Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:26]([CH:27]=[CH:28][C:29]([O:31]CC)=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:26]([CH:27]=[CH:28][C:29]([OH:31])=[O:30])=[CH:25][CH:24]=[CH:23][N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)C=Cc1cccnc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2ncccc2C=CC(=O)O)cc1
Temperature: 70 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a mixture of ethyl 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoate (2.00 g), tetrahydrofuran (10 mL) and ethanol (10 mL) was added a 1N aqueous sodium hydroxide solution (7 mL) and the mixture was stirred at 70° C. for 3 hrs. The reaction mixture was concentrated, and dilute hydrochloric acid was added to acidify the residue. The precipitated solid was collected by filtration and dried with air to give crystals (1.77 g, yield 94%) of 3-[2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]-3-pyridyl]propenoic acid. Recrystallization from tetrahydrofuran-diisopropyl ether gave colorless prism crystals. melting point: 174-175° C.
Reaction SMILES: [CH3:1]N(C)CCN(C)C.BrCBr.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)([CH2:25][O:26][C:27](=O)[C:28]2[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[C:30]([C:38]([F:41])([F:40])[F:39])[CH:29]=2)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]>[Ti](Cl)(Cl)(Cl)Cl.[Zn].O1CCCC1>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=2)([CH2:25][O:26][C:27]([C:28]2[CH:29]=[C:30]([C:38]([F:40])([F:41])[F:39])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=2)=[CH2:1])[CH2:23][CH2:24]1)=[O:18])([CH3:13])([CH3:15])[CH3:14]
Reactant: CN(C)CCN(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(COC(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)(c2ccccc2)CC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: C1CCOC1
Solvent: BrCBr
Product: C=C(OCC1(c2ccccc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 18 h

Procedure:
Titanium tetrachloride (1.06 g) was added to cooled (0° C.) stirred tetrahydrofuran under a dry nitrogen atmosphere. After the exotherm had subsided the solution was allowed to warm to room temperature and tetramethylethylene diamine (1.69 g) added followed 15 minutes later by freshly activated zinc dust (819 mg). The resulting mixture was stirred for 30 minutes at room temperature at which point dibromomethane (0.21 ml) and the compound of step (b) above (716 mg) were added. The reaction was allowed to proceed for 18 hours at room temperature. After this time the reaction was quenched with saturated K2CO3 (7 ml) and diluted with diethyl ether. The resulting black suspension was filtered through a plug of grade III neutral alumina, eluting with 1 % triethylamine/diethyl ether. The filtrate was dried over MgSO4, filtered and the solvent removed under reduced pressure. The residual oil was purified by chromatography on silica gel (10% ethyl acetate/n-hexane) to afford the title compound. 1H NMR (360 MHz, CDCl3) δ 1.2 (9H, s), 1.95 (2H, m), 2.38 (2H, m), 3.05 (2H, m), 3.8 (2H, s), 3.95 (2H, m), 4.21 (1H, d, J=1.0 Hz), 4.63 (1H, d, J=1.0 Hz), 7.1-7.3 (5H, m), 7.7 (1H, s), 7.76 (2H, s).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][NH:4][C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2.[F:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[O:21][CH3:22])[C:15](Cl)=[O:16].C(N(CC)CC)C.Cl>ClCCl>[O:1]1[CH2:6][CH2:5][N:4]([C:15]([C:14]2[CH:18]=[CH:19][C:20]([O:21][CH3:22])=[C:12]([F:11])[CH:13]=2)=[O:16])[C:3]2[CH:7]=[N:8][CH:9]=[CH:10][C:2]1=2
Reactant: COc1ccc(C(=O)Cl)cc1F
Reactant: c1cc2c(cn1)NCCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)N2CCOc3ccncc32)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.1 %

Procedure:
In a 10 ml flask, 3,4-dihydro-2H-pyrido[4,3-b][1,4]oxazine (50 mg, 0.441 mmol) and 3-fluoro-4-methoxy-benzoyl chloride (125 mg, 0.661 mmol) were dissolved in dichloromethane. Triethylamine (0.77 ml, 1.288 mmol) was added thereto and then stirred at room temperature for 2 hours. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of ethyl acetate. The fractions containing the product were collected and evaporated to obtain white solid (42.1 mg, 33%).
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][C@H:9]1[C:17]([OH:19])=O)=O)(C)(C)C.[CH2:20]([N:22](CC)[CH2:23]C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CNC>C(Cl)Cl>[CH3:20][N:22]([CH3:23])[C:17]([C@@H:9]1[CH2:10][C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[NH:8]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1c2ccccc2C[C@H]1C(=O)O
Reactant: CCN(CC)CC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)[C@@H]1Cc2ccccc2N1
Reaction time: 0.25 h

Procedure:
A mixture of 5 g of (2S)-1-(tert-butoxycarbonyl)-2,3-dihydro-1H-indole-2-carboxylic acid (commercial) and of 5.8 g of triethylamine in 100 ml of DCM is cooled in an ice bath, 8.4 g of BOP are added and the mixture is left stirring for 15 minutes. Dimethylamine gas is then added by sparging for 10 minutes and the mixture is left stirring for 3 hours at AT. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with water, with a 5% Na2CO3 solution and with a 5% KHSO4 solution and dried over Na2SO4, and the solvent is evaporated under vacuum. The residue is chromatographed on silica gel, elution being carried out with a DCM/AcOEt (85/15, v/v) mixture. 4.1, g of the expected product are obtained.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[C:13]([O:14][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:12][CH:11]=[CH:10][N:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)c1ncccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cccnc1C(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.1 %

Procedure:
A mixture of give 2-(4-fluorobenzoyl)-3-hydroxypyridine (2.2 g, 11.3 mmol), ethyl bromoacetate (1.6 ml, 14.15 mmol) and potassium carbonate (4.34 g, 31.4 mmol) in acetone (40 ml) was heated at reflux. After 3 h, the reaction was cooled to room temperature, filtered and concentrated in vacuo to give ethyl 2-[2-(4-fluorobenzoyl)pyridin-3-yloxy]acetate (3.5 g) which was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].I[C:17]1C=CC=C(C)C=1C(O)=O.FC1C=CC(I)=C(C=1)C(O)=O>>[CH3:17][C:10]1[CH:2]=[CH:3][CH:4]=[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)[C:6]=1[C:7]([OH:9])=[O:8]
Reactant: Cc1cccc(I)c1C(=O)O
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Agent: O=C(O)c1cc(F)ccc1I
Product: Cc1cccc(-n2nccn2)c1C(=O)O

Procedure:
The title compound was prepared in a manner analogous to Intermediate 1, substituting for 2-iodo-6-methyl benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.89 (s, 2H), 7.72 (d, J=8.1 Hz, 1H), 7.48 (t, J=7.9 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 2.46 (s, 3H).
Reaction SMILES: Cl.[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH2:14])[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22](O)=[O:23].C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.C(Cl)CCl>C(Cl)Cl>[CH3:2][C:3]1[C:7]([CH2:8][N:9]2[CH:13]=[C:12]([NH:14][C:22](=[O:23])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH:11]=[N:10]2)=[C:6]([CH3:15])[O:5][N:4]=1
Reactant: Cc1noc(C)c1Cn1cc(N)cn1
Reactant: O=C(O)c1ccccn1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1noc(C)c1Cn1cc(NC(=O)c2ccccn2)cn1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.6 %

Procedure:
1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-amine hydrochloride (example 4-1a) (400 mg, 2.1 mmol), picolinic acid (256 mg, 2.1 mmol), and HOBt (388 mg, 2.50 mmol) were mixed in DCM (7 mL). The reaction was treated with triethylamine (670 mL, 4.8 mmol) and stirred for 15 minutes at room temperature under a nitrogen atmosphere. EDC (598 mg, 3.1 mmol) was added and the reaction was stirred for an additional 4 hours. The reaction was then diluted with dichloromethane (5 mL) and washed with aqueous saturated NaHCO3 solution (5 mL, 2×) and then with aqueous saturated NaCl solution (5 mL). The organic layer was collected, dried, and filtered. Solvents were removed under vacuum. The crude product was re-suspended in EtOH (5 mL) and purified by reversed phase HPLC (5%-95% ACN in H2O:25 minute gradient). The pure fractions were combined and concentrated to afford N-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)picolinamide (372 mg, 60%) as a white solid. 1H NMR (CDCl3, 400 MHz): δ 2.21 (s, 3H), 2.44 (s, 3H), 5.05 (s, 2H), 7.49-7.47 (m, 1H), 7.59 (s, 1H), 7.93-7.88 (dt, J=14, 2 Hz, 1H), 8.07 (s, 1H), 8.24-8.21 (d, J=8 Hz, 1H), 8.61-8.56 (m, 1H), 9.83 (bs, 1H). LC/MS; [M+H] calculated for C15H15N5O2; expected 297.1; found 298.3. Melting point: 135-137° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=2[C:14]([OH:16])=[O:15])[N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:34](O)[C:35]#[CH:36].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.O>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([O:11][C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=2[C:14]([O:16][CH2:36][C:35]#[CH:34])=[O:15])[N:6]=1
Reactant: C#CCO
Reactant: COc1cc(OC)nc(Oc2cccc(F)c2C(=O)O)n1
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCOC(=O)c1c(F)cccc1Oc1nc(OC)cc(OC)n1
Yield: 53.1 %

Procedure:
2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoic acid (3.0 g) and carbonyldiimidazole (1.8 g) was dissolved in tetrahydrofuran (50 ml), and the solution was refluxed under heating for one hour. The reaction solution was cooled. Then, propargyl alcohol (2.0 g) and potassium carbonate (1.7 g) were added thereto, and the mixture was refluxed under heating for one hour. The mixture was poured into water and extracted with ethyl ether. The extract was washed with water and dried. Then, the solvent was distilled off, and the residue thereby obtained was purified by silica gel column chromatography to obtain propargyl 2-(4,6-dimethoxypyrimidin-2-yl)oxy-6-fluorobenzoate (1.8 g). Yield: 53%, white crystals, Melting point: 49°-50° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:7]1[NH:8][C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6].Br[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([CH:31]2[CH2:35][CH2:34][CH2:33][CH2:32]2)[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:3]([C:7]1[N:8]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)[C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])=[CH:21][CH:22]=2)[C:9]([CH:13]=[O:14])=[C:10]([Cl:12])[N:11]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(C(C(=O)OC(C)(C)C)C2CCCC2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
1.6 g (0.053 mol) of sodium hydride (80%) are suspended under protective gas in 50 ml of DMF, 10 g (0.053 mol) of 2-butyl-5-formyl-4-chloroimidazole (preparation as described in EP 324,377) in 100 ml of DMF are added dropwise at 0° C., the mixture is subsequently stirred for 15 minutes at 0° C., and 18.9 g (0.053 mol) of tert-butyl 2-(4-bromomethylphenyl)-2-cyclopentyl-acetate in 100 ml of DMF are added dropwise. Stirring is continued for 2 hours at 0° C., the solvent is evaporated, the residue is taken up in diethyl ether, the mixture is filtered, and the product is concentrated and then chromatographed over silica gel 60 using dichloromethane. Yield: 16.2 g (66.7% of theory)
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10].[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:11]([NH:18][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][OH:10])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OCCOCCOCCCl
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: OCCOCCOCCNCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
2-[2-(2-Chloroethoxy)ethoxy]ethanol 31 (9.273 g, 55 mmol) and benzylamine (26.3 mL, 240 mmol) were dissolved in absolute acetonitrile (150 mL) whereupon potassium carbonate (25.0 g, 180 mmol) was added. The suspension was heated at reflux with vigorous stirring under an argon atmosphere for 18 hours. The suspension was allowed to cool to room temperature, diluted with acetonitrile (100 mL) and filtered through a Celite™ pad. The acetonitrile was removed under reduced pressure and the unreacted benzylamine distilled from the concentrated pale greenish oil under high vacuum (90° C., 5 torr). The resulting viscous oil (14.2 g) was purified by flash chromatography using 13% methanol in dichloromethane as the eluent. Fractions contained the desired product (Rf=0.45) were combined, solvent removed under reduced pressure, and the residue dried in vacuo to yield the title compound as a viscous oil (10.1 g, 77%). CIMS (MH+): m/e 240. 1H-NMR (CDCl3): δ 7.31 (m, 5H, phenyl), 3.79 (s, 2H, CH2-Ph), 3.70-3.61 (m, 12 H, OCH2CH2O). 13C-NMR (CDCl3): δ 140.3, 129.0, 128.8, 127.6, 73.3, 70.9, 70.8, 70.7, 62.0, 54.4, 49.0.
Reaction SMILES: CN=C=S.[S:5]1[CH:9]=[CH:8][C:7]([CH2:10][NH:11][CH2:12][CH2:13][NH2:14])=[N:6]1.[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][N:19]=[C:20]=[S:21]>>[CH3:15][N:16]([CH3:22])[CH2:17][CH2:18][NH:19][C:20]([NH:14][CH2:13][CH2:12][NH:11][CH2:10][C:7]1[CH:8]=[CH:9][S:5][N:6]=1)=[S:21]
Reactant: NCCNCc1ccsn1
Reactant: CN(C)CCN=C=S
Agent: CN=C=S
Product: CN(C)CCNC(=S)NCCNCc1ccsn1

Procedure:
By the procedure of Example 40(a) (ii), N-(3-isothiazolylmethyl)ethylenediamine is reacted with 2-dimethylaminoethyl isothiocyanate to give N-(2-dimethylaminoethyl)-N'-[2-(3-isothiazolylmethylamino)ethyl]thiourea. Reacting with hydrobromic acid gives the hydrobromide salt.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1O.[OH-:9].[Na+].Cl[C:12]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][N:13]=1.C1(C)C=CC=CC=1>[Br-].C([P+](CCCC)(CCCC)CCCC)CCCCCCCCCCCCCCC.C(OCC)(=O)C.O>[Cl:18][C:17]1[C:12]([O:9][C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)=[N:13][CH:14]=[CH:15][CH:16]=1
Reactant: [OH-]
Reactant: Clc1cccnc1Cl
Reactant: Oc1ccccc1Br
Agent: CCCCCCCCCCCCCCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: Clc1cccnc1Oc1ccc(Br)cc1
Temperature: 100 °C

Procedure:
Bromophenol (3.74 g, 22 mmol) is stirred with 50% sodium hydroxide solution (16 mL) for about 1 hour then treated with hexadecyltributylphosphonium bromide (3.25 g, 6.4 mmol), 2.3-dichloro-pyridine (3.2 g, 21.6 mmol) and toluene (15 mL). The mixture is heated to 100° C. for 18 hours, cooled and diluted with ethyl acetate and water. The organic layer is separated, washed with dilute NaOH and saturated NaCl, dried (MgSO4) and concentrated. Flash chromatography (5% EtOAc/hexanes) yielded the title compound (4.4 g, 15 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11](Cl)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1.[CH:16]1[CH:17]=[CH:18][N:19]2[CH2:25][C:24]3[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=3[NH:22][CH2:21][C:20]=12.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:1][C:2]1[CH:3]=[N:4][N:5]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([N:22]3[C:23]4[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=4[CH2:25][N:19]4[CH:18]=[CH:17][CH2:16][C:20]4=[CH:21]3)=[O:12])=[CH:9][CH:8]=2)[CH:6]=1
Reactant: Cc1cnn(-c2ccc(C(=O)Cl)cc2)c1
Reactant: c1ccc2c(c1)Cn1cccc1CN2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1cnn(-c2ccc(C(=O)N3C=C4CC=CN4Cc4ccccc43)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 62.5 %

Procedure:
The 4-(4-methylpyrazol-1-yl)benzoyl chloride (0.72 g) was added to an ice-cooled solution of 10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine (0.60 g) and diisopropylethylamine (0.48 g) in dichloromethane (25 ml). After stirring at room temperature for 18 hours, the reaction mixture was washed with water and saturated aqueous sodium bicarbonate. The dichloromethane solution was dried over anhydrous sodium sulfate and filtered through a short column of hydrous sodium magnesium silicate and further eluted with several volumes of dichloromethane. The combined organic phase was concentrated on a hot plate with the gradual addition of hexane until crystallization occurred. After cooling, the crystals were collected by filtration to yield the title compound (0.75 g), m.p. 179-181° C.; MS m/z: 369 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])(=[O:3])N.S(=O)(=O)(O)[OH:25].N([O-])=O.[Na+]>O>[C:1]([C:4]1[CH:5]=[C:6]2[N:12]([CH:13]=1)[CH:11]=[CH:10][C:9]1[CH:14]=[CH:15][CH:16]=[CH:17][C:8]=1[C:7]2=[CH:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])([OH:3])=[O:25]
Reactant: O=S(=O)(O)O
Reactant: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(N)=O)cc21
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CN(C)CCC=C1c2ccccc2C=Cn2cc(C(=O)O)cc21

Procedure:
To 2-carbamoyl-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine (0.112 moles) in 300 ml. of 50% sulfuric acid maintained at 50° C. is added slowly 25 g. of sodium nitrite in 75 ml. of water. At the end of the addition, the solid is filtered, washed with water and air-dried to yield 2-carboxy-11-(3-dimethylaminopropylidene)-11H-pyrrolo[2,1-b][3]benzazepine.
Reaction SMILES: FC(F)(F)[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:5](N2C=CN=C2)[CH:4]=1.CC(C)=[O:25].OS(O)(=O)=O.O=[Cr](=O)=O>C(O)(=O)C>[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:25])[C:6]1[CH:7]=[CH:8][CH:3]=[CH:4][CH:5]=1
Reactant: CC(C)=O
Reactant: FC(F)(F)c1ccc(Cc2ccccc2)c(-n2ccnc2)c1
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(c1ccccc1)c1ccccc1

Procedure:
In the manner given in Example 24, 1-[4-(trifluoromethyl)-α-phenyl-0-tolyl]imidazole in acetic acid is heated with Jones' reagent to give 5-(trifluoromethyl)-2-imidazo-1-yl)benzophenone.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][N:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=3)[C:15]=2[CH3:16])=[O:10])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)[CH2:37][CH:36]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O1CCOCC1.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[CH3:16][C:15]1[N:14]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][N:18]=2)[N:13]=[CH:12][C:11]=1[C:9]([NH:8][C:5]1[CH:4]=[N:3][C:2]([C:35]2[CH2:40][CH2:39][CH:38]([N:41]3[CH2:42][CH2:43][O:44][CH2:45][CH2:46]3)[CH2:37][CH:36]=2)=[CH:7][N:6]=1)=[O:10]
Reactant: CC1(C)OB(C2=CCC(N3CCOCC3)CC2)OC1(C)C
Reactant: Cc1c(C(=O)Nc2cnc(Br)cn2)cnn1-c1ccc(C(F)(F)F)cn1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(C(=O)Nc2cnc(C3=CCC(N4CCOCC4)CC3)cn2)cnn1-c1ccc(C(F)(F)F)cn1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.1 %

Procedure:
A mixture of N-(5-bromopyrazin-2-yl)-5-methyl-1-[5-(trifluoromethyl)pyridin-2-yl]-1H-pyrazole-4-carboxamide (300 mg), 4-[4-(4,4,5,5-tetramethyl[1,3,2] dioxaborolan-2-yl)cyclohex-3-en-1-yl]morpholin (185 mg), tetrakis(trophenylphosphine)palladium (0) (81 mg) and sodium carbonate (186 mg) in 1,4-dioxane (7.0 ml) was stirred at 90° C. for four hours. Then, N,N-dimethylformamide (7.0 ml) and bis(diphenylphosphine)ferrocenepalladium (II) dichloride dichloromethane adduct (57 mg) were added at room temperature and stirred at 90° C. for five hours. After completion of the reaction, the reaction solution was cooled to room temperature, water was added, and the precipitated solid was collected by filtration. The resulting residue was purified with silica gel column chromatography (chloroform/methanol) twice to give the titled compound (143 mg) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=2)=[N:10]1.Cl.CN.C1C=[C:36]2[N:38]=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.O.C(N(CC)CC)C>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:17]2[CH:16]=[CH:15][N:14]=[C:13]([O:18][CH3:19])[C:12]=2[C:11]([C:20]2[CH:21]=[CH:22][C:23]([C:24]([NH:38][CH3:36])=[O:25])=[CH:27][CH:28]=2)=[N:10]1
Reactant: On1nnc2ccccc21
Reactant: COc1nccc2c1c(-c1ccc(C(=O)O)cc1)nn2-c1c(F)cccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(-c2nn(-c3c(F)cccc3F)c3ccnc(OC)c23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a solution of 4-(1-(2,6-difluorophenyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl)benzoic acid (2.59 g), methylamine hydrochloride (688 mg), HOBt monohydrate (1.56 g) and triethylamine (1.89 mL) in DMF (20 mL) was added EDCI hydrochloride (1.95 g) at 0° C., and the mixture was stirred overnight at room temperature. To the reaction mixture was added water, and the white precipitate was filtered, washed with water and hexane, and dried in vacuum to give the title compound (2.68 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[CH:3]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[NH:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]([CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:20]1>>[OH:1][C:2]1[CH:6]([CH:7]([CH3:9])[CH3:8])[NH:5][C:4](=[O:10])[C:3]=1[CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:20]1[NH:19][C:27]2[C:22]([C:21]=1[CH2:28][CH2:29][NH:30][C:31](=[O:33])[CH3:32])=[CH:23][CH:24]=[CH:25][CH:26]=2
Reactant: CC(=O)NCCc1c[nH]c2ccccc12
Reactant: CC(C)C1NC(=O)C=C1O
Reactant: O=Cc1ccccc1
Product: CC(=O)NCCc1c(C(C2=C(O)C(C(C)C)NC2=O)c2ccccc2)[nH]c2ccccc12

Procedure:
Using general procedure C, 4-hydroxy-5-isopropyl-1,5-dihydro-pyrrol-2-one (Literature (hereinafter mentioned as Lit.). 11) was reacted with benzaldehyde and N-[2-(1H-indol-3-yl)-ethyl]-acetamide to give the title compound as a pale yellow solid. MS: 432.5 ([M+H]+).
Reaction SMILES: [NH2:1][S:2]([C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH3:13])[CH:11]=2)[N:6]([CH3:14])[C:5]=1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[O:3].[Mn]([O-])(=O)(=O)=[O:21].[Na+]>>[CH3:14][N:6]1[C:7]2[C:12](=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)[C:4]([S:2](=[O:21])(=[O:3])[NH2:1])=[C:5]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: CCOC(=O)c1c(S(N)=O)c2cc(C)ccc2n1C
Agent: [Na+]
Product: CCOC(=O)c1c(S(N)(=O)=O)c2cc(C)ccc2n1C
Yield: 104.8 %

Procedure:
8.0 gm (29 millimols) of ethyl 3-aminosulfinyl-1,5-dimethyl-indole-2-carboxylate were reacted analogous to Example 18(c) with 3.0 gm (19 millimols) of sodium permanganate to yield b 5.9 gm (70% of theory) of ethyl 1,5-dimethyl-3-sulfamoyl-indole-2-carboxylate, M.p.: 148° C., and 2.0 gm (28% of theory) of 4,7-dimethyl-2H-isothiazolo[4,5-b]-indole-3(2H)-one-1,1-dioxide; M.p.: 295° C. (decompositon).