Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([O-:12])=[O:11])=[C:8](CC)[C:7]=1[NH2:17])(=O)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:40]=[CH:39][C:28]([CH2:29][O:30][C:31]2[CH:38]=[CH:37][C:34]([CH2:35]Br)=[CH:33][CH:32]=2)=[CH:27][CH:26]=1.[C:41](OCC)(=O)[CH3:42]>O>[CH2:41]([O:12][C:10]([C:9]1[CH:13]=[CH:14][C:6]2[N:5]=[C:1]([CH2:2][CH3:3])[N:17]([CH2:35][C:34]3[CH:37]=[CH:38][C:31]([O:30][CH2:29][C:28]4[CH:39]=[CH:40][C:25]([F:24])=[CH:26][CH:27]=4)=[CH:32][CH:33]=3)[C:7]=2[CH:8]=1)=[O:11])[CH3:42]
Reactant: Fc1ccc(COc2ccc(CBr)cc2)cc1
Reactant: CCOC(C)=O
Reactant: CCC(=O)Nc1ccc(C(=O)[O-])c(CC)c1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1ccc2nc(CC)n(Cc3ccc(OCc4ccc(F)cc4)cc3)c2c1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of 4-propionylamino-3-amino-ethylbenzoate (0.534 g), potassium carbonate (0.374 g), 4-(4-fluorobenzyloxy)benzyl bromide (0.800 g), ethyl acetate (5 ml) and water (3 ml) is stirred for 16 hours at 75° C. The organic layer is concentrated, and ethanol and 36% hydrochloric acid (0.46 g) are added to the obtained residue. The residue is stirred for two hours as it is refluxed by heating. After neutralizing it by adding potassium carbonate, the solvent is concentrated under reduced pressure. Ethyl acetate and water are added and extraction is performed. The organic layer is concentrated under reduced pressure, purified using silica gel column chromatography (eluate: hexane/ethyl acetate=1/1), and thus, 6-ethoxycarbonyl-2-ethyl-1-[4-(4-fluorobenzyloxy)benzyl]benzimidazole (0.228 g) is obtained. 1H-NMR (CDCl3δ): 1.40 (3H, t, J=7.1 Hz), 1.42 (3H, t, J=7.5 Hz), 2.86 (2H, q, J=7.5 Hz), 4.38 (2H, q, J=7.1 Hz), 4.97 (2H, s), 5.32 (2H, s), 6.88 (2H, q, J=8.7 Hz), 6.98 (2H, d, J=8.7 Hz), 7.05 (2H, t, J=8.7 Hz), 7.37 (2H, m), 7.76 (2H, d, J=8.4 Hz), 7.98 (1H, dd, J=1.5 and 8.5 Hz), 8.02 (1H, s).
Reaction SMILES: CC1C=[C:5](C)[N:4]([C:8](=[O:22])[CH:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)N=1.[CH2:23]([C:25]1[O:29]C(N)=[N:27][N:26]=1)[CH3:24]>>[CH2:23]([C:25]1[O:29][C:5]([NH:4][C:8](=[O:22])[CH:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[N:27][N:26]=1)[CH3:24]
Reactant: Cc1cc(C)n(C(=O)C(c2ccccc2)c2ccccc2)n1
Reactant: CCc1nnc(N)o1
Product: CCc1nnc(NC(=O)C(c2ccccc2)c2ccccc2)o1

Procedure:
The title compound, white solid, m.p. 123-125° C. and MS: m/e=308.2 (M+H+) was prepared in accordance with the general method of example 48a from l-(3,5-dimethyl-pyrazol-1-yl)-2,2-diphenyl-ethanone and 5-ethyl-[1,3,4]oxadiazol-2-ylamine. The 1-(3,5-dimethyl-pyrazol-1-yl)-2,2-diphenyl-ethanone, white solid, m.p. 91-92° C. and MS: m/e=291.2 (M+H+) used in the above reaction was prepared in accordance with the general method of example 48c from 2,2-diphenylacetic acid hydrazide [Chem. Zentralblatt. 100, 2414(1929)] and acetylacetone.
Reaction SMILES: [F:1][C:2]1([F:48])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=4)[CH2:15][C:14]([CH3:29])([CH3:28])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:42]=[CH:41][C:40]([C:43]([F:46])([F:45])[F:44])=[CH:39][CH:38]=2)[CH2:4][CH2:3]1.Cl[C:50]1[N:55]=[CH:54][C:53]([O:56][CH2:57][C:58]2([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]2)=[CH:52][N:51]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>O>[F:48][C:2]1([F:1])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([O:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[CH:24][CH:25]=4)[CH2:15][C:14]([CH3:28])([CH3:29])[CH2:13][C:12]=3[N:11]=[C:10]([CH:30]3[CH2:35][CH2:34][N:33]([C:50]4[N:51]=[CH:52][C:53]([O:56][CH2:57][C:58]5([CH3:66])[CH2:63][O:62][C:61]([CH3:65])([CH3:64])[O:60][CH2:59]5)=[CH:54][N:55]=4)[CH2:32][CH2:31]3)[C:9]=2[C@@H:36]([F:47])[C:37]2[CH:38]=[CH:39][C:40]([C:43]([F:45])([F:46])[F:44])=[CH:41][CH:42]=2)[CH2:4][CH2:3]1
Reactant: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCNCC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Reactant: CC1(COc2cnc(Cl)nc2)COC(C)(C)OC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(CO[C@H]2CC(C)(C)Cc3nc(C4CCN(c5ncc(OCC6(C)COC(C)(C)OC6)cn5)CC4)c([C@@H](F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Temperature: 120 °C
Reaction time: 26 h
Yield: 92.1 %

Procedure:
To 377 mg (0.559 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 127 mg (0.466 mmol) of 2-chloro-5-[(2,2,5-trimethyl-1,3-dioxan-5-yl)methoxy]pyrimidine, which was prepared by a method similar to that of Reference Example 17, and 154 mg (1.11 mmol) of potassium carbonate, 1 ml of 1,4-dioxane was added, and the reaction mixture was stirred at 120° C. for 26 hours. After completion of the reaction, water was added to the reaction solution and the reaction solution was extracted with ethyl acetate twice. The obtained organic phases were combined and washed with saturated sodium chloride aqueous solution, and then the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography [n-hexane/ethyl acetate=89/11-68/32 (V/V)] and the fraction including the desired compound was concentrated under reduced pressure to provide 391 mg of the title compound as a foam (yield: 92%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:11](=[O:23])[NH:12][C:13]2([C:16]3[N:21]=[CH:20][C:19]([I:22])=[CH:18][N:17]=3)[CH2:15][CH2:14]2)[CH2:10][CH2:9]1)(C)(C)C.[ClH:25].O1CCOCC1>C(Cl)Cl>[ClH:25].[ClH:25].[I:22][C:19]1[CH:20]=[N:21][C:16]([C:13]2([NH:12][C:11]([C:8]3([NH2:7])[CH2:10][CH2:9]3)=[O:23])[CH2:15][CH2:14]2)=[N:17][CH:18]=1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NC1(C(=O)NC2(c3ncc(I)cn3)CC2)CC1
Reaction time: 1.5 h

Procedure:
{1-[1-(5-iodo-pyrimidin-2-yl)-cyclopropylcarbamoyl]-cyclopropyl}-carbamic acid tert-butyl ester (426 mg, 0.96 mmol) was dissolved in CH2Cl2 (2 mL) and 4M HCl in dioxane 3 mL, 6 mmol) was added. After 90 minutes, the volatiles were removed at 60° C. under a stream of N2. The resulting while solid was dried under vacuum overnight to yield crude 400 mg of 1-amino-cyclopropanecarboxylic acid[1-(5-iodo-pyrimidin-2-yl)-cyclopropyl]-amide dihydrochloride. This material was used without further purification.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[CH:7]1([C:10]2[N:15]=[C:14]([C:16]([NH:18][C:19]3[CH:27]=[N:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[O:17])[C:13]([NH:28][C:29]3[CH:30]=[N:31][CH:32]=[N:33][CH:34]=3)=[CH:12][CH:11]=2)[CH2:9][CH2:8]1>>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:21]([C:20]1[CH:24]=[CH:25][N:26]=[CH:27][C:19]=1[NH:18][C:16]([C:14]1[C:13]([NH:28][C:29]2[CH:30]=[N:31][CH:32]=[N:33][CH:34]=2)=[CH:12][CH:11]=[C:10]([CH:7]2[CH2:9][CH2:8]2)[N:15]=1)=[O:17])=[O:22]
Reactant: CC1CCCN1
Reactant: O=C(O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Product: CC1CCCN1C(=O)c1ccncc1NC(=O)c1nc(C2CC2)ccc1Nc1cncnc1
Yield: 14 %

Procedure:
According to the general method described in step 3 of example 53, reaction of 2-methyl-pyrolidine with 3-{[6-cyclopropyl-3-(pyrimidin-5-ylamino)-pyridine-2-carbonyl]-amino}-isonicotinic acid provided the title compound (14%) as sticky yellow solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[N:7]1[CH:12]=[CH:11][CH:10]=[N:9][C:8]=1[N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]=O.O>C1(C)C=CC=CC=1>[Cl:19][C:20]1[CH:27]=[CH:26][CH:25]=[CH:24][C:21]=1[CH:22]([N:16]1[CH2:17][CH2:18][N:13]([C:8]2[N:9]=[CH:10][CH:11]=[CH:12][N:7]=2)[CH2:14][CH2:15]1)[N:1]1[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: O=Cc1ccccc1Cl
Reactant: O=C1CCCN1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1CCCN1C(c1ccccc1Cl)N1CCN(c2ncccn2)CC1
Yield: 87 %

Procedure:
A solution of 2-pyrrolidinone (4.25 g, 0.05 mole), 1-(pyrimidin-2-yl)piperazine (8.2 g, 0.05 mole) and 2-chlorobenzaldehyde (7.05 g, 0.05 mole) in 200 mL toluene was stirred and heated for 16 hour with an attached Dean-Stark trap for azeotropic removal of water. The solution was concentrated in vacuo to provide 16.2 g, (87%) of product. Recrystallization from ethanol gave white crystals, m.p. 166°-177°.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]([CH3:11])([CH3:10])[C:8]#[N:9])[CH:3]=1.C(C1C=C(N[C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)ON=1)(C)C>>[C:8]([C:7]([C:4]1[CH:3]=[C:2]([NH:1][C:21](=[O:29])[O:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:6][N:5]=1)([CH3:11])[CH3:10])#[N:9]
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)on1
Reactant: CC(C)(C#N)c1cc(N)on1
Product: CC(C)(C#N)c1cc(NC(=O)Oc2ccccc2)on1
Yield: 40 %

Procedure:
Prepared from 2-(5-aminoisoxazol-3-yl)-2-methylpropanenitrile (130 mg, 0.861 mmol) according to the method described for phenyl 3-isopropylisoxazol-5-ylcarbamate in Example 122A Step 3, to afford phenyl 3-(2-cyanopropan-2-yl)isoxazol-5-ylcarbamate as a colorless solid (93 mg, 40%). 1H NMR (300 MHz, CDCl3) δ 7.82 (brs, 1H), 7.41-7.46 (m, 2H), 7.32 (m, 1H), 7.18-7.21 (m, 2H), 6.29 (s, 1H), 1.83 (s, 6H); LC-MS (ESI) m/z 272 (M+H)+.
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])[C:9](=[O:15])[CH2:8][CH2:7][CH2:6]2.Cl.[CH:17]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C=O.[C:38](=O)([O-])O.[Na+]>O.C(OCC)C.C(O)C>[CH:17]([N:30]1[CH2:35][CH2:34][N:33]([CH2:38][CH:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[C:9]2=[O:15])[CH2:32][CH2:31]1)([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: COc1cc2c(cc1OC)C(=O)CCC2
Reactant: c1ccc(C(c2ccccc2)N2CCNCC2)cc1
Reactant: O=C([O-])O
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: COc1cc2c(cc1OC)C(=O)C(CN1CCN(C(c3ccccc3)c3ccccc3)CC1)CC2
Temperature: 80 °C
Reaction time: 8 h

Procedure:
In 100 ml. of ethanol is dissolved a mixture of 5 g. of 6,7-dimethoxy-3,4-dihydro-1(2H)-naphthalenone, 8 g. of 1-benzhydrylpiperazine hydrochloride and 10 g. of 37% aqueous formalin and the solution is allowed to stand at room temperature overnight, after which time it is heated at 80° C. for 7 hours. To the reaction mixture is added 500 ml. of water and, after shaking with 100 ml. of diethyl ether, the water layer is neutralized with sodium hydrogen carbonate and extracted with chloroform. The extract is dried and distilled under reduced pressure. To the oily residue is added methanol, whereupon 5 g. of 2-(4-benzhydryl-1-piperazinylmethyl)-6,7-dimethoxy-3,4-dihydro-1(2H)-naphthalenone is obtained as colorless crystals melting at 142°-144° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[OH:13])([CH3:3])[CH3:2].[C:14](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5]=1[O:13][CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)c1cccc(C(C)C)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1c(C(C)C)cccc1C(C)C
Yield: 72.7 %

Procedure:
A mixture of 2,6-diisopropyl phenol (20 g, 0.11 mol), potassium carbonate (62 g, 0.45 mol), acetone (160 ml) and methyl iodide (28 ml, 0.45 mole) is refluxed for three days. The reaction mixture is filtered through celite, evaporated, dissolved in ether, washed twice with 1M sodium hydroxide, dried over magnesium sulphate and concentrated to afford 15.1 g (0.08 mol, 70%) of 2,6-diisopropyl anisole as a slightly yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[CH:10]=[CH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]([O-])([O-])=[O:19].[Na+].[Na+].[C:24]1(C)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:18][O:19][C:24]1[CH:29]=[CH:28][C:27]([C:14]2[CH:15]=[C:16]3[C:11]([CH:10]=[CH:9][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:12][CH:13]=2)=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(Br)cc21
Reactant: O=C([O-])[O-]
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Product: COc1ccc(-c2ccc3ccn(C(=O)OC(C)(C)C)c3c2)cc1
Temperature: 25 °C
Yield: 58 %

Procedure:
To a solution of 1-tert-butoxycarbonyl-6-bromoindole (5.0 g, 17 mmol) in toluene (200 mL) was added tetrakis(triphenylphosphine)palladium(0) (0.94 g, 0.84 mmol), 2N aqueous Na2CO3 (100 mL), and a solution of 4-methoxyboronic acid in ethanol (50 mL). The 2-phase mixture was heated at 110°-125° C. for two hours. The reaction mixture was cooled to ambient temperature and the layers where separated. The aqueous phase was extracted twice with ether. The combined organic layers where washed twice with brine, dried over MgSO4, filtered, and concentrated in vacuo to give a brown oil. Chromatography on silica gel (250 g, 5% ether, hexanes) afforded 6-(4-methoxyphenyl)-1-tert-butoxycarbonylindole (3.2 g, 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[N:11]1([CH2:16][CH2:17][CH2:18][CH2:19][NH2:20])[CH:15]=[CH:14][N:13]=[CH:12]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:20][CH2:19][CH2:18][CH2:17][CH2:16][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1)=[O:10]
Reactant: O=C=Nc1ccccc1Cl
Reactant: NCCCCn1ccnc1
Solvent: Cc1ccccc1
Product: O=C(NCCCCn1ccnc1)Nc1ccccc1Cl

Procedure:
A solution of 2.30 g. of o-chlorophenyl isocyanate in 30 ml. of toluene was added with stirring to a solution of 2.09 g. of 1H-imidazole-1-butanamine in 20 ml. of toluene and the mixture was allowed to stir overnight and them evaporates to a crystalline residue. The crystals were dissolved in methylene chloride and purified by HPLC (silica gel column, eluted with 10% ethanol/ethyl acetate) to obtain the desired compound, mp. 87°-88° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[NH:16][CH:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.[CH:24](I)([CH3:26])[CH3:25].CCOC(C)=O.O>CN(C=O)C.CC([O-])(C)C.[K+]>[NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:24]([CH3:26])[CH3:25])[CH:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.[NH2:1][C:2]1[C:3]([C:21]([NH2:23])=[O:22])=[N:4][C:5]([C:14]2[CH:15]=[N:16][C:17]([O:20][CH:24]([CH3:26])[CH3:25])=[CH:18][CH:19]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: CC(C)I
Reactant: NC(=O)c1nc(-c2ccc(=O)[nH]c2)c(-c2ccccc2)nc1N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)cn1
Product: CC(C)n1cc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Amino-6-(6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (92.1 mg) was dissolved in DMF (1 ml) To the solution were added 1M i-PrI solution in DMF (0.33 ml) and 0.1M t-BuOK solution in DMF (3.3 ml). The mixture was stirred at 20-30° C. for 2 hours. The reaction mixture was portioned EtOAc and water. The organic layer was separated. The aqueous layer was extracted with EtOAc. The combined organic solution was washed with brine and dried over MgSO4. Evaporation of solvent gave oily residue. The above residue was purified by chromatography on silica gel (EtOAc only-EtOAc:MeOH=96:4, v/v) to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (18 mg) and 3-amino-6-(6-isopropoxy-3-pyridyl)-5-phenyl-2-pyrazinecarboxamide (42 mg).
Reaction SMILES: [NH2:1]/[C:2](=[N:13]\[OH:14])/[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH3:4].C(N(CC)CC)C.[C:22](Cl)(=[O:24])[CH3:23]>C(Cl)Cl>[C:22]([O:14]/[N:13]=[C:2](\[NH2:1])/[C@@H:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:10])([CH3:9])[CH3:11])[CH3:4])(=[O:24])[CH3:23]
Reactant: CC(=O)Cl
Reactant: C[C@H](NC(=O)OC(C)(C)C)/C(N)=N/O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O/N=C(\N)[C@H](C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To a mixture of tert-butyl [(1S,2Z)-2-amino-2-(hydroxyimino)-1-methylethyl]carbamate (Step 3, 100 mg, 0.5 mmol) in methylene chloride (2 mL) cooled at 0° C. was added triethylamine (0.10 mL, 0.74 mmol). To the mixture was then added acetyl chloride (42 mg, 0.54 mmol) dropwise and the reaction was warmed to room temperature. After stirring at room temperature for 1 h, the reaction was concentrated. The residue was dissolved in dichloromethane (DCM), washed with water and brine, dried over MgSO4, filtered and concentrated to afford the desired crude product (100 mg, 82.8%) which was directly used in the next step reaction without further purification. 1H-NMR (300 MHz, DMSO-d6): 6.90 (d, J=9.0 Hz, 1H), 6.22 (s, 2H), 4.05 (m, 1H), 2.01 (s, 3H), 1.36 (s, 9H), 1.20 (d, J=7.0 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[F:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:33][C:34](=O)[O:35]C(C)=C.CN1CCCC1>O1CCOCC1.C(OCC)(=O)C>[F:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([C:27]3[CH:28]=[N:29][N:30]([CH3:32])[CH:31]=3)[CH:22]=2)[CH:17]=[CH:16][C:15]=1[NH:33][C:34]([NH:1][C:2]1[C:3](=[O:12])[NH:4][CH:5]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:7]=1)=[O:35]
Reactant: C=C(C)OC(=O)Nc1ccc(Oc2ccnc(-c3cnn(C)c3)c2)cc1F
Reactant: Nc1cc(C(F)(F)F)c[nH]c1=O
Agent: CN1CCCC1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cn1cc(-c2cc(Oc3ccc(NC(=O)Nc4cc(C(F)(F)F)c[nH]c4=O)c(F)c3)ccn2)cn1
Temperature: 25 °C
Reaction time: 13 h
Yield: 57.6 %

Procedure:
3-Amino-5-(trifluoromethyl)pyridin-2(1H)-one (44 mg, 0.247 mmol), prop-1-en-2-yl 2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenylcarbamate from Example 21 (85 mg, 0.231 mmol) and N-methylpyrrolidine (7.5 mg, 0.088 mmol) were combined in 1,4-dioxane (0.8 mL). The resultant mixture was heated to 80° C. After 13 h, the mixture was cooled to RT and diluted with ethyl acetate (3 mL). The resultant precipitate was collected by filtration, washed with ethyl acetate and dried in vacuo to provide 1-(2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)-3-(2-oxo-5-(trifluoromethyl)-1,2-dihydropyridin-3-yl)urea as an off-white solid (65 mg, 58% yield). 1H NMR (400 MHz, DMSO-d6): δ 12.47 (s, 1 H), 9.56 (s, 1 H), 9.35 (s, 1 H), 8.36 (d, J=5.3 Hz, 1 H), 8.25 (br s, 2 H), 8.17 (t, J=9.4 Hz, 1 H), 7.96 (s, 1 H), 7.59 (s, 1 H), 7.25-7.22 (m, 2 H), 7.00 (d, J=8.5 Hz, 1 H), 6.68 (m, 1 H), 3.84 (s 3 H); MS (ESI) m/z: 489.1 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CCCCCC.[C:16]1([C:26](Cl)=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1>O1CCCC1.C([Li])CCC>[C:16]1([C:26]([C:7]2[C:2]([Cl:1])=[CH:3][C:4]([CH3:9])=[CH:5][C:6]=2[Cl:8])=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: Cc1cc(Cl)cc(Cl)c1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Cc1cc(Cl)c(C(=O)c2cccc3ccccc23)c(Cl)c1
Temperature: -60 °C
Reaction time: 1 h
Yield: 104.1 %

Procedure:
To a stirred, cold (-60° C.) solution of 3,5-dichlorotoluene (3.5 g, 21.7 mmol) in dry tetrahydrofuran (30 ml), 2.6 M n-butyllithium in hexane (8.78 ml, 22.8 mmol) was added dropwise over 15 minutes. The reaction mixture was stirred for one hour at -60° C. and then treated with a solution of 1-naphthoyl chloride (4.14 g, 21.7 mmol) in 15 ml of dry tetrahydrofuran over a period of 15 minutes. The mixture was stirred for 3.5 hours at -60° C. and then quenched with 4.8 ml of saturated NH4Cl solution. The mixture was permitted to warm to room temperature and then diluted with 30 ml of water and 30 ml of ether. The layers were thoroughly mixed and then separated. The etheral layer was backed-washed with brine and dried with anhydrous magnesium sulfate. Concentration afforded 7.12 g of crude product which was chromatographed on silica gel (20:1 hexane:ethyl acetate) to give 1.59 g (23 %).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=[O:6].O.[OH-].[Li+]>CO.O1CCCC1.O>[F:1][C:2]([F:12])([F:11])[CH2:3][CH:4]([CH3:10])[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(C)CC(F)(F)F
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(CC(F)(F)F)C(=O)O
Reaction time: 48 h
Yield: 99.6 %

Procedure:
A solution of ethyl 4,4,4-trifluoro-2-methylbutyrate (7.7 g) in methanol (21 mL), tetrahydrofuran (21 mL) and water (8.4 mL) was treated with lithium hydroxide monohydrate (3.5 g). The mixture was stirred for 48 hours and the organic solvents evaporated. The resulting aqueous solution was diluted with water and acidified with 6N hydrochloric acid. The aqueous solution was exhaustively extracted with ethyl acetate. The combined organic extract was washed (water and brine), dried (MgSO4), filtered and evaporated to give 4,4,4-trifluoro-2-methylbutyric acid as a pale yellow liquid (6.5 g, 99%); partial NMR (300 MHz, CDCl3): 1.34 (d, 3H, CH3), 2.18 (m, 1H, H-C(3)), 2.67, (m, 1H, H-C(3)), 2.74 (m, 1H, H-C(2)), 10.6 (br, 1H, CO2H).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:21]=1.[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH2:31])=[C:27]([O:32][CH3:33])[CH:26]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH3:22][O:23][C:24](=[O:34])[C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:2]2[N:3]=[CH:4][C:5]3[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]4[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]4)[C:6]=3[N:21]=2)=[C:27]([O:32][CH3:33])[CH:26]=1
Reactant: CC1CN(C2CCCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: COC(=O)c1ccc(N)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)O
Product: COC(=O)c1ccc(Nc2ncc3c(n2)N(C2CCCCC2)CC(C)C(=O)N3C)c(OC)c1
Yield: 96.5 %

Procedure:
A solution of 0.10 g (0.00032 mole) of (rac)-2-chloro-9-cyclohexyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-19), 0.060 g (0.00032 mole) of 4-amino-3-methoxy-benzoic acid methyl ester, 0.10 g (0.00049 mole) of p-toluene-sulfonic acid monohydrate and 4 mL of 2-propanol at 150 degrees for 1 hour in a microwave reactor. The reaction mixture was concentrated under reduced pressure. The residue was diluted with dichloromethane and washed twice with saturated sodium bicarbonate solution. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (100:0-85:15%), to give 0.14 g of (rac)-4-(9-cyclohexyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid methyl ester as white powder.