Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li]CCCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1Br.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH:19]=[O:20].Cl>CCOCC.O.C1COCC1>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=1)[OH:20]
Reactant: Brc1ccccn1
Reactant: O=Cc1ccccn1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccccn1)c1ccccn1
Temperature: -10 °C
Reaction time: 1 h
Yield: 52.2 %

Procedure:
To a solution of 80 mL n-BuLi in hexanes (2.5 M, 0.2 mol) was added 2-pyridylbromide (31.6 gram 0.2 mol) in 100 mL of ether at −80° C.-−60° C. The suspension was stirred for 1 h, and the temperature was allowed to rise to −45° C. Subsequently 2-pyridinecarboxaldehyde (21.42 gram 0.2 mol) in of ether (100 mL) was added during 30 min. To the thick slurry was added additional THF (200 mL) and the mixture was stirred for 1.5 h at −40° C.-−30° C. and then the mixture was allowed to warm up to −10° C. The mixture was poured into water (200 ml) and acidified with 2 M HCl to pH=1-2 and the layers were separated. The aqueous layer was extracted twice with ether (100 mL) and neutralized with saturated Na2CO3(aq) to pH=8. The aqueous layer was extracted CH2Cl2 (3×100 ml). Drying (Na2SO4) and evaporation of the solvent yielded a brown oil. Vacuum distillation (118° C., 0.2 mmHg) afforded di(2-pyridinyl)methanol (19.42 gram, 104.4 mmol, 52%) as a yellow oil. 1H-NMR (200 MHz. CDCl3) δ 5.88 (s, 2H), 7.11-7.19 (m, 2H), 7.47-7.67 (m, 4H). 8.50-8.54 (m, 2H). 13C-NMR (50.3 MHz, CDCl3) δ 75.0 (d), 121.0 (d), 122.5 (d), 136.8 (d), 1448.1 (d), 160.7 (s).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12]O)=[O:4].C([O-])(=O)C.[NH4+:22]>CO>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[CH:8][N:7]([CH3:10])[C:6]=1[C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][NH2:22])=[O:4]
Reactant: [NH4+]
Reactant: COC(=O)C(=CO)c1c(C(=O)OC)ccn1C
Agent: CC(=O)[O-]
Solvent: CO
Product: COC(=O)C(=CN)c1c(C(=O)OC)ccn1C
Yield: 26.6 %

Procedure:
2-(2-Hydroxy-1-methoxycarbonyl-vinyl)-1-methyl-1H-pyrrole-3-carboxylic acid methyl ester (12.46 g), ammonium acetate (20.09 g) and methanol (200 ml) were refluxed under argon for 5 hours. After cooling the solvent was evaporated and the residue dissolved in ethyl acetate and washed with water, the aqueous was separated and extracted three times with ethyl acetate. The combined organics were washed with saturated brine solution and the organic layer was dried (MgSO4), filtered and evaporated. The residue was then taken up in the minimum amount of ethyl acetate and a precipitate formed which was filtered off to yield the title compound as an off-white solid (3.3 g). The filtrate was evaporated to yield the title compound as a brown solid (6.36 g). Both were taken through without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1.[CH2:18]([N:25]1[CH2:29][CH2:28][C@H:27](OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CC(C)([O-])C.[K+].O>C1COCC1>[CH2:18]([N:25]1[CH2:29][CH2:28][C@@H:27]([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]#[N:11])[CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@H]2CCN(Cc3ccccc3)C2)cc1
Reactant: COc1cccc(C(C#N)c2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cccc(C(C#N)(c2ccccc2)[C@@H]2CCN(Cc3ccccc3)C2)c1
Temperature: 80 °C
Yield: 77.3 %

Procedure:
To a stirred solution of (3-methoxyphenyl)phenylacetonitrile (5.2 g, 23 mmol; prepared as described in Preparation 6) in THF (100 mL) was added toluene-4-sulfonic acid (S)-1-benzylpyrrolidin-3-yl ester (7.2 g, 22 mmol), followed by the addition of potassium t-butoxide (4.0 g, 36 mmol). The mixture was heated to 80° C. for 1 hour, then allowed to cool and H2O (10 mL) was added. The mixture was filtered through a pad of Celite®. The mixture was washed with a saturated aqueous NaCl solution (100 mL) and the organic phase was separated, dried over MgSO4, and filtered. The solvent was removed under reduced pressure. The crude material was purified via silica gel chromatography to afford the title compound (6.2 g, 17 mmol). MS m/z: {M+H+] calcd for C26H26N2O, 382.5. found 383.4.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH2:5]P(=O)(OC)OC.[CH:17]([C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:43])([CH3:42])[CH3:41])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=O.C(O)(=O)C>C1COCC1>[O:3]=[C:4]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])/[CH:5]=[CH:17]/[C:19]1[O:20][C:21]([CH2:37][O:38][C:39](=[O:44])[C:40]([CH3:41])([CH3:42])[CH3:43])=[CH:22][C:23](=[O:36])[C:24]=1[O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)CCCCCOc1c(C=O)oc(COC(=O)C(C)(C)C)cc1=O
Reactant: CCCCCC(=O)CP(=O)(OC)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCCC(=O)/C=C/c1oc(COC(=O)C(C)(C)C)cc(=O)c1OCCCCCC(=O)OCC
Reaction time: 1 h
Yield: 22.1 %

Procedure:
To a solution, under nitrogen, of 0.206 g (4.3 mmole) of sodium hydride (50% dispersion in mineral oil) in 15 ml of dry THF was added dropwise 1.04 g (4.69 mmole) of dimethyl (2-oxoheptyl)-phosphonate. The heterogeneous mixture was stirred for 1.0 hour then a solution of 1.55 g (3.9 mmole) of 2-formyl-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone in 5 ml of THF was added. The mixture was stirred for 15 min then was neutralized to pH 7 with glacial acetic acid. The neutralized solution was concentrated by rotary evaporation and the residue dissolved in methylene chloride. The organic solution was washed with saturated brine solution and dried over magnesium sulfate. Removal of the solvent left an oil which was purified by chromatography on silica gel using ether as the eluent. Concentration of the fractions containing product furnished 0.425 g (22%) of pure 2-(3-oxo-trans-1-octenyl)-3-(5-carboethoxypentyloxy)-6-(trimethylacetoxymethyl)-4-pyrone as an oil. NMR (CDCl3): δ0.88 (3H, t, J=5 Hz); 1.25 (9H, s), 2.27 (2H, t, J=6.5 Hz); 2.60 (2H, t, J=6.5 Hz); 4.91 (2H, s).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.CN1CCOCC1.[NH2:21][C:22]1[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=1)[C:27]([OH:29])=[O:28].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:12][C:2]([F:1])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([C:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([Cl:31])=[C:26]([CH:30]=2)[C:27]([OH:29])=[O:28])=[O:9])=[CH:10][CH:11]=1
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1
Reactant: Nc1ccc(Cl)c(C(=O)O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(Nc1ccc(Cl)c(C(=O)O)c1)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87.8 %

Procedure:
To a suspension of 4-(trifluoromethyl)benzoic acid (1.0 g, 5.3 mmol) in DCM (20 mL) were added CDMT (1.1 g, 6.3 mmol) and NMM (2.3 mL, 21 mmol). The mixture was stirred at RT for 30 min under an argon atmosphere. 5-amino-2-chlorobenzoic acid (1.4 g, 7.9 mmol) was added and the mixture stirred at RT for additional 2 h. The reaction mixture was poured into saturated NaHCO3 solution and then extracted with DCM. The organic layer was dried (Na2SO4), filtered and the filtrate concentrated to afford the title compound (1.6 g, 88%) as a cream solid.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]2)=[CH:4][C:3]=1[C:18]([F:21])([F:20])[F:19].C[O:23][CH:24]1[CH:28]([CH:29]=O)[CH2:27][CH:26](OC)O1.O>C(O)(=O)C>[CH:24]([C:28]1[CH:27]=[CH:26][N:1]([C:2]2[CH:11]=[C:10]3[C:5]([NH:6][C:7](=[O:17])[CH:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:9]3)=[CH:4][C:3]=2[C:18]([F:21])([F:20])[F:19])[CH:29]=1)=[O:23]
Reactant: CCOC(=O)C1Nc2cc(N)c(C(F)(F)F)cc2NC1=O
Reactant: COC1CC(C=O)C(OC)O1
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C1Nc2cc(-n3ccc(C=O)c3)c(C(F)(F)F)cc2NC1=O
Reaction time: 1.5 h
Yield: 56.6 %

Procedure:
To a solution of ethyl 7-amino-3-oxo-1,2,3,4-tetrahydro-6-trifluoromethylquinoxaline-2-carboxylate (3.60 g, 11.9 mmol) in acetic acid (60 ml) was added dropwise 2,5-dimethoxytetrahydrofuran-3-aldehyde (2.01 ml, 14.2 mmol) at 50° C., and the mixture was stirred for 1.5 hours at the same temperature. The reaction mixture was poured into water (300 ml), which was extracted with ethyl acetate. After dried over anhydrous sodium sulfate, solvent was distilled off. Methylene chloride was added to the residue obtained and the crystals were collected by filtration. These were washed with methylene chloride and then air-dried to obtain 2.57 g of the title compound as yellow powder. The filtrate and the washings were combined, concentrated under reduced pressure, and purified by means of silica gel column chromatography [ethyl acetate-hexane=2:1] to obtain further 973 mg. Total yield by weight 3.54 g. Yield 78%.
Reaction SMILES: Cl[C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[CH3:11][NH:12][CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1>>[CH3:11][N:12]([C:2]1[N:6]([CH3:7])[N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])[CH:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1
Reactant: Cn1ncc([N+](=O)[O-])c1Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Product: CN(c1c([N+](=O)[O-])cnn1C)C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 36 %

Procedure:
Reaction of 5-chloro-1-methyl-4-nitro-1H-pyrazole and tert-butyl 4-(methylamino)piperidine-1-carboxylate gave tert-butyl 4-(methyl(1-methyl-4-nitro-1H-pyrazol-5-yl)amino)piperidine-1-carboxylate (75 mg, 36%). 1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 4.15-4.05 (m, 2H), 3.75 (s, 3H), 3.32 (tt, J=11.1, 3.9 Hz, 1H), 2.81 (s, 3H), 2.72 (t, J=12.9 Hz, 2H), 1.79-1.70 (m, 2H), 1.48 (s, 9H), 1.40-1.25 (m, 2H)
Reaction SMILES: C([O:3][C:4]([C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1)=O)C.O1CCCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CC(C)=O.ClCCl>ClCCl>[OH:3][CH2:4][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1ccc(Cn2c(NC3CCN(C(=O)OCC)CC3)nc3ccccc32)o1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2ccc(CO)o2)CC1
Reaction time: 5.5 h

Procedure:
Combine (1-(5-(ethoxycarbonyl)fur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine (1.0 g, 2.27 mmol) and tetrahydrofuran (10 mL). Add dropwise a solution of lithium aluminum hydride (2.3 mL, 1 M in THF, 2.3 mmol). After 5.5 hours, dilute the reaction mixture with dichloromethane and quench by slow portionwise addition of Glauber's salt (Na2SO4.10 H2O) until gas evolution ceases. Add dichloromethane and celite and stir. Filter, rinse the solids with dichloromethane, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 40% acetone/dichloromethane to give a residue. Recrystallization from ethyl acetate/hexane to give (1-(5-hydroxymethylfur-2-ylmethyl)-1H-benzimidazol-2-yl)(1-ethoxycarbonylpiperidin-4-yl)amine: mp; 138-140° C. Elemental Analysis calculated for C21H26N4O4: C 63,30; H 6.58; N 14.06; Found: C 63.29; H 6.50; N 14.06.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18](Cl)(=[O:20])=[O:19].[CH2:22]([NH2:30])[CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C.O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:17])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[CH:4][C:3]=1[S:18]([NH:30][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)Cl)c2)cc1
Reactant: NCCc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(=O)(=O)NCCc3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 5.2 %

Procedure:
2-Chloro-5-(4-methoxy-benzoyl)-benzenesulfonyl chloride (0.2 g, 5.79 mmol) is dissolved in methylene chloride (10 mL). Phenethylamine (0.077 g, 6.36 mmol) is added, followed by the addition of triethylamine (0.146 g, 14.5 mmol). The reaction mixture is stirred for 2 h at room temperature. Water is added, and the mixture extracted with methylene chloride. The solvent is removed and the mixture is purified by flash column chromatography, using 50% of ethyl acetate-hexane as an eluent. The product is obtained as a colorless oil (0.13 g, 52% yield). 1H NMR (CDCl3): δ 8.4 (m, 1H), 7.90 (m, 1H), 7.50 (d, J=8 Hz, 2H), 7.28 (m, 3H), 7.00 (d, J=8 Hz, 2H), 7.17 (m, 2H), 4.97 (m, 1H), 3.91 (s, 3H), 3.20 (m, 2H), 2.80 (m, 2H). Analytics calculated for C22H20ClNO4S: C, 61.46; H, 4.69; N, 3.26. Found: C, 61.20; H, 4.95; N, 3.10. MS (m/z): 430.0 (M+1).
Reaction SMILES: [C:1]([C:6]1[CH:47]=[C:46]([C:48]([CH2:51][CH3:52])([CH3:50])[CH3:49])[CH:45]=[CH:44][C:7]=1[O:8][CH:9]([CH2:42][CH3:43])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][CH:41]=1)[C:16]([NH:18][C:19]1[CH:23]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)[C:22](=[O:29])[N:21]([C:30]2[C:35]([Cl:36])=[CH:34][C:33]([Cl:37])=[CH:32][C:31]=2[Cl:38])[N:20]=1)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:60](OCl)(=[O:64])[CH2:61][CH2:62][CH3:63].C(OCC)(=O)C>O1CCCC1>[C:1]([C:6]1[CH:47]=[C:46]([C:48]([CH2:51][CH3:52])([CH3:49])[CH3:50])[CH:45]=[CH:44][C:7]=1[O:8][CH:9]([CH2:42][CH3:43])[C:10]([NH:12][C:13]1[CH:14]=[C:15]([CH:39]=[CH:40][CH:41]=1)[C:16]([NH:18][C:19]1[C:23]([N:24]2[CH:28]=[CH:27][CH:26]=[N:25]2)=[C:22]([O:29][C:60](=[O:64])[CH2:61][CH2:62][CH3:63])[N:21]([C:30]2[C:31]([Cl:38])=[CH:32][C:33]([Cl:37])=[CH:34][C:35]=2[Cl:36])[N:20]=1)=[O:17])=[O:11])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1cccc(C(=O)NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2n2cccn2)c1
Reactant: CCCC(=O)OCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCC(=O)Oc1c(-n2cccn2)c(NC(=O)c2cccc(NC(=O)C(CC)Oc3ccc(C(C)(C)CC)cc3C(C)(C)CC)c2)nn1-c1c(Cl)cc(Cl)cc1Cl
Reaction time: 1 h

Procedure:
30.6 g of 3-{3-[2-(2,4-di-tert-amylphenoxy)butyramido]benzamido}-1-(2,4,6-trichlorophenyl)-4-(1-pyrazolyl)-5-oxo-2-pyrazoline (prepared by the method described in German Patent Application (OLS) No. 2,536,191) was dissolved in 100 ml of tetrahydrofuran and 5 g of triethylamine was added. To the solution, a solution containing 3.5 g of butanoyloxy chloride dissolved in 10 ml of tetrahydrofuran was dropwise added. After the addition of the solution, the mixture was stirred for 1 hour. 500 ml of ethyl acetate was added to the reaction mixture and washed several times with water. The oil layer was dried with anhydrous sodium sulfate and concentrated. Upon crystallization of the residue from acetonitrile, 24 g of Coupler (5) was obtained. The melting point of the coupler was 63° to 68° C.
Reaction SMILES: C[CH2:2][N:3](C(C)C)[CH:4](C)C.[CH3:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:38]=[N:37][C:26]4[NH:27][C:28]5[CH:33]=[N:32][C:31]([C:34](O)=[O:35])=[CH:30][C:29]=5[C:25]=4[CH:24]=3)=[CH:19][CH:18]=2)[CH2:13][CH2:12]1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.Cl.CNC.S(=O)(=O)(O)O>CN(C=O)C>[CH3:2][N:3]([CH3:4])[C:34]([C:31]1[N:32]=[CH:33][C:28]2[NH:27][C:26]3[N:37]=[CH:38][C:23]([C:20]4[CH:21]=[CH:22][C:17]([N:14]5[CH2:13][CH2:12][N:11]([CH3:10])[CH2:16][CH2:15]5)=[CH:18][CH:19]=4)=[CH:24][C:25]=3[C:29]=2[CH:30]=1)=[O:35]
Reactant: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)O)cc5c4c3)cc2)CC1
Reactant: CCN(C(C)C)C(C)C
Agent: CNC
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc(-c3cnc4[nH]c5cnc(C(=O)N(C)C)cc5c4c3)cc2)CC1
Reaction time: 0.17 h

Procedure:
DIPEA (14 μL, 77 μmol) was added to a solution of 3-[4-(4-methylpiperazin-1-yl)-phenyl]-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carboxylic acid (20.0 mg, 51.6 mop, PyBOP (28.2 mg, 54.2 μmol) and HOBt (8.4 mg, 62 μmol) in DMF (0.6 mL). After 10 min at ambient temperature, dimethylamine hydrochloride (20.0 mg, 0.258 mmol) and DIPEA (45 μL, 0.26 mmol) were added to the reaction mixture. After 30 min the reaction mixture was acidified with 10% aqueous sulfuric acid, the solid removed by filtration and the resultant filtrate was purified by preparative HPLC (0-30% MeCN over 30 min, 35 mL/min) to afford the title compound. 1H NMR (DMSO-D6, 400 MHz): 12.40 (s, 1H), 9.03 (m, 1H), 8.92 (m, 1H), 8.89 (m, 1H), 8.55 (m, 1H), 7.75 (d, J=8.9 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 3.97 (d, J=12.2 Hz, 2H), 3.56 (d, J=12.2 Hz, 2H), 3.21 (m, 2H), 3.08 (m, 6H), 3.02 (m, 2H), 2.98 (s, 3H). LCMS (Method D): RT=6.19 min, M+H+=415.
Reaction SMILES: [N:1]1([C:7]2[O:8][C:9]3[C:17](OS(C(F)(F)F)(=O)=O)=[CH:16][CH:15]=[CH:14][C:10]=3[C:11](=[O:13])[N:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:26][C:27]1[CH:28]=[C:29]([NH2:42])[CH:30]=[CH:31][C:32]=1B1OC(C)(C)C(C)(C)O1.CCN(CC)CC>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:42][C:29]1[CH:30]=[CH:31][C:32]([C:17]2[C:9]3[O:8][C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)=[N:12][C:11](=[O:13])[C:10]=3[CH:14]=[CH:15][CH:16]=2)=[C:27]([F:26])[CH:28]=1
Reactant: O=c1nc(N2CCOCC2)oc2c(OS(=O)(=O)C(F)(F)F)cccc12
Reactant: CC1(C)OB(c2ccc(N)cc2F)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: Nc1ccc(-c2cccc3c(=O)nc(N4CCOCC4)oc23)c(F)c1
Temperature: 70 °C

Procedure:
To a mixture of trifluoro-methanesulfonic acid 2-morpholin-4-yl-4-oxo-4H-benzo[e][1,3]oxazin-8-yl ester, 3 (60 mg, 0.16 mmol, 1 eq), 3-fluoro-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (47 mg, 0.20 mmol, 1.3 eq), Pd(PPh3)4 (7.6 mg, 0.007 mmol, 5 mol %) in dioxane (2 mL) and H2O (1mL) was added Et3N (66 mL, 0.48 mmol, 3 eq) dropwise. The reaction mixture was heated up in a pressure tube at 70° C. for 6 h. Upon cooling, the solution was partitioned between EtOAc (15 mL) and H2O (10 mL). The aqueous layer was further extracted with EtOAc (2×5 mL) and DCM (5 mL). The combined organic extracts were dried over MgSO4 and the solvent was removed in vacuuo. The residue was further purified by silica gel column chromatography with EtOAc:MeOH (1:0-13:1) to yield the product, B, as a pale brown solid (47 mg, 87%). 1HNMR (400 MHz, CDCl3+10% MeOD) δH: 7.98 (dd, J=7.5, 1.5 Hz, 1H), 7.62 (dd, 1.5 Hz, 1H), 7.42 (t, J=7.5 Hz, 1H), 7.12 (t, J=8.3 Hz, 1H), 6.59 (dd, J=8.3, 2.3 Hz, 1H), 6.52 (dd, J=12.5, 2.0 Hz, 1H), 3.49-3.90 (m, 10H). MS (ES+) 342.1 (100%, [M+H]+).
Reaction SMILES: [C:1]([C:5]1[N:9]=[C:8]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:17][N:18]([CH3:22])[C:19](Cl)=[O:20].C(N(CC)CC)C.Cl>C1COCC1.CN(C)C1C=CN=CC=1.O.C(OCC)C>[CH3:17][N:18]([CH3:22])[C:19]([N:7]1[C:8]([S:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[N:9][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[N:6]1)=[O:20]
Reactant: CCOC(=O)CSc1nc(C(C)(C)C)n[nH]1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CSc1nc(C(C)(C)C)nn1C(=O)N(C)C
Yield: 96.8 %

Procedure:
To a solution of 813 g (3.34 mole) of 3-t-butyl-5-carboethoxymethylthio-1,2,4-1H-triazole in 2 liters of THF was added 395 g (3.67 mole) of dimethyl carbamoyl chloride and 50 g (0.4 mole) of 4-dimethylaminopyridine. To this solution is slowly added 675 g (6.68 mole) of triethylamine, whereon the reaction exotherms to reflux. The reaction is allowed to react for an additional 1.5 hours whereon the temperature slowly returns to room temperature. One liter of ethyl ether, 2 liters of water, 2 kgs of ice are added and the mixture is acidified with concentrated aqueous hydrochloric acid. The aqueous layer is separated and backwashed with 1 liter of ethyl ether before discarding. The combined aqueous layers are washed with 2 liters of brine, dried over magnesium sulfate, and concentrated under vacuum to afford 1016 g of 1-dimethylcarbamoyl-3-t-butyl-5-carboethoxymethylthio-1,2,4-1H-triazole as a tan solid.
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])=[CH:5][CH:4]=1.[N:15]([O-])=[O:16].[Na+]>C1COCC1.C(OCC)C>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:14])/[C:10](=[N:15]\[OH:16])/[CH2:11][CH2:12][CH3:13])=[CH:7][CH:8]=1
Reactant: CCCCC(=O)c1ccc(Br)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCC/C(=N/O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.1 %

Procedure:
The conc. HCl (40 mL) was added dropwise to a solution of 1-(4-bromophenyl)pentan-1-one (4.68 g, 19.41 mmol) and sodium nitrite (4.02 g, 58.2 mmol) in THF (80 ml) at 0° C. and allowed to warm to room temperature and stirred 18 hours. The reaction mixture was diluted with diethyl ether and the organic phase washed with sat'd NaHCO3 and brine. Concentration gave (Z)-1-(4-bromophenyl)-2-(hydroxyimino)pentan-1-one 3.1 g (33%) as an oil which was used without further purification.). RT=2.1 min, (Condition 1) LCMS: Anal. Calcd. for C11H12BrN1O2 270.01; found: 270.15 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@@:16]3(C)[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([O-:7])=[O:6].[Na+].[Na+].[Cl-]>C(O)C(N)(CO)CO.Cl>[CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:29])[C@@H:13]([OH:28])[CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23]([OH:25])[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]
Reactant: C[C@H](CCC(=O)[O-])[C@H]1CC[C@H]2[C@]3(C)CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: [Cl-]
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3C[C@H](O)[C@]12C
Reaction time: 3 h

Procedure:
A pellet containing recombinant prothrombin immobilized on Ca3 (PO4)2 was obtained from a prothrombin-containing cell culture, as described above. Five 0.6 gram samples of moist adsorbate were suspended in 3 ml of 20 mM Tris-HCl buffer (pH 8.3) containing 50 mM, 100 mM, 250 mM, 350 mM or 500 mM sodium deoxycholate. Sixty microliter aliquots of 0.76 mg/ml trypsin were added to each sample, and the mixtures were incubated for three hours at room temperature with shaking. After incubation, the buffers of the samples were changed against 0.9% NaCl.
Reaction SMILES: CON(C)[C:4](=[O:26])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[CH3:28][Mg]Cl>C1COCC1>[O:26]=[C:4]([CH3:28])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:25])[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CON(C)C(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(=O)CCCCCCCCCCNC(=O)OCc1ccccc1
Reaction time: 6 h
Yield: 79.6 %

Procedure:
To a solution of 20 (1.11 g, 2.94 mmol) in THF (anhydrous, 10 mL) and cooled in an ice bath was added dropwise MeMgCl (3 M solution in diethyl ether, 3.92 mL, 11.75 mmol) over 10 min, and stirring continued at 0° C. for 6 h. The reaction was quenched by the slow addition of methanol (10 mL), and then concentrated under vacuum. The residue was chromatographed (silica gel, a gradient of 0:100 to 18:82 ethyl acetate/hexanes) to afford the desired product 21 (0.78 g, 80% yield) as a white solid: 1H NMR (300 MHz, CDCl3) δ 1.26 (m, 12H), 1.49-1.57 (m, 4H), 2.13 (s, 3H), 2.41 (m, 2H), 3.19 (m, 5H), 5.09 (s, 2H), 7.34 (m, 5H); m/z (ESI) 334 [M+H]+.