Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)=[CH:27][C:26]=1[F:36].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(OCC)(=O)C>[F:36][C:26]1[CH:27]=[C:28]([N:31]2[CH:35]=[CH:34][CH:33]=[N:32]2)[CH:29]=[CH:30][C:25]=1[CH2:24][C:9]1[C:10]([CH3:13])=[C:11]([CH3:12])[C:2]([OH:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: Fc1cc(-n2cccn2)ccc1CCl
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)c(C)c(C)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2F)c(C)c(C)c1O
Temperature: 80 °C
Reaction time: 8 h
Yield: 91.7 %

Procedure:
To a mixture of methyl 2-hydroxy-3,4-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (0.51 g), 1-(4-(chloromethyl)-3-fluorophenyl)-1H-pyrazole (0.35 g) and sodium carbonate (0.35 g) in 1,2-dimethoxyethane (7.80 mL)-water (2.60 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.10 g), and the mixture was stirred overnight at 80° C. under argon atmosphere. To the reaction mixture were added water and ethyl acetate, and the mixture was partitioned. The organic layer was washed with water and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.54 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([F:12])[CH:3]=1.O.[C:14](OC(=O)C)(=[O:16])[CH3:15]>C(O)(=O)C>[C:9]([NH:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:14](=[O:16])[CH3:15])=[CH:3][C:4]=1[F:12])(=[O:11])[CH3:10]
Reactant: CC(=O)OC(C)=O
Reactant: CC(=O)Nc1ccc(N)cc1F
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(NC(C)=O)c(F)c1
Temperature: 15 °C

Procedure:
134.5 g (0.8 mol) of the 1-amino-4-acetylamino-3-fluorobenzene prepared above under A. are heated at 85° C. together with 800 ml of water and 34 g of acetic acid. 86.5 g of acetic anhydride are added to this mixture in the course of one hour. The reaction mixture is subsequently stirred at the same temperature for a further hour and cooled to 15° C. The product which has precipitated is then filtered off, washed twice with 150 ml of water each time and dried.
Reaction SMILES: [CH3:1][C:2]([CH3:6])=[CH:3][CH2:4][OH:5].[CH3:7][C:8]([CH3:12])=[CH:9][CH:10]=O.COCCO.OO>O>[CH3:7][C:8](=[CH:9][CH2:10][CH2:1][C:2](=[CH:3][CH:4]=[O:5])[CH3:6])[CH3:12]
Reactant: CC(C)=CCO
Reactant: CC(C)=CC=O
Agent: OO
Solvent: COCCO
Solvent: O
Product: CC(C)=CCCC(C)=CC=O
Yield: 88 %

Procedure:
A mixture of 100 parts of 3-methyl-2-buten-1-ol, 100 parts of 3,3-dimethylacrolein, 200 parts of ethylene glycol monomethyl ether and 3 parts of 30% aqueous hydrogen peroxide solution is heated under reflux for six hours while stirring and the water formed is removed continuously using pentane as entrainer. Fractional distillation of the reaction product gives 84.5 parts of citral, equivalent to a yield of 88% of theory, at a conversion of 53% (based on 3,3-dimethylacrolein).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][C@@H:5]([CH3:8])[CH2:4][N:3]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].[F:16][C:17]1[CH:24]=[C:23](F)[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN1C(=O)N(C)CC1.C(#N)C>[C:19]([C:18]1[CH:21]=[CH:22][C:23]([N:6]2[C@@H:5]([CH3:8])[CH2:4][N:3]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[C@H:2]([CH3:1])[CH2:7]2)=[CH:24][C:17]=1[F:16])#[N:20]
Reactant: C[C@@H]1CN[C@@H](C)CN1C(=O)OC(C)(C)C
Reactant: N#Cc1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN1CCN(C)C1=O
Solvent: CC#N
Product: C[C@@H]1CN(c2ccc(C#N)c(F)c2)[C@@H](C)CN1C(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 48 h
Yield: 38.9 %

Procedure:
Into a solution of 9.74 g of tert-butyl (2R,5S)-2,5-dimethylpiperazine-1-carboxylate in 25 ml of DMI and 25 ml of acetonitrile were added 5 g of 2,4-difluorobenzonitrile and 11.4 g of cesium carbonate, followed by 2 days of stirring at 120° C. The reaction solution was poured into water, followed by extraction with ethyl acetate. After the organic layer was washed with saturated saline, it was dried over anhydrous sodium sulfate. The solvent was removed by evaporation and the resulting residue was purified by silica gel column chromatography to obtain 4.66 g of the title compound from an eluate eluted with hexane-ethyl acetate (80:20, v/v).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Cl[CH2:6][C:7]([O:9][CH3:10])=[O:8].[Cl:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:22]=1[O:23][CH3:24])[CH:18]=O.C[O-].[Na+].CO>CS(C)=O.CO.O>[CH3:10][O:9][C:7](=[O:8])[C:6]([N:1]=[N+:2]=[N-:3])=[CH:18][C:17]1[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:15]([O:14][CH2:13][CH2:12][Cl:11])[CH:16]=1
Reactant: COC(=O)CCl
Reactant: COc1ccc(C=O)cc1OCCCl
Reactant: [N-]=[N+]=[N-]
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CS(C)=O
Product: COC(=O)C(=Cc1ccc(OC)c(OCCCl)c1)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.8 %

Procedure:
NaN3 (22.2 g, 341 mmol) was added slowly to a solution of methyl chloroacetate (20.0 mL, 227 mmol) in DMSO (100 mL). After stirring at room temperature for 24 h, water (150 mL) was added and the mixture was extracted with Et2O (3×100 mL). The combined organic fractions were dried (MgSO4) and concentrated in vacuo to 50 mL. Then, a solution of aldehyde 15 (5.37 g, 25.0 mmol) in MeOH (50 mL) was added and the mixture was cooled to −30° C. After that, the reaction mixture was treated with 5.4 M NaOMe/MeOH (35.0 mL, 189 mmol) within 30 min at −30° C., warmed to 0° C. and diluted with MeOH (50 mL). After stirring for 16 h at 0° C., water (200 mL) was added and the mixture was extracted with CH2Cl2 (3×200 mL). The combined organic fractions were washed with brine (200 mL), dried (MgSO4), and the solvent was removed in vacuo to give 16 (6.84 g, 88% from 15) as a pale yellow solid that was used for the next step without further purification. 1H NMR (300 MHz, CDCl3): δ=3.84 (t, J=6.1 Hz, 2 H, 2″-H2), 3.87, 3.88 (2×s, 6 H, OMe, CO2Me), 4.29 (t, J=6.1 Hz, 2 H, 1″-H2), 6.83 (s, 1 H, 1′-H), 6.87 (d, J=8.5 Hz, 1 H, 5-H), 7.36 (dd, J=8.5, 2.1 Hz, 1 H, 6-H), 7.53 (d, J=2.1 Hz, 1 H, 2-H) ppm; 13C NMR (50.3 MHz, CDCl3): δ=41.6 (C-2″), 52.8 (CO2Me, 56.0 (OMe), 69.3 (C-1″), 111.5 (C-2), 116.2 (C-5), 123.4 (C-2′), 125.4, 126.0, 126.2 (C-1, C-1′, C-6), 147.1, 150.9 (C-3, C-4), 164.1 (C═O) ppm.
Reaction SMILES: Cl.[CH3:2][N:3](C)[OH:4].[CH2:6](N(CC)CC)C.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[C:22]([OH:24])=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(OC(Cl)=O)C(C)C.CN1CCOCC1.CN(C)O>C(Cl)Cl.C1COCC1>[CH:26]1([CH2:25][C@H:21]([NH:20][C:18](=[O:19])[O:17][C:13]([CH3:14])([CH3:15])[CH3:16])[C:22]([N:3]([O:4][CH3:6])[CH3:2])=[O:24])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C(=O)O
Reactant: CN(C)O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CON(C)C(=O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 105.2 %

Procedure:
To a solution of dimethylhydroxylamine hydrochloride (3.98 g, 40.6 mmol) in DCM (50 mL) at 0° C. was added triethylamine (5.43 mL, 41.9 mmol). In a separate flask (S)-2-((tert-butoxycarbonyl)amino)-3-cyclohexylpropanoic acid (10.0 g, 36.9 mmol) in DCM (50 mL) and THF (50 mL) was cooled to 0° C. and isobutylchloroformate (4.83 mL, 36.9 mmol) was added followed by N-methylmorpholine (4.06 mL, 36.9 mmol). After 1 h it was added to the dimethylhydroxylamine mixture. The combined mixture was allowed to warm to ambient temperature over 16 h at which time it was quenched with water, washed with sodium bicarbonate (sat.), extracted with EtOAc (2×), washed with brine, dried with sodium sulfate, filtered, and concentrated. (S)-tert-Butyl (3-cyclohexyl-1-(methoxy(methyl)amino)-1-oxopropan-2-yl)carbamate (12.2 g) was provided as a colorless oil that was carried forward without further purification. MS (EI) for C16H30N2O4, found 215.3 [M-Boc]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:11]2[CH2:13][CH2:12]2)=[CH:5][C:6]=1[C:7]([O:9]C)=O.ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[C:33]1([CH2:39][CH2:40][NH2:41])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C(Cl)Cl>[CH:11]1([C:4]2[S:3][C:2]3[NH:1][C:18](=[O:24])[N:41]([CH2:40][CH2:39][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:7](=[O:9])[C:6]=3[CH:5]=2)[CH2:13][CH2:12]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc(C2CC2)sc1N
Reactant: NCCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]c2sc(C3CC3)cc2c(=O)n1CCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 108.6 %

Procedure:
To a solution (15 mL) of methyl 2-amino-5-cyclopropylthiophene-3-carboxylate (0.5 g) in methylene chloride were added triphosgene (0.9 g) and triethylamine (1.5 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added 2-phenylethanamine (0.92 g), and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methanol (10 mL), sodium methoxide (0.5 g) was added, and the mixture was stirred at 60° C. for 2 hr. The reaction mixture was neutralized with hydrochloric acid (10% methanol solution), insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The precipitated solid was collected by filtration to give the title compound as a colorless solid (0.86 g, 100%).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]#N)[CH2:15][CH2:14]2)=[CH:9][CH:8]=1.[OH2:18]>>[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:16]([OH:2])=[O:18])[CH2:15][CH2:14]2)=[CH:9][CH:8]=1
Reactant: O
Reactant: N#CC1(c2ccc(I)cc2)CC1
Reactant: O=S(=O)(O)O
Product: O=C(O)C1(c2ccc(I)cc2)CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a mixture of concentrated sulfuric acid (20 ml) and water (30 ml) at room temperature, there was added 1-(4-iodophenyl)cyclopropanecarbonitrile (7.0 g, 0.026 m). The reaction mixture was refluxed for 15 hrs under nitrogen atmosphere. The reaction mixture was cooled to room temperature and extracted with ether-chloroform mixture (4×100 ml). The organic layer was washed with water (2×50 ml), brine (50 ml) and dried over magnesium sulfate. The solvent was removed to give 7.2 g of product (96% yield; M.P. 150°-152° C.). ##STR5## Xn =2-chloro, 6-fluoro.
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[C:4]([C:7]2[S:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:14][CH:13]=3)[N:11]=2)[N:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36]Cl)[CH:33]=[CH:32][N:31]=1>CN(C=O)C.O>[Cl:29][C:30]1[CH:35]=[C:34]([CH2:36][N:6]2[C:2]([CH3:1])=[N:3][C:4]([C:7]3[S:8][CH:9]=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:16][CH:17]=4)[N:11]=3)=[N:5]2)[CH:33]=[CH:32][N:31]=1
Reactant: ClCc1ccnc(Cl)c1
Reactant: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)n[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)nn1Cc1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.5 %

Procedure:
To a stirred mixture of 2-(5-methyl-1H-1,2,4-triazol-3-yl)-4-(4-(trifluoromethoxy)phenyl)thiazole (3 g, 9.2 mmol) and Cs2CO3 (4.8 g, 13 mmol) in DMF (20 mL) was added 2-chloro-4-(chloromethyl)pyridine (2.1 g, 13 mmol). The mixture was stirred at RT for 16 h, then diluted with H2O (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with H2O (20 mL), concentrated under reduced pressure and the residue was purified by silica gel column chromatography (Petroleum ether:EtOAc=4:1) to afford the title compound as an oil (2.1 g, 50.6%).
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36]([N:38]1[CH2:43][CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH2:40][CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[C:31]([O:35][C:36]([N:38]1[CH2:39][CH:40]=[C:41]([C:19]2[CH:20]=[CH:21][C:9]3[C:8](=[O:30])[C:7]4[C:6]5[C:14](=[CH:15][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[NH:13][C:12]=4[C:11]([CH3:17])([CH3:16])[C:10]=3[CH:18]=2)[CH2:42][CH2:43]1)=[O:37])([CH3:34])([CH3:32])[CH3:33]
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc3c(c2)C(C)(C)c2[nH]c4cc(C#N)ccc4c2C3=O)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 7.80 g, 18.0 mmol), 4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (6.11 g, 19.8 mmol, 1.1 eq.), Pd(PPh3)2Cl2 (630 mg, 0.898 mmol, 0.05 eq.), and sodium carbonate (5.71 g, 53.9 mmol, 3.0 eq.), DME (125 ml) and water (25 ml) were added. The mixture was subjected to reduced pressure under ultrasonication treatment, followed by flushing with nitrogen gas. This procedure was repeated five times and then degassed. After further stirring at 80° C. for 2 hr under nitrogen atmosphere, the mixture was cooled to room temperature, added with water (250 ml), and further stirred for 30 min. The precipitates were filtered and washed with water (50 ml). They were further washed with CH3CN (50 ml) to obtain the target compound as a crude product (gray powder, 7.54 g, 90%).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][CH2:29][N:30]1[CH2:33][CH:32]([C:34]([O:36]C)=[O:35])[CH2:31]1)[CH3:2].[OH-:38].[Na+].Cl.C([OH:44])(C)C>O>[F:25][C:24]([F:27])([F:26])[C:16]([OH:44])=[O:38].[CH2:1]([C:3]1[C:8]([C:9]2[S:10][C:11]([C:14]3[CH:19]=[CH:18][C:17]([O:20][CH:21]([CH3:23])[CH3:22])=[C:16]([C:24]([F:27])([F:26])[F:25])[CH:15]=3)=[N:12][N:13]=2)=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:28][CH2:29][N:30]1[CH2:31][CH:32]([C:34]([OH:36])=[O:35])[CH2:33]1)[CH3:2]
Reactant: CCc1c(CCN2CC(C(=O)OC)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Reactant: [OH-]
Reactant: CC(C)O
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCc1c(CCN2CC(C(=O)O)C2)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Product: O=C(O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 1-[2-(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)ethyl]-3-azetidinecarboxylate (D20) (25 mg) in isopropanol (2 mL) and water (2 mL) at room temperature was added sodium hydroxide (1.874 mg). The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was neutralized with 1 M HCl solution. The solvent was removed in vacuo. The residue was dissolved in THF, and filtered. The filtrate was purified by Mass Directed AutoPrep to give 1-[2-(2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}phenyl)ethyl]-3-azetidinecarboxylic acid (E7) (10 mg) as a TFA salt (off-white solid). δH (DMSO-d6, 400 MHz): 1.11 (3H, t), 1.34 (6H, d), 2.88 (4H, m), 3.43 (2H, m), 3.62 (1H, m), 4.29 (4H, m), 4.94 (1H, m), 7.39 (1H, t), 7.51 (3H, m), 8.24 (2H, m), 10.08 (1H, br s), 13.13 (1H, br s). δF (DMSO-d6, 376 MHz): −73.4, −61.3. MS (ES): C26H28F3N3O3S requires 519. found 520.2 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.CS([C:21]1[N:26]=[CH:25][C:24]2=[CH:27][CH:28]=[C:29]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]2[N:22]=1)=O.C(N(CC)C(C)C)(C)C.COCC(O)C>>[OH:17][C@@H:15]([CH3:16])[CH2:14][N:11]1[CH2:10][CH2:9][N:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:21]3[N:26]=[CH:25][C:24]4=[CH:27][CH:28]=[C:29]([C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[N:36]([CH3:41])[S:37]([CH3:40])(=[O:39])=[O:38])[N:23]4[N:22]=3)=[CH:7][CH:6]=2)[CH2:13][CH2:12]1
Reactant: CN(c1ccccc1-c1ccc2cnc(S(C)=O)nn12)S(C)(=O)=O
Reactant: C[C@H](O)CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCC(C)O
Product: C[C@H](O)CN1CCN(c2ccc(Nc3ncc4ccc(-c5ccccc5N(C)S(C)(=O)=O)n4n3)cc2)CC1
Yield: 56.2 %

Procedure:
(S)-1-[4-(4-Amino-phenyl)-piperazin-1-yl]-propan-2-ol (129.1 mg, 0.5488 mmol), N-[2-(2-M ethanesulfinyl-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide (100.0 mg, 0.2744 mmol) and N,N-Diisopropylethylamine (0.1434 mL, 0.8232 mmol) were dissolved in 1-Methoxy-2-propanol (1.00 mL, 10.2 mmol). The reaction was irradiated at 300 watts, 200° C. for 20 minutes or until HPLC showed consumption of starting material. The mixture was then reduced under nitrogen and the product was isolated and purified by Gilson prep HPLC to afford 82.63 mg of N-[2-(2-{4-[4-((S)-2-Hydroxy-propyl)-piperazin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-phenyl]-N-methyl-methanesulfonamide as a lyophilized powder. (M+H)=536.1. 1H NMR (400 MHz, DMSO, d6) δ 9.51 (s, 1H), 9.24 (s, 1H), 8.95 (s, 1H), 8.01 (d, 1H, J=7.52 Hz), 7.65 (d, 1H, J=7.65 Hz), 7.50 (m, 4H), 6.97 (m, 2H), 6.85 (m, 2H), 4.12 (m, 1H), 3.66 (m, 4H), 3.17 (m, 3H), 3.08 (s, 3H), 2.95 (m, 3H), 2.89 (s, 3H), 1.13 (d, 3H, J=5.08 Hz).
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:14]1([CH:20]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([OH:23])=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(Cl)(Cl)(Cl)Cl>[C:5]([C:20]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[C:21]([OH:23])=[O:22])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCCCCCCCCCCCCCCCC(C(=O)O)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)(Cl)Cl
Product: CCCCCCCCCCCCCCCCC(C(=O)O)(C(=O)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a one-liter glass reactor equipped with a mechanical stirrer, condenser, thermometer and addition funnel was charged 300 mls freshly distilled carbon tetrachloride. The flask and its contents were cooled to 0°-5° C. and 40 grams (0.30 mole) AlCl3 added slowly. This was followed by the dropwise addition of 42 grams (0.30 mole) benzoyl chloride and then 26.9 grams (0.075 mole) phenylstearic acid. The mixture was maintained at 0°-5° C. for one hour with agitation and then allowed to warm to room temperature and stirred overnight. A yield of 40.4 percent crude benzoylphenylstearic acid was obtained upon work up of the reaction mixture.
Reaction SMILES: [C:1]([C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]CC)=O)=[O:8])=[CH:5][CH:4]=1)#[N:2].[NH2:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([CH2:34][CH3:35])[C:26]3[C:31]([C:32]=2[CH:33]=1)=[CH:30][CH:29]=[CH:28][CH:27]=3.[CH3:36][CH2:37]N(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([C:7]([N:9]([CH2:36][CH3:37])[CH2:10][CH2:11][CH2:12][C:13]([NH:20][C:21]2[CH:22]=[CH:23][C:24]3[N:25]([CH2:34][CH3:35])[C:26]4[C:31]([C:32]=3[CH:33]=2)=[CH:30][CH:29]=[CH:28][CH:27]=4)=[O:15])=[O:8])=[CH:18][CH:19]=1)#[N:2]
Reactant: CCOC(=O)CCCNC(=O)c1ccc(C#N)cc1
Reactant: CCn1c2ccccc2c2cc(N)ccc21
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CCCC(=O)Nc1ccc2c(c1)c1ccccc1n2CC)C(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 11.4 %

Procedure:
To a solution of the compound obtained in Step 1 (0.23 g, 0.76 mmol), 3-amino-N-ethylcarbazole (159 mg, 0.76 mmol) and DIEA (0.396 mL, 2.27 mmol) in DMF (6 mL) was added HATU (359 mg, 0.94 mmol), and the mixture was stirred at room temperature for 14 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 10 to 100% ethyl acetate/hexane) to give the title compound (43.4 mg, 0.087 mmol, 11.56%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)[C:14]([O:16]C)=O)[C:7]2=[O:12].[NH3:25]>CO>[NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([CH:13]([C:18]1[CH:19]=[CH:20][C:21]([Cl:24])=[CH:22][CH:23]=1)[C:14]([NH2:25])=[O:16])[C:7]2=[O:12]
Reactant: N
Reactant: COC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Solvent: CO
Product: NC(=O)C(c1ccc(Cl)cc1)n1ccc2c(N)cccc2c1=O
Temperature: 70 °C

Procedure:
A pressure tube was charged with methyl 2-(5-amino-1-oxoisoquinolin-2(1H)-yl)-2-(4-chlorophenyl)acetate (1.35 g, 0.00394 mol) and ammonia in methanol (7 mL, 2M solution) was added and the reaction heated at 70° C. for 16 hours. The reaction mixture was cooled to room temperature and checked for completion. The reaction was only 20% complete. Further heating of the reaction for another 6 hours did not seem to help in the progress of the reaction. The solvent was removed and the residue was purified by flash chromatography to obtain the product as a light yellow solid. MS m/z=328.2 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9]1([OH:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC(C)([O-])C.[K+]>CS(C)=O>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:15][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:3]=1
Reactant: Brc1cccc(Br)n1
Reactant: Oc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Brc1cccc(Oc2ccccc2)n1
Temperature: 160 °C

Procedure:
2,6-Dibromo-pyridine (2 g, 8.44 mmol) and phenol (0.794 g, 8.44 mmol) were dissolved in DMSO (20 mL) and potassium tert-butoxide (0.947 g, 8.44 mmol) was added. The reaction was heated to 160° C. overnight then allowed to cool to room temperature. The reaction was submitted to aqueous workup and silica gel chromatography to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[N:5]([CH3:11])[C:6](=[O:10])[C:7]=1[C:8]#[N:9].[O:14]([CH2:21][CH:22]([OH:28])[CH2:23][NH:24][CH2:25][CH2:26][NH2:27])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CN(C)C=O>[ClH:1].[O:14]([CH2:21][CH:22]([OH:28])[CH2:23][NH:24][CH2:25][CH2:26][NH:27][C:2]1[N:3]([CH3:13])[C:4](=[O:12])[N:5]([CH3:11])[C:6](=[O:10])[C:7]=1[C:8]#[N:9])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cn1c(Cl)c(C#N)c(=O)n(C)c1=O
Reactant: NCCNCC(O)COc1ccccc1
Solvent: CN(C)C=O
Product: Cl
Product: Cn1c(NCCNCC(O)COc2ccccc2)c(C#N)c(=O)n(C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5 g. 4-Chloro-5-cyano-1,3-dimethylpyrimidine-2,6(1H,3H)-dione are added in small portions, with cooling, to a solution of 5.26 g. 1-phenoxy-3-(2-aminoethylamino)-propan-2-ol in 20 ml. dimethylformamide. The reaction mixture is stirred for 2 hours at ambient temperature, mixed with 60 ml. isopropyl alcohol, filtered with suction and the solid obtained subsequently washed with isopropyl alcohol. There are obtained 8.7 g. (85% of theory) of the desired product in the form of colorless crystals; m.p. 202°-204° C.