Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH2:28].[CH3:29][O:30][C:31](=[O:37])[CH:32]([CH3:36])[C:33](O)=[O:34].CCN(CC)CC.[OH-].[Na+]>CCOC(C)=O>[I:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][CH2:27][NH:28][C:33](=[O:34])[CH:32]([CH3:36])[C:31]([O:30][CH3:29])=[O:37]
Reactant: NCCc1ccccc1I
Reactant: COC(=O)C(C)C(=O)O
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)C(C)C(=O)NCCc1ccccc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 78.5 %

Procedure:
A solution of T3P in AcOEt (50%, 26.2 mL, 44.0 mmol) was added dropwise at 0° C. under N2 to a clear solution of 2-(2-iodophenyl)ethanamine (9.45 g, 38.2 mmol), 3-methoxy-2-methyl-3-oxopropanoic acid (5.05 g, 38.2 mmol) and Et3N (10.7 mL, 76.0 mmol) in AcOEt (350 mL). The mixture was stirred at RT for 6 days. A 2N aqueous solution of NaOH (50 mL) was then added to the reaction and the mixture was extracted with AcOEt. The combined org. layers were then dried over Na2SO4, filtered and concentrated in vacuo. The yellow oil obtained was purified by flash chromatography (SiO2, cHEx/AcOEt 100:0 to 50:50) to afford the title compound (10.83 g) as a clear oil. UPLC-MS: MS 362.2 (M+H+); UPLC rt 0.95 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[S:37]1[CH:41]=[CH:40][CH:39]=[C:38]1[S:42](Cl)(=[O:44])=[O:43]>ClC(Cl)C>[C:1]([O:5][C:6](=[O:29])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[S:25][CH:26]=[CH:27][N:28]=3)=[CH:22][CH:23]=2)[S:42]([C:38]2[S:37][CH:41]=[CH:40][CH:39]=2)(=[O:44])=[O:43])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3nccs3)cc2)c1
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3nccs3)cc2)S(=O)(=O)c2cccs2)c1
Reaction time: 24 h
Yield: 53.1 %

Procedure:
To a solution of {3-[(4-thiazol-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester (87.3 mg, 0.213 mmol), prepared in Step A of Example 13i, triethylamine (47.3 mg, 0.234 mmol) and dichloroethane (10 mL) was added thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol). The reaction was stirred for 24 h and additional triethylamine (0.234 mmol) and thiophene-2-sulfonyl chloride (42.7 mg, 0.234 mmol) were added. The reaction was stirred for an additional 24 h. The organic solution was washed sequentially with 5.5% HCl, water, saturated sodium bicarbonate solution, and brine. The organic solution was dried (MgSO4), filtered, and concentrated. Flash chromatography (CHCl3:MeOH 99:1) provided the title compound of Step A (63 mg). MS 556 (M+1)
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)[NH2:2].C(O[CH:15]=[CH:16][C:17](=O)[C:18]([F:21])([F:20])[F:19])C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[OH-].[Na+]>CCO.C(Cl)(Cl)Cl>[F:19][C:18]([F:21])([F:20])[C:17]1[N:1]([C:3]2[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=2)[N:2]=[CH:15][CH:16]=1
Reactant: CCOC=CC(=O)C(F)(F)F
Reactant: NNc1ccc(C(=O)O)cc1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: O=C(O)c1ccc(-n2nccc2C(F)(F)F)cc1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
A mixture of 4-hydrazinobenzoic acid (0.501 g, 3.29 mmol) and 4ethoxy-1,1,1-trifluoro-3-buten-2-one (0.48 mL, 3.4 mmol) in EtOH (15 mL) was heated to 75° C. for 17 hours, allowed to cool to room temperature, and concentrated under reduced pressure to provide a solid. The obtained solid was suspended in CHCl3 (15 mL), treated with P2O5 (0.50 g, 3.5 mmol), and heated at 65° C. for 6 hours. After cooling to room temperature, the mixture was treated with 1N NaOH (5 mL) and stirred for 30 minutes. The mixture was quenched with 1N HCl (6 mL) and extracted with CH2Cl2 (3×8 mL). The extracts were combined, dried (Na2SO4), filtered, and the filtrate concentrated to provide the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.NC(N)=O.[C:13](=[O:18])([O:15][CH2:16][CH3:17])N.C(O)C>ClC1C=CC=CC=1>[CH2:16]([O:15][C:13](=[O:18])[NH:6][C:5]1[CH:7]=[CH:8][C:2]([Cl:1])=[CH:3][CH:4]=1)[CH3:17]
Reactant: Nc1ccc(Cl)cc1
Reactant: CCOC(N)=O
Agent: NC(N)=O
Solvent: CCO
Solvent: Clc1ccccc1
Product: CCOC(=O)Nc1ccc(Cl)cc1

Procedure:
Following the procedure described in Example 1, 638 g of 4-chloroaniline, 240 g of urea, 89 g of ethyl carbamate, 625 g of ethanol (approximately 96%) and 1400 g of chlorobenzene were reacted for 6.5 hours at 200° C. in the pressure apparatus described in Example 1. After the apparatus had been cooled and vented, the reaction mixture was removed. Excess ethanol was removed by fractional distillation at atmospheric pressure. The mixture (while being stirred) was then exposed to hydrogen chloride gas at room temperature, filtered and subjected to fractional distillation in vacuo. Chlorobenzene was separated off at 15 mbar. Subsequent distillation at 0.2 mbar yielded 785 g (78.6% of the theoretical yield) of N-(4-chlorophenyl)-carbamic acid ethyl ester melting at from 68° to 70° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][NH2:16].C(O)(=O)C>CCO>[CH3:15][NH:16][C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[CH:9][C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CN
Reactant: CCOC(=O)CC(=O)c1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C=C(NC)c1ccccc1
Reaction time: 15 h
Yield: 99.9 %

Procedure:
To a solution of ethyl benzoylacetate (30 g, 156 mmol) and methylamine (2 M in THF, 390 mL, 780 mmol) in EtOH (150 mL), was added acetic acid (44.7 mL, 780 mmol). The reaction mixture was heated to reflux with stirring for 15 hours. The reaction mixture was cooled, concentrated and partitioned between DCM and 1M HCl. The phases were separated and the organic layer dried over Na2SO4, filtered and concentrated to give the title compound (32 g), used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1.ClC1C=CC=C(C(OO)=[O:27])C=1.C(OCC)C>ClCCl>[CH3:1][C:2]1([CH3:18])[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=2[O-:27])[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[O:3]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC1(C)C=C(c2ccccn2)c2ccccc2O1
Solvent: ClCCl
Solvent: CCOCC
Product: CC1(C)C=C(c2cccc[n+]2[O-])c2ccccc2O1
Yield: 2 %

Procedure:
1.61 g of 2,2-dimethyl-4-(2-pyridyl)-2H-1-benzopyran were dissolved in 10 ml of dichloromethane at room temperature and 2.0 g of m-chloroperbenzoic acid were added. After 1 hour the mixture was washed with sodium bisulphite solution, sodium bicarbonate solution and water. The organic phase was dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel using ethyl acetate/ethanol/formic acid (40:4:1) for the elution. The product was obtained as an oil which solidified upon trituration with diethyl ether. Recrystallization from toluene gave 0.034 g of 2-(2,2-dimethyl-2H-1-benzopyran-4-yl)pyridine N-oxide of melting point 148°-150° C.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[OH:22])/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].N.Br[CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2[O:22][CH2:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2O)s1
Reactant: CC(C)(C)C(=O)CBr
Agent: N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)(C)C(=O)COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1

Procedure:
A mixture of (R,Z)-N-(5-tert-butyl-3-((tetrahydrofuran-2-yl)methyl)thiazol-2(3H)-ylidene)-2-hydroxy-5-(trifluoromethyl)benzamide (isolated as a byproduct from Example 62B; MS (DCI/NH3) m/z 429 (M+H)+) (330 mg, 0.77 mmol), 1-bromo-3,3-dimethylbutan-2-one (165 mg, 0.92 mmol) and potassium carbonate (106 mg, 0.77 mmol) in acetone (20 mL) was warmed to reflux for 36 hours and then concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The acetate layer was washed with brine, dried with MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, eluted with hexane-EtOAc: 2:1) to afford 255 mg of the title product. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.15-1.20 (m, 9 H), 1.32 (s, 9 H), 1.59-1.70 (m, 1 H), 1.74-2.00 (m, 3 H), 3.61-3.69 (m, 1 H), 3.71-3.84 (m, 1 H), 4.14-4.37 (m, 3 H), 5.30 (s, 2 H), 6.99 (d, J=8.7 Hz, 1 H), 7.26 (s, 1 H), 7.69 (dd, J=8.9, 2.2 Hz, 1 H), 7.97 (d, J=2.8 Hz, 1 H). MS (DCI/NH3) m/z 527 (M+H)+. Anal calculated for C26H33F3N2O4S: C, 59.30; H, 6.32; N, 5.32. Found: C, 59.27; H, 6.59; N, 5.34.
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:29](Cl)(=[O:33])[CH:30]([CH3:32])[CH3:31]>C1(C)C=CC=CC=1>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:29](=[O:33])[CH:30]([CH3:32])[CH3:31])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: CC(C)C(=O)Cl
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)C(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
(R)—N2-indan-1-yl-quinoline-2,6-diamine (0.05 g, 0.18 mmol), triethylamine (0.028 mL, 0.2 mmol) and isobutyryl chloride (0.021 mL, 0.2 mmol) were dissolved in toluene (2.0 mL).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH2:10])[C:5]=1[NH2:11])[CH3:2].CO[C:14]1C(OC)=C[C:17]2[NH:18][C:19](CCCNC)=N[C:16]=2[CH:15]=1>>[CH2:1]([O:3][C:4]1[C:5]2[N:11]=[C:14]([CH2:15][CH2:16][CH2:17][NH:18][CH3:19])[NH:10][C:6]=2[CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CNCCCc1nc2cc(OC)c(OC)cc2[nH]1
Reactant: CCOc1cccc(N)c1N
Product: CCOc1cccc2[nH]c(CCCNC)nc12

Procedure:
Prepared from 3-ethoxy-benzene-1,2-diamine in analogy to the methods described for [3-(5,6-dimethoxy-1H-benzoimidazol-2-yl)-propyl]-methyl-amine.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8](=[S:28])[NH:9][C:10]=2[C:11]2[C:20]([F:21])=[C:19]3[C:14]([CH:15]=[CH:16][C:17]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:18]3)=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.F[B-](F)(F)F.[Br:34][C:35]1[CH:40]=[CH:39][C:38]([N+]#N)=[CH:37][CH:36]=1.CS(C)=O>C(Cl)Cl>[Br:34][C:35]1[CH:40]=[CH:39][C:38]([S:28][C:8]2[N:4]3[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]3=[C:10]([C:11]3[C:20]([F:21])=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:22]5[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=5)=[N:18]4)=[CH:13][CH:12]=3)[N:9]=2)=[CH:37][CH:36]=1
Reactant: Nc1nccn2c(=S)[nH]c(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Reactant: N#[N+]c1ccc(Br)cc1
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CS(C)=O
Product: Nc1nccn2c(Sc3ccc(Br)cc3)nc(-c3ccc4ccc(-c5ccccc5)nc4c3F)c12
Reaction time: 0.5 h

Procedure:
Into a round bottom flask was added 8-amino-1-(8-fluoro-2-phenyl-quinolin-7-yl)-2H-imidazo[1,5-a]pyrazine-3-thione (21 mg, 0.000053 mol), 4-bromobenzenediazonium tetrafluoroborate (0.018 g, 0.000064 mol) and dimethyl sulfoxide (0.1 mL, 0.002 mol) and the reaction mixture was stirred in ice for 30 min. The reaction mixture was cooled, dissolved in DCM and washed with water. Purification by Gilson HPLC eluting with 10→90% acetonitrile: H2O afforded the title compound as a yellow solid. 1H NMR (400 MHz, CDCl3): δ=7.13-7.17 (m, 2H), 7.23 (d, J=5.05 Hz, 1H), 7.42 (d, J=8.59 Hz, 2H), 7.49-7.59 (m, 3H), 7.61 (d, J=5.05 Hz, 1H), 7.75-7.78 (m, 2H), 8.05 (d, J=8.59 Hz, 1H), 8.22-8.27 (m, 2H), 8.32 (dd, J=8.72, 1.39 Hz, 1H). MS (ES+): m/z 544.15 (100)[MH+]. HPLC: tR=2.69 min (Open Lynx polar—5 min).
Reaction SMILES: [C:1]([OH:5])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17](Cl)=[O:18])=[CH:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:18])=[CH:15][CH:14]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(Br)cc1
Reaction time: 48 h
Yield: 77.6 %

Procedure:
To a mixture of 5.5 g of dry tert.-butanol and 7.08 g of dry pyridine is added a solution of 9.79 g of 4-bromobenzoyl chloride in 20 ml of anhydrous methylene chloride. The mixture is stirred under nitrogen for 2 days. The reaction mixture is then diluted with methylene chloride, and the organic solution extracted with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residual oil is distilled under reduced pressure to give 8.9 g (70%) of tert.-butyl 4-bromobenzoate as a colorless oil: b.p. 91°-92° C./1.2 mm; NMR (CDCl3, 80 MHz) delta 1.59 (s, 9H), 7.53 (d, 2H, J=8.7 Hz); IR (neat) 2970, 1710, 1585, 1475, 1390, 1290, 1160, 1110, 1070, 845 and 745 cm-1.
Reaction SMILES: Cl[C:2]1[N:22]=[C:5]2[C:6]([C:10]3[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=3[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH2:41])=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:36][CH2:35][C:34]2[CH:37]=[CH:38][C:39]([NH:41][C:2]3[N:22]=[C:5]4[C:6]([C:10]5[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=5[O:20][CH3:21])=[CH:7][CH:8]=[CH:9][N:4]4[N:3]=3)=[CH:40][C:33]=2[CH2:32][CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2CC1
Reactant: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Cl)nc12
Product: COc1ccc(C(F)(F)F)cc1-c1cccn2nc(Nc3ccc4c(c3)CCN(C(=O)OC(C)(C)C)CC4)nc12

Procedure:
2-Chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine was prepared from 8-bromo-2-chloro-[1,2,4]triazolo[1,5-a]pyridine (0.500 g, 2.15 mmol) and 2-methoxy-5-trifluoromethylbenzeneboronic acid (0.710 g, 3.23 mmol) in a manner analogous to Example 311a to give product (0.636 g, 90%). MS=328 (MH)+. 315b) 7-[8-(2-Methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamino]-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester was prepared from 2-chloro-8-(2-methoxy-5-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridine (0.630 g, 1.92 mmol) and 7-amino-1,2,4,5-tetrahydro-3-benzazepine-3-carboxylic acid tert-butyl ester (0.605 g, 2.31 mmol) in a manner analogous to Example 311b to give product (0.750 g, 71%). 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.56 (s, 1H), 8.79 (d, 1H), 7.95 (s, 1H), 7.82 (d, 1H), 7.65 (d, 1H), 7.42 (m, 3H), 7.05 (m, 2H), 3.85 (s, 3H), 3.42 (m, 4H), 2.75 (m, 4H), 1.41 (s, 9H): MS=554 (MH)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1.CO[C:20]1[CH:21]=C([C@@H]2C[C@H]2CNC(=O)CCC)C=C[CH:25]=1.B(Br)(Br)Br>ClCCl>[CH2:21]([O:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[CH2:10][C@H:9]2[CH2:11][NH:12][C:13](=[O:17])[CH2:14][CH2:15][CH3:16])[CH:5]=[CH:6][CH:7]=1)[CH:20]=[CH2:25]
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(O)c1
Reactant: CCCC(=O)NC[C@@H]1C[C@H]1c1cccc(OC)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: C=CCOc1cccc([C@@H]2C[C@H]2CNC(=O)CCC)c1
Reaction time: 18 h
Yield: 75 %

Procedure:
(trans)-N-[[2-(3-Hydroxyphenyl)cyclopropyl]methyl]butanamide: To a stirred solution of (trans)-N-[[2-(3-methoxyphenyl)cyclopropyl]methyl]butanamide (3.50 g, 14.2 mmol) in dichloromethane (50 mL) at -78° C. was added BBr3 (28.4 mL, 1N in CH2Cl2, 28.4 mmol) dropwise. After addition was complete, the cooling bath was removed and stirring was continued for 18 h. The solution was poured over ice/H2O(100 mL) and extracted with 2.5 N NaOH. The basic extracts were combined, washed with dichloromethane, and acidified (conc. HCl). The acidic solution was extracted with dichloromethane, the organics were combined, washed with brine, dried (MgSO4), and concentrated to afford 2.49 g (75%) of the title compound: 1H NMR (300 MHz, DMSO-d6) δ 0.72-0.84 (m, 5H), 1.09-1.15 (m, 1H), 1.42-1.54 (m, 2H), 1.63-1.69 (m, 1H), 2.02 (t, J=5.0 Hz, 2H), 2.99-3.11 (m, 2H), 6.39-6.50 (m, 3H), 6.98 (t, J=7.8 Hz, 1H), 7.91 (s, 1H), 9.19 (br s, 1H); IR (NaCl Film) 3300, 2964, 1642, 1585, 1542, 1466 cm-1 ; MS (isobutane-DCI) m/e 233; Analysis calc'd for C14H19NO2.0.1 H2O: C, 71.52; H, 8.23; N, 5.96; found: C, 71.53; H, 8.32; N, 5.92.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])[NH:22][N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19].C(N1N=C(C2C=CC(OC)=C(OC)C=2)[C@H]2[C@H](CCCC2)C1=O)C1C=CC=CC=1>>[CH3:10][O:11][C:12]1[CH:13]=[C:14]([C:20]2[C@H:29]3[C@H:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)[C:23](=[O:30])[N:22]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=3)[N:21]=2)[CH:15]=[CH:16][C:17]=1[O:18][CH3:19]
Reactant: BrCCc1ccccc1
Reactant: COc1ccc(C2=NNC(=O)[C@H]3CCCC[C@@H]23)cc1OC
Agent: COc1ccc(C2=NN(Cc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC
Product: COc1ccc(C2=NN(CCc3ccccc3)C(=O)[C@H]3CCCC[C@@H]23)cc1OC

Procedure:
Prepared from 2-bromoethylbenzene and compound 1 as described for compound 78. Purified by chromatography [ethyl acetate: petroleum ether (60°-80° C.)/1:3]. Crystallized from methanol. M.p. 99°-100° C.
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:21]=[CH:22][N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[CH3:25])([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CON(C)[C:42](=[O:44])[CH3:43].[Cl-].[NH4+]>C1COCC1>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([C:42](=[O:44])[CH3:43])[N:23]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:32])([CH3:31])[CH3:33])[C:24]=1[CH3:25])([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)ncn1COCC[Si](C)(C)C
Reactant: CON(C)C(C)=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(=O)c1nc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(C)n1COCC[Si](C)(C)C
Temperature: -78 °C
Reaction time: 2 h

Procedure:
4-(tert-Butyldiphenylsilyloxymethyl)-5-methyl-1-(2-trimethylsilylethoxymethyl)-1H-imidazole (24.6 g) was dissolved in THF (300 mL), and cooled to −78° C. while stirring under an argon atmosphere. To the present solution was added dropwise n-butyl lithium (2.66 M hexane solution, 28.9 mL) slowly using a syringe, followed by stirring at the same temperature for 30 minutes. Then, N-methoxy-N-methylacetamide (10.5 mL) was added using a syringe, and stirring was continued for 2 hours while the temperature was raised to room temperature. A saturated aqueous ammonium chloride solution was added to the reaction solution to terminate the reaction, followed by extraction with ethyl acetate. The combined extract was washed with saturated brine, dried over anhydrous sodium sulfate, and subsequently the solvent was distilled off under reduced pressure. The resulting residue was purified by flash chromatography (ethyl acetate/hexane=0%→50%) using silica gel column (product name: Hi-Flash Column 5 L, manufactured by Yamazen Corporation) to afford the title compound (11.7 g).
Reaction SMILES: [Br:1]Br.[CH3:3][O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:6]=1[C:7]([OH:9])=[O:8]>C(Cl)(Cl)Cl.O1CCOCC1>[Br:1][C:13]1[C:5]([O:4][CH3:3])=[C:6]([C:10]([O:14][CH3:15])=[CH:11][CH:12]=1)[C:7]([OH:9])=[O:8]
Reactant: BrBr
Reactant: COc1cccc(OC)c1C(=O)O
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: COc1ccc(Br)c(OC)c1C(=O)O
Reaction time: 8 h

Procedure:
A solution of 15 ml of bromine (0.3 mol) in 50 ml of chloroform is added dropwise while stirring and cooling in ice to 54.9 g (0.3 mol) of 2,6-dimethoxybenzoic acid in 150 ml of dioxan. The solution is left at room temperature overnight. The solvent is evaporated and the residue recrystallized from aqueous ethanol. Yield: 59.3 g, m.p. 144°-45° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.[F:13][C:14]1[CH:15]=[C:16]2[C:21](=[CH:22][C:23]=1[F:24])[N:20]=[N:19][C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[C:17]2[OH:30]>CN(C=O)C>[CH:8]1([N:20]2[C:21]3[C:16](=[CH:15][C:14]([F:13])=[C:23]([F:24])[CH:22]=3)[C:17](=[O:30])[C:18]([C:25]([O:27][CH2:28][CH3:29])=[O:26])=[N:19]2)[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: IC1CCCC1
Reactant: CCOC(=O)c1nnc2cc(F)c(F)cc2c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C2CCCC2)c2cc(F)c(F)cc2c1=O
Temperature: 80 °C
Reaction time: 0.67 h

Procedure:
Potassium carbonate and iodocyclopentane were added to a DMF solution of ethyl 6,7-difluoro-4-hydroxycinnoline-3-carboxylate, for stirring at 80° C. for 40 minutes, to obtain ethyl 1-cyclopentyl-6,7-difluoro-4-oxo-1,4-dihydrocinnoline-3-carboxylate.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:28][O:29][C:30]1[CH:31]=[C:32]([NH:42][C:43]([NH2:45])=[NH:44])[CH:33]=[CH:34][C:35]=1[N:36]1[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]1>>[Cl:18][C:13]1[CH:12]=[C:11]([CH:8]2[C:9]3[N:45]=[C:43]([NH:42][C:32]4[CH:33]=[CH:34][C:35]([N:36]5[CH:40]=[C:39]([CH3:41])[N:38]=[CH:37]5)=[C:30]([O:29][CH3:28])[CH:31]=4)[N:44]=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)[CH:16]=[CH:15][C:14]=1[Cl:17]
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(c2ccc(Cl)c(Cl)c2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(Cl)c(Cl)c2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(3,4-dichloro-phenyl)-cyclohexanone (119 mg, 0.40 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (148 mg, 0.40 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (92 mg, 48%). MS ISP (m/e): 480.0 [(M+H)+]. mp 167-169° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[C:9]2[CH2:14]Cl)=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:3]=1.[CH3:24][NH:25][CH3:26]>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[N:11][N:10]=[C:9]2[CH2:14][N:25]([CH3:26])[CH3:24])=[C:4]([C:16]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[O:17])[CH:3]=1
Reactant: CNC
Reactant: Cc1nnc(CCl)n1-c1ccc(Br)cc1C(=O)c1ccccn1
Solvent: CCO
Product: Cc1nnc(CN(C)C)n1-c1ccc(Br)cc1C(=O)c1ccccn1

Procedure:
A mixture of 0.25 g of 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-chloromethyl-5-methyl-4H-1,2,4-triazole, 10 ml. of ethanol and 0.5 ml. of dimethylamine is refluxed for 1.5 hours. After evaporation of the solvent, the residue is diluted with water and extracted with chloroform. The chloroform extract is washed with water, dried over sodium sulfate, followed by evaporation of the solvent to give 4-[4-bromo-2-(2-pyridinecarbonyl)phenyl]-3-dimethylaminomethyl-5-methyl-4H-1,2,4-triazole as colorless crystals. Recrystallization from a mixture of acetone and n-hexane gives colorless prisms, melting at 127° to 128° C.