Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:34][CH2:33]3)[CH:21]=1)[CH2:16][C:17]([OH:19])=O)[C:9]2=[O:14])(=[O:3])[CH3:2].C(N1C=CN=C1)([N:38]1C=CN=C1)=O.[OH-].[NH4+].O>O1CCCC1>[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7](=[O:35])[N:8]([CH:15]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH:27]([F:29])[F:28])=[C:22]([O:30][CH2:31][CH:32]3[CH2:33][CH2:34]3)[CH:21]=1)[CH2:16][C:17]([NH2:38])=[O:19])[C:9]2=[O:14])(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1cccc2c1C(=O)N(C(CC(=O)O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1cccc2c1C(=O)N(C(CC(N)=O)c1ccc(OC(F)F)c(OCC3CC3)c1)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
To a solution of 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionic acid (100 mg, 0.22 mmol) in tetrahydrofurane was added carbonyldiimidazole (53 mg, 0.33 mmol) at room temperature. The solution was stirred for 2 hours at room temperature. To the mixture was added ammonium hydroxide (0.05 ml, 0.66 mmol). The resulted mixture was stirred at room temperature for 2 hours. Water (5 ml) was added to the reaction mixture. THF was removed in vacuo and the resulted mixture was taken up in ethyl acetate (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×10 ml), water (10 ml), brine (10 ml) and was dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was purified by HPLC (acetonitrile: water=45:55) to give 3-(4-acetylamino-1,3-dioxo-1,3-dihydro-isoindol-2-yl)-3-(3-cyclopropylmethoxy-4-difluoromethoxy-phenyl)-propionamide as a white solid (80 mg, 81%): mp 77-79° C.; 1HNMR (CDCl3): δ 0.32-0.38 (m, 2H), 0.60-0.67 (m, 2H), 1.20-1.31 (m, 1H), 2.27 (s, 3H), 3.03 (dd, J=5.5, 15.5 Hz, 1H), 3.70 (dd, J=8.4, 15.5 Hz, 1H), 5.28-5.40 (m, 1H), 5.74-5.80 (m, 1H), 5.79 (dd, J=5.8, 10.5 Hz, 1H), 6.60 (t, JH-F=75 Hz, 1H), 7.09-7.13 (m, 3H), 7.47 (d, J=7.3 Hz, 1H), 7.63 (t, J=7.5 Hz, 1H), 8.75 (d, J=8.5 Hz, 1H), 9.49 (s, 1H). 13C NMR (CDCl3): δ 3.8, 3.9, 10.74, 25.6, 38.1, 51.9, 474.5, 112.5, 114.8, 115.8, 116.7, 118.7, 120.8, 123.5, 125.6, 131.8, 136.7, 137.8, 138.1, 140.8, 151.2, 168.6, 169.9, 170.5, 172.1; Anal. Calcd. for C24H23F2N3O6+0.5 H2O: C, 58.06%; H, 4.87; N, 8.46. Found: C, 57.77; H, 4.60; N, 8.33; 1% H2O.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][N:23]=1.[F:29][C:30]([F:34])([F:33])[CH2:31]I>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[N:12][C:11]=2[CH3:20])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:31][C:30]([F:34])([F:33])[F:29])=[CH:24][N:23]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(O)cn2)c1
Reactant: FC(F)(F)CI
Product: Cc1nc(C(F)(F)F)ccc1C(=O)Nc1ccc(Cl)c(-c2ccc(OCC(F)(F)F)cn2)c1

Procedure:
N-(4-chloro-3-(5-hydroxypyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide (0.12 mmol) was used in Procedure L with excess trifluoroethyl iodide. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield N-(4-chloro-3-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)phenyl)-2-methyl-6-(trifluoromethyl)nicotinamide as a white solid: TLC Rf=0.64 (40% ethyl acetate/hexanes); MS (Q1) 490 (M)+.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7]([NH2:9])=[S:8])=[CH:5][N:4]=1.FC(F)(F)C1C=CC(C(O)=O)=CN=1.ClCC1OC(C2(C)CCCCC2)=NC=1C.ClCC1SC(C2CCC(F)(F)CC2)=NC=1COC.[CH3:60][O:61][C:62](=[O:70])[CH:63](Cl)[C:64](=O)[CH2:65][O:66][CH3:67]>C(O)C>[CH3:60][O:61][C:62]([C:63]1[S:8][C:7]([C:6]2[CH:5]=[N:4][C:3]([C:2]([F:1])([F:12])[F:13])=[CH:11][CH:10]=2)=[N:9][C:64]=1[CH2:65][O:66][CH3:67])=[O:70]
Reactant: COCC(=O)C(Cl)C(=O)OC
Reactant: NC(=S)c1ccc(C(F)(F)F)nc1
Agent: COCc1nc(C2CCC(F)(F)CC2)sc1CCl
Agent: Cc1nc(C2(C)CCCCC2)oc1CCl
Agent: O=C(O)c1ccc(C(F)(F)F)nc1
Solvent: CCO
Product: COCc1nc(-c2ccc(C(F)(F)F)nc2)sc1C(=O)OC
Yield: 11.2 %

Procedure:
10.5 g 6-Trifluoromethyl-thionicotinamide (derived from 6-Trifluoromethyl-nicotinic acid according to the method described for 5-Chloromethyl-4-methyl-2-(1-methyl-cyclohexyl)-oxazole and 5-Chloromethyl-2-(4,4-difluoro-cyclohexyl)-4-methoxymethyl-thiazole) and 10.0 g 2-Chloro-4-methoxy-3-oxo-butyric acid methyl ester were dissolved in 100 ml ethanol and heated under reflux overnight. The cooled reaction mixture was evaporated under reduced pressure and the resulting residue was purified by RP-HPLC to obtain 1.9 g 4-Methoxymethyl-2-(6-trifluoromethyl-pyridin-3-yl)-thiazole-5-carboxylic acid methyl ester.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=3)[CH:18]([CH3:20])[CH3:19])=[C:14]([CH3:39])[C:13]=2[CH:40]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]2[O:16][C:15]([CH:17]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]([N:30]([CH3:38])[CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=3)[CH:18]([CH3:19])[CH3:20])=[C:14]([CH3:39])[C:13]=2[CH:40]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(OCc4ccccc4)cc3c2C)C(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C(C)C)oc2ccc(OCc3ccccc3)cc12
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
Ethyl 3-[{[4-({1-[5-(benzyloxy)-3-methyl-1-benzofuran-2-yl]-2-methylpropyl}amino)phenyl]carbonyl}(methyl)amino]propanoate (1.25 g) optically resolved in the above-mentioned (1) was dissolved in ethanol (15 mL), 1N aqueous sodium hydroxide solution (4 mL) was added at room temperature, and the mixture was stirred at 50° C. for 0.5 hr. Ethanol was evaporated under reduced pressure, 1N hydrochloric acid (4 mL) was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with ethanol-water to give the title object compound (1.08 g, 93%, 99.9% ee) as a colorless solid.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:32][O:33][P:34](=[O:51])([O:43]CC3C=CC=CC=3)[O:35]CC3C=CC=CC=3)[N:13]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([NH:11][C:12]2[C:21]3[C:16](=[CH:17][C:18]([C:22]4[C:27]([C:28]([F:31])([F:30])[F:29])=[CH:26][CH:25]=[CH:24][N:23]=4)=[CH:19][CH:20]=3)[N:15]=[C:14]([CH2:32][O:33][P:34](=[O:35])([OH:43])[OH:51])[N:13]=2)=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)c1ccc(Nc2nc(COP(=O)(OCc3ccccc3)OCc3ccccc3)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)c1ccc(Nc2nc(COP(=O)(O)O)nc3cc(-c4ncccc4C(F)(F)F)ccc23)cc1

Procedure:
Dissolve phosphoric acid dibenzyl ester 4-(4-tert-butyl-phenylamino)-7-(3-trifluoromethyl-pyridin-2-yl)-quinazolin-2-ylmethyl ester (225 mg, 0.316 mmol) in methanol and add 10% palladium on carbon (218 mg). Stir the solution for 2 hours under 1 atmosphere of hydrogen gas. Filter the solution through celite and wash through with additional methanol. Concentrate under reduced pressure and triturate with ether to yield the desired product as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH:11]=[CH:10][N:9]=[CH:8]2)=[C:4]([CH3:14])[CH:3]=1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17].CO.CCOC(C)=O>C(N(CC)CC)C.[Cu]I>[CH3:14][C:4]1[CH:3]=[C:2]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1
Reactant: Cc1cc(Br)ccc1Cn1ccnc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1cc(C#C[Si](C)(C)C)ccc1Cn1ccnc1
Temperature: 70 °C
Yield: 82 %

Procedure:
Using General Procedure D; 1-(4-bromo-2-methyl-benzyl)-1H-5 imidazole (Intermediate 139, 160.0 mg, 0.64 mmol) in triethylamine (8 mL) was treated with copper(I)iodide (12.0 mg, 0.07 mmol) and then sparged with argon for 5 minutes. Trimethylsilyl acetylene (0.70 g, 0.71 mmols) was then added followed by dichlorobis(triphenylphosphine)palladium(1I) (45.0 mg, 0.07 mmol). The resulting reaction mixture was heated to 70° C. for 5 days. The title compound (140.0 mg, 82%) was isolated by chromatography (5% MeOH-EtOAc) as an orange oil.
Reaction SMILES: Br[C:2]1[C:11]([O:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][CH:14]=2)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[OH:27][CH2:28][C:29]1[CH:30]=[C:31](OB=O)[CH:32]=[CH:33][CH:34]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:24][O:23][C:20]1[CH:21]=[C:22]2[C:17](=[CH:18][C:19]=1[O:25][CH3:26])[N:16]=[CH:15][CH:14]=[C:13]2[O:12][C:11]1[C:2]([C:33]2[CH:34]=[C:29]([CH2:28][OH:27])[CH:30]=[CH:31][CH:32]=2)=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: O=BOc1cccc(CO)c1
Reactant: COc1cc2nccc(Oc3cc4ccccc4nc3Br)c2cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3cc4ccccc4nc3-c3cccc(CO)c3)c2cc1OC
Temperature: 25 °C
Yield: 101.3 %

Procedure:
4-(2-Bromo-quinolin-3-yloxy)-6,7-dimethoxy-quinoline (compound 281) (50 mg), tetrakistriphenylphosphine palladium(0) (14 mg), and (3-hydroxymethylphenyl)boranic acid (55 mg) were suspended in a mixed solvent composed of N,N-dimethylformamide (1 ml) and a 2 N aqueous potassium carbonate solution (1 ml), and the suspension was stirred at 80° C. for 2.5 hr. The reaction solution was cooled to room temperature, the reaction solution was then filtered, and the solvent was removed from the filtrate by distillation under the reduced pressure. Water was then added to the residue, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-hexane to give the title compound (54 mg, yield 97%).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C@H:7]([C:15]([OH:17])=[O:16])[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:18](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:18][O:16][C:15](=[O:17])[C@H:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:6]
Reactant: O=C([O-])[O-]
Reactant: N[C@@H](Cc1ccccc1)C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)[C@@H](N)Cc1ccccc1
Temperature: 90 °C
Reaction time: 5 h

Procedure:
To a mixture of 10.2 liters of methanol and 335 ml of conc. sulfuric acid was added 1050 g of L-phenylalanine. The mixture was stirred at 90° C. for 5 hours to effect esterification. The reaction solution was adjusted with 15% sodium carbonate aqueous solution to a Ph of 7. L-Phenylalanine methyl ester was extracted with toluene to give 10.7 liters of toluene solution of L-phenylalanine methyl ester.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=4)=[CH:28][N:27](COCC[Si](C)(C)C)[C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.FC(F)(F)C(O)=O.N>>[CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30]4[CH:31]=[C:32]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:33]=[CH:34][CH:35]=4)=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(-c3cccc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Agent: N
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(-c5cccc(NS(C)(=O)=O)c5)c34)n(-c3ccccc3)c(=O)c12
Yield: 34.6 %

Procedure:
(S)—N-(3-(4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenyl)methanesulfonamide (79 mg, 0.12 mmol) was treated with trifluoroacetic acid (1.58 mL, 20.51 mmol) and a solution of ammonia (7N in methanol, 1.58 mL, 11.06 mmol) according to the method described in Example 27 to give 23 mg (36% yield) of the title compound. Purity 97%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22](Cl)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:24][C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[N:29][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3=[N:19][CH:20]=[N:21][C:22]([O:24][C:25]4[CH:30]=[N:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=4)=[C:17]3[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COc1ccc(Oc2ncnc3c2cnn3C2CCN(C(=O)OC(C)(C)C)CC2)cn1
Temperature: 160 °C
Yield: 53.1 %

Procedure:
A mixture of 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (Intermediate 19; 50 mg, 0.15 mmol), 5-hydroxy-2-methoxypyridine (Tyger Scientific, Ewing, N.J., USA; 24 mg, 0.19 mmol), and potassium carbonate (27 mg, 0.19 mmol) in dimethylformamide (2 mL) was heated in the microwave oven at 160° C. for 10 min. Ethyl acetate and water were added, and the aqueous layer was extracted twice with ethyl acetate. The ethyl acetate layers were combined, evaporated, and purified by preparative C18 HPLC, eluting with 10-100% acetonitrile/water. Samples containing the product were extracted twice with dichloromethane and the solvent was evaporated to give 4-[4-(6-methoxy-pyridin-3-yloxy)-pyrazolo[3,4-d]pyrimidin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (34 mg, 54%) as a white powder. Mass spectrum (ES) MH+=427. HRMS Calcd. for C21H27N6O4 (MH+): 427.2089. Found: 427.2088.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:6]=[C:7]([C:11]2[N:15]=[CH:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][C:23]([F:26])([F:25])[F:24])=[CH:18][CH:17]=3)[N:12]=2)[CH:8]=[CH:9][CH:10]=1)=[C:2]=[O:3].[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH2:38])=[S:37])=[C:31]([CH3:39])[CH:30]=1>>[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]([NH:38][C:2]([NH:1][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]3[N:15]=[CH:14][N:13]([C:16]4[CH:21]=[CH:20][C:19]([O:22][C:23]([F:25])([F:24])[F:26])=[CH:18][CH:17]=4)[N:12]=3)[CH:6]=2)=[O:3])=[S:37])=[C:31]([CH3:39])[CH:30]=1
Reactant: O=C=NCc1cccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)c1
Reactant: COc1ccc(NC(N)=S)c(C)c1
Product: COc1ccc(NC(=S)NC(=O)NCc2cccc(-c3ncn(-c4ccc(OC(F)(F)F)cc4)n3)c2)c(C)c1

Procedure:
The title compound was prepared as described in Example 75 using 3-(3-(isocyanatomethyl)phenyl)-1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazole (CB34) and 1-(4-methoxy-2-methylphenyl)thiourea and isolated as an off-white solid (0.212 g, 50%).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH2:6])[NH2:5])#[N:2].[P:7](=[O:11])([OH:10])([OH:9])[OH:8].[NH2:12][C:13]([NH2:15])=[O:14]>O>[P:7]([OH:11])([OH:10])([OH:9])=[O:8].[C:4]([NH:3][C:1]([NH2:2])=[O:14])(=[NH:6])[NH2:5].[NH2:12][C:13]([NH2:15])=[O:14]
Reactant: N#CN=C(N)N
Agent: NC(N)=O
Agent: O=P(O)(O)O
Solvent: O
Product: N=C(N)NC(N)=O
Reaction time: 0.75 h

Procedure:
To prepare the solution, water was placed within a container and then agitated while dicyandiamide was added. The phosphoric acid was subsequently added. The resulting mixture was heated to approximately 85° centigrade and held at that temperature for approximately 45 minutes. The mixture was then cooled to approximately 25° centigrade and urea was then added. The resultant solution is hereinafter denoted as solution 6 and produced guanyl urea phosphate and urea.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]#[N:10])=[N:6][CH:7]=1.Br[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Br.[OH-].[Na+]>[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.[Cl-].[NH4+]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:9]#[N:10])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[N:6][CH:7]=1
Reactant: BrCCOCCBr
Reactant: N#CCc1ccc(Br)cn1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Product: N#CC1(c2ccc(Br)cn2)CCOCC1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
A mixture of 5-bromo-2pyridineacetonitrile (400 mg), triethylbenzylammonium chloride (462 mg), bis(2-bromoethyl)ether (281 μL), and 50% sodium hydroxide solution (10 mL) was stirred at 70° C. for 1 hour. After decantation of aqueous layer, the residue was diluted with saturated ammonium chloride solution and extracted with ethyl acetate. The organic extracts were dried over anhydrous magnesium sulfate, filtered, and then concentrated in vacuo. Flash chromatography (silica, hexane:ethyl acetate=7:3) of the residue gave 5-bromo-2-(4-cyanotetrahydropyran-4-yl)pyridine (104 mg).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN([CH:9]=[O:10])C.[C:11]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:24]3[C:19]2=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:13][CH:12]=1>O>[C:31]1([C:11]2[CH:16]=[CH:15][C:14]([CH2:17][N:18]3[C:19]4[CH:20]=[CH:21][C:22]([CH:9]=[O:10])=[CH:23][C:24]=4[C:25]4[C:30]3=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:13][CH:12]=2)[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: CN(C)C=O
Reactant: c1ccc(-c2ccc(Cn3c4ccccc4c4ccccc43)cc2)cc1
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1ccc2c(c1)c1ccccc1n2Cc1ccc(-c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Under a atmosphere of nitrogen at 0° C. phosphorous oxychloride (3.0 ml, 33 mmol) was added dropwise to N,N'-dimethylformamide (1.2 ml, 15.8 mmol). After the addition was complete, the mixture was stirred at 0° C. for 1 h and heated to 45° C. At 45° C. the above carbazole (5.00 g, 15 mmol) was added during 15 minutes. The solid reaction mixture was then heated at 95° C. for 16 h. To the cooled reaction mixture water (125 ml) was added and the mixture was stirred vigorously at room temperature for 4 h. The solid formed was filtered off, washed with water and dried in vacuo at 50° C. affording almost quantitatively 9-(4-phenylbenzyl)-9H-carbazole-3-carboxaldehyde as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]#[C:10][C:11]2[CH:12]=[N:13][CH:14]=[C:15]([CH:18]=2)[C:16]#[N:17])[CH:5]=[CH:6][C:7]=1[F:8].[C:19](Cl)(=[O:21])[CH3:20]>N1C=CC=CC=1.O1CCCC1.O>[C:16]([C:15]1[CH:18]=[C:11]([C:10]#[C:9][C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([NH:1][C:19](=[O:21])[CH3:20])[CH:3]=2)[CH:12]=[N:13][CH:14]=1)#[N:17]
Reactant: N#Cc1cncc(C#Cc2ccc(F)c(N)c2)c1
Reactant: CC(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(=O)Nc1cc(C#Cc2cncc(C#N)c2)ccc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.6 %

Procedure:
Dissolve 5-(3-amino-4-fluorophenylethynyl)-nicotinonitrile, (prepared as described in EXAMPLE 160), (0.2 g, 0.8 mmol) in anhydrous pyridine. A solution of acetyl chloride (0.07 g, 0.88 mmol) in tetrahydrofuran is added to the reaction and stirred overnight at room temperature. Concentrate and dissolve the crude reaction in ethyl acetate and water. Wash the organic layer with water, an aqueous saturated solution of sodium chloride, dry (potassium carbonate), filter, concentrate and purify (silica gel chromatography, eluting with 95:5 to 80:20 dichloromethane:ethyl acetate), to give the title compound as a white solid (180 mg, 81%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([OH:15])[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:16](Cl)([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.N1C=CN=C1>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH:13]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CC(O)C1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](OC1CN(C(=O)OCc2ccccc2)C1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 98.3 %

Procedure:
Subsequently, to a solution of 1-benzyloxycarbonyl-3-hydroxyazetidine (1.91 g, 9.22 mmol) in dimethylformamide (96 ml) were added t-butyldiphenylsilyl chloride (2.88 ml, 11.1 mmol) and imidazole (756 mg, 11.1 mmol) in an ice bath. The resulting mixture was stirred in the ice bath for 6 hours. After checking the completion of the reaction, the reaction mixture was partitioned between ethyl acetate and 10% aqueous sodium chloride solution. The organic layer was washed with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1) as the eluant to afford 1-benzyloxycarbonyl-3-t-butyldiphenylsilyloxyazetidine (4.04 g, yield 98%) as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C([BH3-])#N.[Na+].[OH-].[Na+]>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH2:7][CH2:6]2
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 99.1 %

Procedure:
5-Methoxyindole (50 g, 0.34 mol) was dissolved in glacial acetic acid (500 mL) in a 3 L 3-necked flask fitted with a mechanical stirrer, a dropping funnel and a thermometer. The solution was cooled to 10–12° C. with an ice bath and sodium cyanoborohydride (64 g, 1.0 mol) was added in portions while ensuring the temperature remained at or below 15–16° C. After the addition was complete the cooling bath was removed and the reaction was warmed to ambient temperature for 0.5 hour. TLC (1:1 EtOAc/hexane) confirmed a complete reaction. The reaction was cooled to 5–10° C. and 50% aqueous sodium hydroxide was added until the pH was 8–10. The product oiled out and was extracted with ethyl acetate (3×700 mL). The combined organic layers were washed with water (2×500 mL) and brine (400 mL), dried over anhydrous potassium carbonate, filtered and concentrated to afford 5-methoxyindoline (50 g, 0.337 mol, 99% yield) as a thick oil. This product was used without further purification.
Reaction SMILES: O1CCN(S(F)(F)[F:8])CC1.[N:11]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:26][C@H:24](O)[CH2:23][C@H:12]1[C:13]([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>C(Cl)Cl.O>[CH2:16]([O:15][C:13](=[O:14])[C@H:12]1[CH2:23][C@H:24]([F:8])[CH2:26][N:11]1[C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: FS(F)(F)N1CCOCC1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)OCc1ccccc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](F)C[C@@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48 %

Procedure:
Morpholinosulfur trifluoride (morph-DAST; 3.5 mL, 29 mmol) was added by syringe to a solution of 1 (6.5 g, 20 mmol) in dry CH2Cl2 (200 mL) under Ar(g) at −78° C. The solution w allowed to warm to room temperature and stirred overnight. Following a quench with methanol, the reaction mixture was washed with 2×100 mL saturated NaHCO3(aq). An emulsion resulted, so the mixture was diluted with H2O and CH2Cl2 and filtered through Celite. The biphasic filtrate was separated, and the organic layer was washed with water, dried over MgSO4(s), and concentrated by rotary evaporation under reduced pressure. The resulting oil was purified by flash chromatography (1.5% v/v MeOH in CH2Cl2), which afforded 11 (3.1 g, 9.6 mmol, 48%) as a yellow oil. An additional 2.32 g of 11 that were contaminated with a minor impurity, as indicated by TLC, were also obtained from the column.