Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]3[CH2:23][CH2:22][CH2:21][C:20]=3[C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[O:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC1C=CC=C(C(OO)=[O:45])C=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH2:18][C:19]34[O:45][C:20]3([C:24]3[CH:25]=[C:26]([CH:34]=[CH:35][CH:36]=3)[O:27][CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:21][CH2:22][CH2:23]4)[O:10][C:11]=2[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)COc1cccc(C2=C(Cc3nc(-c4ccccc4)c(-c4ccccc4)o3)CCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)COc1cccc(C23CCCC2(Cc2nc(-c4ccccc4)c(-c4ccccc4)o2)O3)c1
Reaction time: 4 h
Yield: 67.7 %

Procedure:
To a solution of ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-1-cyclopenten-1-yl]phenoxy]acetate (1.0 g) in methylene chloride (20 ml) were added m-chloroperbenzoic acid (540 mg) and sodium carbonate (330 mg) at room temperature. After being stirred for 4 hours, the mixture was washed with saturated sodium bicarbonate aqueous solution and brine. The dried solvent was evaporated and the residue was purified by column chromatography on silica gel to give ethyl [3-[2-[(4,5-diphenyloxazol-2-yl)methyl]-1,2-epoxycyclopentyl]phenoxy]acetate (700 mg).
Reaction SMILES: [OH:1][C:2]1[N:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].NC(N)=O.[N+:15]([O-])([OH:17])=[O:16].[N+]([O-])=O>C(OC(=O)C)(=O)C>[OH:1][C:2]1[N:9]=[C:8]([CH3:10])[C:7]([N+:15]([O-:17])=[O:16])=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: Cc1ccc(C#N)c(O)n1
Reactant: O=[N+]([O-])O
Agent: NC(N)=O
Agent: O=[N+][O-]
Solvent: CC(=O)OC(C)=O
Product: Cc1nc(O)c(C#N)cc1[N+](=O)[O-]
Temperature: 2 °C
Reaction time: 3 h

Procedure:
A suspension of 2-hydroxy-6-methylnicotinonitrile (16.5 g) in acetic anhydride (60 mL) was stirred and cooled in an ice-salt bath. Separately, acetic anhydride (16 mL) containing a crystal of urea (21 mg) was cooled in an ice-salt bath to 2° C. To the latter mixture was added fuming nitric acid (8.6 mL). The mixture evolved nitrogen dioxide gas and became hot. Cooling in the bath was continued until the temperature reached 8° C. This solution was then added to the nitrile suspension, which was at −2° C. The temperature rose to 0° C., and the cooling bath was removed. The temperature rose slowly as the mixture was stirred, and the rate of temperature rise increased as the temperature rose. When the temperature reached 35° C., the flask was cooled in the bath until the temperature fell to 25° C. The bath was again removed. The temperature rose more slowly this time, and reached a maximum of 34° C. The reaction was allowed to cool on its own, and did not reach ambient temperature for about 3 hours. The resulting mixture was allowed to stir at ambient temperature overnight. The mixture was poured into a beaker containing crushed ice (300 g). The mixture was stirred until the ice melted, and the resulting precipitate was collected by filtration, washed with ice water, and air-dried to give about 13 g of light yellow solid. This material was recrystallized from boiling glacial acetic acid (130 mL). The resulting mixture was allowed to cool to ambient temperature and stirred overnight. The precipitate was collected by filtration, washed with a small amount of glacial acetic acid, and dried under vacuum to provide the title compound (8.2 g) with the following physical data.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[CH:22]=[C:21]([F:23])[C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:6]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>O1CCOCC1>[C:31]([N:18]1[C:19](=[O:20])[C:21]([F:23])=[CH:22][N:15]([C@@H:7]2[O:8][C@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[C@@H:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:6]2)[C:16]1=[O:17])(=[O:38])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)[nH]c2=O)C[C@@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(F)c(=O)n(C(=O)c3ccccc3)c2=O)C[C@@H]1OC(C)=O
Reaction time: 1 h
Yield: 79.1 %

Procedure:
1.0 g of 2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine and 0.76 ml of triethylamine were dissolved in 10 ml of dry dioxane, and the resulting solution was cooled with ice. To the solution was added 0.65 g of benzoyl chloride, and the resulting mixture was allowed to stand at room temperature for 60 minutes and then at 45° C. for 30 minutes. The crystals formed were filtered off, and the filtrate was concentrated under reduced pressure. The oily residue was purified by column chromatography on silica gel [column, diameter 3.5 cm; length, 21 cm; solvent, chloroform-methanol (99/1)]. The purified oily substance was dissolved in 10 ml of dimethylsulfoxide and added dropwise to 300 ml of water with vigorous agitation to be deposited as a solid. This solid was collected by filtration, washed sufficiently with water and dried at room temperature under reduced pressure. There was obtained 1.04 g (yield: 79.1%) of 3-benzoyl-2'-deoxy-3',5'-di-O-acetyl-5-fluorouridine as powder. The structure was supported by the absorption spectra and elemental analysis.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([O-:15])(=[O:14])=[O:13])=[CH:4][CH:3]=1.[K+].[N+:17]([O-])([OH:19])=[O:18]>C(OCC)C>[Br:1][C:2]1[C:11]2[C:6](=[C:7]([N+:17]([O-:19])=[O:18])[CH:8]=[CH:9][CH:10]=2)[C:5]([S:12]([OH:15])(=[O:13])=[O:14])=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)([O-])c1ccc(Br)c2ccccc12
Agent: [K+]
Solvent: CCOCC
Product: O=[N+]([O-])c1cccc2c(Br)ccc(S(=O)(=O)O)c12
Temperature: -15 °C
Reaction time: 1.5 h

Procedure:
Potassium 1-bromo-4-naphthalenesulfonate (1.38 g, 4.24 mmol) was added portionwise over 20 minutes to 90% nitric acid (2 mL), which was cooled in a methanol/ice bath to approximately -15° C. After 1.5 hours, the mixture was placed in a refrigerator for 20 hours. Diethyl ether (20 mL) was added and the precipitated solid was filtered, washed with ether (100 mL) and isopropanol (20 mL), and dried under a stream of nitrogen to give the title compound as an approximately 4:1 mixture of the 5- and 8-nitro isomers (1.25 g).
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Reactant: Nc1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4)c3c2s1
Yield: 89 %

Procedure:
Prepared from VII and 4-chloroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 89%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2850, 2229, 1643, 1609, 1583, 1550, 1491, 1480, 1457, 1377, 1355, 1307, 1270, 1214, 1164, 1130, 1092, 1010, 980, 831; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=8.7 Hz), 8.18 (s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.38 (m, 2H), 7.04 (m, 2H); HRMS calcd for C16H9N5SCl (M+H+): 338.0267, found 338.0274.
Reaction SMILES: [CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:22]=[C:21](S(C)(=O)=O)[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1.[CH:39]([NH2:42])([CH3:41])[CH3:40]>CN1C(=O)CCC1.O>[CH:1]1([C:4]2[N:9]=[C:8]([C:10]3[CH:11]=[C:12]4[C:16](=[CH:17][CH:18]=3)[NH:15][CH:14]=[C:13]4[C:19]3[CH:24]=[C:23]([O:25][CH2:26][C:27]4[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=4)[N:22]=[C:21]([NH:42][CH:39]([CH3:41])[CH3:40])[N:20]=3)[CH:7]=[N:6][CH:5]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(S(C)(=O)=O)n2)cc1
Reactant: CC(C)N
Solvent: CN1CCCC1=O
Solvent: O
Product: COc1ccc(COc2cc(-c3c[nH]c4ccc(-c5cncc(C6CC6)n5)cc34)nc(NC(C)C)n2)cc1
Temperature: 120 °C

Procedure:
A glass microwave reaction vessel was charged with 5-(6-cyclopropylpyrazin-2-yl)-3-(6-(4-methoxybenzyloxy)-2-(methylsulfonyl)pyrimidin-4-yl)-1H-indole (26 mg, 0.049 mmol) and isopropylamine (0.4 ml, 4.66 mmol) in NMP (0.5 mL). The reaction was stirred and heated in a Initiator microwave reactor (Personal Chemistry, Biotage AB, Inc., Upssala, Sweden) at 120° C. for 1 h. The mixture was diluted with water and extracted with CHCl3/iPrOH (4:1). The combined organic layer was washed with water, dried, filtered and concentrated to give the crude compound, which was used in the next step without further purification. MS (ESI, pos. ion) m/z: 507.0 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23]Cl)[CH2:2][CH2:3][CH3:4].[C:25]1(=[O:35])[NH:29][C:28](=[O:30])[C:27]2=[CH:31][CH:32]=[CH:33][CH:34]=[C:26]12.[K].O>CN(C)C=O>[CH2:1]([O:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([F:16])[CH:14]=2)[C:9](=[O:17])[N:8]([CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])[C:7]=1[CH2:23][N:29]1[C:25](=[O:35])[C:26]2[C:27](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:28]1=[O:30])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1c(CCl)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCOc1c(CN2C(=O)c3ccccc3C2=O)n(CC(C)(C)C)c(=O)c2ccc(F)cc12
Yield: 86.6 %

Procedure:
A solution of 4-butoxy-6-fluoro-3-chloromethyl-2-neopentyl-1(2H)-isoquinolinone (1.59 g, 4.5 mmol) and potassium phthalimide (1.26 g, 6.8 mmol) in N,N-dimethylformamide (20 ml) was stirred at room temperature for 6 h. The reaction mixture was poured into water and extracted with ethyl acetate. After washing the extract with water, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained crystals were recrystallized from ethyl acetate-diisopropyl ether to give 2-{(4-butoxy-6-fluoro-2-neopentyl-1-oxo-1,2-dihydro-3-isoquinolinyl)methyl}-1H-isoindole-1,3(2H)-dione (1.81 g, 86.6%) as crystals.
Reaction SMILES: [CH3:1][S:2][C:3](SC)=[C:4]([C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=1[S:22]([CH3:25])(=[O:24])=[O:23])=[O:11])[C:5]([CH:7]1[CH2:9][CH2:8]1)=[O:6].Cl.[NH2:29]O.C([O-])(=O)C.[Na+]>ClCCl.C(O)C>[CH:7]1([C:5]2[O:6][N:29]=[C:3]([S:2][CH3:1])[C:4]=2[C:10](=[O:11])[C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[S:22]([CH3:25])(=[O:24])=[O:23])[CH2:9][CH2:8]1
Reactant: CSC(SC)=C(C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O)C(=O)C1CC1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CSc1noc(C2CC2)c1C(=O)c1ccc(C(F)(F)F)cc1S(C)(=O)=O
Temperature: 20 °C
Reaction time: 48 h
Yield: 92.9 %

Procedure:
To a solution of 12.5 g (28.4 mmol) 2-(bis-methylsulfanylmethylene)-1 -cyclopropyl-3-(2-methanesulfonyl-4-trifluoromethylphenyl)propane-1,3-dione in 80 ml dichloromethane, 140 ml each of ethanol, 2.82 g (39.8 mmol) hydroxylamine hydrochloride and 3.4 g (41.2 mmol) anhydrous sodium acetate is successively added. The reaction mixture is then agitated for 48 hours at a temperature of 20° C. Then 50 ml dichloromethane, 50 ml ethanol, 1.4 g hydroxylamine hydrochloride and 1.7 g anhydrous sodium acetate are added, and the mixture is agitated for a further 3 days at 20° C. The reaction mixture is subsequently heated to a temperature of 30° C., and 2.8 g hydroxylamine hydrochloride and 3.4 g sodium acetate are added. After 18 hours' agitation at a temperature of 30° C., the solvents are distilled off and the residue taken up in 300 ml ethyl acetate. The organic phase is washed twice with water and once with concentrated aqueous sodium chloride solution. After the organic phase has been dried over sodium sulfate, it is treated with activated charcoal, filtered and evaporated to dryness. After recrystallization from a little diisopropylether, 10.7 g 5-cyclopropyl-3-methylsulfanyl-4-(2-methanesulfonyl-4-trifluoromethylbenzoyl)isoxazole is obtained in the form of crystalline solid matter with a melting point of 145-146° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:14])([F:13])[F:12])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2.Br[CH2:18][C:19]1[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=1>>[CH3:1][C:2]1[N:3]([CH2:18][C:19]2[O:20][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:22][CH:23]=2)[C:4]2[C:9]([CH:10]=1)=[C:8]([C:11]([F:12])([F:14])[F:13])[C:7]([C:15]#[N:16])=[CH:6][CH:5]=2
Reactant: FC(F)(F)c1ccc(CBr)o1
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2[nH]1
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1ccc(C(F)(F)F)o1

Procedure:
Synthesized as described in Example 4 using 2-methyl-4-(trifluoromethyl)-1H-indole-5-carbonitrile and 2-(bromomethyl)-5-(trifluoromethyl)furan: 1H NMR (400 MHz, CDCl3) δ 7.54 (d, J=8.6 Hz, 1H), 7.51 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.9 Hz, 1H), 6.63 (s, 1H), 6.11 (d, J=2.9 Hz, 1H), 5.32 (s, 2H), 2.55 (s, 3H); MS (ES) m/z 373 (M+1).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([O-:3])=O.O.O.[OH-].C[N+:14]([CH3:17])(C)C>C(#N)C1C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[N:14][C:17]1[CH:8]=[CH:9][CH:4]=[CH:5][CH:6]=1)[O-:3]
Reactant: O=[N+]([O-])c1ccccc1
Reactant: C[N+](C)(C)C
Agent: [OH-]
Solvent: O
Solvent: N#Cc1ccccc1
Product: [O-][N+](=Nc1ccccc1)c1ccccc1
Temperature: 60 °C
Yield: 45 %

Procedure:
A solution containing 10 g of nitrobenzene, 1.27 g of tetramethylammonium hydroxide dihydrate and 1 g of benzonitrile was stirred at 60° C. with nitrogen bubbled into the solution via a syringe needle for 1 hour. Analysis of a sample of the reaction product by HPLC revealed N-(4-nitrophenyl)-benzamide was produced in 45% yield and azoxybenzene was generated in 22% yield based on tetramethylammonium hydroxide.
Reaction SMILES: [BH4-].[Na+].CO.[CH2:5]([N:7]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]2[CH:19]=[C:20]([CH2:23][N:24]([CH2:38][C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH:41]=[O:42])[CH2:25][CH2:26][N:27]3[CH:32]=[CH:31][C:30]4[O:33][C:34]([CH3:36])=[CH:35][C:29]=4[C:28]3=[O:37])[CH:21]=[CH:22][C:8]1=2)[CH3:6]>O>[CH2:5]([N:7]1[C:13](=[O:14])[C:12]([CH3:16])([CH3:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]2[CH:19]=[C:20]([CH2:23][N:24]([CH2:38][C:39]3[CH:46]=[CH:45][CH:44]=[CH:43][C:40]=3[CH2:41][OH:42])[CH2:25][CH2:26][N:27]3[CH:32]=[CH:31][C:30]4[O:33][C:34]([CH3:36])=[CH:35][C:29]=4[C:28]3=[O:37])[CH:21]=[CH:22][C:8]1=2)[CH3:6]
Reactant: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3C=O)ccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCN1C(=O)C(C)(C)C(=O)N(C)c2cc(CN(CCn3ccc4oc(C)cc4c3=O)Cc3ccccc3CO)ccc21
Temperature: 0 °C
Reaction time: 3 h
Yield: 70.9 %

Procedure:
Sodium borohydride (47 mg) were added to a methanol solution(10 ml) of 2-({N-(1-Ethyl-3,3,5-trimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-7-ylmethyl)-N-[2-(2-methyl-4-oxo-4H-furo[3,2-c]pyridin-5-yl)ethyl]amino}methyl)benzaldehyde (0.59 g) and the mixture was stirred for 3 hours at 0° C. Water was added to the reaction mixture, followed by extraction by ethyl acetate. The organic layer was dried by anhydrous sodium sulfate, and condensed under reduced pressure. The residue was recrystallized from ethyl acetate-ether mixture to give the title compound(0.42 g) as a pale brown white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:4]=1[C:5]#[N:6].C1CCCCC=1>CCO.[Pd]>[NH2:11][C:7]1[CH:8]=[CH:9][CH:10]=[C:3]([O:2][CH3:1])[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc([N+](=O)[O-])c1C#N
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCCCC1
Product: COc1cccc(N)c1C#N
Temperature: 25 °C
Yield: 98.5 %

Procedure:
A solution of 2-methoxy-6-nitrobenzonitrile (1.01 g, 5.69 mmol), cyclohexene (2.84 g, 3.51 mL, 34.58 mmol) and 10% Pd/C (0.58 g) in EtOH (25 mL) was refluxed for 1.5 h. The mixture was cooled to room temperature, filtered and evaporated, to afford the title compound 0.83 g (98%). The crude product was used in the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J=8.0 Hz, 1H), 6.31-6.35 (m, 1H), 6.17-6.21 (m, 1H), 5.97 (broad s, 2H), 3.76 (s, 3H).
Reaction SMILES: Cl.Cl.[CH3:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH2:13].[CH2:20]([C:22]([CH2:29]C)([CH2:27]C)[C:23]([O-])([O-])[O-:24])C>C(#N)C>[CH3:3][NH:4][CH:5]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[NH:13][C:23](=[O:24])[C:22]([CH3:29])([CH3:27])[CH3:20]
Reactant: CNC(Cc1ccccc1N)c1ccccc1
Reactant: CCC(CC)(CC)C([O-])([O-])[O-]
Agent: Cl
Solvent: CC#N
Product: CNC(Cc1ccccc1NC(=O)C(C)(C)C)c1ccccc1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
A heterogeneous mixture of N-methyl-2-amino-α-phenylphen-ethylamine dihydrochloride (150g, 0.5 mol) in acetonitrile (500 ml) was treated with triethylorthoacetate (202 ml, 1.1 mol) and heated to 70° C. for 2 hours with stirring under a dry nitrogen atmosphere. The reaction mixture was filtered, concentrated in vacuo, and the residual solid recrystallized from 2-propanol at -10° C. to give 2,3-dimethyl-4-phenyl-3H-1,3-benzodiazepine hydrochloride (118g, 0.413 mol) in 83% yield. The product had a melting point of 239.5°-241° C.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([OH:3])=O.C(N(C(C)C)CC)(C)C.CN(C(ON1N=[N:47][C:42]2[CH:43]=[CH:44][CH:45]=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.C1(CN)CC1>CN(C)C=O>[CH:43]1([CH2:42][NH:47][C:1]([C:4]2[CH:5]=[CH:6][C:7]([CH:10]3[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:12][CH2:11]3)=[CH:8][CH:9]=2)=[O:3])[CH2:45][CH2:44]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NCC1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)NCC3CC3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.8 %

Procedure:
500 mg tert-butyl 4-(4-carboxyphenyl)-piperidine-1-carboxylate are placed in 28 ml dimethylformamide, then 1.14 ml diisopropylethylamine and 747 mg HATU are added. The reaction mixture is stirred for 15 min at ambient temperature, then 194 mg cyclopropylmethylamin hydrochloride are added. The reaction mixture is stirred overnight at ambient temperature. Then the product is purified by preparative HPLC (method A). 480 mg product are obtained as an oil. Analytical HPLC-MS (method B): RT=1.64 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH2:16])[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[OH:23][CH2:24][CH2:25][O:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=1[O:36][CH3:37]>>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[O:12][CH2:13][C@@H:14]([NH:16][C:31](=[O:32])[C:30]2[CH:34]=[CH:35][C:27]([O:26][CH2:25][CH2:24][OH:23])=[C:28]([O:36][CH3:37])[CH:29]=2)[CH3:15])[N:5]=[C:4]([CH3:17])[C:3]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: COc1cc(C(=O)O)ccc1OCCO
Reactant: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)N)c2c1N
Product: CCOC(=O)c1c(C)nc2cccc(OC[C@H](C)NC(=O)c3ccc(OCCO)c(OC)c3)c2c1N

Procedure:
Prepared as in Example 24a from (S)-ethyl 4-amino-5-(2-aminopropoxy)-2-methylquinoline-3-carboxylate (Example 26b) and 4-(2-hydroxyethoxy)-3-methoxybenzoic acid (Uto, Y. et al. Bioorg. Med. Chem. Lett. 2009, 19, 4151) as a brown solid. MS 498 (MH+).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6].CCN(C(C)C)C(C)C.Cl[C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]>CN(C=O)C>[CH2:21]([O:20][C:18]([N:1]1[CH2:4][CH2:3][C@H:2]1[C:5]([OH:7])=[O:6])=[O:19])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C(O)[C@@H]1CCN1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Temperature: 0 °C

Procedure:
(S)-Azetidine-2-carboxylic acid (250.4 mg, 2.5 mmol) was dissolved in DMF (15 mL) and distilled water (6 mL). The solution was cooled to 0° C., and DIEA (645 μL, 3.7 mmol) was added followed by benzyl chloroformate (530 μL, 3.7 mmol). The reaction was stirred at 0° C. and allowed to warm to ambient temperature overnight. The reaction was filtered and purified by reverse phase HPLC to give the desired product.
Reaction SMILES: [SH2:1].[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17]#[N:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12>N1C=CC=CC=1.C(N(CC)CC)C>[O:2]=[C:3]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]2[CH:14]=[N:15][C:16]([C:17](=[S:1])[NH2:18])=[C:6]2[C@@H:5]2[CH2:19][CH2:20][N:4]12
Reactant: S
Reactant: N#Cc1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: NC(=S)c1ncn2c1[C@@H]1CCN1C(=O)c1ccccc1-2
Reaction time: 70 h
Yield: 67 %

Procedure:
A stream of hydrogen sulphide was conducted for 1/2 hr. through a solution of 5.0 g (0.020 mol) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-carbonitrile in 100 ml of pyridine and 1 ml of triethylamine. The dark brown solution was left to stand for 70 hrs., then de-gassed with a stream of nitrogen and subsequently completely freed from the solvents. The residue was partitioned between dichloromethane and water and extracted. The pale yellow product was chromatographed over silica gel with ethyl acetate as the eluent, stirred vigorously in ether for 16 hrs. and subsequently filtered off under suction. There were obtained 3.8 g (67%) of (S)-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a][1,4]benzodiazepine-1-thiocarboxamide as pale yellow crystals; m.p. 227-230° and [α]D20 =-473.7° (DMF, c=1%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH2:16])[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4].[C:18]1([N:24]=[C:25]=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3]([CH:5]1[N:9]2[C:10](=[O:17])[CH:11]([NH:16][C:25]([NH:24][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:26])[CH2:12][CH:13]=[CH:14][CH2:15][CH:8]2[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C=Nc1ccccc1
Reactant: COC(=O)C1CCC2CC=CCC(N)C(=O)N21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C1CCC2CC=CCC(NC(=O)Nc3ccccc3)C(=O)N21

Procedure:
6-Amino-5-oxo-1,2,3,5,6,7,10,10a-octahydro-pyrrolo[1,2-a]azocine-3-carboxylic acid methyl ester, 8, (120 mg, 0.5 mmol), phenyl isocyanate (110 μL, 1 mmol) and triethyl amine (200 μL) are stirred in CH2Cl2 (10 mL) at room temperature. After complete consumption of starting material, the reaction is poured into 1 N HCl; washed with brine; and dried of sodium sulfate. The organics are evaporated and the residue is purified over silica (40% ethyl acetate: hexane). The desired product is obtained as a clear oil. 1H NMR (CDCl3): δ 7.81 (s, 1H), 7.35 (m, 2H), 7.23 (t, J=7.3 Hz, 2H), 6.98 (t, J=7.4 Hz, 1H), 6.85 (bs, 1H), 5.81 (m, 2H), 5.28 (m, 1H), 4.52 (dd, J=8.9, 2.5 Hz, 1H),4.27 (m, 1H), 3.58 (s, 3H), 2.95–2.82 (m, 2H), 2.45 (m, 1H), 2.29 (m, 1H), 2.16–1.96 (m, 4H). 13C NMR (CDCl3): δ 173.0, 172.4, 155.8, 139.4, 129.1, 129.0, 126.2, 122.8, 119.9, 60.6, 58.9, 52.1, 51.3, 34.9, 33.1, 33.0, 27.5. ESI MS: 358.15 (M+H).