Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:6]2[S:14][C:15]([C:24]([O-])=[O:25])=[C:16]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:5]=2[CH:4]=[CH:3]1.[NH4+].C(N1C=CN=C1)([N:30]1C=CN=C1)=O.[OH-].[NH4+]>CN(C=O)C>[O:1]=[C:2]1[N:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:6]2[S:14][C:15]([C:24]([NH2:30])=[O:25])=[C:16]([NH:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:5]=2[CH:4]=[CH:3]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C([O-])c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: NC(=O)c1sc2c(ccc(=O)n2-c2ccccc2)c1Nc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 33.4 %

Procedure:
To a suspension of the compound of Example 14 (370 mg, 1.02 mmol) in anhydrous DMF (5 mL) was added 1,1′-carbonyldiimidazole (182 mg, 1.12 mmol) and the reaction stirred at r.t. under nitrogen for 20mins. Ammonium hydroxide (2 mL of 28% NH3 in water) was added and the reaction stirred for 72 h. Solvents were removed in vacuo and the crude residue purified by chromatography on silica (0-15% THF in DCM) to give the title compound as a white solid (123 mg). δH (DMSO-d6) 8.74 (1H, s), 7.67-7.34 (3H, m), 7.33-7.27 (2H, m), 7.22-7.00 (5H, m), 6.82-6.71 (3H, m), 6.21 (1H, d, J 9.7 Hz). LCMS (ES+) RT 3.04 minutes, 362 (M+H)+.
Reaction SMILES: [O:1]1[CH:6]([CH2:7][OH:8])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12.[F:12][C:13]([F:27])([C:17]([F:26])([F:25])[C:18]([F:24])([F:23])[C:19]([F:22])([F:21])[F:20])[C:14](O)=[O:15].CCN=C=NCCC[N+](C)(C)C.[I-].CNC1C=NC=CC=1NC>ClCCl>[O:1]1[CH:6]([CH2:7][O:8][C:14](=[O:15])[C:13]([F:12])([F:27])[C:17]([F:25])([F:26])[C:18]([F:23])([F:24])[C:19]([F:22])([F:21])[F:20])[CH2:5][O:4][C:3]2=[CH:9][S:10][CH:11]=[C:2]12
Reactant: OCC1COc2cscc2O1
Reactant: O=C(O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: CCN=C=NCCC[N+](C)(C)C
Agent: CNc1ccncc1NC
Agent: [I-]
Solvent: ClCCl
Product: O=C(OCC1COc2cscc2O1)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of (2,3-Dihydro-thieno[3,4-b][1,4]dioxin-2-yl)-methanol (“hydroxymethyl EDOT”, 1.20 g, 6.97 mmol) in dichloromethane (30 mL) was chilled to 0° C. under argon. Neat 2,2,3,3,4,4,5,5,5-nonafluoropentanoic acid (1.93 g, 7.35 mmol) was added by pipette. Quickly 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide methiodide (2.30 g, 7.80 mmol) and 3,4-dimethylaminopyridine (0.1 g, 0.82 mmol) were added and the solution was allowed to come to room temperature overnight. The solvent was evaporated at <30° C. and the residue purified by repeated column chromatography on silica gel using a gradient elution starting with 3:1 hexane/dichloromethane and ending with 1:1 hexane/dichloromethane. The product (2.10 g, 5.02 mmol) was a colorless oil that solidifies at −20° C. (Formula (4), left-hand side). Overall product yield was 53%.
Reaction SMILES: C[N:2]1[CH2:7][CH:6]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:3]1.C(N(C(C)C)CC)(C)C.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])O.[Na+]>C1C=CC=CC=1>[CH2:26]([O:25][C:23]([N:2]1[CH2:3][CH:4]=[C:5]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:7]1)=[O:24])[CH3:27]
Reactant: CCOC(=O)C1=CCN(C)CC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccccc1
Product: CCOC(=O)C1=CCN(C(=O)OCC)CC1
Temperature: 25 °C
Reaction time: 1.17 h
Yield: 71.4 %

Procedure:
In 640 ml of benzene, 108.9 g of ethyl 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylate and 41.6 g of diisopropylethylamine were dissolved, and subsequently, 279.1 g of ethyl chloroformate was added dropwise thereto over 70 minutes. The reaction mixture was heated under reflux for 30 minutes, followed by cooling the reaction mixture to room temperature. A saturated aqueous solution of sodium hydrogencarbonate was poured thereinto. After the reaction mixture was extracted with ethyl acetate, the extract was washed with saturated brine and was then dried over anhydrous sodium sulfate. The desiccant was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane-ethyl acetate=7:1) to yield 104.4 g of ethyl 1-ethoxycarbonyl-1,2,3,6-tetrahydropyridine-4-carboxylate as an oil.
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=[O:7].S(Cl)([Cl:14])=O>>[C:6]([O:8][Cl:14])(=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)CCCCC(=O)[O-]
Reactant: O=S(Cl)Cl
Product: COC(=O)CCCCC(=O)OCl

Procedure:
Chloro methyl adipate was prepared from mono-methyl adipate (10 g, 62.4 mmol) by refluxing with thionyl chloride (20 mL) for 2 h. Distillation gave the acid chloride (bp 80° C., 0.35 mm Hg, 7.4 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:11]=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1.[I:12]N1C(=O)CCC1=O.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[C:11]([I:12])=[CH:10][NH:9][N:8]=2)[S:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Clc1csc(-c2cc[nH]n2)c1
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CN(C)C=O
Product: Clc1csc(-c2n[nH]cc2I)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.2 %

Procedure:
3-(4-chloro-2-thienyl)-1H-pyrazole (24.0 mmol) was dissolved in 50 mL N,N-dimethylformamide under argon atmosphere. N-Iodosuccinimide (25.1 mmol) was added in small portions. The reaction mixture was stirred at room temperature overnight. 5% aqueous sodium thiosulfate solution and saturated aqueous sodium carbonate solution were added and the mixture was stirred at room temperature for 1 h. The white precipitate was filtered, washed thoroughly with water and dried in vacuum to afford 6.80 g of 3-(4-chloro-2-thienyl)-4-iodo-1H-pyrazole (91% yield) that was used without further purification.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([OH:14])=O)[CH2:9][NH:8][C:7]=2[CH:15]=1)#[N:2].[NH2:16][C:17]1[CH:22]=[C:21]([O:23][C:24]([O:26][CH3:27])=[O:25])[C:20]([CH:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)=[CH:19][C:18]=1[CH:33]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35][CH2:34]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.N1C=CC=CC=1>ClCCl>[C:42]([O:41][C:39]([N:36]1[CH2:37][CH2:38][CH:33]([C:18]2[CH:19]=[C:20]([CH:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)[C:21]([O:23][C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:17]=2[NH:16][C:12]([CH:10]2[CH2:9][NH:8][C:7]3[CH:15]=[C:3]([C:1]#[N:2])[CH:4]=[CH:5][C:6]=3[O:11]2)=[O:14])[CH2:34][CH2:35]1)=[O:40])([CH3:45])([CH3:44])[CH3:43]
Reactant: COC(=O)Oc1cc(N)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Reactant: N#Cc1ccc2c(c1)NCC(C(=O)O)O2
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)Oc1cc(NC(=O)C2CNc3cc(C#N)ccc3O2)c(C2CCN(C(=O)OC(C)(C)C)CC2)cc1C1CCCC1
Yield: 76.5 %

Procedure:
6-Cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carboxylic acid (146 mg, 0.72 mmol), tert-butyl 4-(2-amino-5-cyclopentyl-4-methoxycarbonyloxy-phenyl)piperidine-1-carboxylate (300 mg, 0.72 mmol), T3P (570 mg, 533 μL of 50% w/w solution, 1.79 mmol) were dissolved in pyridine (142 mg, 145 μL, 1.79 mmol) and dichloromethane (10 mL) and stirred for 30 min at room temperature. Purification by silica gel chromatography (10-75% ethyl acetate/hexanes) provided tert-butyl-4-[2-[(6-cyano-3,4-dihydro-2H-1,4-benzoxazine-2-carbonyl)amino]-5-cyclopentyl-4-methoxycarbonyloxy-phenyl]piperidine-1-carboxylate (333 mg, 77% yield). LC/MS m/z 605.6 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([O:25]C)=[O:24])=[CH:15]2.[OH-].[Na+]>CO.O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[NH:17][C:16]([CH2:21][CH:22]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:23]([OH:25])=[O:24])=[CH:15]2
Reactant: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCCC(Cc1cc2cc(OCCCNc3ccccn3)ccc2[nH]1)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 891.9 %

Procedure:
To a solution of methyl 2-({5-[3-(2-pyridylamino)propoxy]indolyl}methyl)octanoate (0.04 g, 0.09 mmol), as prepared in the preceding step, in methanol (5.0 mL) was added a solution of NaOH (0.1 g, 2.5 mmol) in H2O (0.3 mL), and the reaction was stirred at ambient temperature overnight. After evaporating the solvent in vacuo, the residue is taken up in H12O (5 mL) and acidified to pH 4–5 with 10% HCl, and extracted with ethyl acetate (2×15 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified by flash chromatography on silica gel (4% methanol in methylene chloride) to give the title compound as an oil (0.34 g, 90%). 1H-NMR (400 MHz, CDCl3) δ 7.72 (m, 1H), 7.48 (m, 1H), 7.26 (d, 8.9 Hz, 1H), 7.02 (d, J=2.7 Hz, 2H), 6.77 (dd, J=8.9, 2.4 Hz, 1H), 6.50 (m, 2H), 6.28 (d, J=2.9 Hz, 1H), 4.27 (dd, J=14.2, 8.6 Hz, 1H), 3.99 (m, 3H), 3.32 (t, J=6.7 Hz, 2H), 2.85 (br s, 1H), 1.95 (m, 2H), 1.67 (m, 1H), 1.30 (m, 9H), 0.84 (t, J=6.6 Hz, 3H). Mass spectrum (LCMS, ESI pos.) Calcd. for C25H33N3O3 424.2 (M+H); Found: 424.7.
Reaction SMILES: Br[C:2]1[CH2:6][CH2:5][C:4](=[O:7])[C:3]=1[CH3:8].[N:9]1[CH:14]=[CH:13][CH:12]=[C:11](B(O)O)[CH:10]=1>>[CH3:8][C:3]1[C:4](=[O:7])[CH2:5][CH2:6][C:2]=1[C:11]1[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=1
Reactant: OB(O)c1cccnc1
Reactant: CC1=C(Br)CCC1=O
Product: CC1=C(c2cccnc2)CCC1=O
Yield: 31 %

Procedure:
Synthesized from 3-bromo-2-methylcyclopent-2-enone and 3-pyridine boronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 100% ethyl acetate/hexanes) and further recrystallization yielded the product (38 mg, 31%) as a brown oil. 1H NMR (CDCl3, 300 MHz): δ 8.78 (s, 1H), 8.63 (br d, J=3.6 Hz, 1H), 7.82 (dt, J=8.1, 2.1 Hz, 1H), 7.40 (dd, J=8.1, 4.8 Hz, 1H), 2.91-2.96 (m, 2H), 2.56-2.59 (m, 2H), 1.98 (t, J=2.1 Hz, 3H). 13C NMR (CDCl3, 75 MHz): δ 208.8, 162.5, 150.1, 148.3, 137.9, 134.5, 129.1, 123.4, 33.9, 29.0, 9.9. LCMS (ESI): mass calcd for (C11H11NO) m/z 173.08; measured [M+H]+: m/z 174.07.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:6]1)=[O:4].CN(C)C=O.Cl.Cl.[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)[C:35]#[N:36].F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>>[C:35]([C:34]1[CH:37]=[CH:38][C:39]([N:40]2[CH2:45][CH2:44][N:43]([C:11]([C@H:10]3[CH2:9][CH2:8][N:7]([C:14]([O:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])[CH2:6][C@@H:5]3[C:3]([O:2][CH3:1])=[O:4])=[O:13])[CH2:42][CH2:41]2)=[C:32]([CH3:31])[CH:33]=1)#[N:36]
Reactant: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)O
Reactant: Cc1cc(C#N)ccc1N1CCNCC1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1CN(C(=O)OCc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccc(C#N)cc2C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture of (3R,4S)-piperidine-1,3,4-tricarboxylic acid 1-benzyl ester 3-methyl ester (0.554 g, 0.00172 mol) in N,N-dimethylformamide (8.500 mL, 0.1098 mol) was added 3-methyl-4-piperazin-1-ylbenzonitrile dihydrochloride (0.6146 g, 0.002241 mol), (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (1.017 g, 0.001896 mol), and, N,N-diisopropylethylamine (1.509 mL, 0.008620 mol). The reaction mixture was stirred overnight at room temp. Reaction quenched with KH2PO4 (sat solution). Layers separated and aq layer extracted with ethyl acetate 3×. Organic layers were washed with brine and dried over magnesium sulfate. Filtered and concentrated. The residue was purified by Combiflash with 40-70% EtOAc/Hex to give the product (75% in yield). MS (ESI): (M+H)+=505.
Reaction SMILES: Cl[CH2:2][CH:3]([OH:24])[CH2:4][N:5]1[CH2:23][CH2:22][N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1.C(=O)([O-])[O-].[Na+].[Na+].[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>[I-].[Na+].CC(C)CC(=O)C>[OH:24][CH:3]([CH2:2][N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)[CH2:4][N:5]1[CH2:23][CH2:22][N:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH:7]2[CH2:6]1
Reactant: OC(CCl)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: OC(CN1CCOCC1)CN1CCN2c3ccccc3Cc3ccccc3C2C1
Yield: 43.6 %

Procedure:
5 g of 2-(3-chloro-2-hydroxypropyl)-1,2,3,4,10,14b-hexahydrodibenzo [c,f]pyrazino [1,2-a]azepine (prepared as described in Example 41), 2.7 g of sodium carbonate, 0.014 g of sodium iodide and 0.254 g of morpholine were added to 10 ml of 4-methyl-2-pentanone, and the mixture was heated under reflux for 2 hours. At the end of this time, the reaction mixture was filtered, and then the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through silica gel, using ethyl acetate as the eluent, to afford 0.50 g (yield 87%) of the title compound as a colorless foam.
Reaction SMILES: [O:1]([C:8]1[CH2:13][CH2:12][CH2:11][C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:25](Cl)(=[O:34])[CH:26]=[CH:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>C1COCC1>[O:1]([C:8]1[CH2:13][CH2:12][CH:11]([C:25](=[O:34])[CH:26]=[CH:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:10](=[O:14])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1C=C(Oc2ccccc2)CCC1
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(C=Cc1ccccc1)C1CCC(Oc2ccccc2)=CC1=O
Reaction time: 0.25 h
Yield: 43.2 %

Procedure:
A solution of 3-phenoxy-cyclohex-2-enone (301 mg, 1.6 mmol) in 1 mL of THF was added to a stirred solution of 1.0 M solution of lithium bis(trimethylsilyl)amide in THF (3.2 mL) at −78° C. After 15 min, cinnamoyl chloride (266 mg, 1.6 mmol) was added all at once. After 15 min, the reaction mixture was poured into 0.5 N HCl and extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl solution, dried (MgSO4), filtered, and concentrated under reduced pressure. Chromatography of the residue with 4:1 hexanes/ethyl acetate as eluant provided 220 mg (43%) of 3-phenoxy-6-(3-phenyl-acryloyl)-cyclohex-2-enone as a yellow solid (220 mg, 43%): 1H NMR (CDCl3) (enol form) δ 2.66 (t, 2H, J=7.2 Hz), 2.84 (t, 2H, J=7.1 Hz), 5.11 (s, 1H), 6.86 (d, 1H, J=15.6 Hz), 7.02 (d, 2H, J=8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m, 3H). HRMS M+H+ calc: 319.1334, found 319.1340.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([O:15][CH3:16])([O:13][CH3:14])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[F:17][C:18]1[CH:23]=[CH:22][C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][C:19]=1[C:33]1[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=1>>[CH3:14][O:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([C:21]3[CH:22]=[CH:23][C:18]([F:17])=[C:19]([C:33]4[C:34]([C:39]#[N:40])=[CH:35][CH:36]=[CH:37][CH:38]=4)[CH:20]=3)=[CH:3][N:4]=[C:5]2[N:10]=1)([O:15][CH3:16])[CH3:12]
Reactant: COC(C)(OC)c1ccn2c(Br)cnc2n1
Reactant: CC1(C)OB(c2ccc(F)c(-c3ccccc3C#N)c2)OC1(C)C
Product: COC(C)(OC)c1ccn2c(-c3ccc(F)c(-c4ccccc4C#N)c3)cnc2n1
Yield: 100.2 %

Procedure:
3-Bromo-7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidine (860 mg, 3 mmol) was coupled with 2′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (1.45 g, 4.5 mmol) as described in Example 1 to give crude 5′-[7-(1,1-dimethoxyethyl)imidazo[1,2-α]pyrimidin-3-yl]-2′-fluorobiphenyl-2-carbonitrile (1.21 g).
Reaction SMILES: [C:1]([C:5]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:6]=1[C:7]1[C:8](=[O:18])[CH2:9][CH2:10][CH2:11][C:12]=1[NH:13]2)([O:3][CH3:4])=[O:2].Br[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH2:27][N:13]2[C:12]3[CH2:11][CH2:10][CH2:9][C:8](=[O:18])[C:7]=3[C:6]3[C:14]2=[CH:15][CH:16]=[CH:17][C:5]=3[C:1]([O:3][CH3:4])=[O:2])[CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)c1cccc2[nH]c3c(c12)C(=O)CCC3
Reactant: Cc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc2c1c1c(n2Cc2cccc(C)c2)CCCC1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
A suspension of 5-carbomethoxy-1,2-dihydro-9H-carbazol-4(3H)-one (870 mg, 3.58 mM), a-bromo-m-xylene (662 mg, 3.58 mM), and potassium carbonate (500 mg, 3.61 mM) in 20 mL DMF was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate, washed with H2O and saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated to afford 1.18 g (95%) of the 9-[(3-methylphenyl)methyl]-5-carbomethoxy-1,2-dihydrocarbazol-4(3H)-one as a dark oil. 1H NMR (DMSO-d6) δ7.65 (dd, 1H, J=1 and 8 Hz), 7.3-7.1 (m, 3H), 7.05 (d, 1H, J=8 Hz), 7.0 (s, 1H), 6.85 (d, 1H, J=8 Hz), 5.5 (s, 2H), 3.8 (s, 3H), 3.0 (m, 2H), 2.45 (m, 2H), 2.3 (s, 3H), and 2.1 (m, 2H). IR (CHCl3, cm−1) 3010, 2953, 1724, 1652, 1605, 1465, 1442, 1288, 1174, and 1119. MS (ES) m/e 348.5.
Reaction SMILES: [C:1]([O:8]CC)(=O)[C:2]([O:4]CC)=O.[Cl:11][C:12]1[C:13]([NH2:20])=[C:14]([NH2:19])[CH:15]=[C:16]([Cl:18])[CH:17]=1>>[Cl:11][C:12]1[CH:17]=[C:16]([Cl:18])[CH:15]=[C:14]2[C:13]=1[NH:20][C:2](=[O:4])[C:1](=[O:8])[NH:19]2
Reactant: Nc1cc(Cl)cc(Cl)c1N
Reactant: CCOC(=O)C(=O)OCC
Product: O=c1[nH]c2cc(Cl)cc(Cl)c2[nH]c1=O
Temperature: 25 °C

Procedure:
The title compound (Leeson, P. D. et al., J. Med. Chem 34:1243 (1991)) was prepared using an adaptation of the method of Cheeseman. (Cheeseman, G. W. H. J. Chem. Soc. 1171 (1962)). A mixture of diethyl oxalate (4.12 g, 28.2 mmol) and 3,5-dichloro-1,2-diaminobenzene (500 mg, 2.82 mmol) was heated to reflux under N2 for 6 h. The reaction was allowed to cool to room temperature and the pale yellow shiny solid collected by vacuum filtration and rinsed with EtOH (20 mL) and air dried to give 286 mg (44%). mp 326°-328° C. (dec) Lit 337°-340° C.). 1H NMR (d6 -DMSO) δ7.05 (d, 1H, J=1.8, H-8), 7.32 (d, 1H, J=1.8, H-6), 11.5 (br s, 1H, NH), 12.1 (br s, 1H, NH). EIMS m/e 234 (M+4, 12), 232 (M+2, 67), 230 (M+, bp), 204 (52), 202 (77), 141 (19), 142 (59) EIHRMS calc. for C8H4Cl2N2O2 229.9650, found 229.9646.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[N+:10]([C:13]1[CH:20]=[CH:19][CH:18]=[C:17]([N+]([O-])=O)[C:14]=1[C:15]#[N:16])([O-:12])=[O:11].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[CH:1]1([O:7][C:17]2[CH:18]=[CH:19][CH:20]=[C:13]([N+:10]([O-:12])=[O:11])[C:14]=2[C:15]#[N:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Reactant: OC1CCCCC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(OC2CCCCC2)cccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
To a solution of cyclohexanol (46.8 grams, 0.467 mol) in anhydrous THF (1 L) was added sodium hydride (20.3 grams, 0.508 mol) at −40° C. under nitrogen. The reaction mixture was allowed to warm slowly to room temperature and stir for another 1 hour. It was then cooled down to −55° C. and 2,6-dinitrobenzonitrile (78.4 g, 0.406 mol) was added. The reaction was stirred at room temperature overnight, then cooled down to −20° C., and citric acid (23.4 grams, 0.122 mol) was added. The mixture was then poured into ice water (5 L) which contained citric acid (7.8 g, 0.041 mol), stirred for 15 minutes, and the precipitated product was collected by filtration. The crude product was recrystallized from isopropanol (750 mL, heated to boiling, then cooled down to 0° C.), filtered, washed with isopropanol (300 mL), then air dried to give 84.4 g yellow solid. The solid was dissolved in dichloromethane (169 mL) and filtered through a plug of alumina to give the title compound as a pale yellow solid (83.2 g, 83.2%). 1H NR (400 MHz, DMSO-d6) δ 1.4 (m, 4H), 1.6 (m, 2H), 1.7 (m, 2H), 1.9 (m, 2H), 4.75 (m, 1H), 7.79 (dd, J=2.0, 8.0 Hz, 1H), 7.84-7.91 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11](OCC)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8].[NH2:17][C:18]1[N:22]=[CH:21][NH:20][N:19]=1.BrC1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[C:3]([OH:16])=[C:4]([C:11]([NH:17][C:18]2[N:22]=[CH:21][NH:20][N:19]=2)=[O:12])[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[CH3:8]
Reactant: Nc1nc[nH]n1
Reactant: CCOC(=O)c1c(O)c(Cl)c(C)n(C)c1=O
Solvent: Brc1ccccc1
Solvent: CCCCCC
Product: Cc1c(Cl)c(O)c(C(=O)Nc2nc[nH]n2)c(=O)n1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.9 %

Procedure:
161 mg of ethyl 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxylate and 51 mg of 3-amino-1,2,4-triazole were added to 1.5 ml of bromobenzene, then, the mixture was stirred for 5 hours under heat refluxing condition. The reaction mixture was cooled to room temperature, then, hexane was added to this and the resultant mixture was allowed to stand still. The resulting solid was collected by filtration, and washed with a mixture of t-butyl methyl ether and n-hexane and dried to obtain 153 mg of 5-chloro-1,6-dimethyl-4-hydroxy-2-oxo-N-(1,2,4-triazol-3-yl)-1,2-dihydropyridine-3-carboxamide (hereinafter, referred to as present compound 29) represented by the formula:
Reaction SMILES: [CH2:1]([O:8][C:9]([O:11]N1C(=O)CCC1=O)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][NH:20][CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1.C(N(CC)CC)C>CN(C=O)C>[CH2:1]([O:8][C:9]([N:20]([CH2:21][C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH:23]=1)[CH3:19])=[O:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: CNCc1c[nH]c2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(Cc1c[nH]c2ccccc12)C(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 73.2 %

Procedure:
N-(Benzyloxycarbonyloxy)succinimide (8.9 g, 35.7 mmole) was added to a solution of 3-(methylaminomethyl)-1H-indole (5.2 g, 32.5 mmole), from Preparation 16, and triethylamine (5.0 mL, 65.7 mmole) in DMF (100 mL) at RT. The reaction was stirred overnight then was concentrated in vacuo. The residue was diluted with water and the mixture was extracted with ethyl acetate. The combined extracts were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (33% ethyl acetate/hexanes) gave the title compound (7.0 g, 74%) as an off-white solid: MS (ES) m/e 295 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:23]=[CH:22][C:6]([CH2:7][N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11](=[O:18])[C:10]([C:19]([OH:21])=O)=[CH:9]2)=[CH:5][CH:4]=1.Cl.[CH3:25][NH:26][O:27][CH3:28].C(N(CC)CC)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(#N)C>[CH3:28][O:27][N:26]([CH3:25])[C:19]([C:10]1[C:11](=[O:18])[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:8]([CH2:7][C:6]2[CH:22]=[CH:23][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH:9]=1)=[O:21]
Reactant: COc1ccc(Cn2cc(C(=O)O)c(=O)c3ccccc32)cc1
Reactant: CNOC
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2cc(C(=O)N(C)OC)c(=O)c3ccccc32)cc1

Procedure:
Experimental conditions analogous to those described for Step 5 of Example 60, from crude 1-(4-Methoxy-benzyl)-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid, 1.03 g (10.6 mmol) of N,O-dimethylhydroxylamine hydrochloride, 6.1 mL (4.43 g, 43.8 mmol) of triethylamine and 6.3 mL (6.80 g, 10.7 mmol) of 50% 1-propanephosphonic acid cyclic anhydride in 30 mL acetonitrile to give 1.90 g of the product as an off-white solid.