Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:18])=[N:7][N:6]=[CH:5]2.[B:19]1(B2OC(C)(C)C(C)(C)O2)[O:23]C(C)(C)C(C)(C)[O:20]1.C([O-])(=O)C.[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]1([CH3:18])[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:8]1[C:9]2[C:4](=[CH:3][C:2]([B:19]([OH:23])[OH:20])=[CH:11][CH:10]=2)[CH:5]=[N:6][N:7]=1
Reactant: Cc1ccccc1-c1nncc2cc(Cl)ccc12
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [Pd]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: Cc1ccccc1-c1nncc2cc(B(O)O)ccc12
Temperature: 125 °C

Procedure:
In a sealed glass tube, a mixture of 6-chloro-1-o-tolylphthalazine (127 mg, 0.50 mmol), bis(pinacolato)diboron (146 mg, 0.57 mmol), potassium acetate (98 mg, 1.0 mmol), tris(dibenzylideneacetone)dipalladium (18 mg, 20 μmol) and tricyclohexylphosphine (11 mg, 40 μmol) in 1,4-dioxane (2 mL) was heated in a Personal Chemistry microwave at 125° C. for 30 min. The reaction mixture was filtered through a pad of Celite, and rinsed with ethyl acetate (5 mL). The filtrate was concentrated, then treated with 2 N aq. HCl (2 mL), and extracted with hexanes (5 mL). The acidic layer was diluted with 1 mL of DMSO and put on a reversed phase HPLC (5-90% [0.1% TFA in acetonitrile] in [0.1% TFA in water]) to provide 1-o-tolylphthalazin-6-ylboronic acid as a white fluffy solid. MS (ESI, pos. ion.) m/z: 255 (M+1).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]([NH:12][NH:13][C:14]1[C:23](=[O:24])[N:22](CC2C=CC(OC)=CC=2OC)[C:21]2[C:20]3[CH:36]=[CH:37][CH:38]=[CH:39][C:19]=3[CH:18]=[CH:17][C:16]=2[N:15]=1)=O)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>C(O)(=O)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[N:15]2[C:16]3[CH:17]=[CH:18][C:19]4[CH:39]=[CH:38][CH:37]=[CH:36][C:20]=4[C:21]=3[NH:22][C:23](=[O:24])[C:14]2=[N:13][N:12]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(CC(=O)NNc1nc2ccc3ccccc3c2n(Cc2ccc(OC)cc2OC)c1=O)OCC
Solvent: CC(=O)O
Product: CCOP(=O)(Cc1nnc2c(=O)[nH]c3c4ccccc4ccc3n12)OCC
Yield: 52.2 %

Procedure:
A solution of 3-(2-diethoxyphosphorylacetyl)hydrazino-1-(2,4-dimethoxybenzyl)benzo[f]quinoxalin-2(1H)-one (1.1 g crude product) and glacial acetic acid (40 ml) was heated under reflux for 12 h. The mixture was evaporated to dryness. The residue was recrystallized from isopropanol to give 400 mg of the title compound m.p. 195°-197° C. 1H-NMR (DMSO-d6): δ 1.18 (t, 6H), 4.08 (quint, 4H), 4.35 (d, 2H), 7.68 (m, 2H), 7.90 (d, 1H), 8.08 (m, 1H), 8.35 (d, 1H), 8.82 (m, 1H), 12.25 (s, 1H).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14])[CH2:7]O.[N:17]1C=CC=C[CH:18]=1.S(Cl)(Cl)=O.FC(F)OC1C=C(C=CC=1OC(F)F)CCl.[C-]#N.[Na+]>C(Cl)(Cl)Cl>[F:1][CH:2]([F:16])[O:3][C:4]1[CH:5]=[C:6]([CH2:7][C:18]#[N:17])[CH:9]=[CH:10][C:11]=1[O:12][CH:13]([F:15])[F:14]
Reactant: c1ccncc1
Reactant: OCc1ccc(OC(F)F)c(OC(F)F)c1
Agent: FC(F)Oc1ccc(CCl)cc1OC(F)F
Agent: [C-]#N
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: N#CCc1ccc(OC(F)F)c(OC(F)F)c1
Temperature: 45 °C
Yield: 98.5 %

Procedure:
A solution of 3,4-bisdifluoromethoxybenzyl alcohol (26.4 g, 110 mmol) and pyridine (9.79 mL, 120 mmol) in chloroform (200 mL) under an argon atmosphere was treated with thionyl chloride (9.62 mL, 130 mmol) and the mixture was heated at reflux for 1 h. The solvent was removed, ether was added and the precipitate was removed by filtration. The filtrate was concentrated to a purple oil. To a solution of this 3,4-Bisdifluoromethoxybenzyl chloride in dimethylflormamide (200 mL) under an argon atmosphere was added sodium cyanide (11.86 g, 240 mmol). The resulting mixture was stirred and gently heated at 45° C. for 3 h, was cooled and was concentrated. The mixture was partitioned between ether and 5% aqueous sodium carbonate and was extracted five times with ether. The organic extract was washed once with brine, was dried (sodium carbonate) and the solvent was removed in vacuo to provide an oil (27 g).
Reaction SMILES: C([O:5][C:6]([NH:8][NH:9][C:10](=[NH:20])[C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)=O)(C)(C)C>C(#N)C>[N+:17]([C:14]1[CH:15]=[CH:16][C:11]([C:10]2[NH:9][NH:8][C:6](=[O:5])[N:20]=2)=[CH:12][CH:13]=1)([O-:19])=[O:18]
Reactant: CC(C)(C)OC(=O)NNC(=N)c1ccc([N+](=O)[O-])cc1
Solvent: CC#N
Product: O=c1nc(-c2ccc([N+](=O)[O-])cc2)[nH][nH]1
Temperature: 200 °C

Procedure:
N′-[Imino-(4-nitro-phenyl)-methyl]-hydrazinecarboxylic acid tert-butyl ester (made above, 410 mg) was suspended in 3 mL of acetonitrile and the mixture was heated at 200° C. for 5 min. The mixture was cooled and the solid was filtered and dried. 341 mg.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(N(CC)CC)C.[F:16][C:17]([F:25])([C:21]([F:24])([F:23])[F:22])[C:18](Cl)=[O:19]>O1CCCC1>[C:1]([C:3](=[C:18]([OH:19])[C:17]([F:25])([F:16])[C:21]([F:24])([F:23])[F:22])[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2]
Reactant: O=C(Cl)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)CC#N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(C#N)=C(O)C(F)(F)C(F)(F)F
Temperature: 25 °C

Procedure:
To 20 ml of tetrahydrofuran, 3.39 g (30 mmol) of ethyl cyanoacetate and 6.06 g (60 mmol) of triethylamine were dissolved and stirred at room temperature. Successively, 5.47 g (30 mmol) of pentafluoropropionyl chloride was dropwise added and stirred for 5 hours at room temperature. However, formation of desired product could not be confirmed.
Reaction SMILES: [CH3:1][N:2]1[CH:17]([CH3:18])[C:5]2[CH2:6][N:7](C(OC(C)(C)C)=O)[CH2:8][CH2:9][C:4]=2[NH:3]1.[ClH:19]>CO.CCOC(C)=O>[ClH:19].[CH3:1][N:2]1[C:17]([CH3:18])=[C:5]2[CH2:6][NH:7][CH2:8][CH2:9][C:4]2=[N:3]1
Reactant: CC1C2=C(CCN(C(=O)OC(C)(C)C)C2)NN1C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1c2c(nn1C)CCNC2
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 2,3-dimethyl-6,7-dihydro-1H-pyrazolo[4,3-c]pyridine-5(4H)-carboxylate (3.0 g) in MeOH was added a solution of HCl in EtOAc (3.0 M). White solid was precipitated out after 3.0 h reaction. The resulted mixture was filtered and the residue was dried to give the title compound as a white solid (2.10 g, 91.90%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 152.21 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:48]=[CH:47][C:6]([CH2:7][N:8]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH:30]C(=O)OC(C)(C)C)=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:5][CH:4]=1.C(O)(C(F)(F)F)=O.C1(C)C=CC=CC=1>C(Cl)Cl>[CH3:46][O:45][C:42]1[CH:41]=[CH:40][C:39]([CH2:38][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:48][CH:47]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([NH:23][C:24]4[CH:25]=[CH:26][C:27]([NH2:30])=[N:28][CH:29]=4)=[N:18][CH:19]=[C:20]([Cl:22])[CH:21]=3)[N:10]=2)=[CH:44][CH:43]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(NC(=O)OC(C)(C)C)nc3)n2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3Nc3ccc(N)nc3)n2)cc1
Yield: 94.1 %

Procedure:
A solution of tert-butyl 5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-ylamino)pyridin-2-ylcarbamate (0.827 g, 1.24 mmol) and TFA (5.0 mL, 64.9 mmol) in DCM (10 mL) was stirred at rt for 1.5 h. Toluene (3 mL) was added and the mixture was concentrated in vacuo. Saturated aqueous sodium bicarbonate (50 mL) was added carefully. The aqueous phase was extracted with 25% iPrOH in CHCl3+1% NH4OH (2×50 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give N5-(3-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-5-chloropyridin-2-yl)pyridine-2,5-diamine (0.664 g, 94% yield) as a bright orange solid. 1H NMR (300 MHz, CDCl3) δ 11.46 (s, 1H); 8.72 (d, J=2.48 Hz, 1H); 8.17 (d, J=2.34 Hz, 1H); 8.06-8.13 (m, 1H); 7.64-7.75 (m, 1H); 7.18 (dd, J=12.57, 8.48 Hz, 4H); 6.86 (t, J=7.89 Hz, 4H); 6.49 (d, J=8.77 Hz, 1H); 4.83 (d, J=15.05 Hz, 4H); 4.31 (br. s., 2H); 3.80 (d, J=5.85 Hz, 6H); 2.56 (s, 3H). m/z (ESI, +ve ion) 569.2 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=[O:12])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1.[CH3:19][Si](C=[N+]=[N-])(C)C>CO.CCCCCC>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[CH:15]=[CH:14][C:10]([C:11]([O:13][CH3:19])=[O:12])=[CH:9][C:8]=2[N+:16]([O-:18])=[O:17])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Solvent: CO
Solvent: CCCCCC
Product: COC(=O)c1ccc(N2CCOCC2)c([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-Morpholino-3-nitrobenzoic acid prepared in the same manner as in Example 10(1) (3.0 g) is dissolved in methanol (15 ml), and thereto is added dropwise a 10% solution of trimethylsilyldiazomethane in n-hexane in an equimolar amount, and the mixture is stirred at room temperature for one hour. Methanol is distilled off under reduced pressure, and the residue is extracted with ethyl acetate. The extract is washed with 5% aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution in this order, dried over anhydrous sodium sulfate, and ethyl acetate is distilled off under reduced pressure to give methyl 4-morpholino-3-nitrobenzoate (3.2 g).
Reaction SMILES: [F: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.[CH3:24][C:25]([CH3:44])([Si:27]([CH3:43])([CH3:42])[O:28][CH2:29][C:30]([CH3:41])([NH2:40])[CH2:31][O:32][Si:33]([CH3:39])([CH3:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH3:26].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F: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:40][C:30]([CH3:41])([CH2:29][O:28][Si:27]([CH3:43])([CH3:42])[C:25]([CH3:44])([CH3:26])[CH3:24])[CH2:31][O:32][Si:33]([CH3:38])([CH3:39])[C:34]([CH3:37])([CH3:36])[CH3:35])=[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: Cn1nc(-c2cnc3[nH]cc(C(=O)O)c3n2)c2ccc(F)cc21
Reactant: CC(N)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: Cn1nc(-c2cnc3[nH]cc(C(=O)NC(C)(CO[Si](C)(C)C(C)(C)C)CO[Si](C)(C)C(C)(C)C)c3n2)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.1 %

Procedure:
A mixture of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid (70 mg, 0.225 mmol), 2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-amine (112 mg, 0.338 mmol), HATU (171 mg, 0.45 mmol) and DIPEA (58 mg, 0.45 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was poured into water (5 mL) and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine and dried over Na2SO4. After filtration and concentration, the residue was purified by column chromatography on silica gel eluting with petroleum ether/EtOAc (1:1, v/v) to give 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-N-(2,2,3,3,6,9,9,10,10-nonamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (65 mg, 46%) as a white solid. 1H NMR (300 MHz, DMSO): δ 9.00 (s, 1H), 8.44-8.40 (m, 1H), 8.38 (s, 1H), 7.91 (s, 1H), 7.87 (dd, J=10.2, 2.7 Hz, 1H), 7.06-7.05 (m, 1H), 4.13 (s, 3H), 3.92-3.84 (m, 1H), 1.43 (s, 3H), 0.64 (s, 18H), 0.01 (s, 12H).
Reaction SMILES: [CH3:1][CH:2]([OH:4])[CH3:3].C(N(CC)CC)C.[F:12][C:13]1[C:14]([C:20](F)=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1>O>[F:12][C:13]1[C:14]([C:20]([O:4][CH:2]([CH3:3])[CH3:1])=[O:21])=[N:15][C:16]([F:19])=[CH:17][CH:18]=1
Reactant: O=C(F)c1nc(F)ccc1F
Reactant: CC(C)O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)OC(=O)c1nc(F)ccc1F
Temperature: 25 °C
Reaction time: 6 h
Yield: 48 %

Procedure:
Anhydrous 2-propanol (0.361 g, 6 mmol) and anhydrous tri-ethylamine (0.405 g, 4 mmol) were added dropwise at room temperature to the 3,6-difluoropicolinoyl fluoride provided above. The mixture was stirred at room temperature for 6 hours, poured into a separatory funnel with water and extracted with ethyl ether. The organic phase was then washed with water and dried over MgSO4. The solvent was removed with a rotary evaporator. The concentrated crude product was purified using column chromatography (silica gel) with ethyl acetate/hexanes mixture (1/10) as eluent to give 0.39 g (48% yield, 99% GC purity, 98% LC purity) of desired product as a pale yellow liquid. GC/MS results were consistent with the chemical formula of isopropyl 3,6-difluoropicolinate: 70 eV EIMS (GC) m/z=160 (41%), 142 (100%), 115 (43%), 114 (66%), 64 (31%), 43 (51%). 1H NMR (400 MHz, CDCl3) δ 7.69 to 7.63 (m, 1H), 7.16 to 7.12 (m), 5.33 (hept, J=6.3 Hz, 1H), 1.41 (d, J=6.3 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 161.41 (d, J=6.3 Hz), 158.80 (d, J=1.2 Hz), 158.26 (d, J=4.3 Hz), 156.41 (d, J=1.2 Hz), 155.62 (d, J=4.4 Hz), 134.05 (t, J=13.5 Hz), 131.06 (dd, J=23.9, 8.3 Hz), 114.86 (dd, J=41.7, 5.9 Hz), 70.34 (s), 21.71 (s). 19F NMR (376 MHz, CDCl3) δ−69.40 (d, J=26.9 Hz), −122.76 (d, J=27.4 Hz).
Reaction SMILES: COC(=O)CC[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])=[CH:11][N:10]=1)(=[O:8])=[O:7].[O-]CC.[Na+].ClN1C(=O)CCC1=O.[CH3:48][O:49][CH2:50][CH2:51][NH2:52]>C1COCC1.C(O)C.[Cl-].[NH4+].CCOC(C)=O>[CH3:48][O:49][CH2:50][CH2:51][NH:52][S:6]([C:9]1[N:10]=[CH:11][C:12]([CH2:15][NH:16][C:17]([C:19]2[C:20]3[CH:27]=[N:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)[C:21]=3[CH:22]=[N:23][CH:24]=2)=[O:18])=[CH:13][CH:14]=1)(=[O:7])=[O:8]
Reactant: COCCN
Reactant: COC(=O)CCS(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cn1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Cl
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCO
Product: COCCNS(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cn1
Reaction time: 0.25 h

Procedure:
To a solution of 3-[5-({[1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carbonyl]amino}-methyl)-pyridine-2-sulfonyl]-propionic acid methyl ester (100 mg, 0.2 mmol) in THF (5 mL) was added a freshly prepared 8% solution of sodium ethoxide (200 μL, 0.2 mmol) in ethanol. The mixture was stirred for 15 minutes and was monitored for the disappearance of starting material by TLC (EtOAc). The mixture was then concentrated to dryness under a stream of nitrogen. The mixture was again diluted with THF and then N-chlorosuccinimide (55 mg, 0.41 mmol) was added. After 15 minutes, 2-methoxyethylamine (0.100 mL, 1.15 mmol) was added in one portion. After 15 minutes, the mixture was diluted with saturated ammonium chloride and extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (2×10 mL), dried over magnesium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography eluting with methanol-EtOAc (0:100, then 0.5:99.5, then 1:99, then 2:98). The material from the column was purified a second time by using preparative silica gel TLC eluting with methanol-EtOAc (1:9). The material from the plate was triturated with EtOAc-ether-hexanes to afford the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([OH:17])=O)[CH:3]=1.C(Cl)(=O)C([Cl:21])=O>ClCCl.CN(C=O)C>[CH3:1][C:2]1[N:6]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[N:5]=[C:4]([C:15]([Cl:21])=[O:17])[CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(Cn2nc(C(=O)O)cc2C)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2nc(C(=O)Cl)cc2C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
5-methyl-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid (Intermediate B, 390 mg, 1.69 mmol), was dissolved in dichloromethane (26 mL) and cooled to 0° C. Oxalyl chloride was added (0.79 mL, 8.47 mmol) along with 1 drop of DMF. The ice bath was removed and the mixture was stirred at rt for 30 min before the solvent was evaporated. The residue was used in the next step with no further purification or characterization.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH3:11])[CH:9]=2)[NH:4][C:3]1=[O:12].Cl[CH2:15][CH2:16][O:17]C1CCCCO1>>[OH:17][CH2:16][CH2:15][N:4]1[C:5]2[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=2)[C:2]([CH3:13])([CH3:1])[C:3]1=[O:12]
Reactant: Cc1ccc2c(c1)C(C)(C)C(=O)N2
Reactant: ClCCOC1CCCCO1
Product: Cc1ccc2c(c1)C(C)(C)C(=O)N2CCO

Procedure:
Prepared from 3,3,5-trimethyl-1,3-dihydro-2H-indol-2-one (prepared by the method of Endler and Becker; Organic Syntheses Coll. vol. 4 page 657) and 2-(2-chloroethoxy)tetrahydro-2H-pyran as described above.
Reaction SMILES: [CH3:1][C@H:2]1[N:7](CC2C=CC=CC=2)[C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:27])=[O:26])[C:19]([O:22][CH3:23])=[N:20][CH:21]=2)[CH2:3]1.[H][H].[ClH:43]>C(O)C.[Pd]>[ClH:43].[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:15])[CH2:5][N:4]([C:16]2[CH:17]=[C:18]([NH:24][S:25]([C:28]3[CH:33]=[CH:32][C:31]([C:34]4[O:35][C:36]([CH3:39])=[CH:37][CH:38]=4)=[C:30]([F:40])[CH:29]=3)(=[O:26])=[O:27])[C:19]([O:22][CH3:23])=[N:20][CH:21]=2)[CH2:3]1
Reactant: COc1ncc(N2C[C@@H](C)N(Cc3ccccc3)[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: COc1ncc(N2C[C@@H](C)N[C@@H](C)C2)cc1NS(=O)(=O)c1ccc(-c2ccc(C)o2)c(F)c1

Procedure:
A solution of N-[5-[cis-3,5-dimethyl-4-(phenylmethyl)-1-piperazinyl]-2-(methyloxy)-3-pyridinyl]-3-fluoro-4-(5-methyl-2-furanyl)benzenesulfonamide (D31) (60 mg, 0.1 mmol) in ethanol (5 ml) and 2M hydrochloric acid (0.5 ml) containing 10% palladium on carbon (10 mg) was stirred in a hydrogen atmosphere for 2 hours. The mixture was filtered through ‘celite’ and the solvent evaporated. Purification of the residue by flash chromatography eluting with 5% methanol in dichloromethane followed by treatment with 1.0M hydrogen chloride in diethyl ether gave the title compound (E13). MS (ES+) m/e 475 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15]([N:17]2[CH2:20][CH:19]([OH:21])[CH2:18]2)[C:14]([F:22])=[CH:13][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:12])[C:8]([F:11])([F:10])[F:9])=[O:5].C(O)(=O)C.C(O)(=O)C.IC1C=CC=CC=1.CC1(C)N([O])C(C)(C)CCC1>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:16]=[C:15]([N:17]2[CH2:20][C:19](=[O:21])[CH2:18]2)[C:14]([F:22])=[CH:13][C:3]=1[C:4]([NH:6][C@@H:7]([CH3:12])[C:8]([F:11])([F:9])[F:10])=[O:5]
Reactant: C[C@H](NC(=O)c1cc(F)c(N2CC(O)C2)cc1F)C(F)(F)F
Agent: CC1(C)CCCC(C)(C)N1[O]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: Ic1ccccc1
Product: C[C@H](NC(=O)c1cc(F)c(N2CC(=O)C2)cc1F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.5 %

Procedure:
To a solution of 2,5-difluoro-4-(3-hydroxyazetidin-1-yl)-N-[(1S)-2,2,2-trifluoro-1-methylethyl]benzamide (7.57 g, 23.3 mmol) in methylene chloride (93 mL) was added iodobenzene diacetate (9.40 g, 29.2 mmol) and 2,2,6,6-tetramethyl-1-piperidinyloxy free radical (1.82 g, 11.7 mmol) (TEMPO) at room temperature. The reaction mixture was stirred at room temperature overnight. The mixture was diluted with EtOAc (100 mL), washed with 0.5N NaHCO3 (2×80 mL), 20% brine (100 mL) and water (100 mL). The aqueous layers were extracted with ethyl acetate (75 mL). The organic extracts were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column eluting with 0% to 5% ethyl acetate in methylene chloride to afford the crude product which was recrystallized from MTBE (50 mL) and heptane (100 mL) to give the desired product (5.44 g, 72%) as colorless solid. 1H NMR (300 MHz, DMSO-d6) δ 8.52 (d, J=8.0 Hz, 1H), 7.36 (dd, J=12.5, 6.5 Hz, 1H), 6.63 (dd, J=12.1, 7.6 Hz, 1H), 4.90 (d, J=2.1 Hz, 4H), 4.86-4.68 (m, 1H), 1.31 (d, J=7.1 Hz, 3H) ppm. LCMS cacld. for C13H12F5N2O2 (M+1)+: m/z=323.1. Found: 323.0.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([N+:12]([O-])=O)[C:3]=12.[OH-].[Na+]>Cl>[F:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([NH2:12])[C:3]=12
Reactant: O=[N+]([O-])c1c[nH]c2ncc(F)c(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Nc1c[nH]c2ncc(F)c(F)c12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 81.6 %

Procedure:
SnCl2 dihydrate (3.68 g, 16.3 mmol) at a temperature of about 0° C. to about 5° C. was added to 4,5-difluoro-3-nitro-1H-pyrrolo[2,3-b]pyridine (0.65 g, 3.26 mmol) in 6M HCl (5 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was neutralized to a pH of about 8 with a 6N NaOH solution. The mixture was extracted with CHCl3:IPA (3×30 mL; 3:1) and dried over sodium sulfate. After removal of the solvent, 4,5-difluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (0.45 g, 2.66 mmol, 81% yield) was isolated as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.[CH:29](OCC)=[O:30]>CN(C=O)C>[CH:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[C:9](=[C:16]2\[C:17](=[O:28])[NH:18][C:19]3[C:24]\2=[CH:23][C:22]([N+:25]([O-:27])=[O:26])=[CH:21][CH:20]=3)/[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:4][CH:3]=1)=[O:30]
Reactant: CCOC=O
Reactant: Nc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: O=CNc1ccc(N/C(=C2\C(=O)Nc3ccc([N+](=O)[O-])cc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29b from (Z)-3-[1-(4-aminophenylamino)-1-phenyl-methylidene}-5-nitro-2-indolinone and ethyl formate in DMF.
Reaction SMILES: [OH:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[H][H]>CO.[Pd]>[NH2:12][C:11]1[C:2]([OH:1])=[C:3]([CH:8]=[CH:9][CH:10]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1O
Yield: 95.7 %

Procedure:
A solution of methyl 2-hydroxy-3-nitrobenzoate (2 g, 0.010 mol) in methanol (30 mL), was hydrogenated with a hydrogen balloon in the presence of 10% palladium on chacoal (600 mg) for 7 h. After the reaction is completed, the reaction mixture was filtered through celite bed and the filtrate was concentrated under reduced pressure to obtain 1.6 g of the above required compound (72%) as a grey coloured solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[CH3:27][S:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[CH3:27][S:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH:32][CH:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1
Reactant: CSc1cccc(N)c1
Reactant: COc1cc(-c2cc(CN3CCC(=O)CC3)ccn2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCC(Nc4cccc(SC)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
1-[[2-(3,4,5-trimethoxyphenyl)pyridin-4-yl]methyl]-4-piperidone (1.40 g) and 3-methylthioaniline (655 mg) were reacted in the same manner as described in Preparation Example 37 to give the title compound.