Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:6]1[C:10]2=[N:11][C:12]([Cl:15])=[CH:13][CH:14]=[C:9]2[CH:8]=[CH:7]1)=O)C.[OH-].[Na+]>CO>[Cl:15][C:12]1[N:11]=[C:10]2[NH:6][CH:7]=[CH:8][C:9]2=[CH:14][CH:13]=1
Reactant: CCOC(=O)n1ccc2ccc(Cl)nc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Clc1ccc2cc[nH]c2n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 6-Chloro-pyrrolo[2,3-b]pyridine-1-carboxylic acid ethyl ester (400 mg, 1.78 mmol) in MeOH (35 mL) was added 1N NaOH (13 mL). The solution was stirred at RT for 6 h and evaporated the solvent. The residue was neutralized with sat. NaHCO3 and the resulting precipitate was collected by filtration. After washing with water, the solid was dried on the pump for direct use (260 mg, 1.71 mmol, 96%). MS (ES+): m/e=153.1 (M+H); LC: 2.85 min.
Reaction SMILES: [CH3:1][C:2]([C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:10][N:9]=1)([CH3:7])[C:3](OC)=[O:4].C(O)(=O)C>[Fe]>[CH3:1][C:2]1([CH3:7])[C:8]2=[N:9][CH:10]=[C:11]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:12]=[C:13]2[NH:14][C:3]1=[O:4]
Reactant: COC(=O)C(C)(C)c1ncc(N2CCOCC2)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Product: CC1(C)C(=O)Nc2cc(N3CCOCC3)cnc21
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 2-methyl-2-(5-morpholino-3-nitropyridin-2-yl)-propanoate (1.2 g, 3.88 mmol) in acetic acid (22.2 mL, 388 mmol) was added iron powder (1.08 g, 19.40 mmol). The reaction was heated at 80° C. for 2 h. After this time the reaction was cooled to rt and filtered over Celite™. The Celite™ was washed with acetic acid and the combined filtrates were evaporated in vacuo. Purification by column chromatography (hexane:EtOAc, 1:0 to 0:1) gave 3,3-dimethyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-2(3H)-one. Mass Spectrum (ESI) m/e=248 (M+1).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4].[CH2:12](Br)/[CH:13]=[CH:14]/[CH3:15].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:1][C:2]([F:10])([F:11])[C:3]([NH:5][CH2:6][C:7]([O:9][CH2:12]/[CH:13]=[CH:14]/[CH3:15])=[O:8])=[O:4]
Reactant: C/C=C/CBr
Reactant: O=C(O)CNC(=O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: C/C=C/COC(=O)CNC(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26.5 %

Procedure:
A mixture of 143.1 g (836 mmol) of N-trifluoroacetylglycine in 1 L of DMF is chilled to −8° C. as 100 mL (844 mmol) of E-crotyl bromide is added dropwise, followed by addition of 140 mL (937 mmol) of DBU at −5° C. After 1.5 h at −5° C. and 2 h at −2° C. the mixture is allowed to warm to 25° C. The mixture is cooled to 0° C. and 40 mL more DBU is added. After warming to 25° C. the mixture is concentrated in vacuo. 1 L of 1:1 ether-water is added. The organic layer is separated, washed with water, 1 N HCl, saturated aqueous sodium bicarbonate, and saturated aqueous sodium chloride. Drying and concentration in vacuo is followed by trituration of the oil with hexanes-EtOAC to provide a solid. Chromatography on silica gel (elution with 3:1 hexanes-EtOAc) affords 49.96 g of (2E)-2-buten-1-yl N-trifluoroacetylglycinate as an oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17].O.[CH3:20][N:21](C=O)C>>[CH3:20][NH:21][CH2:2][C:3]1[CH:15]=[CH:14][C:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[CH:5][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: CN(C)C=O
Solvent: O
Product: CNCc1ccc(C(=O)OC(C)(C)C)cc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 36 %

Procedure:
Anhydrous methylamine was bubbled into anhydrous DMF (200 mL) at 0° C. for 15 min. A solution of t-butyl 4-bromomethyl-3-nitrobenzoate (5.0 g, 15.8 mmol) (Int. J. Peptide. Res., 36, 31 (1990)) in DMF (10 mL) was added dropwise to the cold amine solution. The solution was stirred at 0° for 30 min and poured into water. The mixture was extracted with ethyl acetate and the combined organic layers were washed with water, dried (sodium sulfate) and concentrated to give a yellow-brown oil. The oil was purified by chromatography (silica gel, 3% isopropanol/CH2Cl2) to give the title compound (1.5 g, 36%). 1H NMR (400 MHz, CDCl3) δ8.5 (s, 1H), 8.2 (d, 1H), 7.7 (d, 1H), 4.05 (s, 2H), 2.5 (s, 3H), 1.6 (s, 9H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:17][C:18]1[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[Se:20][C:19]=1[C:27]([NH2:29])=[O:28].CN(C=O)C.[OH-].[Na+]>>[C:11]1([C:9]2[O:8][C:4]3[N:5]=[CH:6][N:7]=[C:2]([NH:17][C:18]4[CH:22]=[C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])[Se:20][C:19]=4[C:27]([NH2:29])=[O:28])[C:3]=3[CH:10]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ncnc3oc(-c4ccccc4)cc23)c(C(N)=O)[se]1

Procedure:
The reaction of 4-chloro-6-phenylfuro[2,3-d]pyrimidine with 3-amino-5-tert-butylselenophene-2-carboxamide in the presence of DMF/NaOH as described in Example 1 gave title compound as a pale yellow color solid, mp 280-282° C. IR (KBr) v. 3326, 3188, 2953, 1624, 1386, 1358, 1324, 1283, 1150, 1089, 1016, 921, 822, 778, 755 cm−1; 1H NMR (400 MHz, DMSO-d6): δ 11.94 (1H, s, exchangeable with D2O), 8.53 (1H, s), 8.50 (1H, s), 7.96 (2H, d, J=7.2 Hz), 7.43-7.55 (5H, m), 7.32 (1H, s), 1.40 (9H, s); 13C NMR (100 MHz, DMSO-d6): δ 167.4, 167.1, 166.2, 153.3, 152.5, 152.3, 144.7, 129.3, 129.1, 128.6, 124.7, 121.1, 113.3, 104.4, 97.4, 36.4, 32.2; LC-MS (negative ion mode): m/z 437, 439 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:13]=2[CH2:22][NH:23][CH2:24][CH3:25])[CH:6]=1.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:19])[F:21])=[CH:14][C:13]=2[CH2:22][N:23]([CH2:24][CH3:25])[S:35]([C:32]2[CH:31]=[CH:30][C:29]([O:28][CH3:27])=[CH:34][CH:33]=2)(=[O:37])=[O:36])[CH:6]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1Oc1cccc(CC(=O)OC)c1)S(=O)(=O)c1ccc(OC)cc1

Procedure:
Prepared according to the procedure described in Example 22, Step 1, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-phenyl]-acetic acid methyl ester and 4-methoxybenzenesulfonyl chloride.
Reaction SMILES: [H-].[Na+].[CH:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[NH:13][C:12](=[O:20])[CH:11]([N:21]3[C:25](=[O:26])[C:24]4=[CH:27][CH:28]=[CH:29][CH:30]=[C:23]4[C:22]3=[O:31])[N:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[I-].[Na+].Cl[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C)C=O.C(O)(=O)C>[CH:3]1([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:12](=[O:20])[CH:11]([N:21]3[C:22](=[O:31])[C:23]4=[CH:30][CH:29]=[CH:28][CH:27]=[C:24]4[C:25]3=[O:26])[N:10]=2)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: O=C1Nc2ccccc2C(C2CCCCC2)=NC1N1C(=O)c2ccccc2C1=O
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: O=C1C(N2C(=O)c3ccccc3C2=O)N=C(C2CCCCC2)c2ccccc2N1Cc1ccccn1
Reaction time: 2 h

Procedure:
To a suspension of sodium hydride (54 mg of a 64% dispersion of mineral oil) in N,N-dimethylformamide (3 ml) was added slowly (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1H-1,4-benzo-diazepin-2-one (0.50 g) at ambient temperature and the mixture was stirred for 2 hours under the same condition. To the mixture was added sodium iodide (0.213 g) and followed dropwise a solution of 2-chloromethylpyridine (0.213 g) at the same temperature. The mixture was stirred overnight at ambient temperature To the mixture was added acetic acid (0.4 ml) and stirred for 10 minutes. The resultant mixture was concentrated in vacuo and the residue was taken up with ethyl acetate and water. The aqueous layer was alkalined with sodium carbonate and extracted with ethyl acetate. The combined extracts were dried over sodium sulfate, filtered and concentrated in vacuo to give a crude compound. The crude compound was purified by column chromatography on silica gel with a mixture of chloroform and methanol to give (3RS)-5-cyclohexyl-2,3-dihydro-3-phthalimido-1-(pyridin-2-yl)methyl-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1.[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[C:19]=1[NH2:26].Cl>C(OCC)C.O1CCOCC1>[Br:17][C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([Br:25])[C:19]=1[NH:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)[N:3]=1
Reactant: Cc1cc(Br)c(N)c(Br)c1
Reactant: N#Cc1ccc(Nc2nccc(Cl)n2)cc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: Cc1cc(Br)c(Nc2ccnc(Nc3ccc(C#N)cc3)n2)c(Br)c1
Temperature: 170 °C
Yield: 16 %

Procedure:
4-[(4-chloro-2-pyrimidinyl)amino]benzonitrile (0.003 mol), 2,6-dibromo-4-methyl-benzenamine (0.006 mol) and 1 M HCl in diethyl ether (4.5 ml) in 1,4-dioxane (10 ml) were combined in a tube and heated under Ar until all diethyl ether had evaporated. The tube was sealed and heated at 170° C. for 2.5 days. Silica gel was added, and the solvent was evaporated. The residue was purified by flash column chromatography over silica gel (eluent gradient: CH2Cl2:CH3OH:NH4OH 100:0:0 to 99:0.9:0.1). The desired fractions were collected and the solvent was evaporated. The residue was recrystallized from acetonitrile, filtered off and dried, yielding 0.22 g (15.9%) of 4-[[4-[(2,6-dibromo-4-methylphenyl)amino]-2-pyrimidinyl]amino]benzonitrile (compound 61).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]2[N:7]([C:11]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4([NH2:24])[CH2:23][CH2:22][CH2:21]4)=[CH:16][CH:15]=3)[N:13]=2)[CH:8]=[CH:9][CH:10]=1)=O.[NH3:31]>>[NH2:24][C:20]1([C:17]2[CH:16]=[CH:15][C:14]([C:12]3[N:13]=[C:6]4[C:5]([C:3]([NH2:31])=[O:2])=[CH:10][CH:9]=[CH:8][N:7]4[C:11]=3[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:19][CH:18]=2)[CH2:21][CH2:22][CH2:23]1
Reactant: COC(=O)c1cccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Reactant: N
Product: NC(=O)c1cccn2c(-c3ccccc3)c(-c3ccc(C4(N)CCC4)cc3)nc12
Temperature: 130 °C

Procedure:
A mixture of 2-[4-(1-amino-cyclobutyl)-phenyl]-3-phenyl-imidazo[1,2-a]pyridine-8-carboxylic acid methyl ester (Example 2-23, 128 mg) and ammonia (2.23 mL of a 7M aqueous solution) was heated at 130° C. under microwave irradiation for 90 minutes. On cooling, the reaction mixture was concentrated to give the title compound.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH2:42])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[N:27]1([S:33]([C:36]2[CH:37]=[C:38]([NH:42][C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:1])([F:26])[F:25])=[CH:4][C:5]([C:15]5[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:24])[F:22])=[CH:19][CH:20]=5)=[N:6][C:7]=34)=[O:13])[CH:39]=[CH:40][CH:41]=2)(=[O:35])=[O:34])[CH2:28][CH2:29][O:30][CH2:31][CH2:32]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)N2CCOCC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)N2CCOCC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.1) and 3-(morpholine-4-sulfonyl)-phenylamine [CAS 22184-97-0; commercially available] according to general procedure II. Yellow solid. MS (ISP) 600.3 [(M+H)+]; mp 233° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.[CH:32](=O)[CH:33]([CH3:35])[CH3:34].CO>C(Cl)(Cl)Cl.C(Cl)Cl>[CH2:32]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH:33]([CH3:35])[CH3:34]
Reactant: CC(C)C=O
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: CC(C)CN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 110 mg (0.26 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo[1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 2.5 mL chloroform was treated with 0.24 mL (2.6 mmol) isobutyraldehyde and 170 mg (0.78 mmol) NaBH3(CN), followed by the addition of 2.5 mL methanol. The mixture was stirred at ambient temperature for 1 h when MS showed that all starting materials had converted to product. The reaction mixture was diluted with 50 mL DCM, washed with 50 mL satd. NaHCO3, and dried over anhydrous Na2SO4. After purification by HPLC, the title compound was obtained. MS (ES+): 468 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([C:7](=O)[CH2:8][O:9][CH3:10])[C:3](OC)=[O:4].C(O)(=O)C.[CH:16]([NH2:18])=[NH:17].C[O-].[Na+]>CO>[CH3:1][C:2]1[C:3]([OH:4])=[N:17][CH:16]=[N:18][C:7]=1[CH2:8][O:9][CH3:10]
Reactant: N=CN
Reactant: COCC(=O)C(C)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COCc1ncnc(O)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
To a solution of methyl 2-methyl-4-(methyloxy)-3-oxobutanoate (Intermediate 47, 1.01 g, 6.31 mmol) in methanol (7 mL) was added formamidine acetate (0.722 g, 6.94 mmol) and 25% sodium methoxide in MeOH (3.0 mL, 6.31 mmol) and the resulting mixture was heated under reflux for 2 hours, cooled to room temperature and left to stand overnight. The reaction mixture was evaporated under reduced pressure. The residue was diluted with water, adjusted to pH 7 using aqueous 2M HCl solution and extracted with chloroform (×3). The chloroform layers were combined, dried under magnesium sulfate and evaporated under reduced pressure to give the title compound as a white solid (597 mg);
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[NH:12][C:11](=O)[N:10]=1.O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:11]1[N:10]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[N:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1nc(-c2ccc(Cl)cc2Cl)cc(C(F)(F)F)[nH]1
Product: FC(F)(F)c1cc(-c2ccc(Cl)cc2Cl)nc(Cl)n1

Procedure:
The title compound was prepared from 4-(2,4-dichloro-phenyl)-6-trifluoromethyl-1H-pyrimidin-2-one (10.2 g, 0.033 mol) and phosphoroxychloride (50 ml) according to the general procedure I. Obtained as a light yellow solid (10.6 g, 98%). MS (ISP) 327.0 [(M+H)+]; mp 69.5° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C@H:9]([CH2:14][CH3:15])[C:10](OC)=[O:11])[C:5]([N+:21]([O-])=O)=[CH:4][N:3]=1.[H][H]>C(O)(=O)C.[Ni]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[NH:21][C:10](=[O:11])[C@@H:9]([CH2:14][CH3:15])[N:8]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:7]=1
Reactant: [H][H]
Reactant: CC[C@H](C(=O)OC)N(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1
Agent: [Ni]
Solvent: CC(=O)O
Product: CC[C@@H]1C(=O)Nc2cnc(Cl)nc2N1C1CCCC1
Temperature: 77.5 °C
Reaction time: 12 h
Yield: 66.5 %

Procedure:
Methyl (2R)-2-[(2-chloro-5-nitro-pyrimidin-4-yl)-cyclopentyl-amino]butanoate 1m (1 g, 3 mmol) was dissolved in 10 mL of acetic acid followed by the addition of Raney nickel (0.50 g), filled with hydrogen three times, then heated to 75-80° C. and stirred for 12 hours. The reaction mixture was filtered, washed with dichloromethane (50 mL). The filtrate was concentrated under reduced pressure, added with 100 mL ethyl acetate, washed with water (50 mL×3) and saturated sodium chloride solution (50 mL×3) successively. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (7R)-2-chloro-8-cyclopentyl-7-ethyl-7,8-dihydro-5H-pteridin-6-one 1n (0.56 g, yield: 66.7%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].[CH:20](I)([CH3:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:20]([CH3:22])[CH3:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: CC(C)I
Reactant: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)Oc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Yield: 77.5 %

Procedure:
N-(2-Fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI) (10 g), isopropyl iodide (7 g) and anhydrous potassium carbonate (5.2 g) were dissolved in acetonitrile (100 ml), and the resultant solution was heated under reflux for 2.5 hours. After cooling, the reaction mixture was extracted with ethyl acetate. The extract was concentrated, and the precipitated crystals were collected by filtration to give 9 g of N-(2-fluoro-5-isopropoxyphenyl)-3,4,5,6-tetrahydrophthalimide (II: R=isopropyl). M.P. 62.8° C.
Reaction SMILES: [N+:1]([C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]1[C:16]([Cl:17])=[CH:15][NH:14][N:13]=1)([O-])=O.O>C(O)(=O)C.[Fe]>[NH2:1][C:4]1[C:9]([Cl:10])=[CH:8][C:7]([Cl:11])=[CH:6][C:5]=1[C:12]1[C:16]([Cl:17])=[CH:15][NH:14][N:13]=1
Reactant: O=[N+]([O-])c1c(Cl)cc(Cl)cc1-c1n[nH]cc1Cl
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(Cl)cc(Cl)cc1-c1n[nH]cc1Cl
Temperature: 70 °C
Reaction time: 5 h
Yield: 90 %

Procedure:
14.6 g (0.05 mol) of 3-(2-nitro-3,5-dichlorophenyl)-4-chloropyrazole, in solution in 200 ml of acetic acid, are introduced into a 500 ml, three-necked, round-bottomed flask. The solution is brought to 50° C. and 8.4 g (0.15 mol) of iron powder are introduced in portions. The reaction mixture is then kept stirring at 70° C. for 5 hours. After cooling, the reaction mixture is poured into 800 ml of water, filtered on sintered glass, rinsed with water and dried to lead to the production of a white solid (yield: 90%, M.p.: decomposition at 300° C.) of 3-(2-amino-3,5-dichlorophenyl)-4-chloropyrazole.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4](Cl)[N:3]=1.[C:10]1([Mg]Br)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O1CCCC1>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:3]=1
Reactant: Br[Mg]c1ccccc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: Clc1nc(Cl)nc(-c2ccccc2)n1
Temperature: 25 °C

Procedure:
(Step 1) To 50 g of 2,4,6-trichloro-1,3,5-triazine was added 300 ml of dry tetrahydrofuran and while the mixture was stirred at room temperature, 150 ml of 2M phenylmagnesium bromide-tetrahydrofuran was added dropwise over about 30 minutes. After completion of dropwise addition, the mixture was stirred at room temperature for 1 hour, and then concentrated. To the residue was added iced water and the resultant was extracted with ether. The extract was washed with water, dried over MgSO4, and concentrated. The resulting crystal crop was recrystallized from isopropyl alcohol to provide 21.1 g of 2,4-dichloro-6-phenyl-1,3,5-triazine as pale yellow crystals.
Reaction SMILES: [ClH:1].[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26]C=1.BrC1C=CC=C[N:32]=1.IC1C=CC=CC=1>>[ClH:1].[O:2]=[C:3]1[CH:8]=[C:7]([CH2:9][N:10]2[C:14]([CH2:15][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)=[CH:13][N:12]=[CH:11]2)[CH:6]=[CH:5][N:4]1[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:32]=1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccc3)c(=O)c2)cc1
Reactant: Brc1ccccn1
Agent: Cl
Solvent: Ic1ccccc1
Product: N#Cc1ccc(Cc2cncn2Cc2ccn(-c3ccccn3)c(=O)c2)cc1

Procedure:
4-[3-(2-Oxo-2H-[1,2']bipyridinyl-4-ylmethyl)-3H-imidazol-4-ylmethyl]-benzonitrile hydrochloride salt was prepared in a manner substantially similar to the procedure described above for 4-[3-(2-oxo-1-phenyl-1,2-dihydropyridin-4-ylmethyl)-3H-imidazol-4-ylmethyl]benzonitrile, hydrochloride, but substituting 2-bromopyridine for the iodobenzene in Step 3.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Br[CH2:22][C:23]([O:25]CC)=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([O:16][CH2:22][C:23]([OH:25])=[O:24])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: CCOC(=O)CBr
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1OCC(=O)O
Reaction time: 16 h

Procedure:
To the above phenol (6.0 g=20 mmol) in 100 ml acetonitrile add ethyl bromoacetate (3.0 g=24 mmol) and potassium carbonate (5.4 g=39 mmol). Stir 16 hours, filter, concentrate, and partition between ether and 1.0 N HCl. Dry and concentrate the ether. Partition between 1:1 ether-hexane and 1.0 N NaOH. Acidify the aqueous layer with concentrated HCl and extract with ether. Dry and concentrate. Recrystallize from ether-hexane and dry at 0.1 mm pressure to obtain 2-[4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylphenoxy]acetic acid, m.p. 111°-113° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH2:26])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH2:36]([N:38]=[C:39]=[O:40])[CH3:37].CO>C1COCC1.ClCCl>[CH2:1]([O:8][C:9](=[O:28])[NH:10][C@@H:11]([CH3:27])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:24][C:23]([CH2:25][NH:26][C:39]([NH:38][CH2:36][CH3:37])=[O:40])=[CH:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3oc(CN)cc3c21)NC(=O)OCc1ccccc1
Reactant: CCN=C=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CO
Product: CCNC(=O)NCc1cc2c(ccc3cnn(C[C@H](C)NC(=O)OCc4ccccc4)c32)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.3 %

Procedure:
To a solution of the product from Example 17, Step B (0.20 g, 0.53 mmol) in THF (4 mL) was added polymer supported di-isopropylamine (1.5 eq, 0.79 mmol, 0.22 g) and ethyl isocyanate (0.042 mL, 0.52 mmol); this mixture was stirred at room temperature for three hours followed by the addition of methanol (5 mL). Dichloromethane (15 mL) was added and the mixture was filtered, evaporation of the filtrate gave a solid (0.19 g) which was purified by chromatography (silica gel, hexane/ethyl acetate gradient) to give a white solid (0.14 g, 59%): LC/MS m/z 450 [M+H]+.