Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:22](#[N:25])[CH:23]=[CH2:24]>C1C=CC=CC=1>[CH:12]1[C:8]2[CH:9]=[CH:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH:16]3[CH2:17][CH2:18][N:19]([CH2:24][CH2:23][C:22]#[N:25])[CH2:20][CH2:21]3)[C:7]=2[CH:15]=[CH:14][CH:13]=1
Reactant: C1=Cc2ccccc2C(C2CCNCC2)c2ccccc21
Reactant: C=CC#N
Solvent: c1ccccc1
Product: N#CCCN1CCC(C2c3ccccc3C=Cc3ccccc32)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 1.00 gram (3.62 millimoles) of 4-(5H-dibenzo[a,d]cyclohepten-5-yl)piperidine in 20 milliliters of benzene and 0.38 gram (7.24 millimoles) of acrylonitrile were heated at reflux temperature while progress of the reaction was monitored by TLC. After 2.5 hours, the reaction mixture was cooled to room temperature, and the mixture subjected to reduced pressure to vaporize the benzene solvent and excess acrylonitrile and to obtain a solid residue. The solid was recrystallized from acetonitrile/ethyl acetate to obtain a purified 4-(5H-dibenzo[a,d]cyclohepten-5-yl)-1-(2-cyanoethyl)piperidine product which after drying at 100° C. at 1 millimeter mercury pressure for 2 hours and at room temperature for 15 hours, melted at 165°-168° C. The yield of the product was 760 milligrams (64 percent). A second crop was obtained which after recrystallization from acetonitrile was in the form of white needles, m.p. 169°-170° C. The product had elemental analyses as follows:
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][CH2:3][CH2:2]1.C([Li])CCC.[Br:16]C(F)(F)C(Br)(F)F>O1CCCC1>[Br:16][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[O:4][CH2:3][CH2:2][O:1][C:10]=12
Reactant: c1cnc2c(c1)OCCO2
Reactant: FC(F)(Br)C(F)(F)Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Brc1ccnc2c1OCCO2
Temperature: 25 °C

Procedure:
A solution of 2,3-dihydro-[1,4]dioxino[2,3-b]pyridine (prepared by the method of H. Neunhoffer et al, Chem., Ber., 1990, 123 (12), 2453) (1.37 g, 10 mmol) in tetrahydrofuran (20 ml) under argon at −78° C. was treated over 15 minutes with a solution of n-butyl lithium (20 mmol) in tetrahydrofuran (8 ml). After 30 minutes a solution of 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (2.6 g, 10 mmol) in tetrahydrofuran (10 ml) was added dropwise over 5 minutes. After a further 30 minutes the cooling bath was removed and saturated aqueous ammonium chloride (20 ml) and ether (20 ml) were added. The mixture was allowed to warm to room temperature then partitioned between ether/water. The organic extract was washed with half-saturated brine, dried and evaporated. The residue was chromatographed on silica eluting with a 0-30% gradient of ethyl acetate in dichloromethane affording a yellow solid (1.1 g, 51%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([OH:25])=[O:24].[C:26](Cl)(=O)C(Cl)=O.CO>CN(C=O)C.ClCCl>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:19])[F:20])[CH:13]=1)[C:6]([CH3:22])=[C:5]2[C:23]([O:25][CH3:26])=[O:24]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc2c1C(=O)O
Solvent: CN(C)C=O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 82.3 %

Procedure:
DMF (5 drops) was added to a suspension of 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylic acid (11.2 g, 32.1 mmol) in dichloromethane (120 mL) at 0° C. Oxalyl chloride (4.21 mL, 48.1 mmol) was added slowly. The mixture was stirred at 0° C. for 1 h. Methanol (30 mL) was added to the mixture, the mixture was stirred at 0° C. for 2 h and warmed to room temperature overnight. The solvent was removed under reduced pressure, and the residue was diluted with water and treated with saturated aqueous NaHCO3 until basic. The aqueous mixture was extracted with methylene chloride (three times). The combined organic phases were washed with brine (two times), dried over Na2SO4, filtered, and concentrated. The residue was purified via column chromatography (ISCO, 120 g Silica, 0-30% ethyl acetate/hexanes) to give methyl 6-fluoro-3-methyl-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (9.6 g, 82% yield). MS (m/z) 364.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:10]1([C@H:13]2[CH2:17][CH2:16][N:15]([C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[C:14]2=O)[CH2:12][CH2:11]1)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[C:1]([O:5][C:6]([N:8]([C:10]1([C@@H:13]2[CH2:17][CH2:16][N:15]([C@H:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH3:19])[CH2:14]2)[CH2:11][CH2:12]1)[CH3:9])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](c1ccccc1)N1CC[C@H](C2(N(C)C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccccc1)N1CC[C@@H](C2(N(C)C(=O)OC(C)(C)C)CC2)C1
Temperature: 25 °C
Yield: 99.4 %

Procedure:
3-(R)-[1-[N-(tert-butoxycarbonyl)-N-(methyl)amino]cyclopropyl]-1-[1-(S)-phenylethyl]pyrrolidin-2-one (7.53 g, 21.0 mmol) was dissolved in anhydrous tetrahydrofuran (70 ml) and a 1.0M borane-tetrahydrofuran complex/tetrahydrofuran solution (63.0 ml, 63.0 mmol) was added dropwise gradually thereto while stirring and cooling with ice. After completion of dripping, it was stirred at room temperature for 20 hours. After slowly adding an aqueous solution (72 ml) of potassium carbonate (7.22 g) while cooling with ice, it was heated under reflux for 1.5 hours. After letting the reaction solution cool to room temperature, water (150 ml) was added, extraction with ethyl acetate (200 ml×2) was performed, and then the combined organic layer was washed with saturated saline solution (200 ml) and then dried over anhydrous sodium sulfate. After filtering, the filtrate was concentrated under a reduced pressure, the concentrate was applied to a silica gel chromatography, and 7.19 g (99%) of the title compound was obtained in the form of a colorless syrup from a chloroform:methanol=50:1 eluate.
Reaction SMILES: C(O)(=O)C.C(O)C.[Cl:8][C:9]1[C:14]([N+:15]([O-])=O)=[CH:13][C:12]([C:18]2[C:22]([C:23]([F:26])([F:25])[F:24])=[C:21]([C:27]([F:30])([F:29])[F:28])[N:20]([CH3:31])[N:19]=2)=[C:11]([F:32])[CH:10]=1>[Fe].C(OCC)(=O)C>[NH2:15][C:14]1[C:9]([Cl:8])=[CH:10][C:11]([F:32])=[C:12]([C:18]2[C:22]([C:23]([F:24])([F:25])[F:26])=[C:21]([C:27]([F:30])([F:29])[F:28])[N:20]([CH3:31])[N:19]=2)[CH:13]=1
Reactant: Cn1nc(-c2cc([N+](=O)[O-])c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: CCO
Product: Cn1nc(-c2cc(N)c(Cl)cc2F)c(C(F)(F)F)c1C(F)(F)F
Reaction time: 2 h
Yield: 22 %

Procedure:
4,6 g (83 mmol) of iron powder, 14 ml of glacial acetic acid and 30 ml of ethanol were heated to 70-75° C. and the mixture was treated with 7 g (17 mmol) of 3-(4-chloro-2-fluoro-5-nitrophenyl)-l-methyl-4,5-di(trifluoromethyl)-1H-pyrazole. After the mixture had been stirred for 2 hours at reflux temperature, it was treated with 100 ml of ethyl acetate. The mixture was then filtered through kieselguhr, whereupon the filtrate was washed with saturated aqueous sodium hydrogen carbonate solution, dried over magnesium sulfate and finally concentrated. The residue was purified by means of silica gel chromatography (eluent: hexane/ethyl acetate=4:1). Yield: 22%.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:13]2[CH:9]3[CH2:10][NH:11][CH2:12][CH:8]3[CH2:7][C:6]=2[C:5]=1[O:16][CH3:17].C=O.[C:20]([O-])(=O)C.[Na+]>[Pd].CO>[ClH:1].[CH3:2][O:3][C:4]1[CH:15]=[CH:14][C:13]2[CH:9]3[CH2:10][N:11]([CH3:20])[CH2:12][CH:8]3[CH2:7][C:6]=2[C:5]=1[O:16][CH3:17]
Reactant: COc1ccc2c(c1OC)CC1CNCC21
Reactant: CC(=O)[O-]
Agent: [Pd]
Agent: C=O
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1OC)CC1CN(C)CC21

Procedure:
1.50 g. of the resultant compound of Example 6, 0.15 g. 5% Pd/C in 95 ml. methanol, 5 ml. 37% formaldehyde and 0.8 g. sodium acetate were hydrogenated at 3 atmospheres. The solution was concentrated after removal of the catalyst and the residue was made basic with KOH in water. This was extracted with CHCl3, dried (K2CO3) and concentrated. The residue was dissolved in acetonitrile and acidified with hydrochloric acid in ether to get 1.40 g. product, m.p. 160°-162° C.
Reaction SMILES: CON(C)[C:4](=[O:36])[C@@H:5]([NH:13][C:14]([CH2:16][N:17]1[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[CH:21][N:20]([C:29](=[O:31])[CH3:30])[CH:19]([CH:32]([CH3:34])[CH3:33])[C:18]1=[O:35])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C[Li].O1CCC[CH2:41]1.C1(C(C)C)C=CC=CC=1.[Cl-].[NH4+]>O1CCCC1>[C:29]([N:20]1[CH:21]=[C:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[N:17]([CH2:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4](=[O:36])[CH3:41])=[O:15])[C:18](=[O:35])[CH:19]1[CH:32]([CH3:34])[CH3:33])(=[O:31])[CH3:30]
Reactant: C1CCOC1
Reactant: CON(C)C(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Agent: [Cl-]
Agent: [Li]C
Agent: [NH4+]
Solvent: CC(C)c1ccccc1
Product: CC(=O)[C@H](Cc1ccccc1)NC(=O)CN1C(=O)C(C(C)C)N(C(C)=O)C=C1c1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A solution of N1-methoxy-N1-methyl-(2S)-2-{(3RS)-4-acetyl-3-isopropyl-2-oxo-6-phenyl-1,2,3,4-tetrahydropyrazin-1-yl}methylcarbonylamino-3-phenylpropionamide (122 mg, Compound No. 1-51) in anhydrous tetrahydrofuran (2 ml) is cooled to −78° C., a 1.0 M methyllithium/tetrahydrofuran/cumene solution (1.2 ml) is added thereto, and the mixture is stirred for 15 minutes. A saturated aqueous ammonium chloride solution is added to the reaction mixture, and the temperature is raised to 0° C. The whole is extracted with ethyl acetate, and the extract is washed with saturated brine and dried over anhydrous magnesium sulfate. The extract is concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography to give the titled compound (53.8 mg).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[C:3]1[C:8]([CH2:9][CH2:10][CH2:11][OH:12])=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH2:15][C:4]=12.I(C1C=CC=CC=1C(O)=O)(=O)=O>CS(C)=O.C(OCC)C>[CH3:17][Si:2]([CH3:1])([CH3:16])[C:3]1[C:8]([CH2:9][CH2:10][CH:11]=[O:12])=[CH:7][N:6]=[C:5]2[O:13][CH2:14][CH2:15][C:4]=12
Reactant: C[Si](C)(C)c1c(CCCO)cnc2c1CCO2
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOCC
Solvent: CS(C)=O
Product: C[Si](C)(C)c1c(CCC=O)cnc2c1CCO2
Temperature: 25 °C
Reaction time: 5 h
Yield: 87.8 %

Procedure:
A mixture of 3-[4-(trimethylsilyl)-2,3-dihydrofuro[2,3-b]pyridin-5-yl]propan-1-ol (6.54 g, 26.0 mmol) and orthoiodoxybenzoic acid (9.47 g, 33.8 mmol) in dimethyl sulfoxide (80 mL) was stirred at room temperature for 5 hr. The reaction solution was diluted with diethyl ether, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane=30/70→70/30) to give the title compound (5.69 g, yield 87%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([C:7]1[S:11][C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)[CH2:5][OH:6].C(N(CC)CC)C.FC(F)(F)S(O[Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42])(=O)=O>ClCCl.C1COCC1>[CH3:1][O:2][C:3](=[O:26])[CH:4]([C:7]1[S:11][C:10]([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:24])([F:25])[F:23])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)[CH2:5][O:6][Si:40]([CH:47]([CH3:49])[CH3:48])([CH:44]([CH3:46])[CH3:45])[CH:41]([CH3:43])[CH3:42]
Reactant: COC(=O)C(CO)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(CO[Si](C(C)C)(C(C)C)C(C)C)c1cnc(NC(=O)Nc2cccc(C(F)(F)F)c2)s1

Procedure:
To a mixture of compound 73.1 (1.67 mmol) and triethylamine (2.2 equivalent) in 1:1 dichloromethane/THF (12.0 mL) was added triisopropylsilyl trifluoromethanesulfonate (2.2 equivalents) dropwise at 0° C. After complete consumption of the starting material (TLC 30% EtOAc in hexanes) the reaction mixture is diluted with EtOAc and washed with 0.5 N HCl, saturated sodium bicarbonate, dried and concentrated to give a residue that was purified by flash column chromatography on silica gel (0 to 60% EtOAc in hexanes) to provide 2-{2-[3-(3-trifluoromethyl-phenyl)-ureido]-thiazol-5-yl}-3-triisopropylsilanyloxy-propionic acid methyl ester (compound 73.2) as a foam.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([OH:36])[C:16]1[N:20]([CH2:21][CH2:22][C:23](OC)=[O:24])[C:19]2[C:27]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=1.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:13]=[C:12]([Cl:14])[CH:11]=[CH:10][C:9]=1[CH:15]([OH:36])[C:16]1[N:20]([CH2:21][CH2:22][CH2:23][OH:24])[C:19]2[C:27]([N:31]([CH2:32][CH3:33])[CH2:34][CH3:35])=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=1
Reactant: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCC(=O)OC)c12
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(CC)c1cccc2nc(C(O)c3ccc(Cl)cc3Cl)n(CCCO)c12
Reaction time: 1 h
Yield: 78 %

Procedure:
To a suspension of lithium aluminum hydride (327 mg, 8.61 mmol) in tetrahydrofuran (38 mL) was added a solution of methyl 3-{2-[(2,4-dichlorophenyl)(hydroxy)methyl]-7-(diethylamino)-1H-benzimidazol-1-yl}propanoate (2.00 g, 4.31 mmol) in tetrahydrofuran (5 mL) at −5° C. After the addition, sodium sulfate decahydrate (3.3 g) was added. After 1 h, the resultant mixture was filtrated and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with a 30-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (1.42 g, 3.36 mmol, 78%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([O:27]C)=[O:26])[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-].[Na+].Cl>CO.[Cl-].[Na+].O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([OH:27])=[O:26])[CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: COC(=O)c1cccc(-c2cc(C)cc(Nc3nccc(C(F)(F)F)n3)c2)c1
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: O
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cccc(C(=O)O)c2)c1
Temperature: 110 °C

Procedure:
A suspension of methyl 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylate (550 mg, 1.420 mmol) and aqueous sodium hydroxide (1 M, 1.63 mL, 1.63 mmol) in methanol (9 mL) was heated to 110° C. for 10 minutes in a microwave reactor. The reaction mixture was then diluted with aqueous hydrochloric acid (2 M, 0.89 mL, 1.78 mmol), brine (20 mL), and ethyl acetate (50 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to yield 3′-methyl-5′-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}biphenyl-3-carboxylic acid. MS ESI calc'd. for C19H15F3N3O2 [M+H]+ 374, found 374.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([N:24](CC4C=CC(OC)=CC=4)CC4C=CC(OC)=CC=4)[N:18]=3)=[CH:15][C:14]([C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)([CH3:45])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9].FC(F)(F)S(O)(=O)=O.[OH-].[Na+]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:3]=[C:4]([NH:10][C:11]2[C:16]([C:17]3[N:22]=[C:21]([CH3:23])[N:20]=[C:19]([NH2:24])[N:18]=3)=[CH:15][C:14]([C:43]([N:46]3[CH2:51][CH2:50][O:49][CH2:48][CH2:47]3)([CH3:45])[CH3:44])=[CH:13][N:12]=2)[CH:5]=[N:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(C)(C)N4CCOCC4)cnc3Nc3cnc(OC)c(F)c3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: COc1ncc(Nc2ncc(C(C)(C)N3CCOCC3)cc2-c2nc(C)nc(N)n2)cc1F
Temperature: 80 °C
Yield: 29.1 %

Procedure:
4-(2-(5-Fluoro-6-methoxypyridin-3-ylamino)-5-(2-morpholinopropan-2-yl)pyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (0.363 g, 0.522 mmol) in TFA (3 mL) was treated with trifluoromethanesulfonic acid (0.232 mL, 2.61 mmol). The reaction was sealed and heated at 80° C. for 30 min, cooled, and poured onto ice. The mixture was basified with 10N NaOH and the reaction was partitioned between water and DCM. The aqueous layer was extracted with DCM (3×) and the combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This material was dissolved in DMSO and purified by prep HPLC (10-55% MeCN/H2O with 0.1% TFA). Product-containing fractions were treated with sat'd aq. NaHCO3 and DCM. The aq. layer was extracted with DCM (3×) and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to give 4-(2-(5-fluoro-6-methoxypyridin-3-ylamino)-5-(2-morpholinopropan-2-yl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.069 g, 0.152 mmol, 29.1% yield). m/z (ESI, +ve ion) 455 (M+H)+. 1H NMR (400 MHz, d6-DMSO) δ 11.91 (s, 1H); 8.90 (d, J=2.5 Hz, 1H); 8.48 (d, J=2.5 Hz, 1H); 8.33-8.44 (m, 2H); 7.88 (br. s., 1H); 7.73 (br. s., 1H); 3.93 (s, 3H); 3.57 (br. s., 4H); 2.44 (s, 3H); 2.36-2.43 (m, 4H); 1.35 (s, 6H).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][N:4]=1)[NH2:2].[C:15](OCC)(OCC)(OCC)[CH3:16]>>[C:9]1([C:6]2[N:7]=[CH:8][C:3]3[N:4]([C:15]([CH3:16])=[N:2][N:1]=3)[CH:5]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: NNc1cnc(-c2ccccc2)cn1
Product: Cc1nnc2cnc(-c3ccccc3)cn12

Procedure:
A solution of 0.5 g. (0.0027 mole) of 2-hydrazino-5-phenylpyrazine in 5.0 ml. of triethyl orthoacetate is heated under reflux for 5 hours. The crystalline product precipitates from the hot reaction solution, and at the end of the heating period the mixture is cooled and the product is collected. Recrystallization from ethanol gives 0.36 g. of the product of the example, m.p. 192°-195° C.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=O.[CH2:14]([C:19]1[CH:43]=[CH:42][C:22]([CH:23]=[CH:24][C:25]([NH:27][C:28]2[C:33]3[O:34][CH:35]([CH2:38][C:39]([NH2:41])=O)[CH2:36][O:37][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:26])=[CH:21][CH:20]=1)[CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.O>C1COCC1>[CH2:14]([C:19]1[CH:20]=[CH:21][C:22]([CH:23]=[CH:24][C:25]([NH:27][C:28]2[C:33]3[O:34][CH:35]([CH2:38][C:39]#[N:41])[CH2:36][O:37][C:32]=3[CH:31]=[CH:30][CH:29]=2)=[O:26])=[CH:42][CH:43]=1)[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC(N)=O)CO3)cc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: CCCCCc1ccc(C=CC(=O)Nc2cccc3c2OC(CC#N)CO3)cc1
Reaction time: 0.17 h

Procedure:
Trifluoroacetic anhydride (0.1 m) was added to a solution of 8-(p-pentylcinnamoyl)amino-1,4-benzodioxane-2-acetamide (191 mg; synthesized in reference example 4) in THF (10 ml) cooling with ice. And pyridine (0.02 ml) was added to the mixture. After stirring for 10 min, the mixture was poured into water. The mixture was extracted with ethyl acetate. The extract was dried, concentrated under reduced pressure to give the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6].N(C(OC(C)C)=O)=NC(OC(C)C)=O.[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH2:32]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH3:29][C:30]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[C:31]=1[CH2:32][O:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Reactant: Cc1cccc(C)c1CO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OC)c(OCc2c(C)cccc2C)c1
Temperature: 25 °C

Procedure:
A solution of Ethyl 3-hydroxy-4-methoxy benzoate (Step A, 9.10 g, 46.4 mmol) and diisopropyl azodicarboxylate (DIAD, 10.23 g, 50 mmol) in dry THF (20 ml) was added drop wise to a solution of 2,6-Dimethylbenzyl alcohol (6.94 g, 51 mmol) and triphenylphosphine (TPP, 13.27 g, 50 mmol) in dry THF (60 ml) at 0° C. under argon. The reaction mixture was warmed to room temperature for 4 hours or until all the starting material is consumed, diluted with ether and washed with water (2×). The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography on a silica gel column (hex:ethyl acetate 2:1) to give the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1.[H-].[Na+].I[CH2:31][CH2:32][CH2:33][CH3:34]>CN(C)C=O>[CH2:31]([N:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][C:9]([C:12]([N:14]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[CH2:18][N:17]4[CH:25]=[CH:26][CH:27]=[C:16]4[CH2:15]3)=[O:13])=[CH:8][CH:7]=2)=[N:2]1)[CH2:32][CH2:33][CH3:34]
Reactant: CCCCI
Reactant: O=C(c1ccc(-c2cc[nH]n2)cc1)N1Cc2cccn2Cc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1ccc(-c2ccc(C(=O)N3Cc4cccn4Cc4ccccc43)cc2)n1
Yield: 28.2 %

Procedure:
In the manner of Example 25, employing [4-(1H-pyrazol-3-yl)-phenyl]-(5H,11H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl)-methanone (0.98 g), 60% sodium hydride in oil (0.30 g), dimethylformamide (25 ml), and 1-iodobutane (0.60 g), the title compound (0.32 g) was obtained as a crystalline solid, m.p. 122-123° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=1.[CH:10]1(B(O)O)[CH2:12][CH2:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:10]1([C:2]2[CH:7]=[CH:6][C:5]([C:8]#[N:9])=[CH:4][N:3]=2)[CH2:12][CH2:11]1
Reactant: N#Cc1ccc(Br)nc1
Reactant: OB(O)C1CC1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2CC2)nc1
Temperature: 100 °C
Yield: 53.7 %

Procedure:
Deoxygenate a mixture of 2-bromo-5-cyanopyridine (1.83 g, 10.0 mmol), cyclopropylboronic acid (1.1 g, 13 mmol), palladium(II) acetate (0.11 g, 0.49 mmol), and potassium phosphate (7.4 g, 35 mmol) in toluene (40.00 mL) and water (2 mL) by bubbling nitrogen through the mixture. Add tricyclohexylphosphine (1.0 mL, 1.0 mmol, 1 M in toluene). Heat the reaction mixture at 100° C. for 14 hours and allow the reaction mixture to cool. Decant the supernatant and wash the leftover sludge with dichloromethane. Concentrate the combined organics in vacuo. Purify by silica gel chromatography (0-5% ethyl acetate/hexane) to afford the titled compound as a white crystalline solid (774 mg, 47%). 1H NMR (400 MHz, CDCl3) δ 1.08 (m, 4H), 2.05 (m, 1H), 7.23 (dd, J=8.2, 1.0 Hz, 1H), 7.73 (dd, J=8.0, 2.4 Hz, 1H), 8.66 (d, J=1.2 Hz, 1H).