Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([CH3:35])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:34])([F:33])[C:29]([F:32])([F:31])[F:30])=[O:24])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:4].CCCCCCC>C(O)(C)C>[F:1][C@:2]([CH3:35])([C:23]([NH:25][CH2:26][CH2:27][C:28]([F:33])([F:34])[C:29]([F:32])([F:31])[F:30])=[O:24])[C:3]([NH:5][C@@H:6]1[C:12](=[O:13])[N:11]([CH3:14])[C:10]2[CH:15]=[CH:16][CH:17]=[CH:18][C:9]=2[C:8]2[CH:19]=[CH:20][CH:21]=[CH:22][C:7]1=2)=[O:4]
Reactant: CN1C(=O)[C@@H](NC(=O)C(C)(F)C(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21
Solvent: CC(C)O
Solvent: CCCCCCC
Product: CN1C(=O)[C@@H](NC(=O)[C@](C)(F)C(=O)NCCC(F)(F)C(F)(F)F)c2ccccc2-c2ccccc21
Yield: 11 %

Procedure:
The separation of 0.2 g of the two isomers of (2RS)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide (Example WG) was performed on a preparative chiral HPLC column (CHIRALPAK® AD, pressure: flow: 35 ml/min) using a 4:1 mixture of n-heptane and isopropanol as the eluent. There were obtained 23 mg [11% of theory, optical integrity >99.5% d.e., MS: m/e=502 (M+H)+] of the first eluting isomer (2R)-2-Fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide and 22 mg [11% of theory, optical integrity >99.5% d.e., MS: m/e=502 (M+H)+] of the later eluting isomer (2S)-2-fluoro-2-methyl-N-[(S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-N′-(3,3,4,4,4-pentafluoro-butyl)-malonamide, each as a yellowish foam.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:7]=[N:8][C:9]([O:12][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[N:10][CH:11]=1.O.C(Cl)(Cl)Cl>C(OCC)C>[N+:1]([C:16]1[CH:17]=[CH:18][C:13]([O:12][C:9]2[N:10]=[CH:11][C:6]([Cl:5])=[CH:7][N:8]=2)=[CH:14][C:15]=1[OH:19])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: Oc1cccc(Oc2ncc(Cl)cn2)c1
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCOCC
Product: O=[N+]([O-])c1ccc(Oc2ncc(Cl)cn2)cc1O
Yield: 49.2 %

Procedure:
Fuming nitric acid (1.3 g) was added slowly to a stirred suspension of 3-(5-chloro-2-pyrimidyloxy)phenol (2.2 g) in diethyl ether (20 ml) at 20° C. The temperature rose to 30° C. and the resultant orange solution was allowed to stand for 48 hr before the addition of water and extraction with chloroform (100 ml). The chloroform extracts were dried and evaporated to give a pale yellow crystalline solid (1.3 g). Chromatography on a column of silica gel (80 g) with chloroform elution gave the title compound as a pale yellow-solid from the first fraction (0.7 g, 28%). The compound was identified from its pmr spectrum.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]1[C:11](=[O:42])[CH:12]([CH:15]([OH:41])[C:16]3[N:17]=[CH:18][N:19]([C:22]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C:20]=3[CH3:21])[CH2:13][CH2:14][C:6]1=[C:5]2[CH3:43].N1C=CC=CC=1.[C:50](OC(=O)C)(=[O:52])[CH3:51]>ClCCl>[C:50]([O:41][CH:15]([C:16]1[N:17]=[CH:18][N:19]([C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:20]=1[CH3:21])[CH:12]1[C:11](=[O:42])[N:7]2[C:8]3[C:4]([C:5]([CH3:43])=[C:6]2[CH2:14][CH2:13]1)=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=3)(=[O:52])[CH3:51]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1c2n(c3ccc(Cl)cc13)C(=O)C(C(O)c1ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c1C)CC2
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)OC(c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C)C1CCc2c(C)c3cc(Cl)ccc3n2C1=O

Procedure:
To a solution of 2-chloro-8,9-dihydro-7-[(hydroxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-10-methylpyrido[1,2-a]indol-6(7H)-one (1.64 g) in dichloromethane (32 ml) were added pyridine (0.83 ml) and acetic anhydride (0.53 ml). The solution was refluxed for 24 hours. After being cooled, the solution was washed with water twice and brine, dried over sodium sulfate, and evaporated, to give 7-[(acetoxy)(5-methyl-1-trityl-1H-imidazol-4-yl)methyl]-2-chloro-8,9-dihydro-10-methylpyrido[1,2-a]indol-6(7H)-one (1.49 g).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:6][C:5]=2[C:4]2[C:19]([CH2:30][C:31]#N)=[N:20][N:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:22](=[O:23])[C:3]1=2.[OH-:33].[K+].COCCO.[OH2:40]>>[CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][C:7]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:6][C:5]=2[C:4]2[C:19]([CH2:30][C:31]([OH:40])=[O:33])=[N:20][N:21]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C:22](=[O:23])[C:3]1=2
Reactant: Cn1c2ccc(OCc3ccccc3)cc2c2c(CC#N)nn(-c3ccccc3)c(=O)c21
Reactant: [OH-]
Reactant: O
Agent: [K+]
Solvent: COCCO
Product: Cn1c2ccc(OCc3ccccc3)cc2c2c(CC(=O)O)nn(-c3ccccc3)c(=O)c21

Procedure:
A solution of 1.15 g (2.7 mmol) of 5-methyl-4-oxo-3-phenyl-8-(phenylmethoxy)-3,5-dihydro-4H-pyridazino[4,5-b]indole-1-acetonitrile and of 1.54 g (39 mmol) of potassium hydroxide in a mixture of 10 ml of water and of 20 ml oF 2-methoxyethanol is heated at reflux. The mixture is extracted with dichloromethane, the aqueous phase is acidified and extracted with ethyl acetate, the organic phase is dried over sodium sulphate and the solvent is evaporated under reduced pressure. 0.38 g (0.86 mmol) of solid is isolated, which solid is used as is in the following stage.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[C:9]1(=[O:19])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][NH:10]1>C(#N)C>[Cl:1][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9](=[O:19])[NH:10][CH:11]=1
Reactant: O=c1[nH]ccc2ccccc12
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC#N
Product: O=c1[nH]cc(Cl)c2ccccc12
Temperature: 25 °C
Yield: 91.2 %

Procedure:
A solution of N-chlorosuccinimide (9.66 g, 72 mmol) in acetonitrile (MeCN) (80 mL) was added dropwise to a stirred solution of 1-(2H)-isoquinolone (10 g, 69 mmol) in MeCN (250 mL) which was being heated under reflux. The mixture was heated under reflux for an additional 1.5 h and then cooled to room temperature. The resulting precipitate was collected by filtration, with MeCN rinsing, and then dried in vacuo to give 4-chloro-1(2H)-isoquinolone (11.3 g, 62.9 mmol) as a pale pink solid.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2[CH:44]=[CH:45][CH:46]=[N:47]C1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)CC>>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:47][CH:46]5[CH2:44][CH2:45]5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCCN
Product: COc1cc(C(=O)NC2CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C

Procedure:
The title compound was synthesized from 4-(9-Cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 1-propylamine. The final compound was purified by reverse phase HPLC and basified to give the free base. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.57 (dd, J=3.66, 2.40 Hz, 2 H) 0.70 (dd, J=6.95, 2.15 Hz, 2 H) 1.50-1.77 (m, 6 H) 1.88-1.97 (m, 2 H) 2.82 (td, J=7.33, 3.54 Hz, 1 H) 3.17 (s, 3 H) 3.92 (s, 3 H) 3.99-4.08 (m, 3 H) 4.75 (d, J=8.84 Hz, 1 H) 7.40-7.51 (m, 2 H) 7.96 (s, 1 H) 8.26 (d, J=8.34 Hz, 1 H) 8.35 (d, J=4.04 Hz, 1 H). [M+H] C24H28F2N6O3 calc'd for, 487; found 487.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH:21]=O)[CH3:16].[NH2:30][C:31]([NH2:33])=[O:32].Cl>CCO.CO.CCOC(C)=O>[CH2:15]([O:17][C:18]1[CH:19]=[C:20]([CH:21]2[C:8]([C:9]3[S:10][CH:11]=[CH:12][CH:13]=3)=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:33][C:31](=[O:32])[NH:30]2)[CH:23]=[C:24]([N+:27]([O-:29])=[O:28])[C:25]=1[OH:26])[CH3:16]
Reactant: NC(N)=O
Reactant: O=C(Cc1cccs1)c1ccccc1
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2cccs2)cc([N+](=O)[O-])c1O
Yield: 6.2 %

Procedure:
A mixture of 1-phenyl-2-(thiophen-2-yl)ethanone (Intermediate 1, see Example 178 for synthesis of all Intermediates) (200 mg, 0.99 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (200 mg, 0.94 mmol), and urea (175 mg, 2.82 mmol) in anhydrous EtOH (20 mL) was added concentrated HCl solution (0.1 mL), and the reaction mixture was refluxed for three days. When TLC (EtOAc:MeOH=10:1) showed that about 50% of starting materials were consumed, the reaction mixture was concentrated, and the crude product was purified by column chromatography (EtOAc:MeOH=40:1) and preparative HPLC to afford Compound 4 as a yellow solid (27 mg, yield 6.2%). 1H NMR (DMSO-d6 400 MHz): δ 10.30 (s, 1H), 8.89 (s, 1H), 7.65 (s, 1H), 7.53 (s, 1H), 7.40 (s, 3H), 7.34 (s, 3H), 7.10 (d, J=5.2 Hz, 1H), 6.71-6.73 (m, 1H), 6.56 (s, 1H), 5.24 (s, 1H), 4.10 (q, J=7.2 Hz, 2H); 1.37 (t, J=7.2 Hz, 3H); MS (ESI): m/z 438.2 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[N:3]=1.C(O)C.O.[NH2:26]N>C(O)(=O)C>[NH:1]([C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:5]2[CH:15]=[C:16]([N+:19]([O-:21])=[O:20])[CH:17]=[CH:18][C:4]=2[N:3]=1)[NH2:26]
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Reactant: NN
Solvent: CCO
Solvent: CC(=O)O
Solvent: O
Product: NNC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2)=NC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 5.6 parts of 2-amino-7-nitro-5-phenyl-3H-1,4-benzodiazepine, 200 parts by volume of ethanol and 2.4 parts by volume of glacial acetic acid is added with stirring 5 parts by volume of 80% hydrazine hydrate. The mixture is stirred for 30 minutes at room temperature and treated in a similar manner to Example 1, whereby 2-hydrazino-7-nitro-5-phenyl-3H-1,4-benzodiazepine is yielded as reddish, viscous oily substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:12]=2[N:13]=1.[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28]Br>>[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:22]=1[CH2:28][N:13]1[C:12]2[CH:14]=[C:15]([CH3:19])[CH:16]=[C:17]([CH3:18])[C:11]=2[N:10]=[C:9]1[C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[F:1]
Reactant: Cc1cc(C)c2[nH]c(-c3c(F)cccc3F)nc2c1
Reactant: Fc1cccc(F)c1CBr
Product: Cc1cc(C)c2nc(-c3c(F)cccc3F)n(Cc3c(F)cccc3F)c2c1
Yield: 91.2 %

Procedure:
To 2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (Example 94) (0.50 g, 1.94 mmol) was added 2,6-difluoro-α-bromotoluene (0.52 g, 2.51 mmol, 130 M%). Flash chromatography of the crude product eluting with 2% methanol/CH2Cl2, and recrystallization from hexane gave white crystals of 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4,6-dimethylbenzimidazole (0.68 g, 1.77 mmol, 91% yield). 1H NMR (200 MHz, CD2Cl2): δ7.51 (cm, 1H, H4), 7.23 (m, 1H, H4″), 7.11 (m, 1H, H5), 7.05 (cm, 2H, H3′,5′), 6.93 (m, 1H, H7), 6.80 (cm, 2H, H3″,5″), 5.29 (s, 2H, CH2PhF2), 2.58 (s, 3H, CH3), 2.44 (s, 3H, CH3).
Reaction SMILES: [NH2:1][C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH:25]1[CH:30]=[CH:29][C:28]([CH2:31][O:32][C:33](Cl)=[O:34])=[CH:27][CH:26]=1>O1CCOCC1.O>[NH:1]([C:33]([O:32][CH2:31][C:28]1[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=1)=[O:34])[C@H:2]([C:15]([O:17][CH3:18])=[O:16])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[C:6]([C:11]([CH3:14])([CH3:12])[CH3:13])[CH:5]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: COC(=O)[C@@H](N)Cc1ccc(O)c(C(C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)[C@H](Cc1ccc(O)c(C(C)(C)C)c1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 86 %

Procedure:
To a solution of Tyr(3-tBu)-OMe (41.4 g, 0.165 mol) in 1,4-dioxane (170 ml) and H2O (170 ml), under cooling with ice, sodium carbonate (26.2 g, 0.247 mol) was added and then Z—Cl (24.7 ml 0.173 mol) was further added over 25 min., followed by stirring for 2.5 hours at room temperature. The reaction mixture was mixed with water, extracted with chloroform, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure. The thus precipitated crystals were collected by filtration, washed with n-hexane and dried to give Z-Tyr(3-t-Bu)-OMe (54.7 g, 86%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]=O)[CH:8]=[CH:9][C:2]1=2.[CH3:12][NH2:13].[BH4-].[Na+].O>CO>[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH2:10][NH:13][CH3:12])[CH:8]=[CH:9][C:2]1=2
Reactant: CN
Reactant: O=Cc1ccc2sccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CNCc1ccc2sccc2c1
Reaction time: 3 h
Yield: 89.3 %

Procedure:
Benzo[b]thiophene-5-carbaldehyde (276 mg, 1.70 mmol) was dissolved in anhydrous methanol (8.0 mL). Methylamine (0.68 mL of 33% solution in ethanol, 5.46 mmol) was added and the reaction was stirred for 3 h. The solution was concentrated to a white solid and then dissolved in anhydrous methanol (10 mL). Sodium borohydride (66.0 mg, 1.75 mmol) was added and the mixture was stirred overnight at room temperature. Water (8.0 mL) was added and the solution was concentrated. Sodium hydroxide (10 mL, 1N) was added and the aqueous layer was extracted with ethyl acetate (3×20 mL). Combined organic layers were dried over MgSO4, filtered and concentrated to afford benzo[b]thiophen-5-yl-N-methylmethanamine (269 mg, 89%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 7.90 (d, J=8.7 Hz, 1H), 7.79 (s, 1H), 7.71 (d, J=5.7 Hz, 1H), 7.40 (d, J=5.4 Hz, 1H), 7.32 (d, J=8.1 Hz, 1H), 3.73 (s, 2H), 2.26 (s, 3H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[OH:37]>CCOCC>[Cl:29][C:30]1[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=1[O:37][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[O:12][N:11]=[C:10]([CH3:13])[CH:9]=1)[O:6][CH3:7]
Reactant: COC(c1cc(C)no1)c1ccccc1CCl
Reactant: Oc1cc(Cl)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(c1cc(C)no1)c1ccccc1COc1cc(Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 74 %

Procedure:
To 0.25 g (1 mmol) of 5-(2-chloromethyl-α-methoxybenzyl)-3-methylisoxazole, 2 ml of N,N-dimethylformamide, 0.28 g (2 mmol) of potassium carbonate and 0.33 g (2 mmol) of 2,5-dichlorophenol were added and stirred at 80° C. for 3 hours. After completion of the reaction, 100 ml of ether was added and washed twice with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) and recrystallized from ether/n-hexane to give 5-[2-(2,5-dichlorophenoxymethyl)-α-methoxybenzyl]-3-methylisoxazole (0.28 g, 74.0%) as colorless crystals. mp. 78.5-79.5° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[OH:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:30]=[CH:29][C:25]([C:26]([O-])=[O:27])=[CH:24][CH:23]=3)=[N:21][C:17]=2[CH:16]=1>>[OH:14][C:15]1[CH:32]=[CH:31][C:18]2[NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([NH:11][C:10]4[CH:12]=[CH:13][C:7]([N:4]5[CH2:3][CH2:2][O:1][CH2:6][CH2:5]5)=[CH:8][CH:9]=4)=[O:27])=[CH:29][CH:30]=3)=[N:21][C:17]=2[CH:16]=1
Reactant: Nc1ccc(N2CCOCC2)cc1
Reactant: O=C([O-])c1ccc(-c2nc3cc(O)ccc3[nH]2)cc1
Product: O=C(Nc1ccc(N2CCOCC2)cc1)c1ccc(-c2nc3cc(O)ccc3[nH]2)cc1

Procedure:
Compound 459 was prepared from 4-morpholinoaniline and 4-(5-hydroxy-1H-benzimidazol-2-yl)benzoate by standard conditions. [M+H]+ calcd for C24H22N4O3: 415.17; found: 415.05.
Reaction SMILES: Br[C:2]([CH3:8])([CH3:7])[C:3]([NH:5][CH3:6])=[O:4].[C:9]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>C1(C)C=CC=CC=1.[Ag]=O>[C:12]([O:11][C:9]([N:16]1[CH2:21][CH2:20][N:19]([C:2]([CH3:8])([C:3](=[O:4])[NH:5][CH3:6])[CH3:7])[CH2:18][CH2:17]1)=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CNC(=O)C(C)(C)Br
Agent: O=[Ag]
Solvent: Cc1ccccc1
Product: CNC(=O)C(C)(C)N1CCN(C(=O)OC(C)(C)C)CC1
Yield: 93.2 %

Procedure:
A mixture of 2-bromo-2, N-dimethyl-propionamide (312 mg), 1-BOC-piperazine (323 mg) and silver oxide (800 mg) was stirred in toluene (5 mL) at reflux. After 24 h the reaction mixture was cooled, filtered through celite, diluted with chloroform, washed with brine, dried (MgSO4) and the solvent was removed in vacuo to yield 4-(1-methyl-1-methylcarbamoyl-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (461 mg). Removal of the BOC group with HCl yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([O:27]C)=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+]>C(O)C>[F:32][C:2]([F:1])([F:33])[C:3]1[CH:4]=[C:5]([CH2:9][N:10]2[C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:24][C:25]([OH:27])=[O:26])[C:17]=3[C:16]3[C:11]2=[CH:12][CH:13]=[CH:14][C:15]=3[C:29](=[O:31])[NH2:30])[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1cccc(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: NC(=O)c1cccc2c1c1c(OCC(=O)O)cccc1n2Cc1cccc(C(F)(F)F)c1
Yield: 85 %

Procedure:
A solution of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester (91 mg, 0.153 mM) and 0.22 mL (0.22 mM) of 1 N NaOH in 8 mL of ethanol was stirred for 17 h at 25° C. The ethanol was removed in vacuo. The resultant white precipitate was collected by filtration, washed with small amounts of EtOH and diethyl ether, then dried in vacuo to afford 75 mg (81%) of the {9-[(3-trifluoromethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, sodium salt as a white powder. 1H NMR (DMSO-d6) δ 7.65 (s, 1H), 7.6 (m, 4H), 7.45 (t, 1H, J=8 Hz), 7.35 (t, 1H, J=8 Hz), 7.3 (t, 1H, J=8 Hz), 7.2 (d, 1H, J=8 Hz), 7.1 (d, 1H, J=8 Hz), 7.05 (d, 1H, J=8 Hz), 6.5 (d, 1H, J=8 Hz), 5.75 (s, 2H), and 4.3 (s, 2H). IR (KBr, cm−1) 1665 and 1618. MS (ES) m/e 441, 443.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2=[CH:12][CH:13]=[CH:14][CH:15]=[C:8]2[C:7]1=[O:16].[C:17]([NH:24][OH:25])([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(#N)C.N12CCCN=C1CCCCC2>O.Cl>[C:20]([O:19][C:17]([NH:24][O:25][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]1=[O:16])=[O:18])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NO
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)NOCCCCN1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
To a mixture of commercially available N-(4-bromobutyl)phthalimide (2.82 g, 10 mmol) and N-Boc-hydroxylamine (2.08 g, 15.6 mmol) was added acetonitrile (2 ml) and successively 1,8-diazabicyclo[5.4.0]undec-7-ene (2.25 ml, 15 mmol). The reaction mixture was stirred at room temperature for 30 min and then at 50° C. for 2 days. It was diluted with a mixture of water (30 ml) and 1 N hydrochloric acid (20 ml). It was extracted with ethyl acetate (2×100 ml). The organic phase was washed with brine (50 ml) and was dried over magnesium sulphate. The crude product was purified by chromatography on silica (60 g), using a gradient of heptane/ethyl acetate 1:0 to 0:1 as eluent to give 2.08 g of 2-(4-(tert-butoxycarbonylaminoxy)butyl)isoindole-1,3-dione.
Reaction SMILES: C1(C)C=CC(S([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:18])([F:17])[F:16])(=O)=O)=CC=1.[C:20]([O-])(=[S:22])[CH3:21].[K+].O>CC(C)=O>[C:20]([O:10][CH2:11][CH2:12][O:13][CH2:14][C:15]([F:16])([F:17])[F:18])(=[S:22])[CH3:21]
Reactant: Cc1ccc(S(=O)(=O)OCCOCC(F)(F)F)cc1
Reactant: CC([O-])=S
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CC(=S)OCCOCC(F)(F)F
Temperature: 25 °C
Reaction time: 48 h
Yield: 87.3 %

Procedure:
2-(2,2,2-trifluoroethoxy)ethyl p-toluenesulfonate (14.0 g, 47 mmol) and potassium thioacetate (10.0 g, 88 mmol) were dissolved in acetone (100 ml) and the mixture was stirred at room temperature for 2 days. The mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After concentration, silica gel column chromatography (n-hexane/ethyl acetate=10/1) gave 2-(2,2,2-Trifluoroethoxy)ethyl thioacetate (8.3 g, 87%)
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:17])[F:16])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([N:27]([CH:37]2[CH2:39][CH2:38]2)CC2C=CC(OC)=CC=2)[C:24]2=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]2[N:22]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH:15]([F:17])[F:16])[CH2:10][CH2:9]2)=[CH:6][C:5]([C:18]#[N:19])=[CH:4][C:3]=1[NH:20][C:21]1[N:26]=[C:25]([NH:27][CH:37]2[CH2:38][CH2:39]2)[C:24]2=[N:40][CH:41]=[C:42]([C:43]#[N:44])[N:23]2[N:22]=1
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCN(CC(F)F)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N#Cc1cc(Nc2nc(NC3CC3)c3ncc(C#N)n3n2)c(Cl)c(N2CCN(CC(F)F)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
To the stirred solution of 2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)-piperazin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (120 mg, 0.194 mmol) in dry dichloromethane (2.0 mL) was added anisole (0.1 mL, 0.915 mmol) and trifluoroacetic acid (0.3 mL, 3.87 mmol) at room temperature. The reaction mixture stirred at room temperature for overnight. On completion of the reaction, the reaction mixture was diluted with dichloromethane and washed with saturated sodium bicarbonate. The organic layer was separated and aqueous layer was extracted with dichloromethane twice. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo to give off-white solid. This was purified by preparative HPLC to afford 2-((2-chloro-5-cyano-3-(4-(2,2-difluoroethyl)piperazin-1-yl)phenyl)amino)-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (50 mg, 0.098 mmol, 50.5% yield) as an off-white solid