Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH2:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)([C:6]#[N:7])[CH2:3]1.N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[CH3:20][S:21]([O:1][CH:2]1[CH2:5][C:4]([C:6]#[N:7])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[CH2:3]1)(=[O:23])=[O:22]
Reactant: N#CC1(c2ccccn2)CC(O)C1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)OC1CC(C#N)(c2ccccn2)C1
Temperature: 25 °C
Reaction time: 25 h

Procedure:
To a solution of 3-hydroxy-1-(pyridin-2-yl)cyclobutanecarbonitrile (WO 2007/060484)(10.996 g, 63.1 mmol) in dry DCM (100 mL) and pyridine (20.59 mL, 252 mmol), was added (with stirring and cooling in an ice water bath) methane sulfonyl chloride (4.88 mL, 63.1 mmol). The mixture was stirred at RT for 25 hours. The solvent was removed at reduced pressure, and the residue was partitioned between EtOAc and aqueous NaHCO3. The organic phase was washed with aqueous NaHCO3 and was concentrated at reduced pressure. The residue was eluted through a short pad of silica gel (eluent 30%-50% EtOAc/hexane). The solvent was removed, and the resulting oil was crystallized from toluene on dilution with hexane to afford the title compound as a 3:1 mixture of geometrical isomers (assessed by NMR).
Reaction SMILES: [C:1]1([OH:8])[C:5](=[O:6])[C:3](=O)[C:2]=1O.[C:9]1([NH2:16])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>O.OS(O)(=O)=O>[C:1]1(=[O:8])[C:2]2[NH:15][C:10]3[C:9]([NH:16][C:3]=2[C:5]1=[O:6])=[CH:14][CH:13]=[CH:12][CH:11]=3
Reactant: O=c1c(O)c(O)c1=O
Reactant: Nc1ccccc1N
Agent: O=S(=O)(O)O
Solvent: O
Product: O=c1c2c(c1=O)Nc1ccccc1N2
Temperature: 25 °C

Procedure:
The method of Skujins and Webb, Chem. Comm. 598 (1968), was used. Squaric acid (114 mg, 1.00 mmol; Aldrich Co.) was dissolved in hot water (2 mL) and o-phenylenediamine (108 mg, 1.00 mmol; Aldrich Co.) was dissolved in warm H2SO4 (2 mL, 25% w/v). The mixture was heated at 90°-100° C. for 2-3 min, and then allowed to cool to 25° C. The dark brown precipitate was collected by vacuum filtration and washed with water (10×5 mL), ethanol (10×5 mL), acetone (10×5 mL) and ether (10×5 mL), yielding 105 mg (56.5%): mp dec.>325° C. (lit. mp dec.>330° C.; Skujins and Webb, Chem. Comm. 598 (1968)). 1H NMR (300 MHz, DMSO-d6) δ 10.002 (s, 2H, 2 NH), 6.621-6.633 (m, 2H, H-4+H-7), 6.324-6.354 (m, 2H, H-5+H-6).
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH2:32])[CH:29]=[N:30][CH:31]=1.C[Si](N[Si](C)(C)C)(C)C.[Li].CO>C1COCC1.C(Cl)Cl>[CH3:24][O:25][C:26]1[CH:27]=[C:28]([NH:32][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][N:12]4[CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:29]=[N:30][CH:31]=1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: COc1cncc(N)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Li]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: COc1cncc(Nc2ncccc2-c2nc(C)nc3c2ncn3C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 45.1 %

Procedure:
Argon was bubbled for 2 min through a glass microwave reaction vessel containing 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (100 mg, 0.319 mmol) and 5-methoxypyridin-3-amine (47.5 mg, 0.383 mmol, Astatech, Inc, Bristol, Pa.) in THF (5 mL), and the tube was sealed. The reaction mixture was cooled to 0° C. and lithium bis(trimethylsilyl)amine (1 N in THF, 1 mL, 0.957 mmol) was added dropwise. The red solution was stirred at 0° C. for 1 h and then warmed to room temperature. The mixture was quenched with saturated NH4Cl and extracted with EtOAc (3×).The combined organic extracts were washed with satd. NaCl and dried over Na2SO4. The solution was filtered and concentrated in vacuo. The crude product was purified by chromatography through a Redi-Sep pre-packed silica gel column (25 g) eluting with a gradient of 2% to 5% 2 M NH3.MeOH in DCM to give N-(5-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-amine (60 mg, 0.144 mmol, 45.0% yield) as an orange solid. m/z (ESI, +ve ion) 418 (M+H)+.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-].[Na+]>C1COCC1>[C:1]([N:8]1[CH2:13][CH2:12][C@H:11]([OH:14])[C@H:10]([F:15])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C(F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H](O)[C@H](F)C1
Temperature: 0 °C
Reaction time: 4 h
Yield: 53.5 %

Procedure:
To a solution of 0.5 g (2.30 mmol) of N-Boc-3-fluoro-4-piperidinone 2 (J. Med. Chem. 1999, 42, 2087-2104) in 10 mL of dry THF was added dropwise 2.8 mL (2.76 mmol) of a 1M solution of Li-selectride in THF under N2-atmosphere at 0° C. The solution was stirred at 0° C. for 4 h, then 10 mL of NaOH 2M was added at 0° C. and the mixture was stirred overnight at rt. The reaction mixture was extracted with Et2O, dried over MgSO4, filtered and evaporated under reduced pressure. The crude mixture was subjected to flash silicagel chromatography (hex/EtOAc/Et3N 1:1:0.1) to yield 0.27 g (56%) of pure cis-1-Boc-3-fluoro-4-hydroxypiperidine 3 as a colorless oil which solidified upon standing at −20° C. (freezer). Mp 48° C. 1H NMR (300 MHz, CDCl3): δ 1.46 (9H, s, 3×CH3), 1.67-1.91 (2H, m, CH2), 2.40-2.65 (1H, m, OH), 2.92-3.35 (2H, m, CH2CHaCHbN and CHaHbCHF), 3.55-3.94 (3H, m, CH2CHaHbN and CHOH and CHaHbCHF), 4.52 (1H, dm, J=48.4 Hz, CHF). 19F NMR (282 MHz, CDCl3): δ −201.9 and −203.1 (1F, 2×m). 13C NMR (75 MHz, CDCl3): δ 28.4 (3×), 29.2, 40.4, 44.8, 68.0 (d, J=17.3 Hz), 80.2, 88.6 (d, J=177.7 Hz), 155.1. IR (KBr): v 3413, 1674, 1429, 1167 cm−1. GC-MS (EI): m/z (%): 219 (M+, 4), 164 (46), 146 (50), 57 (C4H9+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18]2[N:22]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:21]3[CH:27]=[CH:28][C:29]([C:31]4[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=4)=[CH:30][C:20]=3[N:19]=2)[N:6]=1)=[O:4].[H-].[CH2:39]([Al+]CC(C)C)[CH:40](C)[CH3:41].[NH4+].[Cl-]>C1COCC1>[CH2:1]([O:2][C:3]([C:5]1[N:9]=[CH:8][N:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[CH:12][C:11]=2[C:18]2[N:22]([C:23]([CH3:26])([CH3:24])[CH3:25])[C:21]3[CH:27]=[CH:28][C:29]([C:31]4[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=4)=[CH:30][C:20]=3[N:19]=2)[N:6]=1)=[O:4])[CH:40]([CH3:41])[CH3:39]
Reactant: COC(=O)c1ncn(-c2ccc(C#N)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Reactant: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)COC(=O)c1ncn(-c2ccc(C#N)cc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To a solution of 1-{2-[5-(2-Amino-pyrimidin-5-yl)-1-tert-butyl-1H-benzoimidazol-2-yl]-4-cyano-phenyl}-1H-[1,2,4]triazole-3-carboxylic acid methyl ester (example 64) (100 mg, 0.2 mmol) in dry THF (10 mL) is added Diisobutyl aluminium hydride (DIBALH) (1 M THF solution) (0.4 mL, 0.4 mmol) at 0° C. under nitrogen atmosphere. The solution is warmed to room temperature for 24 hours. Sat. NH4Cl solution (10 mL) is added and the mixture is extracted with EtOAc (3×10 mL). The combined organic layer is dried with Mg2SO4 (500 mg) and is filtered. The filtrate is concentrated and the residue is purified by silica gel flash column chromatography with 10% MeOH in CH2Cl2 as the eluent to afford the title compound (29 mg, 26%). LCMS (ESMS): m/z 536.40 (M++1)
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:24])=[CH:4][C:5]([I:23])=[C:6]([C:8]2[C:9](=[O:22])[N:10]([CH2:20][CH3:21])[C:11]3[C:16]([CH:17]=2)=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=3)[CH:7]=1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.N1C=CC=CC=1>C(Cl)Cl>[CH2:20]([N:10]1[C:11]2[C:16](=[CH:15][N:14]=[C:13]([NH:18][CH3:19])[CH:12]=2)[CH:17]=[C:8]([C:6]2[C:5]([I:23])=[CH:4][C:3]([F:24])=[C:2]([NH:1][C:32]([NH:31][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[O:33])[CH:7]=2)[C:9]1=[O:22])[CH3:21]
Reactant: CCn1c(=O)c(-c2cc(N)c(F)cc2I)cc2cnc(NC)cc21
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCn1c(=O)c(-c2cc(NC(=O)Nc3ccccc3)c(F)cc2I)cc2cnc(NC)cc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.5 %

Procedure:
A suspension of 3-(5-amino-4-fluoro-2-iodophenyl)-1-ethyl-7-(methylamino)-1,6-naphthyridin-2(1H)-one (0.310 g, 0.707 mmol) in DCM (10 mL) was treated with phenyl isocyanate (0.100 g, 0.839 mmol) followed by pyridine (0.060 g, 0.759 mmol) and stirred at RT for 3 h. The mixture was concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford 1-(5-(1-ethyl-7-(methylamino)-2-oxo-1,2-dihydro-1,6-naphthyridin-3-yl)-2-fluoro-4-iodophenyl)-3-phenylurea (120 mg, 29% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.08 (s, 1H), 8.66 (s, 1H), 8.41 (s, 1H), 8.14 (d, J=8.3 Hz, 1H), 7.77 (d, J=10.6 Hz, 1H), 7.64 (s, 1H), 7.41 (d, J=8.0 Hz, 2H), 7.26 (t, J=7.7 Hz, 2H), 7.05 (m, 2H), 6.24 (s, 1H), 4.14 (d, J=8.1 Hz, 2H), 2.86 (d, J=4.8 Hz, 3H), 1.22 (t, J=7.0 Hz, 3H); MS (ESI) m/z: 558.1 [M+H]+.
Reaction SMILES: S1C2C=CC=CC=2N=C1N(COCC[Si](C)(C)C)C(C1C=CC=C2C=1CN(C1SC(C3C=CC(CO)=CC=3)=C(C(OCC)=O)N=1)CC2)=O.OCC1C=CC(B(O)O)=CC=1.Br[C:61]1[C:65]2[N:66]=[CH:67][N:68]=[C:69]([N:70]3[CH2:75][CH2:74][N:73]([CH3:76])[CH2:72][CH2:71]3)[C:64]=2[S:63][CH:62]=1.CC1(C)C(C)(C)OB([C:85]2[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=2)O1>>[CH3:76][N:73]1[CH2:74][CH2:75][N:70]([C:69]2[C:64]3[S:63][CH:62]=[C:61]([C:85]4[CH:90]=[CH:89][C:88]([OH:91])=[CH:87][CH:86]=4)[C:65]=3[N:66]=[CH:67][N:68]=2)[CH2:71][CH2:72]1
Reactant: CN1CCN(c2ncnc3c(Br)csc23)CC1
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Agent: CCOC(=O)c1nc(N2CCc3cccc(C(=O)N(COCC[Si](C)(C)C)c4nc5ccccc5s4)c3C2)sc1-c1ccc(CO)cc1
Agent: OCc1ccc(B(O)O)cc1
Product: CN1CCN(c2ncnc3c(-c4ccc(O)cc4)csc23)CC1

Procedure:
The compound 79B was prepared in a similar manner to the synthesis of compound 34D by substituting compound 34C and 4-(hydroxymethyl)phenylboronic acid with compound 79A and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol, respectively: 1H NMR (DMSO-d6): δ 9.56 (s, 1H), 8.63 (s, 1H), 8.28 (s, 1H), 7.85-7.89 (m, 2H), 6.48-6.88 (m, 2H), 4.06 (br, 4H), 2.91 (br, 4H), 2.53 (s, 3H). ESI (+)/MS: 327 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:7][CH2:6][N:5]([C:8]2[N:17]=[C:11]3[CH:12]=[CH:13][C:14]([NH2:16])=[CH:15][N:10]3[N:9]=2)[CH2:4]1.[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:46])[C:27]=1[C:28](=[O:45])NC1C=CC2N(N=C(N3CCOCC3)N=2)C=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[N:25][N:26]([CH3:46])[C:27]=1[C:28](=[O:45])[NH:16][C:14]1[CH:13]=[CH:12][C:11]2[N:10]([N:9]=[C:8]([N:5]3[CH2:6][CH2:7][CH:3]([O:2][CH3:1])[CH2:4]3)[N:17]=2)[CH:15]=1)=[O:22])[CH3:19]
Reactant: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCOCC3)nn2c1
Reactant: COC1CCN(c2nc3ccc(N)cn3n2)C1
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(N3CCC(OC)C3)nn2c1

Procedure:
Using 2-(3-Methoxy-pyrrolidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine, this compound was prepared following the same method as for the synthesis of 1-methyl-5-(2-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester. Off white solid (1.2 g, 59%). MS: m/z=414 (M+H+).
Reaction SMILES: Cl.[OH:2][NH2:3].C[O-].[Na+].[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=4[O:29][CH:30]([CH2:33][CH2:34][CH3:35])[C:31]#[N:32])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:10])([CH3:9])[CH3:8]>CS(C)=O.CO>[C:7]([C:11]1[N:12]=[C:13]([C:16]2[O:17][C:18]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]4[CH:39]=[CH:38][CH:37]=[CH:36][C:28]=4[O:29][CH:30]([CH2:33][CH2:34][CH3:35])[C:31](=[N:3][OH:2])[NH2:32])=[CH:21][C:19]=3[CH:20]=2)[S:14][CH:15]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: NO
Reactant: CCCC(C#N)Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CO
Product: CCCC(Oc1ccccc1COc1ccc2oc(-c3nc(C(C)(C)C)cs3)cc2c1)C(N)=NO
Temperature: 25 °C
Yield: 110.8 %

Procedure:
Hydroxyamine hydrochloride (174 mg) was dissolved in dimethylsulfoxide (2 ml) and 28% solution of sodium methoxide in methanol (0.125 g) was added into it. The mixture was stirred for ten minutes at room temperature. 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}-pentanenitrile (224 mg) was added into the solution and the resulting mixture was stirred at 80° C. for an hour. The reaction mixture was collected and diluted with water and was extracted with ethyl acetate. The organic layer was washed with brine and was dried over magnesium sulfate. Concentration gave 2-{2-{[2-(4-tert-butylthiazol-2-yl)benzofuran-5-yloxy]methyl}phenoxy}pentanamide oxime as an amorphous solid (266 mg).
Reaction SMILES: Br[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:15][C:16]1[CH:17]=[C:18]([OH:22])[CH:19]=[CH:20][CH:21]=1>>[NH2:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[O:22][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[N:4][C:3]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: Nc1cccc(O)c1
Reactant: Nc1nnc(Br)c(-c2ccccc2)n1
Product: Nc1cccc(Oc2nnc(N)nc2-c2ccccc2)c1
Yield: 7.5 %

Procedure:
6-(3-Aminophenoxy)-5-phenyl-1,2,4-triazin-3-amine (25 mg, 8%) was prepared from 6-bromo-5-phenyl-1,2,4-triazin-3-amine (0.30 g, 1.19 mmol) and 3-amino phenol (0.19 g, 1.78 mmol) according to the general procedure of Example 3.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]2[NH:12][CH:11]=[CH:10][C:6]=2[CH:7]=[N:8][CH:9]=1.[CH3:13]I>CN(C=O)C.C(Cl)Cl>[Br:3][C:4]1[C:5]2[N:12]([CH3:13])[CH:11]=[CH:10][C:6]=2[CH:7]=[N:8][CH:9]=1
Reactant: Brc1cncc2cc[nH]c12
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ccc2cncc(Br)c21
Temperature: 25 °C
Reaction time: 17 h

Procedure:
Sodium hydride (0.25 g, 6.2 mmol) is added under ice bath cooling to a mixture of 7-bromo-1H-pyrrolo[3,2-c]pyridine (0.8 g, 4.1 mmol) in DMF (10 ml). The mixture is stirred for 30 minutes before methyl iodide (0.25 ml, 4.1 mmol) is added. The mixture is warmed to RT and stirred for 17 h. The mixture is diluted with DCM and extracted with a saturated aqueous sodium hydrogencarbonate solution. The combined organic layers are dried over MgSO4 and concentrated in vacuo. The product is purified by RP HPLC. Yield: 0.61 g (71%). HPLC-MS: tR=0.88 min (METHOD—1).
Reaction SMILES: C[O:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[OH:2][C:3]1[CH:23]=[CH:22][C:6]([C:7]([NH:9][C:10]2([C:19]([OH:21])=[O:20])[CH2:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11]2)=[O:8])=[CH:5][C:4]=1[NH:24][CH2:25][CH2:26][C:27]1[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=1
Reactant: COc1ccc(C(=O)NC2(C(=O)O)Cc3ccccc3C2)cc1NCCc1cccc(C)c1
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccc(CCNc2cc(C(=O)NC3(C(=O)O)Cc4ccccc4C3)ccc2O)c1

Procedure:
10 mg of the compound of example 171 were dissolved in DCM and treated with 200 μl of a 1 M solution of boron tribromide in DCM for 5 h. A 2 M solution of sodium carbonate was added, and the mixture was evaporated in vacuo. The product was purified by preparative RP HPLC (water/ACN gradient).
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.[C:15](=O)([O-])[O-].[K+].[K+].CI>CN(C=O)C>[Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:15])=[O:7])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 94.3 %

Procedure:
To a stirred solution of 4-bromo-5-fluoro-2-nitrobenzoic acid (Ark Pharm, 5.387 g, 20.40 mmol) in DMF (80.0 mL) at 0° C. was added potassium carbonate (5.870 g, 42.47 mmol), followed by methyl iodide (8.789 g, 61.92 mmol). After stirring at 0° C. for 15 min., the reaction was heated to 40° C. for 2 h. The mixture was filtered and concentrated. The residue was dissolved in EtOAc (150 mL), washed with water (2×100 mL), brine (100 mL), dried over Na2SO4, and concentrated under reduced pressure. The resulting residue was purified by flash chromatography on silica gel (0-50% EtOAc in hexanes) to give the sub-title compound as a pale yellow oil (5.348 g, 94%). LCMS calc. for C8H6BrFNO4 (M+H)+: m/z=277.9. found no ionization.
Reaction SMILES: C[C:2]1[CH:10]=[C:9]([C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([C:20]3[C:29]4[C:24](=[CH:25][C:26]([O:32][CH3:33])=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[C:22]([NH:34][CH3:35])[N:21]=3)[CH:15]=2)=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O1CCCC1.[OH-].[Na+].[ClH:43]>CO>[ClH:43].[CH3:31][O:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][C:26]=1[O:32][CH3:33])[N:23]=[C:22]([NH:34][CH3:35])[N:21]=[C:20]2[C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])[C:9]2[CH:10]=[CH:2][C:3]([C:4]([OH:6])=[O:5])=[CH:7][CH:8]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)c(C)c3)c2)c2cc(OC)c(OC)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CNc1nc(-c2cccc(NC(=O)c3ccc(C(=O)O)cc3)c2)c2cc(OC)c(OC)cc2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95.3 %

Procedure:
To a solution of 2.5 g of methyl N-[3-(6,7-dimethoxy-2-methylaminoquinazolin-4-yl)phenyl]terephthalamic acid dissolved in a mixed solvent consisting of 50 mL of tetrahydrofuran and 25 mL of methanol was added 11.3 mL of a 5 N sodium hydroxide solution, followed by stirring at room temperature for 12 hours. The reaction mixture was adjusted to be acidic by addition of 5 N hydrochloric acid, and the obtained solid was then filtrated, washed with 10 mL of water and 20 mL of ether, and dried under aeration to yield 2.5 g of a product of interest. Yield: 95.3%.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([NH2:14])=[O:13])=[CH:8][C:7]([N+:15]([O-])=O)=[CH:6][CH:5]=2.[H][H].CO.CCOC(C)=O>C1COCC1.CCO.[Pd]>[NH2:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:2]([CH3:1])=[C:10]2[CH2:11][C:12]([NH2:14])=[O:13]
Reactant: [H][H]
Reactant: Cc1c(CC(N)=O)c2cc([N+](=O)[O-])ccc2n1Cc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1c(CC(N)=O)c2cc(N)ccc2n1Cc1ccccc1
Yield: 28 %

Procedure:
A solution of 205 mg (0.634 mmol) of 2-methyl-5-nitro-1-(phenylmethyl)-1H-indole-3-acetamide in 30 mL of 2:1 THF/EtOH was hydrogenated at 60 psi (4218 g/cm2) of hydrogen for 4 hours using 0.1 g of Pd/C as catalyst. The catalyst was filtered and the filtrate concentrated at reduced pressure. The residue was chromatographed on silica eluting with EtOAc and then 5% MeOH/EtOAc to give 52 mg (28% yield) of 5-amino-2-methyl-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 175-178° C.
Reaction SMILES: [CH:1]1([N:4]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[C:9]([N+:13]([O-])=O)[CH:10]=3)[C:5]2=[O:16])[CH2:3][CH2:2]1.[Sn](Cl)(Cl)(Cl)Cl>CCO.O>[NH2:13][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[C:5](=[O:16])[N:4]([CH:1]1[CH2:3][CH2:2]1)[CH2:12]2
Reactant: O=C1c2ccc([N+](=O)[O-])cc2CN1C1CC1
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)CN(C1CC1)C2=O
Temperature: 79 °C
Reaction time: 2 h

Procedure:
The 2-cyclopropyl-5-nitroisoindolin-1-one (50 mg, 0.23 mmol) was dissolved in EtOH (1.1 ml) with heating, and tin chloride (117 mg, 0.52 mmol) added. The solution was stirred at 79° C. for 2 hours. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (aq, 100 ml), extracted with EtOAc (3×100 ml), the organics combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 5% MeOH:DCM+1% TEA to give the titled compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6](Cl)[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]=1[C:15]([F:18])([F:17])[F:16].[CH3:19][N:20]([CH3:22])[NH2:21]>C1CCCCC1>[CH3:19][N:20]([CH3:22])[NH:21][C:6]1[C:5]([N+:12]([O-:14])=[O:13])=[CH:4][C:3]([C:15]([F:18])([F:17])[F:16])=[C:2]([Cl:1])[C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Reactant: CN(C)N
Solvent: C1CCCCC1
Product: CN(C)Nc1c([N+](=O)[O-])cc(C(F)(F)F)c(Cl)c1[N+](=O)[O-]
Reaction time: 0.33 h
Yield: 85 %

Procedure:
To 20.0 g. (0.065 mole) of 2,4-dichloro-3,5-dinitrobenzotrifluoride and 300 ml. of cyclohexane in a 500 ml. round-bottom flask equipped with a stirrer and dropping funnel was added 7.86 g. (0.13 mole) of 1,1-dimethylhydrazine at ambient temperature. The addition was drop-wise over a period of about 20 minutes. Stirring was continued for 22 hours at room temperature. The resultant mixture was filtered and the insoluble solid then stirred with 300 ml. of water for one hour to dissolve the hydrazine hydrochloride. The insoluble product was isolated by filtration and washed with water. Recrystallization from 95% ethanol gave 18.3 g. (85%) of the desired product as a yellow solid, m.p. 130°-131° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH2:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([C:16]1[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=1)=[O:15].C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=2[C:14]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[O:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccccc1C(=O)c1ccncc1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=C(Nc1ccccc1C(=O)c1ccncc1)c1ccc(F)cc1
Reaction time: 24 h

Procedure:
4-Fluorobenzoyl chloride (78.0 mg, 0.55 mmol) was added to 4-(2-aminobenzoyl)pyridine (12) (100 mg, 0.50 mmol), triethylamine (0.35 mL, 2.52 mL), and chloroform (5.0 mL) at 23° C. under argon. After 24 h at 23° C., the reaction was poured into water (50 mL), extracted with ethyl acetate (3×50 mL), and dried (MgSO4). After concentration in vacuo, the residue was purified by flash chromatography (ethyl acetate:methylene chloride 1:1) to afford 4-(2-(4-fluoro-N-benzoylamino)benzoyl)pyridine (14): Mass Spectrum (CI) 321 (MH+).