Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:3]=1.Cl.[NH2:18][NH:19][C:20]([NH2:22])=[O:21].O.O.O.C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([O:8][C:9]2[CH:16]=[CH:15][C:12]([CH:13]=[N:18][NH:19][C:20]([NH2:22])=[O:21])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: NNC(N)=O
Reactant: O=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)NN=Cc1ccc(Oc2cc(Cl)ccn2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.5 %

Procedure:
To a solution of 4-(4-chloro-2-pyridinoxy)benzaldehyde (330 mg, 1.41 mmol) in ethanol (10 mL) was added a solution of semicarbazide hydrochloride (213 mg, 1.84 mmol) and sodium acetate trihydrate (224 mg, 1.65 mmol) in water (5 mL). The mixture was stirred at room temperature for 30 min., and the resulting solid was collected by filtration, washed with water and dried in vacuo to yield the title compound as a white solid (400 mg, 1.36 mmol, 96%), mp: 231-233° C. 1H NMR (DMSO-d6): δ 10.22 (s, 1H), 8.22 (d, J=2.5, 1H), 7.97 (dd, J=2.5, 8.7, 1H), 7.85 (s, 1H), 7.77 (d, J=8.7, 2H), 7.15 (d, J=8.7, 2H) 7.12 (d, J=8.7, 1H), 6.47 (s, 2H).
Reaction SMILES: N(C(N(C)C)=O)=NC(N(C)C)=O.C(OC([N:20]1[CH2:25][CH2:24][N:23]([C:26]2[C:27]([O:32][CH2:33][CH2:34][OH:35])=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21]1)=O)(C)(C)C.[N:36]1([C:42]2[CH:43]=[C:44](O)[CH:45]=[CH:46][CH:47]=2)[CH2:41][CH2:40][O:39][CH2:38][CH2:37]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[N:23]1([C:26]2[C:27]([O:32][CH2:33][CH2:34][O:35][C:46]3[CH:45]=[CH:44][CH:43]=[C:42]([N:36]4[CH2:37][CH2:38][O:39][CH2:40][CH2:41]4)[CH:47]=3)=[N:28][CH:29]=[CH:30][N:31]=2)[CH2:22][CH2:21][NH:20][CH2:25][CH2:24]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nccnc2OCCO)CC1
Reactant: Oc1cccc(N2CCOCC2)c1
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCOc2nccnc2N2CCNCC2)cc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 10.5 %

Procedure:
1,1′-Azobis(N,N-dimethylformamide) (TMAD; 256 mg, 1.50 mmol) was added to a solution of 2-[3-(4-tert-butoxycarbonyl-1-piperazinyl)-2-pyrazinyloxy]ethanol (400 mg, 1.24 mmol; prepared in Example 52, Step 2), 3-(4-morpholinyl)phenol (441 mg, 1.23 mmol) and triphenylphosphine (646 mg, 2.46 mmol) in THF (3 mL). The reaction mixture was stirred at room temperature for 2.5 h and then concentrated. The residue was purified by repeated chromatography on silica gel using toluene and toluene/EtOAc (8:2) as eluents. Solvents were evaporated and the residue was treated with CH2Cl2/TFA/H2O (1:0.9:0.1; 5 mL) at room temperature for 0.5 h. After concentration, 5 M NaOH was added followed by extraction with CH2Cl2. The organic phase was dried (K2CO3), filtered, and concentrated. The residue was purified by chromatography on silica gel using CHCl3/MeOH (9:1) as eluent to give 50 mg (10%) of the title product as on oil. HRMS m/z calcd for C20H27N5O3 (M)+ 385.2114, found 385.2100.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10]1([N:16]=[C:17]=[N:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>O1CCCC1>[C:19]1([NH:18][C:17]([NH:9][NH:8][C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)=[N:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: Cc1ccc(NN)cc1
Reactant: C(=Nc1ccccc1)=Nc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(NNC(=Nc2ccccc2)Nc2ccccc2)cc1
Reaction time: 2 h
Yield: 26.5 %

Procedure:
In 250 ml of tetrahydrofuran were dissolved 8.6 g of 4-methylphenylhydrazine and 15.0 g of 1,3-diphenylcarbodiimide and after stirring the solution for 2 hours under ice-cooling, tetrahydrofuran was distilled off under reduced pressure. When 40 ml of benzene and 80 ml of n-hexane were added to the oily product thus formed, crystals deposited. By collecting the crystals thus deposited by filtration, 5.9 g of 1,2-diphenyl-3-(4-methylphenylamino)guanidine was obtained.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[F:6][C:7]1[CH:28]=[CH:27][C:10]([C:11]([CH2:13][CH2:14][CH2:15][N+:16]2[CH:21]=[CH:20][C:19]([C:22]3[O:23][CH:24]=[CH:25][N:26]=3)=[CH:18][CH:17]=2)=[O:12])=[CH:9][CH:8]=1.[BH4-].[Na+]>CO>[F:6][C:7]1[CH:28]=[CH:27][C:10]([CH:11]([OH:12])[CH2:13][CH2:14][CH2:15][N:16]2[CH2:17][CH:18]=[C:19]([C:22]3[O:23][CH:24]=[CH:25][N:26]=3)[CH2:20][CH2:21]2)=[CH:9][CH:8]=1
Reactant: O=C(CCC[n+]1ccc(-c2ncco2)cc1)c1ccc(F)cc1
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: CO
Product: OC(CCCN1CC=C(c2ncco2)CC1)c1ccc(F)cc1

Procedure:
To a 1.75 g. portion of 1-(3-p-fluorobenzoylpropyl)-4-(2-oxazolyl)pyridinium perchlorate, prepared as described in Example 9, in 75 ml. of methanol, is added portionwise with stirring 1.75 g. of sodium borohydride. The mixture is stirred for 11/2 hours, allowed to stand, some of the methanol is evaporated and the mixture is poured into ice water causing the formation of a tan solid which is recovered by filtration, m.p. 100°-103°C.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[O:9][N:8]=1)([CH3:6])[CH2:4][F:5].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[N:30]=[CH:29][N:28]=[C:27]2[O:36][C:37]1[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=1)[NH2:40].C(N(CC)C(C)C)(C)C>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[CH:11]=[C:10]([NH:12][C:13]([NH:40][C:39]2[CH:41]=[CH:42][CH:43]=[C:37]([O:36][C:27]3[C:26]4[C:31](=[CH:32][C:33]([O:34][CH3:35])=[C:24]([O:23][CH3:22])[CH:25]=4)[N:30]=[CH:29][N:28]=3)[CH:38]=2)=[O:21])[O:9][N:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)on1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(CF)CF)no4)c3)c2cc1OC
Temperature: 50 °C
Yield: 57.6 %

Procedure:
A mixture of phenyl 3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-ylcarbamate (0.158 g, 0.5 mmol), 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (0.119 g, 0.4 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) was heated at 50° C. for 5 hours. It was quenched with saturated NaHCO3 and extracted with CH2Cl2. Extracts were dried over MgSO4 and concentrated under reduced pressure. It was purified by silica gel chromatography with 40-95% EtOAc/hexane as eluants to afford 1-[3-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-5-yl]-3-[3-(6,7-dimethoxyquinazolin-4-yloxy]phenyl)urea as solid (0.115 g, 58%). 1H NMR (300 MHz, DMSO-d6) δ 10.33 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.56 (m, 3H), 7.39 (s, 1H), 7.27 (s and d, 2H), 6.24 (s, 1H), 4.73 (m, 2H), 4.56 (m, 2H), 3.99 (s, 3H), 3.98 (s, 3H), 1.30 (s, 3H); LC-MS (ESI) m/z 500 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][NH:25][C:26](=[O:31])[CH2:27][C:28](O)=[O:29]>>[CH3:24][NH:25][C:26](=[O:31])[CH2:27][C:28]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:29]
Reactant: CNC(=O)CC(=O)O
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: CNC(=O)CC(=O)O[C@@]1(C#Cc2cccc(C)c2)CCC[C@@H]2[C@H]1CCN2C(=O)OC

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and 3-(methylamino)-3-oxopropanoic acid to yield (3aR,4S,7aR)-methyl 4-(3-(methylamino)-3-oxopropanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [M+H]=296 (ester elimination ion); RT=1.01 min; UPLC Method I
Reaction SMILES: OC(C(F)(F)F)=O.[NH:8]1[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=3)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=2)[CH2:9]1.[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][C:45](=O)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1>>[O:33]1[C:37]2[CH:38]=[CH:39][C:40]([CH:42]3[CH2:47][CH2:46][CH:45]([N:8]4[CH2:11][CH:10]([NH:12][C:13](=[O:32])[CH2:14][NH:15][C:16]5[C:24]6[C:19](=[CH:20][CH:21]=[C:22]([C:25]([F:28])([F:27])[F:26])[CH:23]=6)[N:18]([CH2:29][CH2:30][OH:31])[N:17]=5)[CH2:9]4)[CH2:44][CH2:43]3)=[CH:41][C:36]=2[O:35][CH2:34]1
Reactant: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CNC1
Reactant: O=C1CCC(c2ccc3c(c2)OCO3)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nn(CCO)c2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccc4c(c3)OCO4)CC2)C1

Procedure:
The title compound was prepared as a white solid from reaction of N-azetidin-3-yl-2-[1-(2-hydroxy-ethyl)-5-trifluoromethyl-1H-indazol-3-ylamino]-acetamide TFA salt (as prepared in Example 74, Step A) and 4-benzo[1,3]dioxol-5-yl-cyclohexanone using the procedure described in Step E of Example 1.
Reaction SMILES: C([O:8][C:9]1[CH:32]=[CH:31][C:12]([C:13]([NH:15][CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][C:21]([OH:30])([C:24]3C=CC=CC=3)[CH2:20][CH2:19]2)=[O:14])=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].C(O)(=O)C>[CH2:24]([C:21]1([OH:30])[CH2:20][CH2:19][N:18]([CH2:17][CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:32][CH:31]=2)[CH2:23][CH2:22]1)[C:9]1[CH:32]=[CH:31][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(NCCN1CCC(O)(c2ccccc2)CC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: O=C(NCCN1CCC(O)(Cc2ccccc2)CC1)c1ccc(O)cc1
Reaction time: 3 h
Yield: 201 %

Procedure:
Palladium on carbon (10%, 150 mg) was added to a solution of 4-benzyloxy-N-[2-(4-hydroxy-4-phenyl-piperidin-1-yl)-ethyl]-benzamide (500 mg, 1.12 mmol) in acetic acid (20 ml). The hydrogenation was complete after 3 h. The catalyst was removed by filtration through celite and the solvent was evaporated. Addition of sodium bicarbonate (10% aq. solution, 2 ml) and extraction with dichloromethane afforded N-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-4-hydroxy-benzamide (399 mg, 95%) as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10](Cl)[N:11]=1)[C:5]([O:7]C)=[O:6].[CH3:13][NH:14][S:15]([CH3:18])(=[O:17])=[O:16]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:14]([CH3:13])[S:15]([CH3:18])(=[O:17])=[O:16])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CNS(C)(=O)=O
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Product: CN(c1cc(C(=O)O)cc(Cl)n1)S(C)(=O)=O

Procedure:
Prepared from Methyl 2,6-dichloroisonicotinate and methyl(methylsulfonyl)amine as described in the preparation of intermediate 4.2c.1, steps A and B.
Reaction SMILES: CN1CCCC1=O.[C:8]([NH:12][C:13]1[C:18]([F:19])=[C:17]([F:20])[N:16]=[C:15](F)[C:14]=1[F:22])([CH3:11])([CH3:10])[CH3:9].[CH2:23]([NH2:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH2:23]([NH:30][C:15]1[C:14]([F:22])=[C:13]([NH:12][C:8]([CH3:9])([CH3:10])[CH3:11])[C:18]([F:19])=[C:17]([F:20])[N:16]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)Nc1c(F)c(F)nc(F)c1F
Solvent: CN1CCCC1=O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)Nc1c(F)c(F)nc(NCc2ccccc2)c1F
Temperature: 115 °C
Reaction time: 24 h
Yield: 84.5 %

Procedure:
To 10 ml of N-methylpyrrolidone were added 6.8 g of 4-(t-butylamino)-2,3,5,6-tetrafluoropyridine together with 7.2 g of benzylamine, and the mixture was stirred at 115° C. for one day and allowed to cool. After adding 40 ml of chloroform, the mixture was washed three times with 400 ml of distilled water. The chloroform layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain about 8.0 g of the title compound as a dark green crude oil.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([F:15])([F:14])[F:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1C(O)=O.C(=O)=O>>[F:15][C:12]([F:13])([F:14])[C:8]1[CH:7]=[C:6]2[C:11]([C:2]([OH:1])=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: O=C(O)c1cnc2cc(C(F)(F)F)ccc2c1O
Agent: O=C=O
Product: Oc1ccnc2cc(C(F)(F)F)ccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 98.6 %

Procedure:
A round bottom flask was charged with 4-hydroxy-7-(trifluoromethyl)-3-quinolinecarboxylic acid (34.1 g, 0.132 mol) and then heated in a Wood's metal bath for 5 minutes during which time carbon dioxide evolution was observed and the material changed from a solid to a liquid. After 5 minutes no further gas evolution was noted so the flask was removed from the bath and allowed to cool to ambient temperature. The resulting solid was isolated by filtration to provide 27.75 g of 7-(trifluoromethyl)-4-quinolinol.
Reaction SMILES: [CH2:1]([C@:4]1([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[CH2:9][CH2:8][N:7]([C@H:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH3:11])[C:6](=[O:16])[NH:5]1)[CH:2]=C.[O:24]=[O+][O-].[BH4-].[Na+]>C(Cl)Cl>[CH3:13][C:12]([CH3:15])([CH3:14])[C@@H:10]([N:7]1[CH2:8][CH2:9][C@@:4]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)([CH2:1][CH2:2][OH:24])[NH:5][C:6]1=[O:16])[CH3:11]
Reactant: C=CC[C@]1(c2ccc(F)cc2)CCN([C@@H](C)C(C)(C)C)C(=O)N1
Reactant: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H](N1CC[C@](CCO)(c2ccc(F)cc2)NC1=O)C(C)(C)C
Temperature: 25 °C
Yield: 42 %

Procedure:
A solution of (R)-4-allyl-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)tetrahydropyrimidin-2(1H)-one (285 mg, 0.90 mmol) in CH2Cl2 (5 mL) was treated with O3 till the mixture was turned blue. Then NaBH4 was added and the mixture was stirred at rt till the reaction was over. The reaction was quenched with H2O, and the mixture was extracted with EtOAc. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by preparative TLC to afford (S)-1-((S)-3,3-dimethylbutan-2-yl)-4-(4-fluorophenyl)-4-(2-hydroxyethyl)tetrahydropyrimidin-2(1H)-one (120 mg, 42%). LC-MS Method 1 tR=1.021, min, m/z=323.1; 1H NMR (CDCl3): 0.72 (s, 9H), 0.99 (d, 3H), 1.35-1.98 (m, 2H), 2.03-2.14 (m, 3H), 2.51 (m, 1H), 3.04 (m, 1H), 3.31 (m, 1H), 3.64 (m, 1H), 4.47 (m, 1H), 6.66 (s, 1H), 6.96-7.01 (m, 2H), 7.24-7.28 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]2[N:10]=[C:11]([C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])[NH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=2[F:21])=[N:6][C:7]=1[OH:8].[N:29]([C@@H:32]([CH3:37])[CH2:33][CH2:34][O:35][CH3:36])=[C:30]=S.Cl.C(N=C=NCCCN(C)C)C>>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:14]=1[C:13]1[NH:12][C:11]([C:22]([CH3:28])([CH3:27])[C:23]([O:25][CH3:26])=[O:24])=[N:10][C:9]=1[C:5]1[N:6]=[C:7]2[O:8][C:30]([NH:29][C@@H:32]([CH3:37])[CH2:33][CH2:34][O:35][CH3:36])=[N:1][C:2]2=[CH:3][CH:4]=1
Reactant: COC(=O)C(C)(C)c1nc(-c2ccc(N)c(O)n2)c(-c2ccc(F)cc2F)[nH]1
Reactant: COCC[C@H](C)N=C=S
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COCC[C@H](C)Nc1nc2ccc(-c3nc(C(C)(C)C(=O)OC)[nH]c3-c3ccc(F)cc3F)nc2o1
Temperature: 65.5 °C
Reaction time: 21 h
Yield: 73.4 %

Procedure:
Dimethyl sulfoxide (713 mL) is degassed with nitrogen at 25-30° C. for 0.5-1 h under a nitrogen atmosphere. Methyl 2-[4-(5-amino-6-hydroxy-2-pyridyl)-5-(2,4-difluorophenyl)-1H-imidazol-2-yl]-2-methyl-propanoate (35.0 g, 90.0 mmol) and (3S)-3-isothiocyanato-1-methoxy-butane (19.58 g, 0.14 mol) are added and the reaction heated to 63-68° C. The reaction mixture is stirred for 18-24 h at this temperature and then add 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (19.3 g, 100.7 mmol) is added in portions. The reaction mixture is stirred for 2-4 h at 60-65° C. Additional 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.9 g, 9.9 mmol) is added if the reaction does not reach complete conversion. The reaction mixture is cooled to 20-30° C. and is filtered over diatomaceous earth. Ethyl acetate (351 mL) and water (350 mL) are added to the filtrate. The layers are separated and the aqueous phase extracted with ethyl acetate (312 mL). The organic layers are combined and washed with water (2×210 mL), and then heptane (626 mL) is added. The solution is stirred for 0.5-1 h and filtered over silica gel, rinsing with a mixture of ethyl acetate (351 mL) and heptane (348 mL). The solution is concentrated under reduced pressure below 45° C. and ethyl acetate (156 mL) is added. Activated carbon (3.5 g) is added and the mixture heated to 60-70° C. with stirring for 0.5-1 h. The mixture is cooled to 20-30° C., filtered, and the filtrate concentrated under reduced pressure below 45° C. Toluene (242 mL) is charged to the resulting residue and the material concentrated under reduced pressure below 45° C. Toluene (40 mL) is added and the mixture heated to 60-70° C. with stirring for 0.5-1 h. The mixture is cooled to 25-30° C., stirred for 2-4 h, and then cooled to 0-5° C. The mixture is stirred at 0-5° C. for 2-4 h and the solids are collected by filtration. The filtercake is washed with toluene (40 mL) and is dried under reduced pressure below 60° C. to give the title compound as an off-white solid (33.0 g, 71%).
Reaction SMILES: [C:1]([O:10]C)(=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:20]2[CH2:25][CH2:24][N:23]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:22][CH2:21]2)[N:15]=1)#[N:13]>C1(C)C=CC=CC=1>[C:26]1([N:23]2[CH2:24][CH2:25][N:20]([C:16]3[N:15]=[C:14]([C:12]4[S:4][C:3]5[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=5[C:1](=[O:10])[N:13]=4)[CH:19]=[CH:18][CH:17]=3)[CH2:21][CH2:22]2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N#Cc1cccc(N2CCN(c3ccccc3)CC2)n1
Reactant: COC(=O)c1ccccc1S
Solvent: Cc1ccccc1
Product: O=c1nc(-c2cccc(N3CCN(c4ccccc4)CC3)n2)sc2ccccc12
Yield: 33.3 %

Procedure:
A mixture of methyl thiosalicylate (0.25 g, 1.5 mmol), 2-cyano-6-(4-phenyl-1-piperazinyl)pyridine (0.40 g, 1.5 mmol) triethylamine (0.32 ml, 2.3 mmol) and toluene (30 ml) was refluxed for 48 hrs. The reaction mixture was concentrated under reduced pressure and the crude crystals were recrystallized from ethanol to give the titled compound (0.20 g, 33%) as crystals.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([O:14]C)=O)[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31].ClC(OCC(C)C)=O.[CH3:40][N:41]1CCOCC1.CN>CN(C)C(=O)C.C(Cl)Cl>[Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:16]=[CH:17][C:18]=2[CH3:19])[C:12]([NH:41][CH3:40])=[O:14])[C:5]([NH:20][CH3:21])=[N:4][C:3]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=1[F:31]
Reactant: CN1CCOCC1
Reactant: CNc1nc(OCc2ccc(F)cc2F)c(Br)c(=O)n1-c1cc(C(=O)OC)ccc1C
Agent: CC(C)COC(=O)Cl
Agent: CN
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CNC(=O)c1ccc(C)c(-n2c(NC)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 27 %

Procedure:
To a cooled (0° C.) solution of methyl 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-(methylamino)-6-oxopyrimidin-1(6H)-yl]-4-methylbenzoate (from Step 3) (0.18 g, 0.38 mmol) in N, N-dimethylacetamide (2 mL) was added isobutyl chloroformate (0.60 mL of a stock solution prepared 0.1 mL in 0.9 mL DCM, 0.46 mmol) and 4-methylmorpholine (0.55 mL of a stock solution prepared 0.1 mL in 0.9 mL DMA, 0.50 mmol). Stirred at 0° C. for 35 min. Added methylamine (0.29 mL of 2M solution in THF, 0.57 mmol). After 1 h, distilled DMA and purified the crude product by preparatory HPLC using a 10–90% CH3CN/H2O (30 min) gradient containing 0.5% TFA at a flow rate of 80 mL/min. Appropriate fractions (M+H m/z=494) were combined and concentrated to approximately 20 mL under reduced pressure. Added 5% NaHCO3 (20 mL) and extracted with DCM (3×15 mL). The organic extracts were dried over Na2SO4, filtered, concentrated under reduced pressure, and dried in vacuo to give the desired product as a white solid (77 mg, 27%). 1H NMR (CD3OD/400 MHz) 67.86 (m, 1H), 7.58 (m, 2H), 7.51 (d, 1H, J=8.0 Hz), 6.98 (m, 2H), 5.52 (q, 2H, J=12.8 Hz), 2.87 (s, 3H), 2.84 (s, 3H), 2.09 (s, 3H). ESHRMS m/z 493.0659 (M+H calculated for C21H20BrF2N4O3 requires 493.0681).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[NH:16][CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2].[H-].[Na+].[CH2:21](Br)[CH3:22]>CN(C=O)C>[CH2:1]([O:3][C:4]([N:6]1[CH2:15][CH2:14][C:13]2[C:12]3[N:16]([CH2:21][CH3:22])[CH:17]=[CH:18][C:11]=3[S:10][C:9]=2[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCBr
Reactant: CCOC(=O)N1CCc2sc3cc[nH]c3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCc2sc3ccn(CC)c3c2CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 78.9 %

Procedure:
To a stirred solution of the product of Example 1, step (g) (0.068 g, 0.26 mmol) in DMF (4 ml) at 0° C. under argon was added NaH (60% dispersion by wt., 0.015 g, 0.39 mmol) followed by ethyl bromide (0.029 ml, 0.39 mmol). The reaction mixture was stirred at 0° C. for 2 hrs and then quenched by slow addition of saturated aqueous citric acid (40 ml). The aqueous mixture was extracted with DCM (3×). The combined DCM extracts were washed with water (2×), brine, dried (MgSO4), filtered, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 50% EtOAc in hexanes) gave the sub-titled compound as a tan solid (0.060 g). 1H NMR (CDCl3) δ 6.75 (d, J=3.0 Hz, 1 H), 6.24 (d, J=3.0 Hz, 1H), 4.40-4.08 (m, 4H), 3.96-3.62 (m, 4 H), 3.34-2.92 (m, 4 H), 1.42 (t, J=6.9 Hz, 3 H), 1.28 (t, J=6.9 Hz, 3H); MS: ESI (positive): 293 (M+H).
Reaction SMILES: Br[CH:2]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4].[CH3:19][S-:20].[Na+]>O1CCOCC1>[CH3:19][S:20][CH:2]([O:10][C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=1)[C:3]([O:5][C:6]([CH3:9])([CH3:8])[CH3:7])=[O:4]
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)C(Br)Oc1cc(Cl)cc(Cl)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: CSC(Oc1cc(Cl)cc(Cl)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 88.1 %

Procedure:
t-Butyl 2-bromo-2-(3,5-dichlorophenoxy)acetate (1.0 g) was dissolved in 1,4-dioxane (3 ml), and sodium thiomethoxide (0.218 g) was added to the mixture. The resulting pale yellow suspension was stirred at ambient temperature for 5 hours and then stored for 18 hours. The solvent was evaporated, water was added and the aqueous layer was extracted twice with ethyl acetate (100 ml). The organic layers were combined, washed with brine, dried over magnesium sulphate, filtered and evaporated to give t-butyl 2-methylthio-2-(3,5-dichlorophenoxy)acetate as a pale yellow solid (0.80 g) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1.Cl.[NH+]1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][CH:9]=[C:10]2[C:13]#[N:14])=[CH:5][CH:4]=1
Reactant: COc1ccc2cccc(C#N)c2c1
Agent: Cl
Agent: c1cc[nH+]cc1
Product: N#Cc1cccc2ccc(O)cc12

Procedure:
The title compound was prepared by reacting 7-methoxy-1-naphthonitrile (1.19 g, 6.50 mmol) with pyridinium HCl (9 g) according to method D to yield 0.88 g (80%) of a white solid: mp 184-188° C.; 1H NMR (DMSO-d6): δ 7.25 (1H, dd, J=2.30 Hz, J=8.88 Hz), 7.38 (1H, d, J=2.20 Hz), 7.39-7.44 (1H, m), 7.98 (1H, d, J=8.91 Hz), 8.04 (1H, d, J=7.14 Hz), 8.17 (1H, d, J=8.19 Hz), 10.48 (1H, s); MS (ESI) m/z 170 ([M+H]+); MS (ESI) m/z 168 (M−H)−.