Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[C:3]=1[CH2:17]O.P(Br)(Br)[Br:20].O>C(OCC)C>[Br:20][CH2:17][C:3]1[C:4]([C:13]([F:16])([F:15])[F:14])=[N:5][N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:2]=1[F:1]
Reactant: OCc1c(C(F)(F)F)nn(-c2ccccc2)c1F
Reactant: BrP(Br)Br
Solvent: O
Solvent: CCOCC
Product: Fc1c(CBr)c(C(F)(F)F)nn1-c1ccccc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 253.5 %

Procedure:
A solution of 27.5 g (105.7 mmoles) of (5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazol-4-yl)-methanol dissolved in 300 ml of diethyl ether was cooled to 0° C. Thereto was added 10.0 g (37.0 mmoles) of phosphorus tribromide. The mixture was stirred at room temperature for 2 hours to give rise to a reaction. After the completion of the reaction, the reaction mixture was poured into water, followed by extraction with diethyl ether. The resulting organic layer was washed with an aqueous sodium chloride solution and then dried over anhydrous magnesium sulfate. The resulting solution was subjected to vacuum distillation to remove the solvent contained therein, to obtain 30.3 g (yield: 88.8%) of 4-bromomethyl-5-fluoro-1-phenyl-3-trifluoromethyl-1H-pyrazole.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1.C(Cl)Cl.[CH3:25][C:26]1[C:27]([Si:35]([CH3:43])([CH3:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:31]([CH3:34])=[CH:32][CH:33]=1)[CH2:29][OH:30]>C(OCC)C>[CH3:25][C:26]1[C:27]([Si:35]([CH3:43])([CH3:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[C:28]([C:31]([CH3:34])=[CH:32][CH:33]=1)[CH:29]=[O:30]
Reactant: Cc1ccc(C)c([Si](C)(C)c2ccccc2)c1CO
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Solvent: CCOCC
Product: Cc1ccc(C)c([Si](C)(C)c2ccccc2)c1C=O
Reaction time: 24 h

Procedure:
Pyridinium dichromate (9.24 g, 1.8 equivalents) was added to a methylene chloride solution of the benzyl alcohol product of step (q), above, at room temperature. The reaction was stirred for 24 hours, then diluted with diethyl ether and filtered. The filtrate was concentrated on a rotary evaporator and the residual oil was taken up in MTBE and washed with 2N hydrochloric acid, aqueous NaHCO3, brine, treated with charcoal, dried and concentrated on a rotary evaporator to give the product of this step as a pale yellow oil. The product was distilled under reduced pressure (~0.5 mm Hg) using a Kugelrohr apparatus to give 3.3 g of refined product as a clear oil.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[NH:12][C:13]([C:15]2[N:19]3[CH:20]=[CH:21][C:22]([CH2:24][CH:25]=O)=[CH:23][C:18]3=[N:17][CH:16]=2)=[O:14])[N:5]([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=2)[N:4]=1)C.[CH3:35][O:36][CH2:37][CH2:38][NH2:39]>>[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH2:25][CH2:24][C:22]1[CH:21]=[CH:20][N:19]2[C:15]([C:13]([NH:12][C:10]3[CH:9]=[CH:8][CH:7]=[C:6]4[C:11]=3[C:3]([CH3:1])=[N:4][N:5]4[CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[N:29]=3)=[O:14])=[CH:16][N:17]=[C:18]2[CH:23]=1
Reactant: CCc1nn(Cc2cccc(C)n2)c2cccc(NC(=O)c3cnc4cc(CC=O)ccn34)c12
Reactant: COCCN
Product: COCCNCCc1ccn2c(C(=O)Nc3cccc4c3c(C)nn4Cc3cccc(C)n3)cnc2c1

Procedure:
Prepared according to procedure for Example 72 from N-(3-ethyl-1-((6-methylpyridin-2-yl)methyl)-1H-indazol-4-yl)-7-(2-oxoethyl)imidazo[1,2-a]pyridine-3-carboxamide and 2-methoxyethanamine. MS (ES+APCI) m/z=498 (M+H) detected.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:12]([CH:17]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:14][CH2:15][CH3:16])=[O:13]>C1COCC1>[CH2:15]([O:14][C:12](=[O:13])/[CH:17]=[CH:4]/[C:3]1[CH:6]=[CH:7][C:8]([O:10][CH3:11])=[CH:9][C:2]=1[F:1])[CH3:16]
Reactant: COc1ccc(C=O)c(F)c1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1ccc(OC)cc1F
Reaction time: 1 h
Yield: 75.2 %

Procedure:
2-Fluoro-4-methoxy-benzaldehyde (1.24 g, 3.56 mmol) and carbethoxy methylene triphenylphosphorane (2.0 g, 5.78 mmol) were dissolved in THF (10 mL), and the mixture was stirred at 65˜75° C. for 1 hour. After the termination of the reaction, the reactant was cooled, concentrated under reduced pressure, and purified by column chromatography (eluent, EtOAc/Hex=1/10) to obtain the title compound (0.6 g, 83%).
Reaction SMILES: [C:1]1([C@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.Cl[C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]=[CH:22][N:21]=1>C(Cl)Cl>[C:1]1([C@H:7]([NH:9][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=3)[N:23]=[CH:22][N:21]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: C[C@@H](N)c1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2ccc([N+](=O)[O-])cc12)c1ccccc1
Reaction time: 48 h

Procedure:
A mixture of 6.40 ml of (R)-(1-phenylethyl)amine and 8.70 ml of diisopropylethylamine in 30 ml methylene chloride is added dropwise to 9.00 g of 4-chloro-6-nitroquinazoline in 70 ml methylene chloride while cooling with an ice bath. The mixture is allowed to come up to ambient temperature, then it is stirred for about another 48 hours. For working up, the reaction mixture is washed with water, 10% citric acid, and again with water. The organic phase is dried over magnesium sulfate and concentrated by evaporation. The solid evaporation residue is stirred with about 100 ml methanol, suction filtered, and washed with a little methanol. Yield: 8.44 g (67% of theory); Rf value: 0.33 (silica gel, cyclohexane/ethyl acetate=1:1); mass spectrum (ESI−): m/z=293 [M−H]−.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]2)=[CH:9][C:8]=1[N:20]([CH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)[C:21](=[O:26])[C:22]([F:25])([F:24])[F:23])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[CH3:19][N:16]1[CH2:15][CH2:14][N:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:33])=[O:5])=[C:8]([N:20]([CH:27]3[CH2:28][CH2:29][O:30][CH2:31][CH2:32]3)[C:21](=[O:26])[C:22]([F:24])([F:25])[F:23])[CH:9]=2)[CH2:18][CH2:17]1
Reactant: CN1CCN(c2ccc(C(=O)OC(C)(C)C)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCN(c2ccc(C(=O)O)c(N(C(=O)C(F)(F)F)C3CCOCC3)c2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-(4-methyl-piperazin-1-yl)-2-[(tetrahydro-pyran-4-yl)-(2,2,2-trifluoro-acetyl)-amino]-benzoic acid tert-butyl ester (12.1 g, 25.7 mmol), trifluoroacetic acid (48.5 mL) and dichloromethane (195 mL) was stirred at room temperature for 2 hours. The volatiles were then evaporated, the residue taken up with diethylether and evaporated again. The procedure was repeated 5 times, then the solid was triturated with diethylether, filtered and dried in oven at 40° C. affording the title compound as a pale brown solid (13.4 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH2:7])=O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][NH2:7])[CH:8]=[C:9]([Cl:11])[CH:10]=1
Reactant: NC(=O)c1cc(Cl)cc(Br)c1
Solvent: C1CCOC1
Product: NCc1cc(Cl)cc(Br)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To 3-bromo-5-chlorobenzamide (1.6 g, 6.8 mmol) in THF (10 mL) was added borane dimethyl sulfide complex (1.36 mL, 13.6 mmol) at room temperature. The mixture was then heated to 60° C. for 7 days. The solvent was pumped off and the reaction cautiously quenched with ethanol. When the bubbling ceased, 1N HCl was added until the pH was ˜2. The mixture was stirred at 50° C. for 4 h. The mixture was partitioned between EtOAc and water. The aqueous layer was washed 3× with EtOAC. The aqueous phase was then adjusted to pH 10 with 2N NaOH and extracted 3× with EtOAc. The combined organics phases were dried over anhydrous Na2SO4, filtered, and evaporated to give the title compound as a clear oil. LC-MS m/z 219.7 (M+H)+, 1.42 min (ret time).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:5]2[C:10]=1[CH:9]=[N:8][C:7](SC)=[N:6]2.CC1N=C(C2C=CC=CC=2)N2C=1C=NC(S(C)(=O)=O)=N2.[CH:39]1([NH2:45])[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1>C(O)C>[CH:39]1([NH:45][C:7]2[N:8]=[CH:9][C:10]3=[C:2]([CH3:1])[N:3]=[C:4]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:5]3[N:6]=2)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: CSc1ncc2c(C)nc(-c3ccccc3)n2n1
Reactant: NC1CCCCC1
Agent: Cc1nc(-c2ccccc2)n2nc(S(C)(=O)=O)ncc12
Solvent: CCO
Product: Cc1nc(-c2ccccc2)n2nc(NC3CCCCC3)ncc12
Yield: 15.3 %

Procedure:
Applying the displacement procedure, using 5-methyl-2-(methylthio)-7-phenylimidazo[5,1-f][1,2,4]triazine (Intermediate 72) (50 mg, 0.17 mmol), cyclohexylamine (0.02 mL, 0.17 mmol) and ethanol (2.5 mL) to afford N-cyclohexyl-5-methyl-7-phenylimidazo[5,1-f][1,2,4]triazin-2-amine (8 mg) as a yellow solid. MS m/z 308 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9].[ClH:13].[N:14]12[CH2:21][CH2:20][CH:17]([CH2:18][CH2:19]1)[C@@H:16]([NH:22][C:23]([C:25]1[S:26][C:27]3[C:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[CH2:40][OH:41])=[CH:32][CH:31]=[CH:30][C:28]=3[CH:29]=1)=[O:24])[CH2:15]2.C1COCC1>CN(C=O)C>[ClH:13].[CH2:8]([NH:10][C:11](=[O:12])[O:41][CH2:40][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=1[C:33]1[C:27]2[S:26][C:25]([C:23]([NH:22][C@@H:16]3[CH:17]4[CH2:18][CH2:19][N:14]([CH2:21][CH2:20]4)[CH2:15]3)=[O:24])=[CH:29][C:28]=2[CH:30]=[CH:31][CH:32]=1)[CH3:9]
Reactant: CCN=C=O
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(-c3ccccc3CO)c2s1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCNC(=O)OCc1ccccc1-c1cccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
32.5 μl (0.23 mmol) of triethylamine and 16.6 mg (0.23 mmol) of ethyl isocyanate are added to a suspension of 50 mg (0.12 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-[2-(hydroxymethyl)phenyl]-1-benzothiophene-2-carboxamide hydrochloride (Example 131) in 1 ml of a 5:1 mixture of THF and DMF. After 18 h at room temperature, a further 16.6 mg (0.23 mmol) of ethyl isocyanate and a catalytic amount of 4-N,N-dimethylaminopyridine are added. The mixture is stirred at room temperature for a further 18 h. The reaction mixture is concentrated in vacuo and purified by preparative HPLC. The product fractions are concentrated and, after addition of a 5:1 mixture of methanol and 1N hydrochloric acid, again concentrated. Drying under high vacuum results in 28 mg (47% of theory) of the title compound.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:42][CH2:41][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH3:40])[CH:26]=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:16][CH2:15]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CCO>[C:1]([O:5][C@@H:6]([C:12]1[C:37]([CH3:38])=[N:36][C:35]2=[CH:39][C:32]3=[N:33][N:34]2[C:13]=1[N:14]1[CH2:15][CH2:16][C:17]([CH3:43])([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]2[CH:24]=[C:25]([CH3:40])[CH:26]=[CH:27][C:28]=2[CH2:29][O:30][CH2:31]3)[CH2:41][CH2:42]1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCCc1cc(C)ccc1COC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc2c(c1)CCCCOC1(C)CCN(CC1)c1c([C@H](OC(C)(C)C)C(=O)O)c(C)nc3cc(nn13)COC2
Temperature: 25 °C
Yield: 82.4 %

Procedure:
A mixture of ethyl (2S)-2-(tert-butoxy)-2-{4,16,24-trimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetate (30 mg, 0.051 mmol) and NaOH (0.152 mL, 0.152 mmol) in EtOH (2 mL) was refluxed for 2 h. It was then cooled to rt and purified by preparative HPLC to obtain (2S)-2-(tert-butoxy)-2-{4,16,24-trimethyl-11,23-dioxa-1,5,7,8-tetraazapentacyclo[22.2.2.16,9.02,7.013,18]nonacosa-2,4,6(29),8,13(18),14,16-heptaen-3-yl}acetic acid (24 mg, 0.042 mmol, 84% yield) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ 7.25 (d, J=7.3 Hz, 1H), 7.03-6.96 (m, 2H), 6.49 (s, 1H), 5.76 (br. s., 1H), 4.87-4.76 (m, 2H), 4.72 (d, J=12.1 Hz, 1H), 4.58 (d, J=12.1 Hz, 1H), 4.54-4.46 (m, 1H), 3.66-3.58 (m, 2H), 3.39 (m, 1H), 3.12 (br. s., 1H), 2.69-2.60 (m, 2H), 2.55 (br. s., 4H), 2.27 (s, 3H), 1.92-1.50 (m, 8H), 1.18 (s, 3H), 1.15 (s, 9H). LCMS (M+1)=565.4.
Reaction SMILES: F[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CCN(C(C)C)C(C)C.ClCCCl>C(=O)(O)[O-].[Na+]>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[C:5]([C:20]([O:22][CH3:23])=[O:21])=[C:4]([CH3:24])[N:3]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(F)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCOC(=O)c1c(NCCOC)nc(C)c(C(=O)OC)c1-c1ccc(C)cc1
Reaction time: 1 h

Procedure:
3-Ethyl 5-methyl 2-fluoro-6-methyl-4-(p-tolyl)pyridine-3,5-dicarboxylate (500 mg, 1.51 mmol) (Example 73, Step A), 2-methoxyethanamine (5 eq., 7.55 mmol, 0.65 mL), DIPEA (2 eq. 3.02 mmol, 0.53 mL) and DCE (5 mL) were combined and heated in a microwave reactor set at 140° C. for 1 hour. The mixture was diluted with saturated sodium bicarbonate solution, extracted with DCM, dried over sodium sulfate and purified by silica-gel chromatography to give the title compound to Step A (285 mg, 49%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm=7.49 (m, 1 H), 7.12 (m, 2 H), 7.03 (m, 2 H), 3.85 (m, 2 H), 3.74 (m, 2 H), 3.60 (m, 2 H), 3.44-3.40 (m, 6 H), 2.44 (s, 3 H), 2.35 (s, 3 H), 0.67 (m, 3 H); LCMS (m/z) ES+=387.33 (M+1).
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([O:16][C:17]2([CH3:21])[CH2:20][NH:19][CH2:18]2)=[C:11]([C:22]([F:25])([F:24])[F:23])[CH:10]=3)=[N:5][N:4](COCC[Si](C)(C)C)[C:3]1=[O:34].[C:35]([OH:41])([C:37]([F:40])([F:39])[F:38])=[O:36]>C(Cl)Cl>[F:38][C:37]([F:40])([F:39])[C:35]([OH:41])=[O:36].[CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([O:16][C:17]2([CH3:21])[CH2:20][NH:19][CH2:18]2)=[C:11]([C:22]([F:24])([F:25])[F:23])[CH:10]=3)=[N:5][NH:4][C:3]1=[O:34]
Reactant: CC1C(=O)N(COCC[Si](C)(C)C)N=C2COc3cc(C(F)(F)F)c(OC4(C)CNC4)cc3N21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC1C(=O)NN=C2COc3cc(C(F)(F)F)c(OC4(C)CNC4)cc3N21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 25 %

Procedure:
A suspension of 6-(1-benzhydryl-3-methyl-azetidin-3-yloxy)-4-methyl-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.031 g, 0.046 mmol) and Pd(OH)2/C (10%, 0.030 g) in EtOH (10 mL) was stirred at 50° C. under an atmosphere of H2 (50 psi) overnight. The reaction mixture was cooled to ambient temperature and filtered. The filtrate was evaporated in vacuo to give 4-methyl-6-(3-methyl-azetidin-3-yloxy)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.021 g crude) as an oil, which was used directly without purification. To a solution of 4-methyl-6-(3-methyl-azetidin-3-yloxy)-7-trifluoromethyl-2-(2-trimethylsilanyl-ethoxymethyl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (0.021 g, 0.042 mmol) in DCM (3 mL) was added TFA (1 mL). The reaction was stirred at ambient temperature for 1.5 h then the solvent was removed in vacuo and the residue was diluted with dioxane (1 mL). Aqueous ammonium hydroxide (25%, 1 mL) was added and the reaction mixture was stirred at ambient temperature for 1.5 h. The solvent was removed in vacuo and the residue was purified by preparative HPLC (Table 3, Method 15) to give 4-methyl-6-(3-methyl-azetidin-3-yloxy)-7-trifluoromethyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid (0.0039 g, 25%). LC/MS (Table 1, Method 5) Rt=2.088 min; MS m/z: 371 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]=1.[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:31][CH2:30]N[CH2:28][CH2:27]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1>C(O)C>[CH:12]1([CH2:15][CH2:16][NH:17][C:18]([C:20]2[N:21]=[N:22][C:23]([N:26]3[CH2:27][CH2:28][N:1]([C:2]4[C:10]5[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=5)[C:4](=[O:11])[N:3]=4)[CH2:30][CH2:31]3)=[CH:24][CH:25]=2)=[O:19])[CH2:14][CH2:13]1
Reactant: NC1=NC(=O)c2ccccc21
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Solvent: CCO
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C3=NC(=O)c4ccccc43)CC2)nn1
Yield: 40 %

Procedure:
3-Aminoisoindol-1-one (0.292 g, 2.00 mmol) and 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (0.825 g, 3.00 mmol) were boiled together in ethanol (20 mL) for 48 hours. The solution was concentrated in vacuo. This residue was purified by column chromatography. The title compound was obtained as a white solid in 40% yield (0.328 g). 1H NMR (300 MHz, CDCl3) δ 8.07 (d, J=9.5 Hz, 1H), 7.97 (t, J=5.8 Hz, 1H), 7.76 (d, J=7.0 Hz, 1H), 7.64 (d, J=7.3 Hz, 1H), 7.52 (m, 1H), 7.01 (d, J=9.5 Hz, 1H), 4.42-4.35 (m, 4H), 4.23-4.20 (m, 2H), 3.93-3.89 (m, 2H), 3.54 (dd, J=6.7 and 13.2 Hz, 1H), 1.49 (m, 1H), 0.79-0.66 (m, 1H), 0.47-0.41 (m, 2H), 0.10-0.05 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 181.5, 174.6, 162.9, 159.6, 145.6, 138.1, 134.9, 132.5, 131.7, 127.3, 124.0 123.3, 112.2, 47.2, 46.4 44.5, 43.2, 39.7, 34.5, 8.7, 4.2. MS (ES+) m/z 405.1 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][C:13]=1[O:14][CH3:15])[CH2:10][CH2:9][C:8]2=[O:16])=[O:4].O[Li].O>C1COCC1.O>[CH3:15][O:14][C:13]1[CH:12]=[C:11]2[C:7]([C:8](=[O:16])[CH2:9][CH2:10]2)=[CH:6][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cc2c(cc1OC)CCC2=O
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2c(cc1C(=O)O)C(=O)CC2
Reaction time: 1 h
Yield: 90.2 %

Procedure:
6-Methoxy-3-oxo-indan-5-carboxylic acid methyl ester (4 g, 18.18 mmol) was added to a solution of LiOH.H2O (2.2 g, 54.5 mmol) in THF (40 ml) and H2O (40 ml), then the mixture was heated to reflux and stirred for one hour. After removal of THF, the residue was acidified to PH=3, and the precipitate was collected and dried to give a white solid (3.38 g, 89.8%). LC-MS: m/e 207 (MH+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:17]([O:19]CC)=[O:18])[C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]([C:17]([OH:19])=[O:18])[C:10]=2[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C1C(c2ccccc2)=C1c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1C(c2ccccc2)=C1c1cccc(Cl)c1
Temperature: 25 °C
Yield: 42.2 %

Procedure:
Ethyl 2-(3-chloro-phenyl)-3-phenyl-cycloprop-2-ene-1-carboxylate (0.55 g, 1.84 mmol) and potassium hydroxide (0.5 g, 9.25 mmol) were dissolved in methanol (20 cm3) and heated to reflux for 2 hours. The mixture was cooled to room temperature and the solvent evaporated. The residue was partitioned between water (30 cm3) and ethyl acetate (30 cm3). The aqueous layer was separated and washed with ethyl acetate (2×30 cm3) before being acidified to pH=1 with dilute hydrochloric acid and extracted with dichloromethane (3×40 cm3). The combined dichloromethane extracts were dried (MgSO4), evaporated, and washed with heptane to give the cyclopropene acid 0.21 g, 42%.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=1)[CH2:11][NH:12]C(=O)OC(C)(C)C)=[NH:5].C(=O)(OCC1C=CC=C(CN)C=1)N>FC(F)(F)C(O)=O>[NH2:12][CH2:11][C:10]1[CH:9]=[C:8]([CH:22]=[CH:21][CH:20]=1)[CH2:7][NH:6][C:4](=[NH:5])[CH2:3][O:2][CH3:1]
Reactant: COCC(=N)NCc1cccc(CNC(=O)OC(C)(C)C)c1
Agent: NCc1cccc(COC(N)=O)c1
Solvent: O=C(O)C(F)(F)F
Product: COCC(=N)NCc1cccc(CN)c1
Yield: 61.8 %

Procedure:
The intermediate tert-butyl N-(3-((2-methoxyacetimidoyl) aminomethyl)benzyl)carbamate (360 mg) prepared from tert-butyl N-(3-(aminomethyl)benzyl carbamate and intermediate G analogous to example 1 was deprotected in trifluoroacetic acid at 20° C. for 16 h. The crude product was purified by C18 reverse phase chromatography eluting with water (0.1% trifluoroacetic acid) to yield 150 mg of N-(3-(Aminomethyl)benzyl)-2-methoxyacetamidine as a yellowed, viscous oil (freeze-dried). Mass spectrum (CI) 208.0 (MH+, 100%). 1H NMR (200 MHz, D2O) δ 7.5-7.3 (m, 4H), 4.57 (s, 2H), 4.37 (s, 2H), 4.15 (s, 2H), 3.44 (s, 3H).
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[CH:7]1([N:12]2[CH:16]=[CH:15][CH:14]=[N:13]2)[CH2:11][CH2:10][CH2:9][CH2:8]1.[Br:17]Br>>[Br:17][C:15]1[CH:14]=[N:13][N:12]([CH:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)[CH:16]=1
Reactant: c1cnn(C2CCCC2)c1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Brc1cnn(C2CCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
To a suspension of Na2CO3 (13 g, 124 mmol) in CH2OH2 (100 mL) was added 1-cyclopentyl-1 H-pyrazole (8.35 g, 62 mmol) and Br2 (3.2 mL). The resulting mixture was stirred at RT overnight. The solid was removed by filtration and the filter cake was washed with DCM. The combined filtrates were washed with water, brine and dried over anhydrous MgSO4. The solvent was concentrated to dryness to give 4-bromo-1-cyclopentyl-1 H-pyrazole (14 g, 93%). 1H NMR (300 MHz, CDCl3): δ7.46 (s, 1 H), 7.44 (s, 1 H), 4.64 (m, 1 H), 2.18-1.67(m, 8 H); MS (ESI) m/z: 215.0 [M+H]+.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([NH:19][CH2:20][CH2:21][NH2:22])[CH2:15][CH2:14]1.[ClH:23].[C:24](=S)=[S:25]>C(O)C>[ClH:23].[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([N:19]2[CH2:20][CH2:21][NH:22][C:24]2=[S:25])[CH2:15][CH2:14]1
Reactant: NCCNC1CCN(CCC2COc3ccccc3O2)CC1
Reactant: S=C=S
Agent: Cl
Solvent: CCO
Product: S=C1NCCN1C1CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 5 h

Procedure:
To the stirred solution of 6 g of 1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-(2-aminoethylamino)-piperidine in 10 ml of 50% aqueous ethanol, 1.4 ml of carbon disulfide are added dropwise at 25°. The mixture is refluxed for one hour, a drop of concentrated hydrochloric acid is added and refluxing is continued for 5 hours. After cooling overnight the mixture is filtered and the residue washed with ethanol, to yield the 1-[1-[2-(1,4-benzodioxan-2-yl)-ethyl]-4-piperidyl]-2-imidazolidinthione hydrochloride melting at 292°.
Reaction SMILES: Cl.N1C=CC=CC=1.C[O:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH3:21])([CH3:20])[C:13](=[O:19])[NH:14]2>CCCCCC>[OH:9][C:10]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:11]=1[C:12]([CH3:21])([CH3:20])[C:13](=[O:19])[NH:14]2
Reactant: COc1cccc2c1C(C)(C)C(=O)N2
Agent: Cl
Solvent: CCCCCC
Solvent: c1ccncc1
Product: CC1(C)C(=O)Nc2cccc(O)c21
Temperature: 220 °C
Reaction time: 0.75 h
Yield: 68.9 %

Procedure:
Pyridine hydrochloride (51.10 g, 442.2 mmol) and 4-methoxy-3,3-dimethyl-1,3-dihydro-indol-2-one (21.61 g, 113.0 mmol) are combined and stirred in a melt at 220° C. for 45 minutes. Heating is removed and when the mixture cooled to 100° C., water (60 mL) is added, followed by ethyl acetate (150 mL) at 65° C. The layers are separated and the aqueous phase is extracted five times with ethyl acetate (50 mL). The combined organic layers are extracted first with a combination of aqueous hydrochloric acid (1N, 10 mL) and a saturated solution of sodium chloride (10 mL), then with a combination of a saturated solution of sodium bicarbonate (10 mL) and a saturated solution of sodium chloride (10 mL). After drying over magnesium sulfate, the solvent is removed via rotary evaporation. The crude material is dissolved in ethyl acetate (200 mL) and hexane (200 mL) at 60° C. Crystallization is allowed to begin slowly over 1 hour at 50° C. After stirring for 12 hours at 24° C., the slurry is cooled to 0° C. for 1 hour, then vacuum filtered washing twice with cold 1:1, ethyl acetate:hexane (35 mL, 0° C.) to provide 13.8 g (98.6% purity, 68% yield) of 4-hydroxy-3,3-dimethyl-1,3-dihydro-indol-2-one, mp 224–225° C. MS (ES+) m/z 178 (M++1). From the filtrate a second crop (5.0 g, 98.4% purity, 25% yield) is obtained to give a total yield of 93%.