Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[C:10]1[O:14][N:13]=[C:12]([CH3:15])[CH:11]=1)[NH2:6].[C:16](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:17]>ClCCl>[N:6]([C:5]1[CH:7]=[CH:8][C:9]([C:10]2[O:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[C:3]([O:2][CH3:1])[CH:4]=1)=[C:16]=[S:17]
Reactant: COc1cc(N)ccc1-c1cc(C)no1
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: COc1cc(N=C=S)ccc1-c1cc(C)no1
Temperature: 25 °C
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Step H (3): Dichloromethane (20 mL) was added to a flask charged with 3-methoxy-4-(3-methylisoxazol-5-yl)aniline (500 mg, 2.448 mmol) and 1,1′-thiocarbonyldipyridin-2(1H)-one (569 mg, 2.448 mmol). The resulting mixture was stirred for 24 h at rt. The crude reaction mixture was concentrated and the crude products were purified using silica gel chromatography (20-50% EtOAc/hexane) linear gradient to afford 5-(4-isothiocyanato-2-methoxyphenyl)-3-methylisoxazole (0.510 g, 84% yield). LC-MS (M+H)+ 247.2. 1H NMR (400 MHz, methanol-d4) δ ppm 7.86 (d, J=8.56 Hz, 1 H) 7.06 (d, J=2.01 Hz, 1 H) 6.99 (dd, J=8.44, 1.89 Hz, 1 H) 6.73 (s, 1 H) 3.97 (s, 3 H) 2.31 (s, 3 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([OH:16])=[O:15])[CH:7]=[CH:6]2.[C:17](=O)(OC)OC.C([O-])([O-])=O.[K+].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][C:14]([O:16][CH3:17])=[O:15])[CH:7]=[CH:6]2
Reactant: COC(=O)OC
Reactant: COc1ccc2cc(CC(=O)O)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)Cc1ccc2cc(OC)ccc2c1
Reaction time: 8 h

Procedure:
Alternatively, the reaction for the selective methylation can be carried out by reacting a mixture of (6-methoxy-2-naphthyl)acetic acid, dimethyl carbonate and K2CO3, in the 1:20:2 molar ratio, in autoclave at a temperature of 220° C. The reaction is completed within about 8 hours. (In this case DMC acts first as a methylating agent for the carboxylic group, through an already known reaction; then the monomethylation reaction takes place on the resulting ester).
Reaction SMILES: C(O[C:9](=O)[N:10](C)[C:11]1[C:16]([O:17][CH3:18])=[CH:15][C:14]([C:19]([O:21][CH3:22])=[O:20])=[CH:13][C:12]=1[O:23][CH3:24])C1C=CC=CC=1.[H][H]>CO.[Pd]>[CH3:22][O:21][C:19](=[O:20])[C:14]1[CH:15]=[C:16]([O:17][CH3:18])[C:11]([NH:10][CH3:9])=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: COC(=O)c1cc(OC)c(N(C)C(=O)OCc2ccccc2)c(OC)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CNc1c(OC)cc(C(=O)OC)cc1OC

Procedure:
A suspension of 33.5 g. of 2,6-dimethoxy-4-(methoxy-carbonyl)-N-methylcarbanilic acid benzyl ester in 1 liter of methanol was hydrogenated in the presence of 1.5 g. of palladium on carbon (5%) until the hydrogen uptake stopped. The suspension was heated to boiling and filtered. The filtrate was evaporated under vacuum and the residue recrystallized from cyclohexane, whereby there was obtained 3,5-dimethoxy-4-(methylamino)-benzoic acid methyl ester having a melting point of 49°-51° C.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([C:22]#N)[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.Cl.CC[O:27]CC>CCCCCC>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2([CH:22]=[O:27])[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1
Reactant: CCOCC
Reactant: N#CC1(c2ccc(Cl)cc2)CCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: CCCCCC
Product: O=CC1(c2ccc(Cl)cc2)CCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A 1M solution of diisobutylaluminium hydride in hexane (100 ml) was added dropwise to a stirred solution of 1-(4-chlorophenyl)cyclobutanecarbonitrile (19.1 g) in dry ether (50 ml) at -30° C. under nitrogen. The mixture was allowed to warm to 0° C. and was kept at that temperature for 30 minutes. The mixture was cooled to -30° C. and 5N hydrochloric acid (100 ml) was added dropwise with stirring. The mixture was filtered to separate a solid and the filtrate was extracted with ether. The solid was added to the ether extracts which were washed with water and dried. Removal of the solvent gave 1-(4-chlorophenyl)cyclobutanecarbaldehyde as a yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].C(N(CC)CC)C.[Br:12][C:13]1[CH:14]=[CH:15][C:16]([F:23])=[C:17]([CH2:19][C:20](Cl)=[O:21])[CH:18]=1>C(OCC)(=O)C>[CH2:1]([O:4][C:20](=[O:21])[CH2:19][C:17]1[CH:18]=[C:13]([Br:12])[CH:14]=[CH:15][C:16]=1[F:23])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: O=C(Cl)Cc1cc(Br)ccc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C=CCOC(=O)Cc1cc(Br)ccc1F
Reaction time: 1 h

Procedure:
To a mixture of allyl alcohol (22.1 g, 380.5 mmol) and triethylamine (Et3N) (5.4 ml, 39 mmol) at 0° C. was added over 1 h crude (5-bromo-2-fluoro-phenyl) -acetyl chloride (intermediate B2A) (7.01 g, ca. 26 mmol). Then the reaction was stirred over 1 h from 0° C. to 23° C. The reaction mixture was diluted with ethyl acetate, washed with water, and the organic layer was dried over sodium sulfate. Removal of the solvent in vacuum left the title compound as a yellow oil (7.290 g, 103%), which was used without further purification. MS (ISP): m/z=280.1 [(M+NH4)+] and 282.1 [(M+2+NH4)+]
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:7]3[N:8]([N:18]=[N:19][N:20]=3)[C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12]=2[N:13]=1.CC([O-])(C)C.[K+].[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31]Br>CN(C=O)C.CC(O)(C)C>[F:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[F:36])[CH2:31][N:11]1[C:12]2[N:13]=[C:3]([S:2][CH3:1])[N:4]=[CH:5][C:6]=2[C:7]2=[N:20][N:19]=[N:18][N:8]2[C:9]2[CH:17]=[CH:16][CH:15]=[CH:14][C:10]1=2
Reactant: Fc1ccc(CBr)cc1F
Reactant: CSc1ncc2c(n1)Nc1ccccc1-n1nnnc1-2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)(C)O
Product: CSc1ncc2c(n1)N(Cc1ccc(F)c(F)c1)c1ccccc1-n1nnnc1-2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
The 11-(methylthio)-9H-benzo[b]pyrimido[5,4-f]tetrazolo[1,5-d][1,4]diazepine (5) (1.03 g) in DMF (20 mL) was treated with 1.1 eq. of 1M t-BuOK in t-BuOH (4 mL). The mixture was stirred at R.T. for 10 minutes then the 3,4-difluorobenzyl bromide (0.6 mL) was added. The mixture was stirred at R.T. for one hour. The reaction mixture was quenched with the addition of saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3×50 mL) and the combined organic extracts were dried over sodium sulfate. Concentration in vacuo provided the titled product as a yellow solid (6) (1.3 g). M.p.=281-283° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.91 (s, 1H), 7.79 (dd, J=8.4, 1.6 Hz, 1H), 7.61 (dd, J=8.4, 1.2 Hz, 1H), 7.54 (ddd, J=8.8, 7.2, 1.6 Hz, 1H), 7.45-7.34 (m, 2H), 7.32-7.25 (m, 1H), 7.17-7.13 (m, 1H), 5.24 (s, 2H), 2.56 (s, 3H); LCMS [M+H]: 410; Calc. for C19H13F2N7S: C, 55.74; H, 3.20; N, 23.95; found C, 55.65; H, 2.96; N, 23.67.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C(N(CC)CC)C.Br[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: CCOC(=O)CBr
Reactant: Nc1ccc2c(c1)CCC2
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCOC(=O)CNc1ccc2c(c1)CCC2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-aminoindan (15.0 g, 0.1128 mol) and triethylamine (11.92 g, 0.1184 mol) in 200 ml ethanol was added dropwise ethyl bromoacetate (18.83 g, 0.1128 mol). After the addition was complete the mixture was stirred at room temperature for 24 h and concentrated in vacuo. The residue was dissolved in ether, washed with H2O (4×300 ml), brine and dried (MgSO4). Concentration of the volatiles in vacuo provided a crystalline material which was recrystallized from petroleum ether; b.p. 30°-60° C., m.p. 49° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([C:14]([N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:18][CH2:17]2)=[O:15])[CH2:10][C:11](O)=[O:12])=[CH:4][CH:3]=1.[N:37]1([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C@H:9]([C:14]([N:16]2[CH2:17][CH2:18][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[N:28]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[S:29]([CH3:32])(=[O:31])=[O:30])[CH2:20][CH2:21]2)=[O:15])[CH2:10][C:11]([N:40]2[CH2:41][CH2:42][N:37]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[CH2:38][CH2:39]2)=[O:12])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)N(CC1CC1)c1ccccc1N1CCN(C(=O)[C@H](CC(=O)O)Cc2ccc(Cl)cc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)C[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCN(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 44 %

Procedure:
To a solution of (3S)-3-[(4-chlorophenyl)methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]phenyl}-piperazinyl)-4-oxobutanoic acid (Step 6) (0.63 g, 0.97 mmol), tert-butyl piperazinecarboxylate (0.272 g, 1.46 mmol), HOBt (0.131 g, 0.97 mmol) and TEA (0.135 mL, 0.97 mmol) in 10 mL of CH2Cl2 at 0° C. was added EDC (0.28 g, 1.46 mmol). The reaction was warmed to RT and stirred for 12 h. The reaction was quenched with satd. NaHCO3, and extracted with 50 mL of EtOAc. The organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude compound was further purified by silica gel column chromatography (EtOAc) to afford tert-butyl 4-[(3S)-3-[(4-chlorophenyl)methyl]-4-(4-{2-[(cyclopropylmethyl)(methylsulfonyl)amino]-phenyl}piperazinyl)-4-oxobutanoyl]piperazinecarboxylate as a white foam (0.3 g). MS (ESI, pos. ion) m/z: 702.5 (M+1). Calc'd for C35H48ClN5O6S: 701.30. Anal. Calc'd for C35H48ClN5O6S.0.5H2O: C, 59.10; H, 6.94; N. 9.85; Cl, 4.98. Found: C, 59.32; H, 6.94; N, 9.81; Cl, 5.17.
Reaction SMILES: [Cl:1][C:2]([Cl:6])([Cl:5])[C:3]#[N:4].[CH2:7]([O:9][CH2:10][CH2:11][NH2:12])[CH3:8]>>[CH2:7]([O:9][CH2:10][CH2:11][NH:12][C:3](=[NH:4])[C:2]([Cl:6])([Cl:5])[Cl:1])[CH3:8]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CCOCCN
Product: CCOCCNC(=N)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To 15 ml (0.5 mole) trichloroacetonitrile in an ice bath, was added 8.9 g (0.10 mole) 2-ethoxyethylamine. The addition was carried out over 20 minutes and the reaction temperature rose to 35° C. After 20 minutes additional stirring at 0° C., it was stirred at room temperature overnight. The mixture was washed to give 12.0 g. Distillation yielded: (1) 9.1 g (B.P. 0.41 mm, 92°-97° C.); (2) 1.9 g (B.P. 0.41 mm, 96° C.). Total yield: 10.9 g (47%). The structure was confirmed via IR, VPC, and elemental analysis.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([F:12])([F:11])[F:10])[C:4]=1[OH:13].C1N2CN3CN(C2)CN1C3.FC(F)(F)[C:26](O)=[O:27]>>[OH:13][C:4]1[C:5]([C:9]([F:11])([F:10])[F:12])=[CH:6][C:7]([CH:26]=[O:27])=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cccc(C(F)(F)F)c1O
Agent: C1N2CN3CN1CN(C2)C3
Product: COc1cc(C=O)cc(C(F)(F)F)c1O

Procedure:
A solution containing 1.9 g of 2-methoxy-6-trifluoromethylphenol and 1.4 g of hexamethylenetetramine in 20 ml of trifluoroacetic acid was refluxed for 1 h. The solvent was removed in reduced pressure, 50 ml of 1 N hydrochloric acid was added to the residue and the solution was extracted with dichloromethane. Most part of the solvent was evaporated in vacuo andpetroleum ether was added, whereupon the product crystallized. Yield 0.7 g (32%), m.p. 151°-152° C.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:12]=[N:13][CH:14]=2)[CH:6]=[CH:7][CH:8]=1>C(O)(=O)C>[F:24][C:2]([F:1])([F:25])[C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][NH:13][CH2:12][CH:11]([NH:15][C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:23])[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Nc1cncc(-c2cccc(C(F)(F)F)c2)c1)c1ccccc1
Solvent: CC(=O)O
Product: O=C(NC1CNCC(c2cccc(C(F)(F)F)c2)C1)c1ccccc1

Procedure:
A solution of 840 mg (1.82 mmol) of N-{5-[3-(trifluoromethyl)phenyl]pyridin-3-yl]benzamide in 100 ml of glacial acetic acid was reacted according to General Method 6A. The solution was concentrated under reduced pressure. The product was purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 700 mg
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([OH:8])[CH2:3][CH2:2]1.[H-].[Na+].F[C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[CH3:22])[C:18](=[O:23])[N:17]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=1)[CH:16]=[CH:15]2.O>CC(N(C)C)=O>[NH:1]1[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][C:21]=2[CH3:22])[C:18](=[O:23])[N:17]([CH2:24][C:25]2[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=2)[CH:16]=[CH:15]3)[CH2:3][CH2:2]1
Reactant: OC1CCCNCC1
Reactant: COc1ccc(Cn2ccc3cc(F)c(C)cc3c2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(Cn2ccc3cc(OC4CCCNCC4)c(C)cc3c2=O)cc1
Yield: 41 %

Procedure:
A solution of 58 mg (0.51 mmol) azepan-4-ol in 5 ml dimethylacetamide was stirred with 45 mg (1.52 mmol) 80 percent sodium hydride for 45 minutes at room temperature. Then 150 mg (0.51 mmol) 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one in dimethylacetamide was added. The reaction mixture was heated to 80° C. for 3 days during which additional amounts of azepan-4-ol and sodium hydride were added until complete conversion of the 6-fluoro-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one was obtained. The reaction mixture was slowly added to 10 ml water and after 1 h of stirring the product was isolated by filtration and dried overnight in vacuum. 82 mg of 6-(azepan-4-yloxy)-2-(4-methoxy-benzyl)-7-methyl-2H-isoquinolin-1-one were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[C:12]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](O)=[O:44])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23>>[Br:26][C:27]1[CH:28]=[C:29]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43](=[O:44])[NH:14][C:13]3[CH:15]=[CH:16][C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:11][C:12]=3[O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[N:31]3[C:32](=[O:38])[C:33](=[O:37])[NH:34][C:35]([CH:36]=1)=[C:30]23
Reactant: O=C(O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Reactant: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1N
Product: CC(C)(C)OC(=O)COc1cc(CNC(=O)OC(C)(C)C)ccc1NC(=O)C[C@@H]1CCc2cc(Br)cc3[nH]c(=O)c(=O)n1c23
Yield: 80.8 %

Procedure:
A procedure similar to that described in Example 18-6) was performed with 4-tert-butoxycarbonylaminomethyl-2-tert-butoxycarbonylmethoxyaniline (990 mg, 2.61 mmol) and (S)-9-bromo-5-carboxymethyl-6,7-dihydro-1H, 5H-pyrido[1,2,3-de]quinoxaline-2,3-dione (1.06 g, 3.12 mmol) to give a total amount of 1.42 g of the title compound (81%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[CH:11][C:10]=2[CH3:17])=[CH:4][C:3]=1[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22].[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:45]=[CH:44][C:38]([O:39][CH2:40][C:41](O)=[O:42])=[CH:37][CH:36]=2)[S:29]1.C(P(=O)(OCC)OCC)#N.C(N(CC)CC)C>O1CCCC1>[O:27]=[C:28]1[NH:32][C:31](=[O:33])[CH:30]([CH2:34][C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C:41]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[C:13]([CH3:15])[C:12]([OH:16])=[CH:11][C:10]=4[CH3:17])=[CH:4][C:3]=3[N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:42])=[CH:44][CH:45]=2)[S:29]1
Reactant: Cc1cc(Oc2ccc(N)c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Oc2ccc(NC(=O)COc3ccc(CC4SC(=O)NC4=O)cc3)c(N(C)C(=O)OC(C)(C)C)c2)c(C)cc1O
Yield: 75.8 %

Procedure:
In a similar manner to that described in Example (2-1), a reaction was carried out using t-butyl N-[2-amino-5-(4-hydroxy-2,5-dimethylphenoxy)phenyl]-N-methylcarbamate (0.54 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.51 g), diethyl cyanophosphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) and the reaction mixture was purified to give the desired product (0.71 g).
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1)[NH2:2].[CH3:13][C:14]([CH3:21])([CH3:20])[C:15](=O)[CH2:16][C:17]#[N:18].Cl>CCO>[NH2:18][C:17]1[N:1]([C:3]2[CH:11]=[C:10]3[C:6]([CH2:7][CH2:8][C:9]3=[O:12])=[CH:5][CH:4]=2)[N:2]=[C:15]([C:14]([CH3:21])([CH3:20])[CH3:13])[CH:16]=1
Reactant: NNc1ccc2c(c1)C(=O)CC2
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccc3c(c2)C(=O)CC3)n1
Yield: 28.6 %

Procedure:
To a solution of the 6-hydrazinoindan-1-one (2.1 g, 14.3 mmol) and 4,4-dimethyl-3-oxo-pentanenitrile (2.15 g, 1.2 eq) in EtOH (50 mL) was added conc. HCl (5 mL). The resulting mixture was heated at reflux overnight. After removal of the solvent, the residue was washed with ether to afford 6-(5-amino-3-t-butylpyrazol-1-yl)indan-1-one (1.1 g, 38.5% yield), which was put to the next reaction without further purification. MS (ESI) m/z: 270 (M+H+).
Reaction SMILES: C(N[C:6]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:8][C:7]=1[N+:19]([O-:21])=[O:20])(CC)C.C(C1C=CC([OH:32])=CC=1)(C)(C)C.[N+]([O-])(O)=O>C(O)(=O)C>[N+:19]([C:7]1[CH:8]=[C:9]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:10]=[C:11]([N+:12]([O-:14])=[O:13])[C:6]=1[OH:32])([O-:21])=[O:20]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: CCC(C)Nc1c([N+](=O)[O-])cc(C(C)(C)C)cc1[N+](=O)[O-]
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: CC(C)(C)c1cc([N+](=O)[O-])c(O)c([N+](=O)[O-])c1

Procedure:
The synthesis of N-sec-butyl-4-tert-butyl-2,6-dinitroaniline is generally described in a number of U.S. patents including, for example, U.S. Pat. Nos. 3,672,866; 3,927,127 and 3,991,116 all to Damiano. The process described in U.S. Pat. Nos. 3,672,866 and 3,991,116 begins with a starting material, 4-tert-butylphenol. The 4-tert-butylphenol is subjected to nitration utilizing nitric acid in acetic acid solution to produce 2,6-dinitro-4-tert-butylphenol. The 2,6-dinitro-4-tert-butylphenol is then chlorinated to produce 2,6-dinitro-4-tert-butylchlorobenzene. This 2,6-dinitro-4-tert-butylchlorobenzene is then converted into N-sec-butyl-4-tert-butyl-2,6-dinitroaniline by amination with sec-butylamine.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21](O)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29].CCN=C=NCCCN(C)C.O>CN(C1C=CN=CC=1)C.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:17]=[C:16]4[C:18]([C:21]([NH:24][C:25]5[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=5)=[O:22])=[CH:19][NH:20][C:15]4=[N:14][CH:13]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(N)c1
Reactant: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)Nc4cccc(C#N)c4)c3n2)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.23 mmol), 3-aminobenzonitrile (41 mg, 0.344 mmol), EDCI (88 mg, 0.46 mmol) and DMAP (56 mg, 0.46 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. Then the mixture was poured into water (5 mL) and filtered to give a crude product. The crude product was triturated with DMSO and MeOH, then decanted and dried to give 2-(6-chloro-1-methyl-1H-indazol-3-yl)-N-(3-cyanophenyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (20 mg, 20%) as a white solid. MS: (M+H)+=428; 1H NMR (300 MHz, DMSO): δ 10.55 (s, 1H), 8.81 (s, 1H), 8.55-8.50 (m, 2H), 8.15 (brs, 1H), 8.03-8.00 (m, 1H), 7.92 (s, 1H), 7.59 (d, 1H, J=8.1 Hz), 7.48 (d, 1H, J=7.8 Hz), 7.26 (d, 1H, J=7.5 Hz), 4.14 (s, 3H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:31]=[CH:30][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23](OC(C)(C)C)=O)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH2:32]([C:37]1[CH:38]=[N:39]C(Br)=[N:41][CH:42]=1)[CH2:33][CH2:34][CH2:35][CH3:36]>>[CH3:1][S:2]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([CH:17]3[CH2:22][CH2:21][N:20]([C:23]4[N:41]=[CH:42][C:37]([CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[CH:38][N:39]=4)[CH2:19][CH2:18]3)=[CH:13][N:12]=2)=[CH:30][CH:31]=1)(=[O:4])=[O:3]
Reactant: CCCCCc1cnc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3ccc(S(C)(=O)=O)cc3)nc2)CC1
Product: CCCCCc1cnc(N2CCC(c3ccc(COc4ccc(S(C)(=O)=O)cc4)nc3)CC2)nc1

Procedure:
The title compound was prepared from tert-butyl 4-[2-(4-methanesulfonylphenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 1) (50 mg, 0.11 mmol) and 5-pentyl-2-bromopyrimidine (37 μL, 0.22 mmol) following a procedure analogous to that in Example 48 as a white crystal (35 mg, yield 64%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][C:14](=[O:16])[O:13][C:12](=O)[CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:18][NH2:19]>C1COCC1>[CH3:18][N:19]1[C:14](=[O:16])[CH2:15][CH:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:11][C:12]1=[O:13]
Reactant: O=C1CC(c2ccc([N+](=O)[O-])cc2)CC(=O)O1
Reactant: CN
Solvent: C1CCOC1
Product: CN1C(=O)CC(c2ccc([N+](=O)[O-])cc2)CC1=O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 82.5 %

Procedure:
A solution of 399 mg (1.70 mmol) of 4-(4-nitro-phenyl)-dihydro-pyran-2,6-dione (as prepared in Example 2, step (b)) in THF (8 mL) was treated with 1.10 mL (2.21 mmol) of 2.0 M methylamine in THF. The mixture was stirred at RT for 45 min, concentrated in vacuo, taken up in 1 N aqueous HCl (10 mL), and extracted with EtOAc (2×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was taken up in acetic anhydride (7 mL), treated with triethylamine (1 mL) and heated to 80° C. for 1 h. The solvents were removed in vacuo. The residue was taken up in EtOAc (20 mL) and washed successively with 1 N aqueous HCl, saturated aqueous NaHCO3, and water (1×10 mL each). The organic layer was dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded 348 mg (83%) of the title compound as an off-white solid: 1H-NMR (CDCl3; 400 MHz): δ 8.25 (d, 2H, J=8.8 Hz), 7.40 (d, 2H, J=8.8 Hz), 3.56-3.45 (m, 1H), 3.21 (s, 3H), 3.10-3.01 (m, 2H), 2.88-2.77 (m, 2H).