Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36](=[O:37])[C:23]5([CH3:38])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)(C)(C)C>C(O)(C(F)(F)F)=O>[NH2:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:26][C:25]4[C:24]5=[N:34][NH:35][C:36](=[O:37])[C:23]5([CH3:38])[CH2:22][CH2:21][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)C3=NNC(=O)C3(C)CC4)cc2)CCC1
Solvent: O=C(O)C(F)(F)F
Product: CC12CCc3nc(-c4ccc(C5(N)CCC5)cc4)c(-c4ccccc4)cc3C1=NNC2=O
Reaction time: 0.01 h
Yield: 92.6 %

Procedure:
tert-butyl(1-(4-(3a-methyl-3-oxo-8-phenyl-3,3a,4,5-tetrahydro-2H-pyrazolo[3,4-f]quinolin-7-yl)phenyl)cyclobutyl)carbamate (12 mg, 0.023 mmol) was dissolved in TFA (1 mL) and stirred for 30 seconds. The solution was immediately concentrated to dryness under reduced pressure. The residue was dissolved in diethyl ether (˜2 mL) and concentrated to dryness under reduced pressure three times. The residue was then slurried in diethyl ether (2 mL) and after settling the supernatant solvent removed by pipette. This was repeated three times. The remaining solvent was removed under reduced pressure and dried to give the desired product as an off-white solid (9 mg, 60% yield). 1H-NMR (500 MHz, CD3OD) δ 8.15 (1H, s), 7.49 (2H, d), 7.44 (2H, d), 7.29-7.36 (3H, m), 7.20-7.26 (2H, m), 3.35-3.45 (1H, m), 3.16-3.26 (1H, dd), 2.72-2.84 (2H, m), 2.54-2.66 (2H, m), 2.19-2.39 (2H, m), 1.92-2.09 (2H, m), 1.43 (3H, s). LCMS (Method A) RT=3.76 min, M+H+=423.16.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:15]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=O)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:24][CH2:23]1)C1C=CC=CC=1)(=[O:14])[CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-:36].[Na+]>ClC1C=CC=CC=1>[C:28]([N:25]1[CH2:24][CH2:23][CH:22]([N:15]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]=[CH:6][C:5]2=[O:14])[CH2:27][CH2:26]1)(=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: [OH-]
Reactant: O=C(c1ccccc1)N1CCC(N(C(=O)C=Cc2ccccc2)c2ccccc2)CC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: O=C(c1ccccc1)N1CCC(n2c(=O)ccc3ccccc32)CC1
Temperature: 0 °C

Procedure:
To crushed aluminum chloride (26 g) are added chlorobenzene (26 ml) and N-cinnamoyl-N-(1-benzoyl-4-piperidinyl)aniline (8.7 g) and the mixture is reacted at 110° C. for 1 hour. After cooling, the reaction mixture is poured into ice-water and the mixture is basified with aqueous sodium hydroxide solution. The mixture is extracted with dichloromethane and the solvent is concentrated. The residue is purified by silica gel column chromatography (solvent: methylene chloride) to give 1-(1-benzoyl-4-piperidinyl)carbostyril (5.9 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH2:17][CH2:16]1)=O)(C)(C)C.[OH-].[Na+].CCOC(C)=O>Cl.O1CCOCC1>[F:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)[CH2:16][CH2:17]2)=[CH:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN1CCC(Cc2ccc(F)cc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Fc1ccc(CC2CCN(CC3CCCCN3)CC2)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
(+/−)-N-(t-butoxycarbonyl)-2-[[4-[(4-fluorophenyl)methyl]-1-piperidinyl]methyl]-piperidine (340 mg, 0.87 mmol) was dissolved in 4M HCl in dioxane (10 mL). The reaction was stirred for 1 h and then conc. in vacuo to a white solid. The solid was partioned between 10% NaOH and EtOAc. The layers were separated and the aqueous layer was extracted with EtOAc. The organic layers were combined, dried over MgSO4, and conc. in vacuo to a white solid yielding 250 mg of product. MS (ESI) 291 (M+H).
Reaction SMILES: C[O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1)=[O:4].CCOC(C)=O.[N+:21]([O-])([OH:23])=[O:22]>S(=O)(=O)(O)O>[C:3]([CH2:5][O:6][C:7]1[C:8]([N+:21]([O-:23])=[O:22])=[CH:9][C:10]([CH3:14])=[N+:11]([O-:13])[CH:12]=1)([OH:2])=[O:4]
Reactant: COC(=O)COc1ccc(C)[n+]([O-])c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1cc([N+](=O)[O-])c(OCC(=O)O)c[n+]1[O-]
Temperature: 40 °C

Procedure:
The pyridine N-oxide (b) (18.5 g) was dissolved in a cold mixture of fuming nitric acid (90 ml) and concentrated sulfuric acid (90 ml) and heated to 40° C. for 1 hour, then 65° C. overnight. The mixture was cooled, poured onto ice and EtOAc (250 ml) added. When the ice had melted, the mixture was shaken and solid filtered off The EtOAc was dried and evaporated, the residue triturated with ether and filtered affording a solid (8.4 g).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[O:9])=[CH:6][CH:5]=1.N12CCCN=C1CCCCC2>C1COCC1>[CH:3]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([NH:10][S:11]([CH3:14])(=[O:12])=[O:13])=[O:9])=[CH:6][CH:5]=1)=[CH2:2]
Reactant: CS(=O)(=O)NC(=O)c1ccc(CCBr)cc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: C=Cc1ccc(C(=O)NS(C)(=O)=O)cc1

Procedure:
N-(4-vinylbenzoyl)methanesulfonarnide was prepared according to step 2 of Example 1 from N-[4-(2-bromoethyl)benzoyl]methanesulfonamide and 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) in THF.
Reaction SMILES: C(O[CH:4]=[C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]3[O:18][CH:17]=[N:16][CH:15]=3)[CH:12]=2)[NH:7][C:6]1=[O:19])C.Cl.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[O:18]1[C:14]([C:11]2[CH:12]=[C:13]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:19])[C:5]3=[CH:4][NH:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([NH2:31])(=[O:29])=[O:30])=[CH:24][CH:23]=2)=[CH:15][N:16]=[CH:17]1
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: CCOC=C1C(=O)Nc2ccc(-c3cnco3)cc21
Agent: Cl
Product: NS(=O)(=O)c1ccc(NC=C2C(=O)Nc3ccc(-c4cnco4)cc32)cc1
Yield: 68 %

Procedure:
The title compound was prepared in 68% yield from ethoxymethylene-5-oxazol-5-yl-1,3-dihydro-indol-2-one and 4-aminobenzenesulfonamide hydrochloride according to Procedure J: 1H NMR (DMSO-d6): δ 10.79 (d, 1H), 10.73 (s, 1H), 8.76 (d, 1H), 8.38 (s, 1H), 8.0 (s, 1H), 7.77 (d, 2H), 7.56 (d, 2H), 7.43 (s,1H), 7.40 (d, 1H), 7.26 (s, 2H), 6.91 (d, 1H); APCI−MS: m/z 381 (MH)−.
Reaction SMILES: [O-:1][C:2]#[N:3].[K+].C(O)(=O)C.[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH:34]3[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]3)=[CH:31][CH:32]=2)[CH:11]=1>C1COCC1>[CH3:9][C:10]1[CH:15]=[C:14]([NH:16][C:17]2[CH:22]=[C:21]([C:23]([F:25])([F:26])[F:24])[CH:20]=[CH:19][N:18]=2)[N:13]=[C:12]([C:27]2[CH:28]=[N:29][C:30]([NH:33][CH:34]3[CH2:39][CH2:38][N:37]([C:2]([NH2:3])=[O:1])[CH2:36][CH2:35]3)=[CH:31][CH:32]=2)[CH:11]=1
Reactant: N#C[O-]
Reactant: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCNCC3)nc2)c1
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1cc(Nc2cc(C(F)(F)F)ccn2)nc(-c2ccc(NC3CCN(C(N)=O)CC3)nc2)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Potassium cyanate (9.47 mg, 0.117 mmol), acetic acid (0.017 mL, 0.292 mmol), 4-methyl-N6′-(piperidin-4-yl)-N6-(4-(trifluoromethyl)pyridin-2-yl)-2,3′-bipyridine-6,6′-diamine (25 mg, 0.058 mmol), and THF (1 mL) were combined. The mixture was stirred at room temperature for 16 hours. The crude solution was purified via reverse phase high pressure liquid chromatography to afford 4-(4-methyl-6-(4-(trifluoromethyl)pyridin-2-ylamino)-2,3′-bipyridin-6′-ylamino)piperidine-1-carboxamide. MS ESI calcd. for C23H25F3N7O [M+H]+ 472. found 472. 1H NMR (500 MHz, DMSO-d6) δ 10.25 (s, 1H), 8.53-8.49 (m, 3H), 8.28 (s, 1H), 8.24 (d, J=6.5 Hz, 1H), 7.44 (s, 1H), 7.39 (s, 1H), 7.22-7.16 (m, 2H), 4.42 (m, 1H), 3.80 (m, 1H), 3.72-3.65 (m, 2H), 3.45 (dd, J=11.0, 4.0 Hz, 1H), 2.36 (s, 3H), 2.22 (m, 1H), 2.00 (m, 1H), 1.82 (s, 3H). rhSyk IC50=4 nM.
Reaction SMILES: Cl[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[NH:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)C>[N:11]1([C:2]2[NH:6][C:5]3[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=3[N:3]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: C1CCNC1
Solvent: CCO
Product: c1ccc2[nH]c(N3CCCC3)nc2c1
Temperature: 165 °C
Yield: 39.7 %

Procedure:
2-Chloro-1H-benzimidazole (10.0 g, 0.066 mol), pyrrolidine (18.5 g, 0.26 mol), and ethanol (100 mL) were combined. The resulting solution was heated at 160-170° C. for 6 hours and then the solvent was evaporated. The resulting residue was mixed with water. The mixture was made strongly acidic with hydrochloric acid and then made basic with ammonium hydroxide. The resulting solid was isolated by filtration, washed with water and then air dried to provide 11.8 g of crude product as a tan powder. This material was recrystallized from ethyl acetate/methanol to provide 4.9 g of 2-pyrrolidino-1H-benzimidazole. Analysis: Calculated for C11H13N3: %C, 70.56; %H, 7.00; %N, 22.44; Found: %C, 70.13; %H, 7.05; %N, 22.70.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[C:8]([NH2:11])[N:9]=2)[N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=1.[CH:20]1([N:26]=[C:27]=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>ClCCCl>[CH:20]1([NH:26][C:27]([NH:11][C:8]2[N:9]=[C:10]3[C:2]([Cl:1])=[CH:3][N:4]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]3=[N:6][CH:7]=2)=[O:28])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C[Si](C)(C)CCOCn1cc(Cl)c2nc(N)cnc21
Reactant: O=C=NC1CCCCC1
Solvent: ClCCCl
Product: C[Si](C)(C)CCOCn1cc(Cl)c2nc(NC(=O)NC3CCCCC3)cnc21
Temperature: 25 °C
Yield: 31 %

Procedure:
7-Chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-ylamine (100 mg, 0.335 mmol) was dissolved in 1,2-dichloroethane (3.4 mL). Cyclohexylisocyanate (0.43 mL, 3.35 mmol) was added and the reaction mixture was heated to reflux overnight, cooled to RT, and concentrated. The residue was dispersed in 3 mL of toluene, cyclohexylisocyanate (0.86 mL, 6.70 mmol) was added and the reaction mixture was heated to reflux overnight, and cooled to 0° C. The precipitates were filtered, washed with toluene and dried under high vacuum to give 44 mg of 1-cyclohexyl-3-[7-chloro-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazin-2-yl]-urea as a white solid (31% yield).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2([CH3:22])[N:13]([CH2:14][C:15]([OH:17])=O)[C:12](=[O:18])[N:11]([CH2:19][CH3:20])[C:10]2=[O:21])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:8][C:6]1[CH:5]=[C:4]([C:9]2([CH3:22])[N:13]([CH2:14][C:15]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:17])[C:12](=[O:18])[N:11]([CH2:19][CH3:20])[C:10]2=[O:21])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCN1C(=O)N(CC(=O)O)C(C)(c2cc(F)cc(F)c2)C1=O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN1C(=O)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(C)(c2cc(F)cc(F)c2)C1=O
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A mixture of [5-(3,5-difluorophenyl)-5-methyl-2,4-dioxo-3-ethylimidazolidin-1-yl]acetic acid, isomer A (18 mg, 0.058 mmol, described in Intermediate 17), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (14 mg, 0.058 mmol, described in Intermediate 3), HOBT (13 mg, 0.086 mmol), EDC (17 mg, 0.086 mmol), and N,N-diisopropylethylamine (0.050 mL, 0.29 mmol) in DMF (0.5 mL) was stirred at 50° C. for 2 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. Lyophilization provided the title compound. MS: m/z=546 (M+1). HRMS: m/z=546.1944; calculated m/z=546.1948 for C29H26F2N5O4.
Reaction SMILES: [C:1]([O:5][C:6](=[O:32])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[C:19]3=[N:20][C:21](SC)=[N:22][CH:23]=[C:18]3[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[N:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].ClC1C=C(C=CC=1)C(OO)=O.[CH2:44]([NH2:46])C>C(Cl)Cl>[CH3:44][NH:46][C:21]1[N:20]=[C:19]2[N:15]([CH2:14][CH:11]3[CH2:12][CH2:13][CH:8]([NH:7][C:6](=[O:32])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:9][CH2:10]3)[N:16]=[C:17]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:18]2=[CH:23][N:22]=1
Reactant: CCN
Reactant: CSc1ncc2c(-c3ccccc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNc1ncc2c(-c3ccccc3)nn(CC3CCC(NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of tert-Butyl-4-((6-(methylthio)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.14 g, 0.3 mmol) in methylene chloride (5 mL) was added meta-chloroperoxybenzoic acid (0.20 g, 0.9 mmol) at room temperature. After stirring at room temperature for 2 h, the light purple solution was quenched with a 1.0 N aqueous solution of NaOH. The aqueous layer was extracted with EtOAc (3×). The organic layers were combined, dried (Na2SO4), and concentrated. The residue was dissolved in THF (1 mL), followed by the addition of ethylamine (1.5 mL, 2.0 M in THF, 3 mmol). The resulting solution was heated at 60° C. for 2 h, cooled to room temperature, and concentrated. The crude mixture was purified by Isco to provide tert-butyl 4-((6-(methylamino)-3-phenyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)cyclohexylcarbamate (0.085 g, 81%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=2[CH:14]=1.Cl[C:16]1[N:21]=[C:20]([NH:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:19]([F:30])=[CH:18][N:17]=1>>[Cl:29][C:26]1[CH:25]=[CH:24][C:23]([NH:22][C:20]2[C:19]([F:30])=[CH:18][N:17]=[C:16]([NH:1][C:2]3[CH:3]=[CH:4][C:5]4[O:9][C:8]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][C:6]=4[CH:14]=3)[N:21]=2)=[CH:28][CH:27]=1
Reactant: Fc1cnc(Cl)nc1Nc1ccc(Cl)cc1
Reactant: COC(=O)c1cc2cc(N)ccc2o1
Product: COC(=O)c1cc2cc(Nc3ncc(F)c(Nc4ccc(Cl)cc4)n3)ccc2o1

Procedure:
In like manner to the preparation of N4-(3-chloro-4-trifluoromethoxyphenyl)-5-fluoro-N2-(3-hydroxyphenyl)-2,4-pyrimidineamine, the reaction of 5-amino-2-methoxycarbonylbenzofuran with 2-chloro-N4-(4-chlorophenyl)-5-fluoro-4-pyrimidineamine gave N4-(4-chlorophenyl)-5-fluoro-N2-(2-methoxycarbonylbenzofuran-5-yl)-2,4-pyrimidinediamine. 1HNMR (DMSO-d6): δ 10.28 (bs, 1H), 10.18 (bs, 1H), 8.25 (d, 1H, J=4.5 Hz), 7.96 (bs, 1H), 7.84 (m, 1H), 7.67 (m, 3H), 7.57 (m, 1H), 7.37 (bd, 2H, J=9.0 Hz), 3.88 (s, 3H); LCMS: purity: 96%; MS (m/e): 413 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[C:8]([N+:20]([O-])=O)[CH:7]=1)[C:3](=[O:5])[CH3:4]>C(OCC)(=O)C.[Pd]>[NH2:20][C:8]1[CH:7]=[C:6]([N:2]([CH3:1])[C:3](=[O:5])[CH3:4])[CH:11]=[CH:10][C:9]=1[NH:12][CH2:13][CH:14]1[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1
Reactant: CC(=O)N(C)c1ccc(NCC2CCOCC2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1ccc(NCC2CCOCC2)c(N)c1
Yield: 100.2 %

Procedure:
N-Methyl-N-{3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}acetamide (21.7 g, 70.5 mmol) was hydrogenated in ethyl acetate (500 mL) catalyzed by 10% Pd/C (1.0 g) at 30-40 psi H2 in Parr shaker for 18 h at room temperature. After filtration through celite and concentration, 19.6 g (100%) of a purple solid was obtained. 1H NMR (400 MHz, CHLOROFORM-D): δ 1.35-1.50 (m, 2 H), 1.67 (s, 1 H), 1.73-1.81 (m, 2 H), 1.88 (s, 3 H), 1.88-1.99 (m, 1 H), 3.04 (d, J=6.64 Hz, 2 H), 3.20 (s, 3 H), 3.33-3.48 (m, 4 H), 3.97-4.08 (m, 2 H), 6.54 (d, J=1.76 Hz, 1 H), 6.60-6.63 (m, 2 H); MS (ESI) (M+H)+: 278.7
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:27])[C:10](=[O:26])[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH3:25])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:28].[CH3:33][Si](C=[N+]=[N-])(C)C.CCCCCC>ClCCl.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([O:27][CH3:33])[C:10](=[O:26])[N:11]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH3:25])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:28]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CNCCCCn1c(C(=O)OC)c2c(c(O)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CO
Product: CNCCCCn1c(C(=O)OC)c2c(c(OC)c1=O)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2

Procedure:
A mixture of methyl 6-(3-chloro-4-fluorobenzyl)-4-hydroxy-2-[4-(methylamino)butyl]-3,5-dioxo-2,3,5,6,7,8-hexahydro-2,6-naphthyridine-1-carboxylate (0.68 g, 1.45 mmol; Example 1, Step 11) and a solution of trimethylsilyldiazomethane in hexane (2.2 mL, 4.35 mmol; 2M) in dichloromethane-methanol (1.5 & 4.5 mL) was stirred at room temperature for one hour. The reaction mixture was concentrated under vacuum to provide the title compound. This was used in the following step without further purification. ES MS M+1=480
Reaction SMILES: [NH2:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][C:7]2[N:12]=[CH:11][N:10]=[C:9]([NH2:13])[CH:8]=2)=[CH:4][CH:3]=1.[CH2:16]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[O:26])=[CH:20][CH:19]=1)[CH3:17]>CN(C=O)C>[NH2:13][C:9]1[N:10]=[CH:11][N:12]=[C:7]([CH2:6][C:5]2[CH:14]=[CH:15][C:2]([NH:1][C:25]([NH:24][C:21]3[CH:22]=[CH:23][C:18]([CH2:16][CH3:17])=[CH:19][CH:20]=3)=[O:26])=[CH:3][CH:4]=2)[CH:8]=1
Reactant: Nc1ccc(Cc2cc(N)ncn2)cc1
Reactant: CCc1ccc(N=C=O)cc1
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)Nc2ccc(Cc3cc(N)ncn3)cc2)cc1
Reaction time: 2 h

Procedure:
The title compound is prepared as described in Example 102 but using 6-(4-aminobenzyl)-pyrimidin-4-ylamine, 4-ethyl-phenyl-isocyanate, and DMF as the solvent. The reaction mixture is stirred for 2 h. The title compound is obtained as a white solid: ES-MS: 348.0 [M+H]+; single peak at tR=6.94 min (System 2).
Reaction SMILES: F[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([N:18](CC)CC)C.CN.CO>CO>[CH3:16][NH:18][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CCOC(=O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCN(CC)CC
Agent: CN
Solvent: CO
Product: CCOC(=O)c1ccc(NC)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
Ethyl 4-fluoro-3-nitrobenzoate (10.0 g, 46.9 mmol) prepared in the Step 1-1-1 was dissolved in methanol (40 ml), and triethylamine (10 ml, 70.4=01) was added thereto. Under an ice cooling, a 40% methylamine-methanol solution (5.50 g, 70.4 mmol) was added to the mixture. After the resulting mixture was stirred for one hour under an ice cooling, ice water was added thereto. The precipitate was separated by filtration and washed with water. The washed product was subjected to through circulation drying overnight to give the title compound (10.4 g, 99%) as a yellow powder.
Reaction SMILES: [C:1]([C:9]1C([N+]([O-])=O)=CC(C(OCC)=O)=CC=1O)(=O)[C:2]1C=CC=C[CH:3]=1.C(I)C.[Cl:27][C:28]1[CH:50]=[CH:49][C:31]([C:32]([C:34]2[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][C:37]([C:38]([O:40]CC)=[O:39])=[CH:36][C:35]=2[OH:48])=[O:33])=[CH:30][CH:29]=1.C(I)CCC>>[CH2:9]([O:48][C:35]1[CH:36]=[C:37]([CH:43]=[C:44]([N+:45]([O-:47])=[O:46])[C:34]=1[C:32](=[O:33])[C:31]1[CH:49]=[CH:50][C:28]([Cl:27])=[CH:29][CH:30]=1)[C:38]([OH:40])=[O:39])[CH2:1][CH2:2][CH3:3]
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccc(Cl)cc2)c([N+](=O)[O-])c1
Reactant: CCOC(=O)c1cc(O)c(C(=O)c2ccccc2)c([N+](=O)[O-])c1
Solvent: CCCCI
Solvent: CCI
Product: CCCCOc1cc(C(=O)O)cc([N+](=O)[O-])c1C(=O)c1ccc(Cl)cc1

Procedure:
By replacing in Example 6, step B, ethyl 4-benzoyl-3-hydroxy-5-nitrobenzoate and ethyl iodide with equimolar amounts of ethyl 4-(4'-chlorobenzoyl)-3-hydroxy-5-nitrobenzoate and n-butyl iodide respectively and following the procedure described, 3-n-butoxy-4-(4'-chlorobenzoyl)-5-nitrobenzoic acid is obtained with a melting point of 180°-182° C.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]1=[O:12])([OH:3])=[O:2].[C:13]1([C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[N+]=[N-])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(OCC)(=O)C.O>CN(C)C(=O)C>[C:13]1([CH:19]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[O:2][C:1]([CH2:4][N:5]2[CH:10]=[CH:9][NH:8][C:7](=[O:11])[C:6]2=[O:12])=[O:3])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)Cn1cc[nH]c(=O)c1=O
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(Cn1cc[nH]c(=O)c1=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 56.4 %

Procedure:
To a solution of 2.6 g of 1-carboxymethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine in 13 ml of N,N-dimethylacetamide was added 3.9 g of diphenyldiazomethane at room temperature, and the mixture was subjected to reaction for for 10 minutes. The reaction mixture was introduced into a mixed solvent of 25 ml of ethyl acetate and 25 ml of water, and the mixture was stirred for 15 minutes. Precipitated crystals were collected by filtration, and washed with 10 ml of ethyl acetate and 10 ml of diethyl ether in this order to obtain 2.9 g (yield, 80.4%) of 1-diphenylmethyloxycarbonylmethyl-2,3-dioxo-1,2,3,4-tetrahydropyrazine having a melting point of 97°-98° C.
Reaction SMILES: [Se]=O.[CH:3]([NH:5][C:6]1[N:11]=[C:10]([CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][N:7]=1)=[O:4].C(OCC)(=[O:19])C>O1CCOCC1>[CH:3]([NH:5][C:6]1[N:11]=[C:10]([C:12](=[O:19])[C:13]([O:15][CH3:16])=[O:14])[CH:9]=[CH:8][N:7]=1)=[O:4]
Reactant: COC(=O)Cc1ccnc(NC=O)n1
Reactant: CCOC(C)=O
Agent: O=[Se]
Solvent: C1COCCO1
Product: COC(=O)C(=O)c1ccnc(NC=O)n1

Procedure:
Selenium oxide (9.92 g.) was added to a solution of methyl 2-(2-formamidopyrimidin-4-yl)acetate (14.52 g.) in dioxane (200 ml.) at 90° to 95° C. over 20 minutes, and stirred at the same temperature for an hour. After cooling the resultant solution, the solution was filtered through a column packed with silica gel (20 g.), washed with dioxane and concentrated under reduced pressure. The residue was dissolved in acetone and filtered, and then the filtrate was concentrated under reduced pressure. The residue was triturated with chloroform to give a crude product (8.2 g.). The product was added to ethyl acetate, heated and an insoluble material was filtered out. The filtrate was cooled, and the precipitates were collected by filtration to give methyl 2-(2-formamidopyrimidin-4-yl)glyoxylate (5.55 g.). The product was recrystallized from ethyl acetate (saturated with water) to give mono hydrate thereof, mp 143° to 144° C.
Reaction SMILES: [CH:1]([C:4]1[C:13]2[O:12][CH2:11][C:10](=[O:14])[NH:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:21][CH2:22][CH2:23][CH2:24]I>CCCCCCC.CCOC(C)=O>[Cl:21][CH2:22][CH2:23][CH2:24][N:9]1[C:8]2[CH:7]=[CH:6][CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[C:13]=2[O:12][CH2:11][C:10]1=[O:14]
Reactant: CC(C)c1cccc2c1OCC(=O)N2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)c1cccc2c1OCC(=O)N2CCCCl
Yield: 69.7 %

Procedure:
8-Isopropyl-4H-benzo[1,4]oxazin-3-one (95MF83) (0.115 g, 0.60 mmol), Cs2CO3 (0.293 g, 0.90 mmol) and 3-chloro-1-iodopropane (0.135 g, 0.66 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF98) (0.112 g, 70%). 1H NMR (CDCl3) δ 7.03-6.95 (m, 2H), 6.93-6.90 (m, 1H), 4.57 (s, 2H), 4.09 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 3.33-3.25 (m, 1H), 2.20-2.13 (m, 2H), 1.22 (d, J=7.2 Hz, 6H); 13CNMR(CDCl3) δ 164.9, 142.8, 137.8, 128.5, 122.8, 121.4, 112.5, 67.7, 42.5, 39.3, 30.3, 27.2, 22.7.