Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[NH:7][C:8](=[O:13])[C:9]([F:12])([F:11])[F:10].[C:18](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:15]([O-:17])=[O:16])=[C:6]([CH:14]=1)[N:7]([CH3:18])[C:8](=[O:13])[C:9]([F:10])([F:12])[F:11]
Reactant: O=C([O-])[O-]
Reactant: O=C(Nc1cc(Cl)ccc1[N+](=O)[O-])C(F)(F)F
Agent: [K+]
Solvent: CC(C)=O
Solvent: COS(=O)(=O)OC
Product: CN(C(=O)C(F)(F)F)c1cc(Cl)ccc1[N+](=O)[O-]
Reaction time: 1.5 h

Procedure:
5-Chloro-2-nitro-N-trifluoroacetylaniline (38 g) from Example 8 was dissolved in acetone (300 ml), followed by addition of potassium carbonate (19.5 g). To the mixture was added dropwise dimethyl sulfate (13.4 ml) for subsequent stirring for 1.5 hours. After filtering off insoluble inorganic materials, the resulting material was washed with ethyl acetate. Removal of the solvent under reduced pressure, hexane was added to the residue under stirring, to separate the crystal by filtration. By washing the crystal further with ether-hexane mixture solution, the title compound was given (33 g; 83.5%).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][NH:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:10]=1[N+:16]([O-])=O)=O)C>CO.C(O)(=O)C.[Fe]>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]2[NH:8][CH2:7][CH2:6][C:4](=[O:3])[NH:16][C:10]=2[CH:11]=1
Reactant: CCOC(=O)CCNc1ccc(C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CO
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)NC(=O)CCN2
Temperature: 25 °C
Yield: 16 %

Procedure:
A mixture of N-(2-ethoxycarbonylethyl)-4-methyl-2-nitroaniline (11.25 g) and iron powder (12.45 g) in a mixture of methanol (70 ml) and acetic acid (7 ml) was refluxed for 1 hour and the solution was cooled to ambient temperature. The mixture was filtered through celite and the filtrate was evaporated in vacuo. The residue was dissolved with chloroform (50 ml) and the solution was basified with saturated sodium bicarbonate aqueous solution. The solution was filtered through celite and the organic layer was washed with brine. The solution was dried over magnesium sulfate and the solvent was removed. A mixture of the residue (8.00 g) in a mixture of concentrated hydrochloric acid (16 ml) and water (12 ml) was refluxed for 1 hour and the solution was cooled to ambient temperature. The mixture was basified with concentrated ammonium hydroxide and then the resulting solution was extracted with chloroform. Drying over magnesium sulfate, filtering and the removal of solvents afforded a crude product. The crude product was triturated with diethyl ether - isopropyl ether (1:1) to give 8-methyl-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (1.26 g) as a brown powder.
Reaction SMILES: [Li].[O:2]1[C@H:4]2[C:5](=[O:31])[CH:6]=[C:7]3[C@:28]([CH3:29])([C@@H:3]12)[C@@H:27]1[C@H:10]([C@H:11]2[C@:24]([CH3:30])([CH2:25][CH2:26]1)[C@@H:14]([C@H:15]([CH3:23])[CH2:16][CH2:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH2:13][CH2:12]2)[CH:9]=[CH:8]3.C(O)C>[NH4+].O1CCCC1>[OH:2][C@@H:3]1[C@@:28]2([CH3:29])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:27]2[CH2:26][CH2:25][C@@:24]2([CH3:30])[C@H:11]3[CH2:12][CH2:13][C@@H:14]2[C@H:15]([CH3:23])[CH2:16][CH2:17][CH:18]([OH:22])[CH:19]([CH3:21])[CH3:20])[CH2:6][C@@H:5]([OH:31])[CH2:4]1
Reactant: CC(C)C(=O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3C=CC4=CC(=O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: [Li]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)C(O)CC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)C[C@H](O)[C@]4(C)[C@H]3CC[C@]12C
Temperature: -75 °C
Yield: 63 %

Procedure:
First, 1.80 g (35 equivalent amount) of metal lithium was dissolved in 130 ml of liquid ammonium under a nitrogen atmosphere and to the solution 3.00 g of 1α, 2α-epoxycholesta-4,6-dien-3,24- dione dissolved in 150 ml of tetrahydrofuran was dropwise added for 90 minutes while maintaining the temperature of the reaction mixture at -75° C. Then 60 minutes later, the temperature of the reaction mixture was increased to -34° C. for about 30 minutes and to the mixture was dropwise added 40.3 g (120 equivalent amount) of ethanol. Stirring was continued until the lithium layer floating as a liquid layer on the reaction mixture disappeared. Next, after evaporating most of the ammonia from the reaction mixture at room temperature, the same procedure as described in Reference Example 1 was carried out to obtain 1α, 3β, 24-trihydroxycholest-5-ene at a yield of 63%.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22](O)[CH3:23])=[CH:18][CH:17]=1>>[F:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]([O:1][C:2]2[N:6]([C:7]3[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=3)[N:5]=[CH:4][CH:3]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CC(O)c1ccc(F)cc1
Product: CC(Oc1ccnn1-c1cc(C#N)ccn1)c1ccc(F)cc1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and 1-(4-fluorophenyl)ethanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.65 (3H, d, J=6.4 Hz), 5.24 (1H, q, J=6.4 Hz), 5.44 (1H, d, J=2.0 Hz), 6.95-7.00 (2H, m), 7.27-7.30 (2H, m), 7.35 (1H, dd, J=0.8 Hz, J=5.2 Hz), 7.41 (1H, d, J=2.0 Hz), 7.97 (1H, s), 8.66 (1H, d, J=4.8 Hz). [M+H] Calc'd for C17H13FN4O, 309. Found, 309.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C:10]2([CH2:14][O:15][CH3:16])[CH2:13][O:12][CH2:11]2)=[C:6]([O:17][CH3:18])[C:5]([O:19][CH:20]([F:22])[F:21])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=[O:46])[O:41][CH2:40]3)O1>CN(C)C=O.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[F:21][CH:20]([F:22])[O:19][C:5]1[CH:4]=[CH:3][C:2]([C:37]2[CH:38]=[C:39]3[C:43](=[CH:44][CH:45]=2)[C:42](=[O:46])[O:41][CH2:40]3)=[C:7]([O:8][CH2:9][C:10]2([CH2:14][O:15][CH3:16])[CH2:13][O:12][CH2:11]2)[C:6]=1[O:17][CH3:18]
Reactant: CC1(C)OB(c2ccc3c(c2)COC3=O)OC1(C)C
Reactant: COCC1(COc2c(Br)ccc(OC(F)F)c2OC)COC1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COCC1(COc2c(-c3ccc4c(c3)COC4=O)ccc(OC(F)F)c2OC)COC1
Temperature: 80 °C
Yield: 12 %

Procedure:
A stirring solution of 3-((6-bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)-3-(methoxymethyl)oxetane (220 mg, 0.574 mmol) in dimethylformamide (10 mL) was purged with argon for 1 h, to this cesium carbonate (561 mg, 1.72 mmol), tetrakis(triphenylphosphine) palladium(0) (19 mg, 0.017 mmol) and 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isobenzofuran-1(3H)-one (178 mg, 0.686 mmol) was added and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT and filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-80% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 12%).
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:17]2[C:16](=[O:18])[N:15]([C:19]3[CH:20]=[C:21]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:31])[N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:7]=[C:6](S(C)(=O)=O)[N:5]=1)[CH3:2].[CH2:36]([NH2:38])[CH3:37].C1COCC1>C1COCC1>[CH2:1]([NH:3][C:4]1[C:17]2[C:16](=[O:18])[N:15]([C:19]3[CH:20]=[C:21]([C:25]4[O:29][C:28](=[O:30])[N:27]([CH3:31])[N:26]=4)[CH:22]=[CH:23][CH:24]=3)[CH2:14][C@H:13]3[N:9]([CH2:10][CH2:11][CH2:12]3)[C:8]=2[N:7]=[C:6]([NH:38][CH2:36][CH3:37])[N:5]=1)[CH3:2]
Reactant: CCN
Reactant: CCNc1nc(S(C)(=O)=O)nc2c1C(=O)N(c1cccc(-c3nn(C)c(=O)o3)c1)C[C@@H]1CCCN21
Solvent: C1CCOC1
Product: CCNc1nc(NCC)c2c(n1)N1CCC[C@H]1CN(c1cccc(-c3nn(C)c(=O)o3)c1)C2=O
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 94.9 %

Procedure:
(S)-5-[3-(7-Ethylamino-9-methanesulfonyl-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)phenyl]-3-methyl-1,3,4-oxadiazol-2(3H)-one (23.6 mg, 0.0472 mmol) obtained in Step 1 was dissolved in THF (2.0 mL), and the mixture was stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (1.0 mL, 2.00 mmol). The mixture was further stirred at 90° C. for 30 minutes under microwave (CEM; Discover; 250 watts) irradiation after adding a 2.0 mol/L ethylamine/THF solution (0.049 mL, 0.0981 mmol). The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound (Compound 158) (20.8 mg, 88%).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:22]([C:24]34[CH2:29][CH:28]3[C:27](=[O:30])[N:26](CC3C=CC(OC)=CC=3OC)[CH2:25]4)=[O:23])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][CH2:19][CH3:20])[CH:13]=3)=[CH:10][C:9]([NH:21][C:22]([C:24]34[CH2:29][CH:28]3[C:27](=[O:30])[NH:26][CH2:25]4)=[O:23])=[N:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCc1cccc(-c2cc(NC(=O)C34CC3C(=O)N(Cc3ccc(OC)cc3OC)C4)nn2-c2ccccc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCc1cccc(-c2cc(NC(=O)C34CNC(=O)C3C4)nn2-c2ccccc2)c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 6.5 %

Procedure:
To 3-(2,4-dimethoxybenzyl)-4-oxo-3-azabicyclo[3.1.0]hexane-1-carboxylic acid[1-phenyl-5-(3-propylphenyl)-1H-pyrazol-3-yl]amide (6.3 mg) were sequentially added anisole (2 μl) and trifluoroacetic acid (0.5 ml) at room temperature, and the mixture was stirred at 80° C. for 3 hours. This reaction mixture was concentrated under reduced pressure, the resulting residue was purified by silica gel thin-layer chromatography (eluent: chloroform/methanol=9/1) to give the titled compound (0.3 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:6](O)=[O:7])=[O:2].S(Cl)([Cl:15])=O.CN(C)C=O>C1(C)C=CC=CC=1>[CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[C:10]([Cl:12])[CH:11]=1)[C:6]([Cl:15])=[O:7])=[O:2]
Reactant: O=S(Cl)Cl
Reactant: O=Cc1cc(Cl)cc(C(=O)O)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=Cc1cc(Cl)cc(C(=O)Cl)c1
Reaction time: 2 h

Procedure:
A mixture of 3-formyl-5-chlorobenzoic acid (66.5 g, 0.36 moles), thionyl chloride (51.5 g, 0.43 moles), and dimethylformamide (1 ml), in toluene (400 ml) was slowly warmed to 70° C. and stirred at that temperature for 2 hours. The toluene was eliminated in the rotavap to yield 3-formyl-5-chlorobenzoyl chloride, used in the next step as such.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][CH:21]=1)[O:5][C:6]1[C:15]2[C:10](=[CH:11][C:12]([OH:18])=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][N:7]=1.[F:22][C:23]([F:43])([F:42])[C:24]([C:27]1[O:31][N:30]=[C:29]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[CH:28]=1)([CH3:26])[CH3:25]>CN(C=O)C>[OH:18][C:12]1[CH:11]=[C:10]2[C:15]([C:6]([O:5][C:4]3[CH:3]=[C:2]([NH:1][C:33]([NH:32][C:29]4[CH:28]=[C:27]([C:24]([CH3:26])([CH3:25])[C:23]([F:43])([F:42])[F:22])[O:31][N:30]=4)=[O:34])[CH:21]=[CH:20][CH:19]=3)=[N:7][CH:8]=[N:9]2)=[CH:14][C:13]=1[O:16][CH3:17]
Reactant: CC(C)(c1cc(NC(=O)Oc2ccccc2)no1)C(F)(F)F
Reactant: COc1cc2c(Oc3cccc(N)c3)ncnc2cc1O
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C(F)(F)F)on4)c3)ncnc2cc1O
Temperature: 60 °C
Reaction time: 72 h
Yield: 23 %

Procedure:
To a stirred solution of 4-(3-aminophenoxy)-6-methoxyquinazolin-7-ol (100 mg, 0.35 mmol) prepared as described in example 95A in anhydrous DMF (3 mL), was added phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate described in Example 260A (111 mg, 0.35 mmol) and the mixture was heated to 60° C. for 2 h. Additional phenyl 5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate (50 mg, 0.16 mmol) was added and heating was continued for a further 72 h. Concentration in vacuo followed by purification via preparative reverse phase HPLC (eluted with a gradient of solvent B=0.05% HOAc/CH3CN and solvent A=0.05% HOAc/H2O), afforded 1-(3-(7-hydroxy-6-methoxyquinazolin-4-yloxy)phenyl)-3-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)urea (40 mg, 23%) as a colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 10.93 (brs, 1H), 9.83 (s, 1H), 9.11 (s, 1H), 8.47 (s, 1H), 7.56 (dd, J=2.1, 2.1 Hz, 1H), 7.53 (s, 1H), 7.40 (dd, J=8.1, 8.1 Hz, 1H), 7.26 (dd, J=8.1, 8.1 Hz, 1H), 7.21 (s, 1H), 6.96 (m, 1H), 6.88 (s, 1H), 3.98 (s, 3H), 1.54 (s, 6H); LC-MS (ESI) m/z 504 (M+H)+.
Reaction SMILES: [Br-].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:6][CH:5]=1.C([Li])CCC.[N:35]1([CH2:40][C:41](=O)[CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[CH:39]=[CH:38][N:37]=[CH:36]1.C(OCC)(=O)C>O1CCCC1.CCCCCC>[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:41]([CH2:42][O:43][CH2:44][C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[CH2:40][N:35]2[CH:39]=[CH:38][N:37]=[CH:36]2)=[CH:6][CH:5]=1
Reactant: COc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: COc1ccc(COCC(=O)Cn2ccnc2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C=C(COCc2ccc(OC)cc2)Cn2ccnc2)cc1
Temperature: -20 °C
Reaction time: 0.33 h

Procedure:
A stirred suspension containing [(4-methoxyphenyl)methyl]triphenylphosphonium bromide (8.3 g, 0.020 mol) in dry tetrahydrofuran (50 ml) at -20° C. under a nitrogen atmosphere was treated with a solution containing n-butyl lithium (14.3 ml of 1.4M; 0.020 mol) in hexane. The resulting deep-red solution was stirred at -20° C. for 20 minutes and was allowed to warm to room temperature. Stirring was maintained for an additional 20 minutes and the solution was cooled to -20° C. The cooled solution was treated with a solution of 1-(1H-imidazol-1-yl)-3-[(4-methoxyphenyl)methoxy]-2-propanone (Example 1c; 2.6 g, 0.010 mol) in dry tetrahydrofuran (20 ml) and the resulting mixture was stirred at room temperature for 14 hours. Ethyl acetate (500 ml) was added to the mixture and the resulting mixture was washed with water (3×150 ml) and dried over sodium sulfate. The solvent was evaporated off under reduced pressure to yield a crude product which was purified by column chromatography (silica gel, 30% hexane in chloroform) to give an isomeric mixture of E- and Z-1-[3-(4-methoxyphenyl)-2-[[(4-methoxyphenyl)methoxy]methyl]-2-propenyl]-1H-imidazole as a pale-yellow oil having the following structural characteristics:
Reaction SMILES: [NH4+:1].[OH-].Br[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]>>[NH2:1][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][O:9][C:10]1[C:11]([O:30][CH3:31])=[CH:12][CH:13]=[C:14]2[C:19]=1[O:18][C:17](=[O:20])[CH:16]=[C:15]2[NH:21][C:22]1[C:27]([Cl:28])=[CH:26][N:25]=[CH:24][C:23]=1[Cl:29]
Reactant: [NH4+]
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCBr
Agent: [OH-]
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1OCCCCCN

Procedure:
The title compound was prepared from 28% NH4OH solution and 8-(5-bromopentyloxy)-4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2H-chromen-2-one (Example 28) following the procedure outlined in Example 52. 1H NMR (400 MHz, DMSO-d6; HCl salt): δ 9.64 (s, 1H), 8.81 (s, 2H), 8.00 (d, 1H), 7.83 (br, 3H), 7.21 (d, 1H), 4.63 (s, 1H), 3.98 (t, 2H), 3.92 (s, 3H), 2.79 (m, 2H), 1.75-1.50 (m, 6H); MS (ESI): 437.9.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[Cl:11][C:12]1[N:17]=[C:16](Cl)[C:15]([Cl:19])=[CH:14][N:13]=1.Cl>CC(O)C>[Cl:11][C:12]1[N:17]=[C:16]([NH:1][C:2]2[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4]([NH2:6])=[O:5])[C:15]([Cl:19])=[CH:14][N:13]=1
Reactant: NC(=O)c1ccccc1N
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: Cl
Solvent: CC(C)O
Product: NC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Temperature: 60 °C

Procedure:
A mixture of 2-aminobenzamide (681 mg, 5.0 mmol), 2,4,5-trichloropyrimidine (2.75 g, 15 mmol, 3 equiv.) and concentrated HCl (aq) (1.72 mL, 20 mmol, 4 equiv.) in 2-propanol (100 mL) is heated at 60° C. for 12 h. The 2-propanol solvent is removed in vacuo. The resulting residue is neutralized to approximately pH=7 by adding 1 N NaOH (aq) followed by partition between EtOAc and water. Upon partition between EtOAc and water, a significant amount of precipitate is produced. This precipitate is collected by vacuum filtration and washed with small amounts of EtOAc and water, providing the product 2-(2,5-dichloropyrimidin-4-ylamino)benzamide; ESMS m/z 283.0 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:11]=1)[C:7](Cl)=[N:8][OH:9].[C:12]([C:14]1[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=1)#[CH:13].N>>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]2[CH:13]=[C:12]([C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[O:9][N:8]=2)[CH:5]=[N:4][CH:3]=1
Reactant: ON=C(Cl)c1cncc(Cl)c1
Reactant: C#Cc1ccc(C#N)cc1
Agent: N
Product: N#Cc1ccc(-c2cc(-c3cncc(Cl)c3)no2)cc1

Procedure:
The titled compound was prepared according to Method CB using the product of Example 69B (57 mg, 0.3 mmol) and 4-ethynylbenzonitrile (Aldrich, 38 mg, 0.3 mmol). 1H NMR (300 MHz, DMSO-d6) δ8.00 (s, 1H), 8.09 (s, 4H), 8.45 (t, J=2.1 Hz, 1H), 8.82 (d, J=2.4 Hz, 1H), 9.09 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 282 (M+H)+, 284 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+].O>C(O)C.CCOC(C)=O>[CH3:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][C:20]=1[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2
Reactant: Brc1ccc2c(N3CCOCC3)nncc2c1
Reactant: Cc1ccc(C(=O)O)cc1B1OC(C)(C)C(C)(C)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Solvent: O
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(N3CCOCC3)nncc2c1

Procedure:
6-Bromo-1-morpholinophthalazine (191 mg, 649 μmol), 4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid (170 mg, 649 μmol), and tetrakis (triphenylphosphine)palladium (75 mg, 65 μmol) were added to a microwave vial before sodium carbonate-2 N in water (1.9 mL, 3892 μmol) and ethanol (3.2 mL) were added. The reaction mixture was reacted in a microwave oven for 10 min at 160° C. The reaction was cooled, diluted with 50 mL of EtOAc, added to an addition funnel and partitioned with sodium bicarbonate (saturated, aqueous). The organic layer was washed 2 times with 50 mL of sodium bicarbonate (saturated, aqueous), and separated. The aqueous layer was acidified to pH 5 with conc. HCl and extracted 4 times with 50 mL of chloroform. The organic layers were combined, dried over sodium sulfate, and concentrated via rotovap to give the title compound. Found MS (ES+): 350 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[O:8]C.C1CCCCC=1.B(Br)(Br)Br.ClCCl>>[F:1][C:2]1[CH:3]=[C:4]([S:10]([N:13]2[CH:26]([CH3:27])[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]2=3)(=[O:11])=[O:12])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccccc3C2C)cc1F
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: C1=CCCCC1
Product: CC1c2ccccc2-c2ccccc2N1S(=O)(=O)c1ccc(O)c(F)c1
Yield: 73.8 %

Procedure:
The title compound was prepared from 5-[(3-fluoro-4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine (0.5 g, 1.3 mmol), cyclohexene (0.33 mL, 3.25 mmol) and 1.0 M boron tribromide in dichloromethane (7.8 mL, 7.8 mmol) according to the procedure and in the same manner as described in Example 1, step b. The crude product was purified by flash column chromatography on silica gel, eluting sequentially with dichloromethane and ethyl acetate to yield 2-fluoro-4-[(6-methylphenanthridin-5(6H)-yl)sulfonyl]phenol (0.35 g, 0.96 mmol, 74%) as a light-yellow solid, m.p. 172-174° C.;
Reaction SMILES: [CH:1]1([C:4]2[O:5][C:6]3[C:7](=[C:9]([C:21]#[N:22])[C:10]([CH3:20])=[C:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:12]=3F)[N:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[C:29]([O:36][CH3:37])(=[O:35])[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(OCC)(=O)C>CS(C)=O.O>[C:21]([C:9]1[C:7]2[N:8]=[C:4]([CH:1]3[CH2:3][CH2:2]3)[O:5][C:6]=2[C:12]([CH:30]([C:29]([O:36][CH3:37])=[O:35])[C:31]([O:33][CH3:34])=[O:32])=[C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]=1[CH3:20])#[N:22]
Reactant: COC(=O)CC(=O)OC
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C3CC3)nc2c1C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)C(C(=O)OC)c1c(-c2ccccc2)c(C)c(C#N)c2nc(C3CC3)oc12
Temperature: 90 °C
Reaction time: 14 h
Yield: 77.4 %

Procedure:
2-Cyclopropyl-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-carbonitrile (I-173) (2.69 g, 9.20 mmol) was dissolved in dimethyl sulfoxide (50 ml), then at room temperature, potassium carbonate (3.82 g, 27.61 mmol) and dimethyl malonate (2.1 ml, 18.41 mmol) were added. The solution was stirred under nitrogen atmosphere at 90° C. for 14 hours. The reaction liquid was cooled to room temperature, then ethyl acetate and water were added to the reaction liquid, followed by vigorously stirring for 10 minutes. The aqueous layer was separated, extracted twice with ethyl acetate. The organic layers were combined, washed with saturated brine, then dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, the solvent was evaporated away, and the resulting residue was purified by middle-pressure liquid chromatography (eluent, n-hexane:ethyl acetate=3:1, v/v) to obtain the entitled compound (2.878 g, 77%) as a colorless gel
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.Cl[C:7]1[S:26][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]3[CH:8]=[CH:7][S:26][C:10]=3[N:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: O=[N+]([O-])c1cccc(CNc2ncnc3sc(Cl)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cncn3)nc3sccc23)c1

Procedure:
Following the procedure of Example 97, the reaction of 1,2,4-triazole with 6-chloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(1,2,4-triazol-1-yl)-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[S:6][C:7]([C:11]([OH:13])=O)=[C:8]([CH3:10])[N:9]=2)[CH2:3][CH2:2]1.C1(NC2SC(C(Cl)=O)=C(C)N=2)CC1.P(Cl)(Cl)(Cl)(Cl)Cl.Cl.[NH2:34][CH:35]([C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)[C:36]#[N:37]>C(N(CC)CC)C>[C:36]([CH:35]([NH:34][C:11]([C:7]1[S:6][C:5]([NH:4][CH:1]2[CH2:2][CH2:3]2)=[N:9][C:8]=1[CH3:10])=[O:13])[C:38]1[CH:42]=[CH:41][S:40][CH:39]=1)#[N:37]
Reactant: N#CC(N)c1ccsc1
Reactant: Cc1nc(NC2CC2)sc1C(=O)O
Agent: Cc1nc(NC2CC2)sc1C(=O)Cl
Agent: Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1nc(NC2CC2)sc1C(=O)NC(C#N)c1ccsc1
Yield: 32.5 %

Procedure:
1.4g of 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid was converted into 2-cyclopropylamino-4-methyl-thiazole-5-carboxylic acid chloride using 1.6g of phosphorus pentachloride according to the same procedure as EXAMPLE 1. Then 1.4g of amino-thiophen-3-yl-acetonitrile hydrochloride and 3.2ml of triethylamine were added thereto and the reaction mixture was treated according to the same procedure as EXAMPLE 1 to obtain 0.73g (Yield 35%) of the title compound.