.2 g of ethyl 2-ethoxycarbonyl-2-(4-methoxyphenyl)acetate was dissolved in 150 ml of tetrahydrofuran. 2.6 g of sodium hydride (oil type, 60%) was added to the above solution while stirring under ice cooling, and the stirring was continued for 20 minutes. To this was further added 17.2 g of 5-bromo-2-bromomethylbenzo[b]thiophene. After stirring at room temperature for 18 hours, the resulting reaction solution was mixed with ammonium chloride aqueous solution, and then extracted with ethyl acetate. After drying to distill off the solvent, the resulting residue was subjected to silica gel column chromatography using chloroform as an elution solvent, thereby obtaining 24.2 g of ethyl 3-(5-bromobenzo[b]thien-2-yl)-2-ethoxycarbonyl-2-(4-methoxyphenyl)propionate.
Reaction SMILES: Cl.[CH3:2][O:3][NH:4][CH3:5].[C:6]([O:10][C:11]([C:13]1[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=O)=[CH:15][CH:14]=1)=[O:12])([CH3:9])([CH3:8])[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:2][O:3][N:4]([CH3:5])[C:20](=[O:22])[CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]([O:10][C:6]([CH3:7])([CH3:8])[CH3:9])=[O:12])=[CH:18][CH:17]=1
Reactant: CC(C)(C)OC(=O)c1ccc(CC(=O)O)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CON(C)C(=O)Cc1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of N-methoxymethanamine hydrochloride (5.00 g) in N,N-dimethylformamide (200 mL) was added triethylamine (7.1 mL), and the mixture was stirred at room temperature for 30 min. [4-(tert-Butoxycarbonyl)phenyl]acetic acid (10.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (12.2 g) and 1-hydroxybenzotriazole (8.60 g) were added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with 1M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and the title compound (9.50 g, yield 80%) was obtained as a colorless amorphous solid from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 280 (MH+).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1.[CH2:14](O)[CH3:15].[OH-].[Na+]>Cl>[NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([O:8][CH2:14][CH3:15])=[O:7])=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: CCO
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1cc(Cl)c(N)cc1OC
Yield: 78 %

Procedure:
A solution of 4-amino-5-chloro-2-methoxybenzoic acid (6.6 g, 0.031 mol) in hydrogen chloride 1.25M in Ethanol (250 mL, 0.31 mol) was stirred in a pressure vessel for 6 h at 65° C. The reaction mixture was basified with sodium hydroxide 2N and extracted with methylene chloride. The organic layer was washed with water, dried and filtered. The solvent was removed under reduced pressure giving the title compound as a white solid (78%), which was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[Cl:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:39][C:38]1[CH:42]=[CH:43][C:35]([Cl:34])=[CH:36][CH:37]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Br)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: OC[C@H]1O[C@@H](n2cc(Cc3ccc(Cl)cc3)c3c(Br)cccc32)[C@H](O)[C@@H](O)[C@@H]1O

Procedure:
The titled compound was prepared from 4-bromo-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 22-(1) and 4-chlorobenzoyl chloride in a manner similar to Example 27 as a colorless powder. APCI-Mass m/Z 482/484 (M+H). 1H-NMR (DMSO-d6) δ 3.21-3.28 (m, 1H), 3.33-3.39 (m, 3H), 3.62-3.71 (m, 2H), 4.28 (s, 2H), 4.54 (t, J=5.5 Hz, 1H), 5.11 (d, J=5.3 Hz, 1H), 5.17 (d, J=5.1 Hz, 1H), 5.23 (d, J=5.8 Hz, 1H), 5.41 (d, J=9.0 Hz, 1H), 7.04 (t, J=7.9 Hz, 1H), 7.19-7.24 (m, 3H), 7.30-7.35 (m, 2H), 7.33 (brs, 1H), 7.60 (d, J=8.3 Hz, 1H).
Reaction SMILES: C(N(CC)CC)C.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1.[NH2:14][CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([N:24]2[CH2:33][C:32]3[CH:31]=[N:30][N:29]([CH3:34])[C:28]=3[NH:27][C:26]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:25]2=3)=[O:23])=[CH:18][C:17]=1[CH3:40].CC1C=C2N=C3C(=NC(NC3=O)=O)N(C[C@H](O)[C@H](O)[C@H](O)CO)C2=CC=1C>ClCCl>[CH3:34][N:29]1[C:28]2[NH:27][C:26]3[CH:35]=[C:36]([CH3:39])[CH:37]=[CH:38][C:25]=3[N:24]([C:22]([C:19]3[CH:20]=[CH:21][C:16]([CH2:15][NH:14][C:11]([CH:8]4[CH2:10][CH2:9]4)=[O:12])=[C:17]([CH3:40])[CH:18]=3)=[O:23])[CH2:33][C:32]=2[CH:31]=[N:30]1
Reactant: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CN)c(C)c1
Reactant: O=C(Cl)C1CC1
Agent: Cc1cc2nc3c(=O)[nH]c(=O)nc-3n(C[C@H](O)[C@H](O)[C@H](O)CO)c2cc1C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)Nc1c(cnn1C)CN2C(=O)c1ccc(CNC(=O)C2CC2)c(C)c1
Reaction time: 20 h
Yield: 51 %

Procedure:
Triethylamine (0.145 ml, 1.04 mmol) and cyclopropanecarbonyl chloride (0.041 ml, 0.45 mmol) were added to a solution of (4-aminomethyl-3-methyl-phenyl)-(3,6-dimethyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulen-9-yl)-methanone from Example E101.2 (150 mg, 0.41 mmol) in dichloromethane (10 ml) at room temperature. The mixture was stirred for 20 h then concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloromethane) to give an off-white solid identified as the title compound (91 mg, 51%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)[C:12]2[CH2:17][O:16][C:15](=[O:18])[NH:14][C:13]=2[N:19]=1.[ClH:33]>O1CCOCC1>[ClH:33].[OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[C:9]1[CH:10]=[C:11]([CH:20]2[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]2)[C:12]2[CH2:17][O:16][C:15](=[O:18])[NH:14][C:13]=2[N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(c2cc(-c3c(O)cccc3O)nc3c2COC(=O)N3)C1
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Nc2nc(-c3c(O)cccc3O)cc(C3CCCNC3)c2CO1
Reaction time: 3 h
Yield: 46 %

Procedure:
A mixture of 7-[2-(cyclopropylmethoxy)-6-hydroxyphenyl]-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-2-one hydrochloride (0.070 g, 0.160 mmol), which was obtained in Example 18-1, and 2.5N HCl in 1,4-dioxane (4 mL) was stirred at 80° C. overnight. After cooled to room temperature, the mixture was concentrated under reduced pressure. The resulting residue was diluted with dichloromethane (3 mL), and triethylamine (0.064 g, 0.497 mmol) was added. To the cooled (0° C.) mixture was added di-tert-butyl dicarbonate (0.047 g, 0.218 mmol) under an argon atmosphere. The stirring was continued at room temperature overnight. After quenched by water, the mixture was extracted with ethyl acetate and water. The separated organic phase was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by preparative TLC (hexane/ethyl acetate=1/1) to give tert-butyl 3-[7-(2,6-di-hydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidine-carboxylate (0.019 g, 19%). To a solution of tert-butyl 3-[7-(2,6-dihydroxyphenyl)-2-oxo-1,4-dihydro-2H-pyrido[2,3-d][1,3]oxazin-5-yl]-1-piperidinecarboxylate in dioxane (1 mL) was added 4N HCl in dioxane (1 mL) at room temperature. The stirring was continued for 3 hrs. After the solvent was removed by evaporation, the resulting residue was washed with acetonitril, and dried under reduced pressure to give 7-(2,6-dihydroxyphenyl)-5-(3-piperidinyl)-1,4-dihydro-2H-pyrido[2,3-d][1,3]-oxazin-2-one hydrochloride as a brown solid (0.007 g, 46%).
Reaction SMILES: [CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][NH:28][CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(N(CC)CC)C>CO>[CH2:1]([N:8]1[C:14]2[CH:15]=[CH:16][C:17]([Cl:19])=[CH:18][C:13]=2[C@@H:12]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])[O:11][C@H:10]([CH2:27][N:28]([C:34](=[O:36])[CH3:35])[CH2:29][C:30]([OH:32])=[O:31])[C:9]1=[O:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CNC[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O
Reactant: CC(=O)OC(C)=O
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N(CC(=O)O)C[C@H]1O[C@H](c2ccccc2Cl)c2cc(Cl)ccc2N(Cc2ccccc2)C1=O

Procedure:
In 4 ml of methanol was dissolved 60 mg of ethyl ester of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]glycine obtained in Example 40. To the solution were added 0.2 ml of acetic anhydride and 0.2 ml of triethylamine. The mixture was heated for one hour under reflux while stirring. The reaction mixture was concentrated under reduced pressure, which was subjected to extraction with ethyl acetate. The organic layer was washed with an aqueous solution of potassium hydrogensulfate, an aqueous solution of sodium hydrogencarbonate and water, which was then dried, followed by distilling off the solvent. The residue was dissolved in 4 ml of methanol, to which was added 2 ml of a 5% aqueous solution of potassium carbonate. The mixture was stirred for 30 minutes at 60° C. The reaction mixture was concentrated under reduced pressure, to which was added 1N hydrochloric acid to acidify the solution, followed by extraction with ethyl acetate. The organic layer was washed with water and dried, then the solvent was distilled off under reduced pressure. From the residue, 45 mg of N-[trans-1-benzyl-7-chloro-5-(2-chlorophenyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepin-3-ylmethyl]-N-acetyl glycine was obtained as crystals, m.p. 143°-145° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:10][OH:11])=[NH:9])=[CH:4][N:3]=1.[F:12][C:13]([F:34])([F:33])[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[N:23]=[C:22]([C:30](O)=O)[N:21]=2)=[CH:16][CH:15]=1>>[F:29][C:26]([F:27])([F:28])[C:24]1[CH:25]=[C:20]([C:17]2[CH:18]=[CH:19][C:14]([C:13]([F:34])([F:33])[F:12])=[CH:15][CH:16]=2)[N:21]=[C:22]([C:30]2[O:11][N:10]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([NH2:1])=[N:3][CH:4]=3)[N:9]=2)[N:23]=1
Reactant: O=C(O)c1nc(-c2ccc(C(F)(F)F)cc2)cc(C(F)(F)F)n1
Reactant: N=C(NO)c1cnc(N)nc1
Product: Nc1ncc(-c2noc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)n2)cn1

Procedure:
The title compound was prepared from 2-amino-N-hydroxy-pyrimidine-5-carboxamidine (example C.4) (0.115 g, 0.75 mmol) and 4-(4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine-2-carboxylic acid (example D.2) (0.17 g, 0.5 mmol) according to the general procedure V. Obtained as a white solid (0.14 g, 62%). MS (EI) 453.1 [(M)+]; mp 216° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH:17]=O)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[C:19]([O:23][C:24]([NH:26][CH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].Cl.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.CCCCCC.CC(C)=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:30]4[CH2:29][CH2:28][CH:27]([NH:26][C:24](=[O:25])[O:23][C:19]([CH3:22])([CH3:20])[CH3:21])[CH2:32][CH2:31]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: O=CC12CC(c3ccccc31)c1ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Reaction time: 2 h
Yield: 51.8 %

Procedure:
To a stirred suspension of 2-chloro-9-formyl-9,10-dihydro-9,10-methanoanthracene (3.64 g, 14.25 mmol, described in Example 107i), 4-t-butoxycarbonylaminopiperidine (3.57 g, 17.81 mmol), and activated 3A sieves (powderized, 3.64 g) in methanol (50 mL, sieve dried) was added methanolic hydrochloric acid (ca. 3.5 mL) until the pH was 7.50. After 2 h, the mixture was treated with sodium cyanoborohydride (895 mg, 14.25 mmol) in four portions over a 4 h period. After stirring the resulting mixture an additional 72 h, ethyl acetate (100 mL) and 3N sodium hydroxide (100 mL) and filtered through celite. The filtrate was treated with 3N sodium hydroxide (250 mL) and extracted with ethyl acetate (2×300 mL). The combined extracts was dried (sodium sulfate), filtered and concentrated to give a tan foam. Chromatography of this material over silica gel (eluting in sequence with 1) 90:10 acetone:hexane (6 L) and 2) 85:15 acetone:hexane (1 L)) to give the title compound as a white foam (3.24 g, 52%), mp 76.5°-80.0° C.; MS(CI): 439 (M+H); NMR (300 MHz,DMSO-d6): 1.37(m, 11H), 1.64(m, 2H), 2.21(m, 2H), 2.46(s, 2H), 2.92(m, 2H), 3.17-3.42(br m, part. submerged by H2O, 3H), 4.33(s, 1H), 6.72(m, 1H), 6.95(m, 3H), 7.19(m, 2H), 7.26(m, 2H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C([C:24]1([OH:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:25]1[C:26](Cl)=[O:27])(=O)C>C(Cl)Cl>[OH:33][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][CH2:2][CH2:3][S:4][C:5]1[N:10]2[CH:11]=[CH:12][N:13]=[C:9]2[CH:8]=[CH:7][CH:6]=1)=[O:27]
Reactant: CC(=O)C1(O)C=CC=CC1C(=O)Cl
Reactant: NCCSc1cccc2nccn12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCSc1cccc2nccn12)c1ccccc1O
Reaction time: 1 h
Yield: 56 %

Procedure:
To a solution of 5-[2-(amino)ethylthio]imidazo[1,2-a]pyridine (3.87 g, 20 mmoles) and triethylamine (5.58 ml, mmoles) in methylene chloride (200 ml) was added o-acetylsalicyloyl chloride (4.77 g, 24 mmoles) under ice-cooling with stirring and the mixture was stirred at room temperature for 30 minutes. After the solvent was distilled off, ethanol (60 ml) and 1N NaOH (40 ml) were added to the residue, followed by strirring for 1 hour. 1N HCl (40 ml) was added and ethanol was distilled off, and then the residue was extracted with chloroform and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by column chromatography (eluent:ethyl acetate/ethanol=10:1) to obtain 3.51 g of the desired product (56.0%, colorless solid).
Reaction SMILES: CN(C)C=[CH:4][C:5]1[CH:10]=[CH:9][N:8]([C:11]2[CH:15]=[CH:14][O:13][CH:12]=2)[C:7](=[O:16])[CH:6]=1.I([O-])(=O)(=O)=[O:19].[Na+]>O1CCCC1>[O:13]1[CH:14]=[CH:15][C:11]([N:8]2[CH:9]=[CH:10][C:5]([CH:4]=[O:19])=[CH:6][C:7]2=[O:16])=[CH:12]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CN(C)C=Cc1ccn(-c2ccoc2)c(=O)c1
Agent: [Na+]
Solvent: C1CCOC1
Product: O=Cc1ccn(-c2ccoc2)c(=O)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 4-(2-dimethylamino-vinyl)-1-furan-3-yl-1H-pyridin-2-one (21 mmol) in 50% aqueous tetrahydrofuran (700 mL) is added sodium periodate (13 g, 63 mmol). After six hours of stirring at room temperature, the reaction mixture is filtered. The filtrate is washed 3× with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to provide 1-furan-3-yl-2-oxo-1,2-dihydro-pyridine-4-carbaldehyde as a yellow powder (2.1 g, 53% over 2 steps).
Reaction SMILES: [OH-].C([N+](C)(C)C)C1C=CC=CC=1.[C:13]1([C:19]2([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:24][CH2:23][C:22](=[O:25])[CH:21]=[CH:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[N+:32]([CH3:35])([O-:34])=[O:33]>CO.CC(O)(C)C.O1CCCC1>[N+:32]([CH2:35][CH:20]1[C:19]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21]1)([O-:34])=[O:33]
Reactant: C[N+](=O)[O-]
Reactant: O=C1C=CC(c2ccccc2)(c2ccccc2)CC1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: CC(C)(C)O
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C(C[N+](=O)[O-])C1
Temperature: 0 °C
Reaction time: 144 h
Yield: 92.4 %

Procedure:
A solution (11.45 g) of benzyltrimethylammonium hydroxide in methanol is added to a solution of 4,4-diphenyl-2-cyclohexenone (60 g) and nitromethane (14.75 g) in 2-methyl-2-propanol (400 cc) and anhydrous tetrahydrofuran (200 cc), and the reaction mixture is stirred at +25° C. for 144 hours: a crystalline solid precipitates slowly. This suspension is filtered and the crystals are washed with petroleum ether (50 cc) cooled to 0° C., drained and dried. (RS)-3-Nitromethyl-4,4-diphenylcyclohexanone (69.1 g) is obtained in the form of white crystals, m.p. 164° C.