Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH3:23][O:24][CH2:25][CH2:26][O:27][C:28]1[CH:29]=[C:30]([NH:38][C:39](=O)[O-:40])[CH:31]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:33]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:39]([NH:38][C:30]2[CH:31]=[C:32]([C:34]([F:36])([F:37])[F:35])[CH:33]=[C:28]([O:27][CH2:26][CH2:25][O:24][CH3:23])[CH:29]=2)=[O:40])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Reactant: COCCOc1cc(NC(=O)[O-])cc(C(F)(F)F)c1
Product: COCCOc1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)cc(C(F)(F)F)c1
Yield: 70 %

Procedure:
The title compound was prepared from 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (94 mg, 0.3 mmol) and 3-(2-methoxyethoxy)-5-(trifluoromethyl)phenylcarbamate from Example 117A (160 mg, 0.45 mmol) using Example 115C to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(3-(2-methoxyethoxy)-5-(trifluoromethyl)phenyl)urea (118 mg, 0.21 mmol, 69%). 1H NMR (300 MHz, DMSO-d6) δ 9.09 (s, 1H), 9.04 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.55 (d, 1H), 7.50-7.41 (m, 2H), 7.35 (s, 1H), 7.34 (s, 1H), 7.29-7.23 (m, 2H), 6.87 (s, 1H), 4.19-4.11 (m, 2H), 4.00 (s, 6H), 3.70-3.63 (m, 2H), 3.31 (s, 3H); LC-MS (ESI) m/z 575 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:20](OC(=O)C)=[O:21].N1CCCCC1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1(C)C(C)=CC=CC=1.C1C=CC=CC=1.ClCCCl.C(Cl)(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[CH:20]([N:11]1[CH2:10][CH2:9][CH:8]([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH2:13][CH2:12]1)=[O:21]
Reactant: CC(=O)OC=O
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: O=CN1CCC(C(c2ccccc2)c2ccccc2)CC1
Reaction time: 18 h

Procedure:
The compounds of the invention of formula (I) may be prepared by the procedure described by C. A. Buehler and D. E. Pearson in "Survey of Organic Syntheses" at pages 900-901, Wiley-Interscience, New York (1970). The procedure comprises reacting 4-diphenylmethylpiperidine available from Reilly Tar and Chemical of Indianapolis, Ind. 46204, with acetic formic anhydride, the anhydride preferably being present in excess. The piperidine and anhydride are combined with cooling and are allowed to stir for about 18 hours. The resulting reaction mixture dissolved in an organic solvent such as, for example, a halocarbon e.g., carbon tetrachloride, chloroform, 1,2-dichloroethane, and the like, an aromatic hydrocarbon e.g., benzene, xylene, toluene, and the like is then treated with an aqueous solution of a weak base e.g., sodium bicarbonate, until the aqueous layer is neutral. The organic layer is separated and any solvent present is removed to obtain the intermediate N-formyl-4-(diphenylmethyl)piperidine. The N-formyl intermediate is then treated either neat or in the presence of an organic solvent such as, for example, a halocarbon, e.g., CHCl3, CH2Cl2 or a hydrocarbon e.g., benzene or toluene, at 25° to 100° C. with a suitable activating agent selected from, for example, phosgene, (CH3)3O+BF4-, (C2H5)3O+BF4-, (CH3O)2SO2, CH3OSO2F, POCl3, PCl5 and the like, for about one-half to three hours, to produce the activated formamide after which the reaction mixture is allowed to cool. Addition of the appropriate primary amine of the formula H2N--Alk--R 1 yields the desired product of formula (I) which may be isolated and purified by techniques known in the art, e.g., by stripping off the solvent and recrystallizing the desired product in the free base or acid addition salt form.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([N:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1)=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH2:66])[CH2:58][C:59]3[CH:64]=[CH:63][C:62]([Cl:65])=[CH:61][CH:60]=3)=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:68]=[CH:67][C:53]2[NH:54][C:55]([C@@H:57]([NH:66][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][C:10]([C:11]([N:13]4[CH2:17][CH2:16][CH2:15][CH2:14]4)=[O:12])=[C:2]([CH3:1])[CH:3]=3)[CH2:58][C:59]3[CH:60]=[CH:61][C:62]([Cl:65])=[CH:63][CH:64]=3)=[N:56][C:52]=2[CH:51]=1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CCCC1
Reactant: N[C@@H](Cc1ccc(Cl)cc1)c1nc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: ClCCl
Product: Cc1cc(C(=O)N[C@@H](Cc2ccc(Cl)cc2)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1

Procedure:
Prepared analogously to Example 1g from 3-methyl-4-(pyrrolidin-1-ylcarbonyl)benzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)-2-(4-chlorophenyl)ethylamine in tetrahydrofuran. Yield: %; Rf value: 0.40 (silica gel: dichloromethane/ethanol=9:1); C28H26Cl2N4O2 (521.45); mass spectrum: (M+H)+=521/523 (chlorine isotope).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[C:12](O)=[N:11][CH:10]=[CH:9]2.P(Cl)(Cl)[Cl:18]>>[Cl:18][C:12]1[C:13]2[C:8](=[CH:7][C:6]([O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:15][CH:14]=2)[CH:9]=[CH:10][N:11]=1
Reactant: COCCOc1ccc2c(O)nccc2c1
Reactant: ClP(Cl)Cl
Product: COCCOc1ccc2c(Cl)nccc2c1
Yield: 80 %

Procedure:
To 6-(2-methoxyethoxy)isoquinolin-1-ol (3.15 g, 14.4 mmol) was added phosphorus trichloride (70 mL) under nitrogen atmosphere. The mixture was heated at reflux giving a nearly opaque brown solution. After 2 h at reflux, the solution was concentrated in vacuo until 20 mL remained and poured onto ice water (100 mL). The pH of the resulting mixture was adjusted to 6.5 with the addition of solid potassium carbonate and extracted with dichloromethane (3×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL) and concentrated in vacuo. The resulting tan solid was taken up in dichloromethane, adsorbed on silica gel and purified by flash chromatography (gradient:hexane/ethyl acetate, 60:40→40:60) to give, after drying in vacuo, 2.73 g (80% yield) of the title compound as a pale yellow solid. MS(AP+), 238 (100, M++1), 202 (33), 179 (33).
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C:7]1[CH:11]=[CH:10][NH:9][N:8]=1)=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:38])([F:37])[F:36])[C:29]=1[CH2:39]Br>C1COCC1>[Br:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([O:34][C:35]([F:36])([F:37])[F:38])[C:29]=1[CH2:39][N:9]1[CH:10]=[CH:11][C:7]([NH:6][C:4](=[O:5])[C:3]2[C:12]([F:16])=[CH:13][CH:14]=[CH:15][C:2]=2[F:1])=[N:8]1
Reactant: FC(F)(F)Oc1cccc(Br)c1CBr
Reactant: O=C(Nc1cc[nH]n1)c1c(F)cccc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(Nc1ccn(Cc2c(Br)cccc2OC(F)(F)F)n1)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,6-difluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 9)(45 mg, 0.202 mmol) in dry THF (3.0 ml) was stirred under nitrogen at ambient temperature, 1.0 M lithium bis(trimethylsilyl)amide (0.20 ml, 0.20 mmol) was added dropwise and the solution stirred for approximately 90 min then 1-bromo-2-(bromomethyl)-3-[(trifluoromethyl)oxy]benzene (67.3 mg, 1 equiv) in THF (2 ml) was added. The solution was stirred for 5 h then left to stand overnight. The solvent was removed using a stream of nitrogen. To the residue was added aqueous sodium bicarbonate and the mixture was extracted with chloroform three times. The combined organic extracts were filtered through a hydrophobic frit and the filtrate was concentrated in vacuo. The residue was purified by MDAP (Method B). The appropriate fractions were combined and evaporated in vacuo to give the title compound as a white solid (80.6 mg) after drying at high vacuum at 45° C.; LCMS: (System 4) MH+=476, tRET=3.01 min.
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12][CH:11]([NH:26][C:27]([NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]CC3C=CC=CC=3)=[O:37])[CH:31]=2)=[O:28])[C:10]1=[O:46])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[C].[Pd].CO>[C:1]([O:5][C:6]([CH2:8][N:9]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]([C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH2:12][CH:11]([NH:26][C:27](=[O:28])[NH:29][C:30]2[CH:31]=[C:32]([CH:33]=[CH:34][CH:35]=2)[C:36]([OH:38])=[O:37])[C:10]1=[O:46])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)OCc3ccccc3)c2)CN(C(=O)C(C)(C)C)c2ccccc21
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)CN1C(=O)C(NC(=O)Nc2cccc(C(=O)O)c2)CN(C(=O)C(C)(C)C)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.1 %

Procedure:
Methanol (20 ml) and 10% palladium carbon (57 mg) were added to 1-(1-tert-butoxycarbonylmethyl-2-oxo-5-pivaloyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl)-3-(3-benzyloxycarbonylphenyl)urea (550 mg), the mixture was stirred at room temperature under hydrogen atmosphere for one hour. The reaction mixture was filtrated and the filtrate was concentrated under reduced pressure. Isopropyl ether was added to the residue for trituration and collected by filtration, to thereby obtain 420 mg of the title compound as a colorless solid.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[NH:19][C:18]2=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=[C:17]2[O:16][CH2:15]1>O1CCCC1.C(N(CC)C(C)C)(C)C>[CH3:13][C:14]1([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=2)[N:19]2[C:2](=[O:4])[NH:24][C:20]3=[CH:21][CH:22]=[CH:23][C:17](=[C:18]23)[O:16][CH2:15]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC1(c2ccccn2)COc2cccc(N)c2N1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(c2ccccn2)COc2cccc3[nH]c(=O)n1c23
Reaction time: 1 h

Procedure:
Triphosgene (40 mg, 0.1 mmol) was added to the solution of 3-methyl-3-pyridin-2-yl-3,4-dihydro-2H-1,4-benzoxazin-5-amine (90 mg, 0.4 mmol) in tetrahydrofuran (10 mL) and N,N-diisopropylethylamine (100 μL) at room temperature. The reaction was stirred for 1 h and was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give crude 4-methyl-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2(1H)-one as a semisolid (0.10 g. 90%). LCMS calculated for C15H14N3O2 (M+H)+: m/z=268.1. found: 268.0.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C@@:5]1([OH:13])[CH:10]2[CH2:11][CH2:12][N:7]([CH2:8][CH2:9]2)[CH2:6]1.C([O-])([O-])=O.[Cs+].[Cs+].[N:20]([C:23]1[CH:28]=[C:27]([O:29][CH3:30])[N:26]=[CH:25][N:24]=1)=[C:21]=S.C(N=C=NC(C)C)(C)C>CN(C)C=O>[CH3:30][O:29][C:27]1[N:26]=[CH:25][N:24]=[C:23]([NH:20][C:21]2[O:13][C@:5]3([CH2:4][N:3]=2)[CH:10]2[CH2:9][CH2:8][N:7]([CH2:12][CH2:11]2)[CH2:6]3)[CH:28]=1
Reactant: COc1cc(N=C=S)ncn1
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: COc1cc(NC2=NC[C@@]3(CN4CCC3CC4)O2)ncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 48.3 %

Procedure:
To (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (from Step B of Example 21) (0.34 g, 1.49 mmol) in N,N-dimethylformamide (15 mL) was added Cs2CO3 (1.22 g, 3.74 mmol) and 4-isothiocyanato-6-methoxypyrimidine (0.25 g, 1.5 mmol). The suspension was stirred at room temperature for 30 minutes. N,N′-diisopropylcarbodiimide (0.7 mL, 4.5 mmol) was then added and the mixture was stirred at room temperature for 18 hours. The mixture was concentrated and purified by silica gel chromatography (5-15% [9:1 methanol:ammonium hydroxide]/chloroform) to afford (R)—N-(6-methoxypyrimidin-4-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (0.21 g, 0.72 mmol, 48.2% yield) as a white solid. M.P. 186-8° C. 1H NMR (400 MHz, MeOD) δ ppm 8.40 (1 H, s), 6.17 (1 H, br. s.), 3.92-4.04 (1 H, m), 3.89 (3 H, s), 3.68 (1 H, d, J=10.32Hz), 3.12-3.23 (1 H, m), 2.98-3.12 (1 H, m), 2.67-2.97 (4 H, m), 2.11 (2 H, br. s.), 148-1.82 (3 H, m). MS (LC/MS) R.T.=0.82; [M+H]+=290.3.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](SC)[N:5]=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH2:21])[CH3:17]>C(OCC)(=O)C>[CH2:16]([N:18]([CH2:22][CH3:23])[CH2:19][CH2:20][NH:21][C:4]1[N:5]=[N:6][C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:2]([CH3:1])[N:3]=1)[CH3:17]
Reactant: CSc1nnc(-c2ccccc2)c(C)n1
Reactant: CCN(CC)CCN
Solvent: CCOC(C)=O
Product: CCN(CC)CCNc1nnc(-c2ccccc2)c(C)n1
Yield: 64.2 %

Procedure:
A mixture of 5-methyl-3-methylthio-6-phenyl-1,2,4-triazine (2.17 g) and N,N-diethylethylenediamine (2.99 g) was heated at 150° C. to 160° C. for 17 hours. The reaction mixture was dissolved in ethyl acetate, washed with water and brine, and then dried over sodium sulfate, which was treated with silical gel and filtered by suction. The filtrate was evaporated to dryness and the resulting residue was crystallized with diisopropyl ether under ice cooling. The resultant crystals were collected by filtration, washed with diisopropyl ether and dried to give 3-(2-diethylaminoethylamino)-5-methyl-6-phenyl-1,2,4-triazine (1.83 g).
Reaction SMILES: [N:1]1([C@H:6]2[CH2:10][CH2:9][CH2:8][C@H:7]2[NH2:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[C:14]=1[C:15](O)=[O:16]>>[CH3:12][C:13]1[CH:21]=[C:20]([C:22]([F:24])([F:25])[F:23])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[C:14]=1[C:15]([NH:11][C@@H:7]1[CH2:8][CH2:9][CH2:10][C@@H:6]1[N:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)=[O:16]
Reactant: N[C@@H]1CCC[C@@H]1N1CCCC1
Reactant: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)O
Product: Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCC[C@@H]1N1CCCC1

Procedure:
The title compound, white solid, MS: m/e=409.3 [(M+H)+], was prepared in accordance with the general method of example 5 from cis-2-pyrrolidin-1-yl-cyclopentylamine (intermediate Q) and 2-methyl-4,6-bis-trifluoromethyl-benzoic acid (CAS 895580-37-7).
Reaction SMILES: C(N(CC)CC)C.Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=1.[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28]([OH:35])=[C:29]([C:32](=O)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]>CO>[C:22]([C:25]1[C:26](=[O:36])[O:27][C:28](=[O:35])[C:29](=[C:32]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[C:12]([NH:17][C:18](=[O:21])[CH2:19][CH3:20])[CH:11]=2)[CH3:33])[C:30]=1[OH:31])(=[O:24])[CH3:23]
Reactant: CCC(=O)Nc1cc(N)ccc1O
Reactant: CC(=O)c1c(O)oc(=O)c(C(C)=O)c1O
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1cc(NC(C)=C2C(=O)OC(=O)C(C(C)=O)=C2O)ccc1O

Procedure:
Following the procedures of Example 3, 2.0 g. (0.0096 mol) of 4-nitro-2-propionamidophenyl (prepared from propionic acid and 2-amino-4-nitrophenyl) is hydrogenated in a mixture of 100 ml. of ethanol, 0.3 g. of 10% palladium-on-carbon and 1.34 ml. of concentrated hydrochloric acid in a Parr apparatus. Filtration and evaporation of the solvent gives 4-amino-2-propionamidophenol hydrochloride. The latter (2.0 g., 0.0096 mol) in a methanol solution is treated with 1 equivalent of triethylamine under nitrogen atmosphere. The solution of the free amine is added to a refluxing mixture of one equivalent of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and 30 ml. of methanol under nitrogen. The reaction mixture is refluxed for 18 hours, filtered and the solid is recrystallized from ethanol to yield 5-acetyl-4-hydroxy-3-[1-(4-hydroxy-3-propionamidophenylamino)ethylidene]-2H-pyran-2,6(3H)-dione, m.p. 228°-229° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[C:9]2[N:14]=[C:13]([S:15][C:16]#[N:17])[C:12]([N+:18]([O-])=O)=[CH:11][N:10]=2)=[CH:4][C:3]=1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>C(O)(=O)C>[NH2:17][C:16]1[S:15][C:13]2[N:14]=[C:9]([N:8]([CH3:21])[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[C:3]([NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH:4]=3)[N:10]=[CH:11][C:12]=2[N:18]=1
Reactant: CN(c1ccc(F)c(NC(=O)OC(C)(C)C)c1)c1ncc([N+](=O)[O-])c(SC#N)n1
Solvent: CC(=O)O
Product: CN(c1ccc(F)c(NC(=O)OC(C)(C)C)c1)c1ncc2nc(N)sc2n1
Temperature: 80 °C
Reaction time: 3 h
Yield: 46 %

Procedure:
To a solution of the above-mentioned crude product of tert-butyl {2-fluoro-5-[methyl(5-nitro-4-thiocyanatopyrimidin-2-yl)amino]phenyl}carbamate in acetic acid (70 mL) was added reduced iron (4.28 g, 76.7 mmol), and the mixture was stirred at 80° C. for 3 hr. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. To the obtained residue was added 0.5N aqueous sodium hydroxide solution (100 mL), and the mixture was extracted with ethyl acetate (200 mL, 30 mL). The combined organic layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was washed with tetrahydrofuran to give the title compound (1.95 g, 46%) as a pale-purple solid.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[N+:10]([C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1)([O-:12])=[O:11].C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:9][O:8][C:7]1[C:2]([C:17]2[CH:18]=[C:13]([N+:10]([O-:12])=[O:11])[CH:14]=[CH:15][CH:16]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: COc1cccnc1Br
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COc1cccnc1-c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 15 h
Yield: 90.2 %

Procedure:
To a suspension of 2-bromo-3-methoxypyridine (1.54 g), 3-nitrophenylboronic acid (1.77 g) and tetrakis(triphenylphosphine)-palladium (473 mg) in 1,2-dimethoxyethane (30 ml) was added 2M aqueous solution of sodium carbonate (10.6 ml). The mixture was stirred at 80° C. for 15 hours under a nitrogen atmosphere, then cooled to room temperature and diluted with ethyl acetate. The organic layer was separated, washed with water and brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by column chromatography (silica gel 40 g, 25% ethyl acetate in n-hexane) to give 3-(3-methoxypyridin-2-yl)nitrobenzene (1.7 g).
Reaction SMILES: [N:1]#[C:2]Br.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]3[CH:18]=[N:19][C:20]([CH2:23][NH2:24])=[CH:21][CH:22]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[CH3:25].CCN(C(C)C)C(C)C.C1(C)C=CC=CC=1>C(#N)C>[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]3[CH:22]=[CH:21][C:20]4[N:19]([C:2]([NH2:1])=[N:24][CH:23]=4)[CH:18]=3)=[CH:15][CH:14]=[CH:13][N:12]=2)=[CH:7][C:6]=1[CH3:25]
Reactant: N#CBr
Reactant: Cc1cc(-c2ncccc2-c2ccc(CN)nc2)ccc1F
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2ncccc2-c2ccc3cnc(N)n3c2)ccc1F
Reaction time: 4 h

Procedure:
Cyanogen bromide (62 mg) in dry acetonitrile (1 mL) was added to a screw capped vial containing a stirring solution of (2′-(4-fluoro-3-methylphenyl)-[3,3′-bipyridin]-6-yl)methanamine.xHCl (120 mg), i-Pr2NEt (0.2 mL) and anhydrous toluene. After 4 h, the reaction mixture was concentrated and purified by reverse phase preparative HPLC conditions provided 6-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)imidazo[1,5-a]pyridin-3-amine (28 mg).
Reaction SMILES: [C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([OH:18])=O)=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:37][N:38]([C:40]([C:42]([CH3:47])([OH:46])[C:43]([NH2:45])=[O:44])=[O:41])[CH3:39]>O1CCCC1>[C:1]([NH:4][C@H:5]([C:7]([NH:9][C@H:10]([C:12]([N:14]1[CH2:21][CH2:20][CH2:19][C@H:15]1[C:16]([NH:37][N:38]([C:40]([C:42]([CH3:47])([OH:46])[C:43]([NH2:45])=[O:44])=[O:41])[CH3:39])=[O:18])=[O:13])[CH3:11])=[O:8])[CH3:6])(=[O:3])[CH3:2]
Reactant: CN(N)C(=O)C(C)(O)C(N)=O
Reactant: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(C)COC(=O)Cl
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)NN(C)C(=O)C(C)(O)C(N)=O
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Acetylalanylalanylproline (2 mmole) and N-methylmorpholine (2 mmole) are dissolved in dry tetrahydrofuran (200 ml) and cooled to -20° to -25°. Isobutyl chloroformate (2 mmole) is added, and the mixture is stirred at -20° for 10 minutes. A solution of 2-azaalanyl-dl-lactamide (2 mmole) in tetrahydrofuran (10 ml) is added dropwise, and the mixture is allowed to warm to room temperature over a period of 2 hours and stirred for a further 3 hours. The precipitate is filtered off and the filtrate is evaporated to dryness. Chromatography of the residue on silica gel (70 gm) and elution with 18% methanol in chloroform gives acetylalanylalanylprolyl-2-azaalanyl-dl-lactamide.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[N:8]=[CH:9][C:10]([O:12][C:13]3[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:18]=3)=[CH:11][C:6]=2[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][O:29]2)[C:3]1=[O:34].[Li+].CC([N-]C(C)C)C.[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]=[O:49])=[CH:46][CH:45]=1>C1COCC1.CC(=O)OCC.O>[Cl:43][C:44]1[CH:51]=[CH:50][C:47]([CH:48]([OH:49])[C:11]2[C:6]3[C:5](=[O:23])[N:4]([CH2:24][CH2:25][CH2:26][O:27][CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][O:29]4)[C:3](=[O:34])[N:2]([CH3:1])[C:7]=3[N:8]=[CH:9][C:10]=2[O:12][C:13]2[CH:14]=[N:15][CH:16]=[C:17]([C:19]([F:22])([F:20])[F:21])[CH:18]=2)=[CH:46][CH:45]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2cc(Oc3cncc(C(F)(F)F)c3)cnc21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)n(CCCOC2CCCCO2)c(=O)c2c(C(O)c3ccc(Cl)cc3)c(Oc3cncc(C(F)(F)F)c3)cnc21
Temperature: -78 °C
Reaction time: 1 h
Yield: 39.1 %

Procedure:
To a solution of 1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (340 mg, 0.708 mmol) in THF (8 mL) at −78° C. was added LDA (2M in THF, 1.42 mL, 2.83 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then a solution of 4-chlorobenzaldehyde (199.7 mg, 1.42 mmol) in THF (2 mL) was added dropwise. The reaction was stirred for 30 min at −78° C. then diluted with EA (10 mL) and water (10 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by chromatography eluted with PE/EA (10:1 to 1:1) to give 5-((4-chlorophenyl)(hydroxy)methyl)-1-methyl-3-(3-((tetrahydro-2H-pyran-2-yl)oxy)propyl)-6-((5-(trifluoromethyl)pyridin-3-yl)oxy)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (172 mg, 39.1% yield) as an oil. LCMS: [MH+-THP] 537 and TR=1.611 min.
Reaction SMILES: [S:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=[CH:2]1.[NH2:9][C:10]1[CH:19]=[CH:18][C:17]2[C:12](=[N:13][C:14]([Cl:20])=[CH:15][CH:16]=2)[N:11]=1>O>[Cl:20][C:14]1[N:13]=[C:12]2[C:17]([CH:18]=[CH:19][C:10]([NH:9][C:6]([C:5]3[S:1][CH:2]=[N:3][CH:4]=3)=[O:8])=[N:11]2)=[CH:16][CH:15]=1
Reactant: Nc1ccc2ccc(Cl)nc2n1
Reactant: O=C(O)c1cncs1
Solvent: O
Product: O=C(Nc1ccc2ccc(Cl)nc2n1)c1cncs1
Yield: 68 %

Procedure:
The procedure is similar to that described in Example 2, but starting with 5-thiazolecarboxylic acid (4.5 g), N,N'-carbonyldiimidazole (6.8 g) and 2-amino-7-chloro-1,8-naphthyridine (5 g). The product obtained by precipitation in water is purified by recrystallization in a dimethylformamide/acetonitrile (5:5 by volume) mixture (120 cc). N-(7-Chloro-1,8-naphthyridin-2-yl)-5-thiazolecarboxamide (5.5 g), m.p. 292° C., is thereby obtained.