Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:16]2C=CC=CC=2)[CH:6]=CC=C[C:2]=1P(C(C)(C)C)C(C)(C)C.Br[C:23]1[CH:24]=[C:25]2[C:38]3([CH2:42][O:41][C:40]([N:43](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[N:39]3)[C:34]3([CH2:37][O:36][CH2:35]3)[C:30]3([CH2:33][CH2:32][CH2:31]3)[O:29][C:26]2=[CH:27][CH:28]=1.[Br-].C([Zn+])C(C)C>C1COCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:2]([C:23]1[CH:24]=[C:25]2[C:38]3([CH2:42][O:41][C:40]([NH2:43])=[N:39]3)[C:34]3([CH2:37][O:36][CH2:35]3)[C:30]3([CH2:31][CH2:32][CH2:33]3)[O:29][C:26]2=[CH:27][CH:28]=1)[CH:1]([CH3:16])[CH3:6]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OC1(CCC1)C21COC1
Reactant: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)C[Zn+]
Solvent: C1CCOC1
Product: CC(C)Cc1ccc2c(c1)C1(COC(N)=N1)C1(COC1)C1(CCC1)O2
Temperature: 25 °C
Reaction time: 17 h
Yield: 324.5 %

Procedure:
To a stirred mixture of palladium (II) acetate (7.9 mg, 0.035 mmol) and biphenyl-2-yl(di-tert-butyl)phosphine (5.3 mg, 0.018 mmol) in THF (5 mL) under argon atmosphere was added di-tert-butyl (6′-bromotrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-yl)imidodicarbonate (100 mg, 0.177 mmol) followed by isobutylzinc bromide (0.5 M THF solution, 1.1 mL). The reaction mixture was stirred at room temperature for 17 hours, and then the reaction was quenched with H2O and brine. The resulting mixture was extracted with chloroform 3 times. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude product was dissolved in toluene (6 mL). To the solution was added silica gel (neutral; 600 mg), and the resulting suspension was stirred at 100° C. for 1 hour. After cooling and concentration, the residue was purified by silica gel column chromatography (EtOH/CHCl3=0:100-20:80) followed by column chromatography (NH-silica gel, EtOAc/hexane=20:80-100:0) to afford 6′-isobutyltrispiro[cyclobutane-1,2′-chromene-4′,4″-[1,3]oxazole-3′,3′″-oxetan]-2″-amine (20 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:28])[CH2:18][N:19]4[CH:23]=[C:22]([C:24]([NH2:27])=[N:25][OH:26])[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:29]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[CH2:15][CH2:14][CH2:13][N:12]([C:17](=[O:28])[CH2:18][N:19]4[CH:23]=[C:22]([C:24]5[N:27]=[CH:29][O:26][N:25]=5)[CH:21]=[N:20]4)[C:11]=3[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: NC(=NO)c1cnn(CC(=O)N2CCCc3c2cnn3-c2ccc(F)cc2)c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: O=C(Cn1cc(-c2ncon2)cn1)N1CCCc2c1cnn2-c1ccc(F)cc1
Temperature: 100 °C
Yield: 93.2 %

Procedure:
A mixture of 1-[2-[1-(4-fluorophenyl)-6,7-dihydro-5H-pyrazolo[4,3-b]pyridin-4-yl]-2-oxo-ethyl]-N′-hydroxy-pyrazole-4-carboxamidine (0.115 g, 0.30 mmol) and p-TsOH.H2O (0.030 g, 0.15 mmol) in HC(OMe)3 (3 mL) was heated at 100° C. for 1.5 hrs. It was then cooled to rt. The mixture was partitioned between IPA/CHCl3 (1:2, 50 mL) and sat. NaHCO3 (30 mL). The organic layer was separated, dried over Na2SO4, concentrated in vacuo and purified by reverse phase HPLC to afford the desired product (0.055 g, 21%). 1H NMR (400 MHz, CDCl3) δ 8.71 (s, 1H), 7.65-8.50 (m, 3H), 7.44 (dd, J=8.4, 4.6 Hz, 2H), 7.17 (dd, J=9.2, 7.6 Hz, 2H), 5.27 (m, 2H), 3.85 (m, 2H), 2.85 (m, 2H), 2.14 (m, 2H); MS: (ES) m/z calculated for C19H16FN7O2 [M+H]+ 394.1, found 394.1.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=O)=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[OH-].[Na+].O.C(O)(=O)C.[CH3:19][C:20]([CH3:22])=[O:21]>>[CH3:19][C:20](/[CH:22]=[CH:7]/[C:6]1[CH:1]=[CH:2][C:3]2[O:11][CH2:10][O:9][C:4]=2[CH:5]=1)=[O:21]
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)/C=C/c1ccc2c(c1)OCO2

Procedure:
A solution of 100 g piperonal in 900 ml acetone was stirred at room temperature with 15 ml of 10% aqueous sodium hydroxide and 30 ml of water. After 3 hours 5 ml of acetic acid was added and the reaction mixture was evaporated. The residue was recrystallized from methanol and dried in vacuo to yield 60 g of piperonalacetone, m.p. 104°-105° C. (EtoAc).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][N:9]([CH:12]([C:14]3[CH:15]=[N:16][C:17]([O:21][CH2:22][C:23]([F:26])([F:25])[CH3:24])=[C:18]([Cl:20])[CH:19]=3)[CH3:13])[C:10](=[O:11])[C:6]=2[CH:5]=[CH:4][N:3]=1.[CH:27]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:28]>>[Cl:20][C:18]1[CH:19]=[C:14]([CH:12]([N:9]2[C:10](=[O:11])[C:6]3[CH:5]=[CH:4][N:3]=[C:2]([C:27]([O:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:28])[C:7]=3[CH2:8]2)[CH3:13])[CH:15]=[N:16][C:17]=1[O:21][CH2:22][C:23]([F:26])([F:25])[CH3:24]
Reactant: O=COc1ccccc1
Reactant: CC(c1cnc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2Cl)C1=O
Product: CC(c1cnc(OCC(C)(F)F)c(Cl)c1)N1Cc2c(ccnc2C(=O)Oc2ccccc2)C1=O
Yield: 74 %

Procedure:
The title compound is prepared in 74% yield (230 mg, pale brown solid) from 4-chloro-2-(1-(5-chloro-6-(2,2-difluoropropoxy)pyridin-3-yl)ethyl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one (250 mg, 0.62 mmol, Intermediate-80, single enantiomer) and phenyl formate (150 mg, 1.2 mmol) in a similar manner to Intermediate-91.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[H-].[Na+].Cl.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20]Cl.C(OCC)(=O)C>CN(C)C=O.O>[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[CH2:20][N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[Cl:1]
Reactant: ClCc1ccccn1
Reactant: Clc1nc2ccccc2[nH]1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Clc1nc2ccccc2n1Cc1ccccn1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
61.0 g of 2-chlorobenzimidazole are first added at 25° C. to a suspension of 41.9 g of sodium hydride (55-60% dispersion) in 500 ml of dimethylformamide, and 66.0 g of 2-picolyl chloride-hydrochloride are then added. The mixture is stirred for 1 hour at room temperature and for a further 2 hours at 60° C. After dilution with 1 liter of ethyl acetate, 250 ml of water are carefully added dropwise, the phases are separated, and the ethyl acetate phase is concentrated in vacuo. The remaining product melts at 75°-77° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)(Cl)Cl>[C:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(N)cc35)CCC4)CC2)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(NC(=O)c6ccccc6)cc35)CCC4)CC2)c1
Yield: 23.7 %

Procedure:
2 g of 8-amino-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]-ethyl}-4H-pyrrolo-[3,2,1-ij]quinoline (preparation see Example 20) were dissolved in 25 ml of chloroform. 1.45 ml of triethylamine and then, dropwise, 1.075 g of benzoyl chloride were added to the solution without exceeding a temperature of 20° C. in this process. The reaction mixture was allowed to react at room temperature for hour. To work up the reaction mixture, it was washed with 20 ml of 10% aqueous sodium hydroxide solution until neutral, dried and evaporated. The crude product obtained was purified by chromatography on a small silica gel column using toluene/ethanol 95:5 as the eluent. After recrystallization from ethanol, 0.6 g of 8-benzoylamino-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)-piperazin-1-yl]-ethyl}-4H-pyrrolo[3,2,1-ij]quinoline was obtained as a cream-colored powder. This was converted into the corresponding 0.5-hydrochloride having a melting point of 218° C. as described in Example 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH2:13][CH2:12][CH2:11][CH2:10][C:9]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)[CH:5]=[CH:4][N:3]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.[Li+].C[Si]([N-:51][Si](C)(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[F:20][C:17]1[CH:18]=[CH:19][C:14]([C:9]2[CH2:10][CH2:11][CH2:12][CH2:13][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:51])[CH:7]=2)=[CH:15][CH:16]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Fc1ccc(C2=C(c3ccnc(Cl)c3)CCCC2)cc1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Product: Nc1cc(C2=C(c3ccc(F)cc3)CCCC2)ccn1
Temperature: 65 °C
Reaction time: 1 h
Yield: 47.1 %

Procedure:
A sealed 8 mL vial is charged with 2-Chloro-4-[2-(4-fluoro-phenyl)-cyclohex-1-enyl]-pyridine (25 mg, 0.087 mmol), Tris(dibenzyldieneacetone)Dipalladium (15.9 mg, 0.017 mmol) and 2-(dicyclohexylphosphino)biphenyl (15.8 mg, 0.045 mmol) in dry THF (3 mL). Argon is bubbled through the mixture for 5 min. Additional THF (1 mL) and LiHMDS (1.0 M in toluene, 0.26 mL, 0.26 mmol) are added. And the resulting mixture is allowed to stir at 65° C. for 1 hour. To the mixture is added saturated ammonium chloride solution and extracted with EtOAc (10 mL×3). The organic extract are washed with water (10 mL×1) and brine (10 mL×1), and dried over anhydrous sodium sulfate. After concentration, the crude is purified by silica flash column chromatography using MeOH in DCM (gradient from 0% to 10%) to give 11 mg of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:5]=[CH:6][CH:7]=1.[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]Cl)(=[O:27])=[O:26])[CH2:23][CH2:22]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:21]1([NH:24][S:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][N:12]2[CH2:11][CH2:10][N:9]([CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:14][CH2:13]2)(=[O:27])=[O:26])[CH2:23][CH2:22]1
Reactant: Clc1cccc(C(c2ccccc2)N2CCNCC2)c1
Reactant: O=S(=O)(CCCCCCCl)NC1CC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(CCCCCCN1CCN(C(c2ccccc2)c2cccc(Cl)c2)CC1)NC1CC1
Yield: 51.8 %

Procedure:
1-[(3-Chlorophenyl)phenylmethyl]piperazine (543.7 mg, 1.90 mmol) and N-cyclopropyl-6-chlorohexanesulfonamide (500 mg, 2.09 mmol) were refluxed in toluene (15 ml) in the presence of triethylamine (211 mg, 2.09 mmol) for 48 hours. The reaction mixture was washed with water, and the organic layer was dried over anhydrous magnesium sulfate. Subsequently, the solvent was removed by evaporation in vacuo. The resulting crude product was purified by column chromatography on silica gel with chloroform-methanol (20:1), to give N-cyclopropyl-6-[4-[(3-chlorophenyl)phenylmethyl]-1-piperazinyl]hexanesulfonamide (482.7 mg) as an oil (yield based on 1-[(3-chlorophenyl)phenylmethyl]piperazine: 52.0%).
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([CH2:9][O:10][C:11]2[C:12]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[N:13][S:14][N:15]=2)=[CH:5][CH:4]=1.C(N(CC)CC)C.[N:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[C:34]([C:42]([F:45])([F:44])[F:43])[CH:33]=1)=[C:30]=[O:31]>ClCCl.CCOC(C)=O>[F:39][C:38]([F:40])([F:41])[C:36]1[CH:37]=[C:32]([NH:29][C:30]([N:19]2[CH2:20][CH2:21][N:16]([C:12]3[C:11]([O:10][CH2:9][C:6]4[CH:7]=[CH:8][N:3]=[CH:4][CH:5]=4)=[N:15][S:14][N:13]=3)[CH2:17][CH2:18]2)=[O:31])[CH:33]=[C:34]([C:42]([F:45])([F:43])[F:44])[CH:35]=1
Reactant: O=C=Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: c1cc(COc2nsnc2N2CCNCC2)ccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCN(c2nsnc2OCc2ccncc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
1-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine, dihydrochloride salt (2.13 g, 6.1 mmol), dichloromethane (40 mL), and triethylamine (2.5 mL, 17.9 mmol) were combined and cooled in an icebath. 1-Isocyanato-3,5-bis-trifluoromethyl-benzene (1.89 g, 7.4 mmol) in dichloromethane (10 mL) was added dropwise and the resulting mixture stirred overnight at room temperature. The reaction mixture was diluted with EtOAc and washed with sat'd NaHCO3 (3×), sat'd NaCl (1×), dried (Na2SO4), and concentrated in vacuo. The crude product was purified by column chromatography (1:1 hexanes:EtOAc, followed by 1:3 hexanes:EtOAc) to give 2.6 g (80%) of 4-[4-(pyridin-4-ylmethoxy)-[1,2,5]thiadiazol-3-yl]-piperazine-1-carboxylic acid (3,5-bis-trifluoromethyl-phenyl)-amide as a white solid after lyophilization from: H2O—AcCN. 1H NMR (CDCl3) 8.62 (d, 2H), 7.84 (s, 2H), 7.50 (s, 1H), 7.31 (d, 2H), 7.06 (s, 1H), 5.49 (s, 2H), 3.68-3.60 (m, 8H) ppm. LC-MS (MH+)=533.
Reaction SMILES: [I-].[K+].CS(O[CH2:8][CH2:9][O:10][C:11]1[C:19]2[C:14](=[N:15][CH:16]=[N:17][C:18]=2[NH:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][C:28]3[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=3)=[C:23]([F:35])[CH:22]=2)[NH:13][N:12]=1)(=O)=O.[NH:36]1[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1>>[F:35][C:23]1[CH:22]=[C:21]([NH:20][C:18]2[N:17]=[CH:16][N:15]=[C:14]3[NH:13][N:12]=[C:11]([O:10][CH2:9][CH2:8][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[C:19]=23)[CH:26]=[CH:25][C:24]=1[O:27][C:28]1[CH:29]=[N:30][C:31]([CH3:34])=[CH:32][CH:33]=1
Reactant: C1COCCN1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCOS(C)(=O)=O)c34)cc2F)cn1
Agent: [I-]
Agent: [K+]
Product: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCN5CCOCC5)c34)cc2F)cn1
Yield: 46 %

Procedure:
The procedure described in Example 23 was repeated (except that potassium iodide was not used) using 2-{[4-({3-fluoro-4-[(6-methylpyridin-3-yl)oxy]phenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate and morpholine to give the title compound in 46% yield; NMR Spectrum: 2.45 (s, 3H), 2.51 (hidden by DMSO, 4H), 2.84 (t, 2H), 3.57 (s, 4H), 4.46 (t, 2H), 7.27 (m, 3H), 7.56 (dd, 1H), 8.00 (dd, 1H), 8.24 (d, 1H), 8.36 (s, 1H), 8.62 (br s, 1H); Mass Spectrum: 466 (MH+).
Reaction SMILES: Cl.[O:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[OH-].[Na+].[S:9]([OH:13])([OH:12])(=[O:11])=[O:10].CS[C:16](=[NH:18])[NH2:17]>O>[S:9]([OH:13])([OH:12])(=[O:11])=[O:10].[C:16]([N:3]1[CH2:4][CH2:5][CH2:6][O:2]1)(=[NH:17])[NH2:18]
Reactant: C1CNOC1
Reactant: CSC(=N)N
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: N=C(N)N1CCCO1

Procedure:
To 14.5 g. (0.13 mole) of isooxazolidine hydrochloride in water (100 ml.) is added 10.4 g. (0.13 mole) of fifty percent (w/w) aqueous sodium hydroxide and the mixture stirred for fifteen minutes. To this solution is added 18.1 g. (0.055 moles) of 2-methyl-2-thiopseudourea sulfate and the entire mixture stirred under a stream of nitrogen overnight. The mixture is refluxed for 11/2 hours, then filtered while still hot. The water is removed under vacuum to give a semi-solid residue which is triturated with hot isopropanol (3×100 ml.). the isopropanol is removed under vacuum to give an oil which is crystallized from isopropanol to give N-amidinoisooxazolidine sulfate.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=2)=[CH:8][C:9]=1[N:10]([C:14]([CH:16]1[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]1[O:23]C(=O)C)=[O:15])[CH:11]([CH3:13])[CH3:12])=[O:4].O[Li].O>C1COCC1.CO.O>[F:33][C:29]1[CH:28]=[C:27]([C:7]2[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C:14]([CH:16]3[CH2:21][CH2:20][CH:19]([CH3:22])[CH2:18][CH:17]3[OH:23])=[O:15])[CH:11]([CH3:12])[CH3:13])[CH:8]=2)[CH:32]=[CH:31][CH:30]=1
Reactant: COC(=O)c1sc(-c2cccc(F)c2)cc1N(C(=O)C1CCC(C)CC1OC(C)=O)C(C)C
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1CCC(C(=O)N(c2cc(-c3cccc(F)c3)sc2C(=O)O)C(C)C)C(O)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
3[(2-Acetoxy-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-5-(3-fluoro-phenyl)-thi-ophene-2-carboxylic acid methyl ester (30 mg, 0.063 mmol) was taken in a mixture of THF:MeOH:H2O (3:2:1, 2 mL) and then added 1N aqueous solution of LiOH.H2O (0.38 mL, 0.380 mmol). The reaction mixture was stirred at room temperature for 12 h. Solvents were removed and the residue was partitioned between water and ethyl acetate. The aqueous layer was acidified using 10% KHSO4 solution. The organic layer was separated, dried (Na2SO4) and concentrated. The residue was purified by silica gel column chromatography using chloroform and methanol (8:2) to obtain 5-(3-fluoro-phenyl)-3-[(2-hydroxy-4-methyl-cyclohexanecarbonyl)-isopropyl-amino]-thiophene-2-carboxylic acid (Compound 44) (15 mg, 58%) as a white solid with two rotamers. 1H NMR (CDCl3, 400 MHz): δ7.50-7.25 (m, 3H), 7.06 (m, 2H), 6.25 (bs, 1H), 5.25 (s, 1H, minor), 4.87 (s, 1H, major), 4.13 (s, 1H, major), 3.87 (s, 1H, minor), 2.38-0.45 (m, 17H). ESI− (M-H): 418.
Reaction SMILES: [CH3:1][C:2]1([CH2:14][OH:15])[O:7][C:6]2=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]2[CH2:4][CH2:3]1.[H-].[Na+].[Br:18][C:19]1[CH:20]=[CH:21][C:22](F)=[N:23][CH:24]=1.C(=O)=O.CC(C)=O>CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([O:15][CH2:14][C:2]2([CH3:1])[O:7][C:6]3=[N:8][C:9]([N+:11]([O-:13])=[O:12])=[CH:10][N:5]3[CH2:4][CH2:3]2)=[N:23][CH:24]=1
Reactant: CC1(CO)CCn2cc([N+](=O)[O-])nc2O1
Reactant: Fc1ccc(Br)cn1
Agent: O=C=O
Agent: [H-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CC1(COc2ccc(Br)cn2)CCn2cc([N+](=O)[O-])nc2O1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 77.7 %

Procedure:
A solution of alcohol 149 (200 mg, 0.938 mmol) in anhydrous DMF (4 mL) under N2 at 0° C. was treated with 60% NaH (53.8 mg, 1.35 mmol), then quickly degassed and resealed under N2. 5-Bromo-2-fluoropyridine (91) (0.245 mL, 2.38 mmol) was added and the mixture was stirred at room temperature for 2.5 h, and then cooled (CO2/acetone), quenched with ice/aqueous NaHCO3 (10 mL), added to brine (40 mL), and extracted with CH2Cl2 (10×50 mL). The combined extracts were evaporated to dryness and the residue was chromatographed on silica gel. Elution with CH2Cl2 firstly gave foreruns, and then further elution with 1-3% EtOAc/CH2Cl2 gave 7-{[(5-bromo-2-pyridinyl)oxy]methyl}-7-methyl-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (150) (269 mg, 78%) as a cream solid: mp (CH2Cl2/pentane) 172-174° C.; 1H NMR (CDCl3) δ 8.17 (br d, J=2.2 Hz, 1H), 7.67 (dd, J=8.8, 2.5 Hz, 1H), 6.64 (dd, J=8.7, 0.4 Hz, 1H), 4.49 (d, J=11.5 Hz, 1H), 4.42 (d, J=11.4 Hz, 1H), 4.17 (dt, J=12.7, 6.1 Hz, 1H), 4.09 (ddd, J=12.6, 7.7, 5.8 Hz, 1H), 2.45 (ddd, J=14.5, 7.6, 5.9 Hz, 1H), 2.18 (dt, J=14.6, 6.1 Hz, 1H), 1.57 (s, 3H). Anal. (C13H13BrN4O4) C, H, N.
Reaction SMILES: [CH3:1][C:2]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-])=O)([CH3:5])[CH2:3][OH:4].[CH2:16](O)[CH3:17]>[Pd]>[CH3:16][C:17]1[N:6]([C:2]([CH3:5])([CH3:1])[CH2:3][OH:4])[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:13]=1
Reactant: CC(C)(CO)Nc1ccccc1[N+](=O)[O-]
Reactant: CCO
Agent: [Pd]
Product: Cc1nc2ccccc2n1C(C)(C)CO
Yield: 98 %

Procedure:
2-(1,1-dimethyl-2-hydroxyethyl)aminonitrobenzene (10 g) in ethanol (200 ml) was hydrogenated at 50 p.s.i. (345 kPa) over 5% Pd/C (0.5 g) for 2 hours. The catalyst was filtered off and the solvent removed under reduced pressure yielding the title compound as a yellow foam 8.4 g (98%).
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([N:11]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]2[C:22](=[O:25])[NH:23][N:24]=[C:14]2[C:13]2[CH:26]=[CH:27][CH:28]=[N:29][C:12]1=2)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].[H-].[Na+].Cl[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36]>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:36][N:35]([CH2:34][CH2:33][N:23]1[C:22](=[O:25])[N:15]2[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[N:11]([C:9](=[O:10])[CH2:8][N:4]([CH2:5][CH2:6][CH3:7])[CH2:1][CH2:2][CH3:3])[C:12]3[N:29]=[CH:28][CH:27]=[CH:26][C:13]=3[C:14]2=[N:24]1)[CH3:37]
Reactant: CN(C)CCCl
Reactant: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1C
Product: CCCN(CCC)CC(=O)N1c2ccccc2-n2c(nn(CCN(C)C)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 21, to 2,9-dihydro-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling with (2-chloroethyl)dimethylamine in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 25 to give 2,9-dihydro-2-[(dimethylamino)ethyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: O=[C:2]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[C:3]([OH:5])=[O:4].Cl.[NH2:12][CH2:13][C:14]([NH2:16])=[O:15].[OH-].[Na+].O>>[C:3]([C:2]1([CH2:6][CH2:7][C:8]([OH:10])=[O:9])[NH:16][C:14](=[O:15])[CH2:13][NH:12]1)([OH:5])=[O:4]
Reactant: NCC(N)=O
Reactant: O=C(O)CCC(=O)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCC1(C(=O)O)NCC(=O)N1
Yield: 42.9 %

Procedure:
A solution of 2-oxoglutaric acid (10 g, 0.068 mol), glycinamide hydrochloride (8.3 g, 0.075 mol) and sodium hydroxide (8.2 g, 0.205 mol) in water (120 mol) was refluxed for 4 hours. After cooling the solution was adjusted to pH 2.5 and the resulting precipitate was collected and dried under vacuum at 60° C. to afford 5.9 g (43%) of the title compound, m.p. 202°-205° C. NMR (DMSO-d6): deltaH =8.5 (s, 1H, CONH); 7.00-4.00 (b.s., 3H, NH, COOH); 3.22 and 3.18 (ABq, J=16 Hz, 2H, NHCH2CO); 2.40-1.75 (c.a., 4H, CH2CH2COOH). MS (E.I., 70 eV, 1.5 mA) m/z=140 (M-H2O-COOH)+, 84 (C3H4N2O)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([CH3:17])[C:5]2=O.C[Si]([N:23]=[C:24]=[N:25][Si](C)(C)C)(C)C>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:14](=[CH:15][CH:16]=1)[O:13][C:7]1([CH2:12][CH2:11][CH2:10][O:9][CH2:8]1)[CH:6]([CH3:17])/[C:5]/2=[N:25]\[C:24]#[N:23]
Reactant: C[Si](C)(C)N=C=N[Si](C)(C)C
Reactant: CC1C(=O)c2cc(Br)ccc2OC12CCCOC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC1/C(=N\C#N)c2cc(Br)ccc2OC12CCCOC2
Temperature: 65 °C
Yield: 137.7 %

Procedure:
A solution of 6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (200 mg, 0.65 mmol) and TiCl4 (864 mg, 4.55 mmol) in anhydrous DCM (8 mL) was heated at 50° C. under microwave for 5 mins. Then bis-trimethylsilylcarbodiimide (360 mg, 1.95 mmol) was added and the mixture was heated at 65° C. for another 1 hr. The reaction mixture was poured into ice-water and extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, filtered and concentrated to give (E)-N-(6-bromo-3-methyl-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-ylidene)cyanamide (300 mg, crude), which was used in the next step without further purification.