Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:14]=[CH:13][S:12][C:11]=2[C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[O:9])=[CH:4][CH:3]=1.CN(C)C=O.[Br:31]N1C(=O)CCC1=O>O.C(=O)(O)[O-].[Na+]>[Br:31][C:13]1[S:12][C:11]([C:15]2[N:19]=[CH:18][N:17]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][O:21]3)[N:16]=2)=[C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)=[O:9])[CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C(c1ccc(Cl)cc1)c1ccsc1-c1ncn(C2CCCCO2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccc(Cl)cc1)c1cc(Br)sc1-c1ncn(C2CCCCO2)n1
Temperature: 25 °C

Procedure:
To a mixture of (4-chlorophenyl){2-[1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl]-3-thienyl}methanone (20.2 g, 54.0 mmol) in N,N-dimethylformamide (350 mL, 4500 mmol) was added dropwise a solution of N-bromosuccinimide (14.42 g, 81.05 mmol) in N,N-dimethylformamide (50 mL, 600 mmol) under argon. The mixture was stirred at rt with care taken to block the reaction from exposure to ambient light. After 3 h reaction, LCMS showed both starting material and product. Additional N-bromosuccinimide (6.732 g, 37.82 mmol) was added and the mixture was stirred at rt again. After stirring overnight, the mixture was diluted with water and sodium bicarbonate solution and then the mixture was extracted with EtOAc. The organic layer was washed with water and brine. The EtOAc layer was dried and evaporated in vacuum to a residue, which was purified by chromatography to afford (5-bromo-2-(1-(tetrahydro-2H-pyran-2-yl)-1H-1,2,4-triazol-3-yl)thiophen-3-yl)(4-chlorophenyl)methanone as a white solid (18.0, 73.5%). LCMS: (FA) ES+ 451.9, 453.9
Reaction SMILES: FC(F)(F)S(O[C:7]1[N:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]=[C:10]2[CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)(=O)=O.[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](B(O)O)=[CH:28][CH:27]=1>>[F:25][C:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([C:7]2[N:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][CH:11]=[C:10]3[CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)=[CH:28][CH:27]=1
Reactant: OB(O)c1ccc(F)c2ccccc12
Reactant: CN1CCC(c2c[nH]c3ccc(OS(=O)(=O)C(F)(F)F)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(-c4ccc(F)c5ccccc45)nc23)CC1
Yield: 84.5 %

Procedure:
O-Trifluoromethanesulfonyl-3-(1-methylpiperidin-4-yl)-5-hydroxy-4-aza-1H-indole (160 mg, 0.441 mmol) and 4-fluoronaphth-1-ylboronic acid (134 mg, 0.71 mmol) were converted to 134 mg of the title compound by the procedure of Example 3. (85%). MS(FD) m/e 359.8 (M+). EA calculated for C23H22FN3: C, 76.88; H, 6.13; N, 11.70. Found: C, 77.15; H, 6.21; N, 11.62.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH:12](I)([CH3:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH:12]([O:1][N:2]=[C:3]([C:9](=[O:11])[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:14])[CH3:13]
Reactant: CC(C)I
Reactant: CCOC(=O)C(=NO)C(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(=NOC(C)C)C(C)=O
Yield: 93.3 %

Procedure:
Ethyl 2-hydroxyimino-3-oxobutyrate (syn isomer, 30 g.), iso-propyl iodide (32.5 g.), potassium carbonate (39.5 g.) and acetone (150 ml.) were treated in a similar manner to that of Example D-(1) to give ethyl 2-iso-propoxyimino-3-oxobutyrate (syn isomer, 35.4 g.), oil.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:12]>>[NH2:12][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: N
Product: N[C@@H](Cc1ccccc1)C(=O)O
Reaction time: 40 h

Procedure:
A microorganism was grown in the same manner as described in Section 11 above. From 30 g of the collected and washed cells, L-phenylalanine ammonia-lyase was extracted and purified according to the same procedure as described in Section 11 above. The purified L-phenylalanine ammonia-lyase was dissolved in 20 ml of a NH4OH—(NH4)2SO4 buffer solution (pH 10.0) containing 8M NH The resulting solution was placed in a dialysis tube (a product of Union Carbide Corp.), which was sealed at both ends. This tube was immersed in a reaction mixture prepared by adding 4 g of cinnamic acid to 200 ml of a NH4OH—(NH4)2SO4 buffer solution (pH 10.0) containing 8M NH3. The reaction was carried out at 30° C. for 40 hours with gentle stirring of the outer liquid. After that time, the procedure of Section 13 was repeated to obtain 2.0 g of L-phenylalanine.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:19]=[C:18]([OH:20])[C:17]([CH2:21][C:22]([O:24]CC)=[O:23])=[CH:16][N:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+]>C(O)C>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:19]=[C:18]([OH:20])[C:17]([CH2:21][C:22]([OH:24])=[O:23])=[CH:16][N:15]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)Cc1cnc(N2CCN(Cc3ccccc3)CC2)nc1O
Yield: 92.3 %

Procedure:
A mixture composed of 20 g (56.1 mmoles) of ethyl 2-(4-benzylpiperazino)-4-hydroxypyrimidine-5-acetate (prepared in accordance with Referential Example 70 of Japanese Laid-Open Patent Publication No. 140568/1986), 7.5 g (114 moles) of 85% KOH tablets and 320 ml of ethanol was refluxed for 1 hour. The reaction mixture was concentrated to a solid. Hydrochloric acid and saturated aqueous sodium bicarbonate solution were added to adjust the pH to 4, and the mixture was again concentrated. The resulting crude crystals were recrystallized from water to give 17 g (yield 92%) of 2-(4-benzylpiperazino)-4-hydroxypyrimidine-5-acetic acid as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]C)=[O:25].C(O)(=O)C.Cl.C(O)(=O)CCCC>O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[O:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25]
Reactant: COC(=O)CCCCOc1cc2c(c(Cl)c1Cl)C(=O)C(C)(C1CCCC1)C2
Agent: Cl
Solvent: CC(=O)O
Solvent: CCCCC(=O)O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCCCCC(=O)O)c(Cl)c(Cl)c2C1=O

Procedure:
A mixture of methyl 5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy]pentanoate (14 g., 0.0339 mole), acetic acid (100 ml) and 6N hydrochloric acid (50 ml) is stirred and refluxed for 6 hours. The mixture is poured into water (400 ml) and the product which solidifies upon standing is removed by filtration and dried. The product is recrystallized from a mixture of tetrahydrofuran, ether and petroleum ether (50/100/200 ml) to give 12.5 g, of 5-[(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)oxy)]pentanoic acid, m.p. 106°-108° C.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([F:26])=[CH:23][C:24]=2[F:25])=[CH:17][C:16]([C:27]([OH:29])=[O:28])=[C:15]([OH:30])[CH:14]=1.[CH:31](O)([CH3:33])[CH3:32].O>CN(C=O)C>[F:25][C:24]1[CH:23]=[C:22]([F:26])[CH:21]=[CH:20][C:19]=1[C:18]1[CH:13]=[CH:14][C:15]([OH:30])=[C:16]([C:27]([O:29][CH:31]([CH3:33])[CH3:32])=[O:28])[CH:17]=1
Reactant: CC(C)O
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)OC(=O)c1cc(-c2ccc(F)cc2F)ccc1O
Temperature: 50 °C
Reaction time: 2 h
Yield: 41.1 %

Procedure:
CDI (972 mg, 5.99 mmol) was added to a solution of diflunisal (1.50 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 50° C. for 2 h and isopropyl alcohol (1.15 mL, 14.97 mmol) was dropwise added. The reaction mixture was stirred at 50° C. for 3 h and allowed to reach r.t. It was poured into H2O (50 mL) and extracted with Et2O (2×60 mL). The organic layer was washed with NaHCO3 (20 mL, saturated aqueous solution), dried over Na2SO4 (anhydrous), filtered and concentrated. The crude residue was flash chromatographed on SiO2 (15% EtOAc/hexanes) to furnish 720 mg of isopropyl 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylate (white solid, yield: 41%).
Reaction SMILES: Cl[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][N:3]=1.[CH2:13]([OH:17])[C:14]#[C:15][CH3:16]>>[CH2:13]([O:17][C:2]1[CH:12]=[CH:11][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1)[C:14]#[C:15][CH3:16]
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: CC#CCO
Product: CC#CCOc1ccc(C(=O)O)cn1
Yield: 38 %

Procedure:
The title compound was synthesized as described for Intermediate example I-92 in 38% yield starting from ethyl 6-chloronicotinate and 2-butyn-1-ol; 1H NMR (400 MHz, DMSO-d6) δ ppm 8.61-8.76 (m, 1 H), 8.03-8.23 (m, 1 H), 6.83-6.98 (m, 1 H), 4.94-5.05 (m, 2 H), 1.74-1.91 (m, 3 H); MS (ESI) m/z 192[M+H+], m/z 190[M−H+].
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[N:14](COCC[Si](C)(C)C)[CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2].CCO.C(O)(C(F)(F)F)=O>C(Cl)Cl.CO>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[C:6]([C:28]2[CH2:33][CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH:29]=2)[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1ccc(NC(=O)c2nc(C#N)c[nH]2)c(C2=CCC(C)(C)CC2)c1
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [4-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (8.2 g, 0.016 mol, as prepared in the previous step) in 50 mL of DCM was treated with 6 mL of EtOH followed by 42 mL of TFA. The reaction was stirred for 1 h 45 min, at which time it was diluted with MeOH (100 mL), concentrated to half of the volume and diluted with diethyl ether (80 mL). The result was concentrated in vacuo and dried under vacuum overnight to afford the title compound as a yellow solid (6.00 g, 100%). Mass spectrum (ESI, m/z): Calcd. for C21H22N4O2, 363.1 (M+H). found 363.1.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18](=[O:19])[N:17]2[C:12]([C:13]([CH3:21])([CH3:20])[O:14][CH2:15][CH2:16]2)=[N:11][C:10]=1[C:22](O)=[O:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH2:33])=[C:28]([N:34]2[CH:38]=[N:37][C:36]([CH3:39])=[N:35]2)[CH:27]=1>>[F:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][NH:33][C:22]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:19])[C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:21])[CH3:20])=[O:23])=[C:28]([N:34]2[CH:38]=[N:37][C:36]([CH3:39])=[N:35]2)[CH:27]=1
Reactant: CC1(C)OCCn2c1nc(C(=O)O)c(OCc1ccccc1)c2=O
Reactant: Cc1ncn(-c2cc(F)ccc2CN)n1
Product: Cc1ncn(-c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CCOC3(C)C)n1

Procedure:
The title compound can be prepared from intermediate 27, 3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido-[2,1-c][1,4]oxazine-2-carboxylic acid and intermediate 85, (4-fluoro-2-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)methanamine. White crystals; mp 203° C. (ethyl acetate). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.65 (6H, s, 2×CH3), 2.50 (3H, s, CH3), 4.03 (4H, m, 2×CH2), 4.46 (2H, d, J=6.6 Hz, NCH2), 5.31 (2H, s, OCH2), 7.06 (1H, dd, J=3 Hz and J=8.6 Hz, aromatic), 7.16 (1H, m, aromatic), 7.30-7.34 (3H, m, aromatics), 7.50 (2H, m, aromatics), 7.74 (1H, dd, J=6.0 Hz and J=8.6 Hz, aromatic), 8.28 (1H, s, CH), 8.45 (1H, broad t, NH). Anal. Calcd for C27H27FN6O4: C, 62.54; H, 5.25; N, 16.21. Found: C, 62.48; H, 5.31; N, 16.29.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:17]=[CH:18][C:19]([CH2:33][C:34]#[N:35])=[C:20]([C:22]5[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=5)[CH:21]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[N-:36]=[N+:37]=[N-:38].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:36]1[C:34]([CH2:33][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:13]([C:10]3([C:8]4[CH:7]=[CH:6][C:5]5[O:1][CH2:2][O:3][C:4]=5[CH:9]=4)[CH2:11][CH2:12]3)=[O:14])=[CH:21][C:20]=2[C:22]2[CH:27]=[CH:26][C:25]([C:28]([N:30]([CH3:32])[CH3:31])=[O:29])=[CH:24][CH:23]=2)=[N:35][N:38]=[N:37]1
Reactant: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2Cc2nnn[nH]2)cc1
Yield: 25.7 %

Procedure:
5′-(1-(Benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (32 mg, 0.070 mmol), sodium azide (55 mg, 0.84 mmol), and ammonium chloride (45 mg, 0.84 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) and irradiated in the microwave at 100° C. for 2 hours. After cooling, the mixture was filtered and purified by reverse phase HPLC to yield 2′-((1H-tetrazol-5-yl)methyl)-5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropane carboxamido)-N,N-dimethylbiphenyl-4-carboxamide (9.2 mg, 26%). ESI-MS m/z calc. 510.2, found 511.5 (M+1)+; Retention time 2.68 minutes.
Reaction SMILES: Cl[SiH:2]1[CH2:7][CH2:6][CH:5]([CH2:8][CH2:9][C@H:10]2[CH2:15][CH2:14][C@H:13]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=3)[CH2:12][CH2:11]2)[CH2:4][CH2:3]1.[Cl-].[CH3:25][CH:26]([CH3:30])[CH2:27][CH2:28][Zn+].Cl[SiH]1CCC(CC[C@H]2CC[C@H](C3C=CC(F)=CC=3)CC2)CC1.[Cl-].C([Zn+])CCCC>>[F:23][C:18]1[CH:17]=[C:16]([C@H:13]2[CH2:14][CH2:15][C@H:10]([CH2:9][CH2:8][C@H:5]3[CH2:6][CH2:7][Si@H:2]([CH2:28][CH2:27][CH:26]([CH3:30])[CH3:25])[CH2:3][CH2:4]3)[CH2:11][CH2:12]2)[CH:21]=[CH:20][C:19]=1[F:22]
Reactant: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1F
Reactant: CC(C)CC[Zn+]
Agent: CCCCC[Zn+]
Agent: Fc1ccc([C@H]2CC[C@H](CCC3CC[SiH](Cl)CC3)CC2)cc1
Agent: [Cl-]
Product: CC(C)CC[Si@H]1CC[C@H](CC[C@H]2CC[C@H](c3ccc(F)c(F)c3)CC2)CC1

Procedure:
The preparation was conducted in the same manner as in Example 6, except that 7.5 g (21 mmol) of 1-chloro-4-(2-(trans-4-(3,4-difluorophenyl)cyclohexyl)ethyl)-1-silacyclohexane and 3-methylbutylzinc chloride were used instead of 7.0 g (21 mmol) of 1-chloro-4-(2-(trans-4-(p-fluorophenyl)cyclohexyl) ethyl)-1-silacyclohexane and n-pentylzinc chloride.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[CH2:37][C:38]#[N:39])[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:3]=12.[CH:41]1([CH:44]=O)[CH2:43][CH2:42]1.N1CCCCC1>CO>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C@@H:30]3[CH2:35][CH2:34][CH2:33][N:32]([C:36](=[O:40])[C:37]([C:38]#[N:39])=[CH:44][CH:41]4[CH2:43][CH2:42]4)[CH2:31]3)[N:9]=[C:10]([C:11]3[CH:12]=[CH:13][C:14]([NH:17][C:18](=[O:29])[C:19]4[CH:20]=[CH:21][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:23][CH:24]=4)=[CH:15][CH:16]=3)[C:3]=12
Reactant: N#CCC(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Reactant: O=CC1CC1
Solvent: C1CCNCC1
Solvent: CO
Product: N#CC(=CC1CC1)C(=O)N1CCC[C@@H](n2nc(-c3ccc(NC(=O)c4ccc(C(F)(F)F)cc4)cc3)c3c(N)ncnc32)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 59.7 %

Procedure:
Into a 10-mL round-bottom flask, was placed (R)—N-(4-[4-amino-1-[1-(2-cyanoacetyl)piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl]phenyl)-4-(trifluoromethyl)-benzamide (65 mg, 0.12 mmol, 1.00 equiv), cyclopropanecarbaldehyde (16.6 mg, 0.24 mmol, 2.00 equiv), piperidine (10 mg, 0.12 mmol, 0.99 equiv), methanol (5 mL). The resulting solution was stirred for 12 h at 25° C. The resulting mixture was concentrated under vacuum and the residue was loaded onto a silica gel column and eluted with dichloromethane/methanol (50:1) to give 43 mg (60%) of (R)—N-[4-(4-amino-1-[1-[2-cyano-2-(cyclopropylmethylidene)acetyl]piperidin-3-yl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl)phenyl]-4-(trifluoromethyl)benzamide as a white solid. MS (ESI, pos. ion) m/z: 601 (M+1), 1HNMR (300 MHz, CDCl3, ppm), 8.6 (1H, s), 8.348 (1Hs), 8.065˜8.038 (2H, d, J=8.1), 7.880˜7.852 (1H, d, J=8.4), 7.768˜7.659 (4H, m), 6.532˜6.496 (1H, d, J=10.8), 5.949 (2H, s), 4.976˜4.907 (1H, m), 4.638˜3.218 (4H, m), 2.436˜1.818 (5H, m), 1.221˜1.198 (2H, m), 0.89˜0.772 (2H, m).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9](/[C:11](=[CH:17]/[NH:18][CH2:19][CH3:20])/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].C(N)C>C(#N)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:5](=[N:6][CH:7]=1)[N:18]([CH2:19][CH3:20])[CH:17]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:9]2=[O:10]
Reactant: CCN/C=C(\C(=O)OCC)C(=O)c1cc(Br)cnc1Cl
Agent: CCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)c1cn(CC)c2ncc(Br)cc2c1=O
Temperature: 80 °C
Yield: 79.4 %

Procedure:
The above crude compound ethyl (2Z)-2-[(5-bromo-2-chloropyridin-3-yl)carbonyl]-3-(ethylamino)prop-2-enoate (Intermediate 14, 700 mg) was suspended in acetonitrile (30 mL) and potassium carbonate (0.9 g, 6.53 mmol) and ethylamine (1 eq) were added. The mixture was heated to 80° C. for 16 h then cooled to room temperature and filtered to remove potassium carbonate. Water was added to the filtrate and the precipitated product was filtered and dried to afford 500 mg, 50% of ethyl 6-bromo-1-ethyl-4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylate.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Br[C:13]1[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][C:13]3[S:17][C:16]([CH:18]=[O:19])=[CH:15][CH:14]=3)=[N:3][C:4]=2[CH:10]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc2[nH]c(Sc3ccc(C=O)s3)nc2c1
Temperature: 110 °C
Yield: 47.4 %

Procedure:
a mixture of 0.82 g of 2-mercapto-5-methyl-benzimidazole (5 mmoles), 0.6 ml of 5-bromo-2-thiophenecarboxaldehyde (5 mmoles) and 1.4 g of potassium carbonate in 10 ml of DMF is heated at 110° C. for 2 hours. The mixture is cooled down to room temperature, then poured into 200 ml of water and extracted twice with 50 ml of ethyl acetate. The combined organic extracts are washed with brine, dried over MgSO4 and concentrated. The crude product is purified on silica gel using DCM/MeOH as eluent to give 0.65 g of 5-(5-methyl-1H-benzimidazol-2-ylsulfanyl)-thiophene-2-carbaldehyde. (Yield=47%). Analytical LC/MS method A: ([M+H]+): 275). RT: 3.42 min (gradient 5 to 85% acetonitrile in 7 min).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]([C:14]([O:16]C)=O)[CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=[O:7])([O-:3])=[O:2].[NH3:18]>>[N+:1]([C:4]1[CH:13]=[C:12]([C:14]([NH2:18])=[O:16])[CH:11]=[CH:10][C:5]=1[C:6]([OH:8])=[O:7])([O-:3])=[O:2]
Reactant: COC(=O)c1ccc(C(=O)OC)c([N+](=O)[O-])c1
Reactant: N
Product: NC(=O)c1ccc(C(=O)O)c([N+](=O)[O-])c1

Procedure:
This invention provides as new compositions of matter 2- and 3-nitroterephthalamic acids. This invention further provides a new process for the preparation of 2- and 3-nitroterephthalamic acids comprising the steps of reaction of a 1-4 carbon dialkyl nitroterephthalate with 20-51% by weight aqueous ammonia at 100°-200° C. under at least autogenous pressure for 1-6 hours at a dialkyl nitroterephthalate concentration of 10-40% by weight. Preferably 30-51% by weight aqueous ammonia is reacted at 150°-175° C. for 2-4 hours. For the preparation of 3-nitroterephthalamic acid it is preferred that the reaction be carried out using 20% by weight dimethyl nitroterephthalate and 25-51% by weight aqueous ammonia for 2-4 hours at 125°-175° C., most preferably at 150° C. 3-Nitroterephthalamic acid is isolated from the reaction mixture by cooling, removal of by-product nitroterephthalamide by filtration, adjustment of the pH of the filtrate to about 4 and removal of 3-nitroterephthalamic acid by filtration. For the preparation of 2-nitroterephthalamic acid, it is preferred that the reaction be carried out using about 10% by weight dimethyl nitroterephthalate and 25-51% by weight aqeuous ammonia for 2-4 hours at 150°-200° C., most preferably at 175° C. 2-Nitroterephthalamic acid is isolated from the reaction mixture by cooling, removal of by-product nitroterephthalamide by filtration, adjusting the pH of the filtrate to about 4, removal of by-product 3-nitroterephthalamic acid by filtration, adjustment of the pH of the filtrate to about 2 and removing 2-nitroterephthalamic acid by filtration. The reaction may be summarized as follows: ##STR1##
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:32])=[CH:4][CH:3]=1.[ClH:33]>C(OCC)(=O)C.C(O)C>[ClH:33].[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:16]=3)[CH2:11][CH2:10][C:9]2=[O:32])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc3c(c2)CCC(=O)N3c2ccc(F)cc2)CC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCc2cc(OC3CCNCC3)ccc2N1c1ccc(F)cc1
Reaction time: 16 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-(1-(4-fluorophenyl)-2-oxo-1,2,3,4-tetrahydroquinolin-6-yloxy)piperidine-1-carboxylate prepared in Example 7-(2) (6.0 g) in a mixture of ethyl acetate (12 mL) and ethanol (4 mL), 4M hydrochloric acid in ethyl acetate (10 mL) was added dropwise at room temperature and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate and stirred at room temperature for 1 hour. The precipitate was collected by filtration and dried to give the titled compound (5.1 g, 99%) as a colorless solid.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([N:25]3[CH2:29][CH2:28][CH2:27][C@@H:26]3[CH3:30])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:25]1[C:22]1[N:20]2[CH:21]=[C:16]([O:12][C@H:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[C@@H:2]([NH2:1])[CH2:3][CH2:4]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: C[C@H]1CCCN1c1nnc2ccc(F)cn12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H]1CCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 38.4 %

Procedure:
Intermediate A (318 mg, 1.95 mmol) was dissolved in DMF (1 mL) and sodium hydride (60% dispersion in oil, 125 mg, 3.25 mmol) was added portionwise. The mixture was stirred at RT for 10 min. A solution of Intermediate 78a (357 mg, 1.62 mmol) in DMF (1 mL) was added and the reaction mixture was heated at 60° C. for 1.5 h. The mixture was cooled to RT and partitioned between EtOAc (10 mL) and water (10 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to afford the title compound as an orange gum (226 mg, 38%). LCMS (Method 3): Rt 0.42, 2.06 min, m/z 364 [MH+].
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[Br:9][C:10]1[C:14]([Br:16])([Br:15])[C:13]([Br:17])=[C:12]([Br:18])[C:11]=1[Br:19]>C1(C)C=CC=CC=1>[Br:17][C:13]12[C:14]([Br:15])([Br:16])[C:10]([Br:9])([C:6]3[C:1]([OH:8])=[CH:2][CH:3]=[C:4]([OH:7])[C:5]=31)[C:11]([Br:19])=[C:12]2[Br:18]
Reactant: O=C1C=CC(=O)C=C1
Reactant: BrC1=C(Br)C(Br)(Br)C(Br)=C1Br
Solvent: Cc1ccccc1
Product: Oc1ccc(O)c2c1C1(Br)C(Br)=C(Br)C2(Br)C1(Br)Br

Procedure:
A mixture of benzoquinone, 10.8 g. toluene (40 ml) and 1,2,3,4,5,5-hexabromo-1,3-cyclopentadiene (60 g.) was heated to reflux temperature and refluxed for four hours. At the end of this reaction period a dark solid had formed. This solid was placed on a Buchner funnel and washed with Skelly B solvent and a small amount of methanol. The solid was then recrystallized from benzene and white crystals were obtained, m.p. 204°-206° C.