Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[S:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[S:3][CH:21]=2)=[CH:24][CH:25]=1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(C(N)=S)c1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(C(F)(F)F)cc3)cs2)c1
Yield: 74 %

Procedure:
In the same manner as in Example 28, methyl 3-thiocarbamoylbenzoate was reacted with 4-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(4- trifluoromethylphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 74%. Colorless prisms. Melting point: 142 to 143° C.
Reaction SMILES: [CH3:1][C:2]([CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][CH2:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=1.[CH2:21](Br)[C:22]#[CH:23]>>[CH2:23]([O:11][C:10](=[O:12])[C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:1])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:14][CH:13]=1)[C:22]#[CH:21]
Reactant: CC(C)=CCCC(C)=CCOc1ccc(C(=O)O)cc1
Reactant: C#CCBr
Product: C#CCOC(=O)c1ccc(OCC=C(C)CCC=C(C)C)cc1

Procedure:
By utilizing the procedure of Example 8, by reacting p-[(3,7-dimethyl-2,6-octadienyl)oxy]benzoic acid with propargyl bromide, there is obtained p-[(3,7-dimethyl-2,6-octadienyl)oxy]benzoic acid propargyl ester; B.P. 135°-137°C/0.01 mmHg.
Reaction SMILES: [C:1](N1C=CN=C1)([N:3]1C=CN=C1)=[S:2].[C:13]([O:17][C:18](=[O:26])[N:19]([CH3:25])[CH:20]1[CH2:24][CH2:23][NH:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:13]([O:17][C:18](=[O:26])[N:19]([CH3:25])[CH:20]1[CH2:24][CH2:23][N:22]([C:1](=[S:2])[NH2:3])[CH2:21]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CN(C(=O)OC(C)(C)C)C1CCNC1
Reactant: S=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)C1CCN(C(N)=S)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.2 %

Procedure:
To a stirring solution of thiocarbonyldiimidazole (1.23 g, 6.91 mmol) in THF (10 mL) under N2 was added methylpyrrolidin-3-yl-carbamic acid tert-butyl ester (1.20 g, 5.99 mmol) in THF (7 mL). The reaction mixture was stirred at room temperature of 1 h, and then at 55° C. for 2 h. The reaction was cooled to room temperature, and most (˜14 mL) of THF was removed. The reaction was transferred to a sealable reaction tube, 2N ammonia in methanol (6 mL) was added, and the reaction was stirred at room temperature overnight. Another portion of 2N ammonia in methanol (6 mL) was added, and the reaction was heated to 45° C. for 8 h. The reaction was concentrated to ˜5 mL, and diethyl ether was added to precipitate product. The product was filtered, washed with diethyl ether, and dried to obtain 0.920 g (64.9%) of pure methyl-(1-thiocarbamoyl-pyrrolidin-3-yl)-carbamic acid tert-butyl ester (132) as a white solid.
Reaction SMILES: Cl.[NH2:2][OH:3].[CH3:4][NH:5][C:6](=[O:15])[C:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>N1C=CC=CC=1>[OH:3][N:2]=[C:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:6]([NH:5][CH3:4])=[O:15]
Reactant: NO
Reactant: CNC(=O)C(=O)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: CNC(=O)C(=NO)c1ccccc1
Temperature: 25 °C
Reaction time: 10 h

Procedure:
Hydroxylamine hydrochloride (5.96 g, 2.5 eq.) was added to a solution of N-methyl-2-oxo-2-phenylacetamide (5.6 g, 34.3 mmol) in pyridine (25 ml). After stirring for 10 h at room temperature, the excess pyridine was removed in vacuo and the residue was taken up in 250 ml of dichloromethane. The organic phase was washed with 200 ml of water and then again with aqueous hydrochloric acid (0.1 M, 250 ml). The precipitated solid was filtered off, giving 2-(hydroxyimino)-N-methyl-2-phenylacetamide as a yellow solid (2.31 g, pure Z isomer). The filtrate was concentrated by evaporation in vacuo. This gave 4.50 g of 2-(hydroxyimino)-N-methyl-2-phenylacetamide (Z/E=mixture of isomers) as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([F:8])=[C:4](Cl)[N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[C:13]([NH:15][CH3:16])=[O:14].C(N(CC)C(C)C)(C)C>C(O)(C)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[C:13]([NH:15][CH3:16])=[O:14])[C:5]([F:8])=[CH:6][N:7]=1
Reactant: CNC(=O)c1ccccc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1F
Yield: 33 %

Procedure:
In a similar fashion as outlined in Example 191a, 2,6-dichloro-5-fluoropyrimidine was reacted with 2-amino-N-methylbenzamide and N,N-diisopropylethylamine in isopropyl alcohol (no microwave −20° C., 24 hours) to afford 2-(2-chloro-5-fluoropyrimidin-4-ylamino)-N-methyl-benzamide as a white solid in 33% yield. Mp: 225° C. (dec); MS: 281.23 (M+H); 1H NMR (chloroform-d): δ 11.78 (br s, 1H), δ 8.80 (d, J=8 Hz, 1H), δ 8.11 (s, 1H), δ 7.60 (t, J=8 Hz, 1H), δ 7.52 (d, J=8 Hz, 1H), δ 7.15 (t, J=8 Hz, 1H), δ 6.31 (br s, 1H), δ 3.06 (dd, J=2.5 Hz, 3H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]3)[CH:13]=2)O1.[NH2:28][C:29]1[C:34]([C:35]2[O:36][C:37]3[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)=[CH:33][C:32](Br)=[CH:31][N:30]=1.[F-].[Cs+]>CO.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>[NH2:28][C:29]1[C:34]([C:35]2[O:36][C:37]3[C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=[CH:40][C:38]=3[N:39]=2)=[CH:33][C:32]([C:9]2[CH:10]=[N:11][N:12]([CH:14]3[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:18][CH2:19]3)[CH:13]=2)=[CH:31][N:30]=1
Reactant: COC(=O)c1cccc2nc(-c3cc(Br)cnc3N)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Product: COC(=O)c1cccc2nc(-c3cc(-c4cnn(C5CCN(C(=O)OC(C)(C)C)CC5)c4)cnc3N)oc12
Temperature: 120 °C
Yield: 69.9 %

Procedure:
A mixture of bis(triphenylphosphine)palladium chloride (17.69 mg) was added to tert-butyl 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazol-1-yl]piperidine-1-carboxylate (380 mg), methyl 2-(2-amino-5-bromo-3-pyridyl)-1,3-benzoxazole-7-carboxylate (390 mg) and caesium fluoride (459 mg) dissolved in degassed methanol (5 ml) under argon. The resulting slurry was heated at 120° C. in the microwave for 30 minutes. The mixture was adsorbed on silica gel. The crude product was purified by flash chromatography on silica gel eluting with 1 to 4% methanol in dichloromethane. The solvent was evaporated to dryness to afford methyl 2-[2-amino-5-[1-(1-tert-butoxycarbonyl-4-piperidyl)pyrazol-4-yl]-3-pyridyl]-1,3-benzoxazole-7-carboxylate (365 mg) as a pale yellow solid. NMR Spectrum: (CDCl3) 1.49 (s, 9H), 1.97 (dd, 1H), 2.02 (dd, 1H), 2.16-2.23 (m, 2H), 2.84-3.01 (m, 2H), 4.06 (s, 3H), 4.19-4.40 (m, 3H), 6.88 (bs, 2H), 7.44 (dd, 1H), 7.70 (s, 1H), 7.80 (s, 1H), 7.94 (dd, 1H), 8.01 (dd, 1H), 8.40 (d, 1H), 8.48 (d, 1H); Mass spectrum: M+H+ 519;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2.Cl.Cl[CH2:27][C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([S:12]([CH2:15][CH2:16][C:17]([N:19]1[CH2:20][CH2:21][N:22]([CH2:27][C:28]3[N:29]=[C:30]([NH2:33])[S:31][CH:32]=3)[CH2:23][CH2:24]1)=[O:18])(=[O:14])=[O:13])[CH:6]=[CH:5]2
Reactant: Nc1nc(CCl)cs1
Reactant: O=C(CCS(=O)(=O)c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Nc1nc(CN2CCN(C(=O)CCS(=O)(=O)c3ccc4cc(Cl)ccc4c3)CC2)cs1
Yield: 71.5 %

Procedure:
A suspension of 1-(3-((6-chloro-2-naphthyl)sulfonyl)propionyl)piperazine (1.5 g) obtained in Example 3a), 4-chloromethyl-1,3-thiazol-2-amine hydrochloride (0.76 g) and potassium carbonate (1.12 g) in acetonitrile (50 mL) was refluxed for 4 hours, and then the solvent was distilled off under reduced pressure. The residue was diluted with potassium carbonate, and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified with a basic silica gel column to give the title compound (1.4 g) as white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH2:3][CH2:4][CH:5]([C:8]1[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=1)[C:6]#[N:7].[OH-].[K+].C(OCC)(=[O:25])C.Cl>CC(O)(C)C>[CH3:20][N:2]([CH3:1])[CH2:3][CH2:4][CH:5]([C:8]1[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=1)[C:6]([NH2:7])=[O:25]
Reactant: COc1cc(C(C#N)CCN(C)C)cc(OC)c1OC
Reactant: CCOC(C)=O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Product: COc1cc(C(CCN(C)C)C(N)=O)cc(OC)c1OC

Procedure:
In 8 ml of 2-methyl-2-propanol was dissolved 0.84 g of 4-dimethylamino-2-(3,4,5-trimethoxyphenyl)butyronitrile, followed by addition of 1.0 g of ground potassium hydroxide. The mixture was refluxed for 1 hour. After cooling the reaction mixture, the insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. To the residue thus obtained were added ethyl acetate and 10% hydrochloric acid. The aqueous layer was separated and made strongly basic with sodium hydroxide for salting-out and the basic substance was extracted with ethyl acetate. The ethyl acetate layer was washed with a mixture of water and saturated aqueous sodium chloride (1:1) and a saturated aqueous solution of sodium chloride in turn, then dried over anhydrous sodium sulfate and concentrated to dryness under reduced pressure. The crystalline residue thus obtained (0.59 g) was recrystallized from ethyl acetate to provide 0.35 g of 4-dimethylamino-2-(3,4,5-trimethoxyphenyl)butyramide.
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH2:31][OH:32])([CH2:29][OH:30])[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([C:25]([F:28])([F:27])[F:26])[CH:12]=1)(C)(C)C.O1CCOCC1.[ClH:40]>C(Cl)Cl>[ClH:40].[NH2:7][C:8]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[C:13]([C:25]([F:28])([F:26])[F:27])[CH:12]=1)([CH2:29][OH:30])[CH2:31][OH:32]
Reactant: CCCCCCCSc1ccc(CCC(CO)(CO)NC(=O)OC(C)(C)C)cc1C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCCCCCSc1ccc(CCC(N)(CO)CO)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Compound 24-1 (390 mg) was dissolved in methylene chloride (5 ml), dioxane containing hydrogen chloride (4 mol/l, 5 ml) was added, and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated, and the residue was washed with diethyl ether to give a white powder. The white powder was purified by preparative HPLC, ether containing hydrogen chloride (1 mol/l, 15 ml) was added to the obtained residue to give a hydrochloride. The precipitate was collected by filtration and dried to give the object product (200 mg) as a white powder.
Reaction SMILES: N[C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1.N([O-])=O.[Na+].[ClH:17]>>[Cl:17][C:2]1[C:3]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cl
Reactant: NCCCCc1ncccc1N
Agent: O=N[O-]
Agent: [Na+]
Product: NCCCCc1ncccc1Cl

Procedure:
a. Reaction of 3-amino-2-(4-aminobutyl)pyridine with sodium nitrite/hydrochloric acid and treatment of the resultant diazonium salt with cuprous chloride yields 3-chloro-2-(4-aminobutyl)pyridine. By a similar procedure employing cuprous bromide and hydrobromic acid 3-bromo-2-(4-aminobutyl)-pyridine may be produced and when the diazonium salt is treated with sulphuric acid the product is 3-hydroxy-2-(4-aminobutyl) pyridine.
Reaction SMILES: [C:1]12([N:11]=[C:12]=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.NC(N)=S>CCOCC>[C:1]12([NH:11][C:12]([NH:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[S:13])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: NC1CCCCC1
Reactant: S=C=NC12CC3CC(CC(C3)C1)C2
Agent: NC(N)=S
Solvent: CCOCC
Product: S=C(NC1CCCCC1)NC12CC3CC(CC(C3)C1)C2

Procedure:
The thiourea is prepared by reacting 19.3 g. (0.1 mole) of 1-adamantyl isothiocyanate with 10 g. (0.1 mole) of cyclohexylamine in 250 ml. of ether at room temperature for 3 hrs. The thiourea which separates from solution is collected: 23.5 g., mp. 175-175.5. Evaporation of the ether filtrate to a small volume gives a second crop, 5.2 g., mp. 176-178. The combined yield is 28.7 g. (98.5 percent). A sample is recrystallized from alcohol and melts at 176°-177°.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:31][C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[O:24][CH2:23]4)=[CH:18][CH:17]=3)[CH2:14][C:9]2=[N:8][N:7]=1)=O)C.[CH3:32][NH2:33]>C(O)C>[CH3:32][NH:33][C:4]([C:6]1[N:10]2[CH2:11][CH2:12][N:13]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C@@H:22]4[O:31][C:26]5=[N:27][CH:28]=[CH:29][CH:30]=[C:25]5[O:24][CH2:23]4)=[CH:18][CH:17]=3)[CH2:14][C:9]2=[N:8][N:7]=1)=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1nnc2n1CCN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)C2
Solvent: CCO
Product: CNC(=O)c1nnc2n1CCN(Cc1ccc([C@H]3COc4cccnc4O3)cc1)C2
Temperature: 25 °C
Reaction time: 18 h

Procedure:
The solution of compound 240 (75 mg, 0.18 mmol) in a solution of 33% methylamine in ethanol (1.0 mL) is stirred at 90° C. in a pressure tube. After 18 hours, the mixture is gradually cooled to rt. The mixture is filtered, and the solids are washed with chilled ethanol and chilled methanol then air dried to give the title product. (LC/MS method 16: ES+ m/z 407.3 [M+H]+, Rt=2.73 min)
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[C:10]1([NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH2:16].N1CCCCC1>CO>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH:1]=[N:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH2:17]
Reactant: Nc1ccccc1N
Reactant: O=Cc1ccccc1O
Solvent: CO
Solvent: C1CCNCC1
Product: Nc1ccccc1N=Cc1ccccc1O
Reaction time: 1 h

Procedure:
Under agitation, 73.3 g. of salicylaldehyde is added dropwise under ice cooling gradually to a solution of 6.4 g. of o-phenylenediamine in 225 ml. of methanol and 0.6 ml. of piperidine. The mixture is allowed to stand for one hour; the thus-separated precipitate is vacuum-filtered, washed twice with ice-cold methanol, and 112 g. of N-(2-hydroxybenzal)-o-phenylenediamine is obtained as a crude product.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH:5]([C:8]([C:10]2[S:14][C:13]([NH2:15])=[N:12][C:11]=2[C:16]2[O:17][CH:18]=[CH:19][CH:20]=2)=[O:9])[CH2:4][CH2:3]1.[C:21](O)(=[O:28])[C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1.CCN=C=NCCCN(C)C.Cl.O.ON1C2C=CC=CC=2N=N1>CN(C=O)C.O>[O:17]1[CH:18]=[CH:19][CH:20]=[C:16]1[C:11]1[N:12]=[C:13]([NH:15][C:21]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[O:28])[S:14][C:10]=1[C:8]([CH:5]1[CH2:6][CH2:7][C:2](=[O:1])[CH2:3][CH2:4]1)=[O:9]
Reactant: O=C(O)c1ccncc1
Reactant: Nc1nc(-c2ccco2)c(C(=O)C2CCC(=O)CC2)s1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C1CCC(C(=O)c2sc(NC(=O)c3ccncc3)nc2-c2ccco2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 56.3 %

Procedure:
Compound 447 (150 mg, 0.517 mmol) was dissolved in DMF (2.5 mL), and isonicotinic acid (191 mg, 1.55 mmol), EDC hydrochloride (298 mg, 1.55 mmol) and 1-hydroxybenzotriazole monohydrate (237 mg, 1.55 mmol) were added thereto, followed by stirring at 60° C. for 3 hours. The reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and then the solvent was distilled away under reduced pressure. The resulting residue was recrystallized from 2-propanol to afford the entitled Compound 448 (115 mg, 66%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]#[N:9])[CH:5]=[CH:4][N:3]=1.[F-:10].[K+]>CN1CCCC1=O.[Br-].C([P+](CCCC)(CCCC)CCCC)CCC.O>[F:10][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][N:3]=1)[C:8]#[N:9]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: [F-]
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: N#Cc1ccnc(F)c1
Temperature: 100 °C
Yield: 43.3 %

Procedure:
Treat a solution of 2-chloro-4-cyanopyridine (6.0 g, 43.5 mmol) and potassium fluoride (7.56 g, 130.3 mmol) in 1-methyl-2-pyrrolidinone (20 mL) with tetrabutylphosphonium bromide (14.8 g, 43.7 mmol) and heat to 100° C. for 18 hours. Dilute with water and extract with EtOAc. Wash EtOAc with water, brine, dry with Na2SO4, and concentrate to give the title compound (2.3 g, 43%). MS (ES) 123.1 (M+1)+. 1H NMR (400 MHz, CHCl3) δ 8.43 (d, 1H, J=5.2 Hz), 7.45 (m, 1H), 7.22 (m, 1H).
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][NH:7][C@H:6]([C:9]2[NH:10][C:11]([C:14]3[CH:19]=[C:18]4[CH2:20][O:21][C:22]5[CH:53]=[C:52]6[C:25]([CH:26]=[CH:27][C:28]7[N:32]=[C:31]([C@@H:33]8[CH2:37][CH2:36][CH2:35][N:34]8[C:38](=[O:51])[C@H:39]([NH:46][C:47](=[O:50])[O:48][CH3:49])[C:40]8[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=8)[NH:30][C:29]=76)=[CH:24][C:23]=5[C:17]4=[CH:16][CH:15]=3)=[CH:12][N:13]=2)[CH2:5]1.[CH3:54][O:55][C:56]([NH:58][C@@H:59]([CH:63]([CH3:65])[CH3:64])[C:60](O)=[O:61])=[O:57].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:49][O:48][C:47]([NH:46][C@H:39]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[C:38]([N:34]1[CH2:35][CH2:36][CH2:37][C@H:33]1[C:31]1[NH:30][C:29]2[C:52]3[C:25]([CH:26]=[CH:27][C:28]=2[N:32]=1)=[CH:24][C:23]1[C:17]2[C:18]([CH2:20][O:21][C:22]=1[CH:53]=3)=[CH:19][C:14]([C:11]1[NH:10][C:9]([C@@H:6]3[CH2:5][C@H:4]([CH2:3][O:2][CH3:1])[CH2:8][N:7]3[C:60](=[O:61])[C@@H:59]([NH:58][C:56](=[O:57])[O:55][CH3:54])[CH:63]([CH3:65])[CH3:64])=[N:13][CH:12]=1)=[CH:15][CH:16]=2)=[O:51])=[O:50]
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC[C@@H]1CN[C@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC[C@H]1C[C@@H](c2ncc(-c3ccc4c(c3)COc3cc5c(ccc6nc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]c65)cc3-4)[nH]2)N(C(=O)[C@@H](NC(=O)OC)C(C)C)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of methyl {(1R)-2-[(2S)-2-(9-{2-[(2S,4S)-4-(methoxymethyl)pyrrolidin-2-yl]-1H-imidazol-5-yl}-1,11-dihydroisochromeno[4′,3′:6,7]naphtho[1,2-d]imidazol-2-yl)pyrrolidin-1-yl]-2-oxo-1-phenylethyl}carbamate (55 mg, 0.077 mmol), (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (14 mg, 0.077 mmol), HATU (32 mg, 0.085 mmol) and 0.4 mL 10% DIPEA in DMF was stirred at room temperature for 1 hour. The product was purified by reverse phase HPLC. The product was converted to the free base by dissolution in 2 mL 1:1 acetonitrile:methanol and passage through a prepacked cartridge of polymer supported carbonate. The eluent was concentrated, the taken up in 1% TFA in 1:1 acetonitrile:water, frozen, and lyophilized to give the product as a trifluoroacetate salt. (30.7 mg)
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(C(C)C)C(C)C.[C:48](OC(=O)C)(=[O:50])[CH3:49]>CN(C=O)C>[C:48]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[N:16]=[C:17]([N:24]4[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31]([N:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:32])[CH2:25]4)[N:18]=[N:19][C:20]=3[C:21]([NH2:23])=[O:22])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:50])[CH3:49]
Reactant: CC(=O)OC(C)=O
Reactant: NC(=O)c1nnc(N2CCC[C@@H](NC(=O)N3CCCCC3)C2)nc1Nc1ccc(C2CCNCC2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1CCC(c2ccc(Nc3nc(N4CCC[C@@H](NC(=O)N5CCCCC5)C4)nnc3C(N)=O)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(R)-5-(4-(Piperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide hydrochloride (494) (70 mg, 0.13 mmol) was dissolved in 4 mL DMF. To it were added DIEA (230 μL, 1.30 mmol) and then acetic anhydride (37 μL, 0.39 mmol). The mixture was stirred at RT for 1 hour, quenched with 0.3 mL TFA, and directly subjected to reverse phase prep HPLC to isolate the title compound, (R)-5-(4-(1-acetylpiperidin-4-yl)phenylamino)-3-(3-(piperidine-1-carboxamido)piperidin-1-yl)-1,2,4-triazine-6-carboxamide (497), as HCl salt (47 mg). LC-MS (ESI): m/z (M+1) 550.3. UV: λ=261, 329, 337 nm.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[NH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[BH4-].[Na+]>C(O)C>[N:10]1([CH2:5][C:4]2[CH:3]=[C:2]([OH:1])[CH:9]=[CH:8][CH:7]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: C1CCNCC1
Reactant: O=Cc1cccc(O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Oc1cccc(CN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
In 800 ml of ethanol was dissolved 122 g of 3-hydroxybenzaldehyde and thereto was gradually added 210 g of piperidine. To the mixture was added 38 g of sodium borohydride under cooling with ice and the mixture was stirred for 8 hours at room temperature. The resulting mixture was concentrated at a reduced pressure. To a residue were added ice-cold water and hydrochloric acid to render a solution acidic. The solution was washed with diethyl ether. An aqueous layer was made alkaline with addition of sodium carbonate and then extracted with ethyl acetate. After removing the solvent, 106 g (yield 55%) of 3-(1-piperidinomethyl)phenol was obtained in the form of white crystal.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:37][CH3:36])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc1C)C2
Reactant: CN
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc1C)C2
Yield: 171.8 %

Procedure:
Using a procedure analogous to Example A2, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.58 g, 1.2 mmol) and methylamine (1 ml, 3 mmol, 3.0M in THF) were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.995 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.31 (brs, 1H), 8.73 (s, 1H), 8.00 (d, J=9 Hz, 1H), 7.94 (brs, 1H), 7.23 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.04 (s, 1H), 4.55 (d, J=14 Hz, 1H), 4.35 (d, J=14 Hz, 1H), 3.24 (brs, 3H), 2.79 (d, J=5 Hz, 3H), 2.08 (s, 3H), 1.22 (s, 9H); MS (ESI) m/z: 483.3 (M+H+).