Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:5][C:6]([NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]2[C:18]=1[CH:17]=[N+:16]([CH3:19])[C:15]1[CH:20]=[C:21]([Cl:25])[C:22]([F:24])=[CH:23][C:14]2=1)=[O:7])(C)(C)C.[OH-].[Na+].[O-:28][Mn](=O)(=O)=O.[K+]>C(Cl)Cl.O>[Cl:25][C:21]1[C:22]([F:24])=[CH:23][C:14]2[C:13]3[C:18](=[C:9]([NH:8][C:6](=[O:7])[OH:5])[N:10]=[CH:11][CH:12]=3)[C:17](=[O:28])[N:16]([CH3:19])[C:15]=2[CH:20]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C[n+]1cc2c(NC(=O)OC(C)(C)C)nccc2c2cc(F)c(Cl)cc21
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cn1c(=O)c2c(NC(=O)O)nccc2c2cc(F)c(Cl)cc21
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a stirred solution of 4-((tert-butoxycarbonyl)amino)-8-chloro-9-fluoro-6-methylbenzo[c][2,7]naphthyridin-6-ium (2.6 g, 2.310 mmol) in a mixture of DCM (10 mL) and water (50 mL) was added NaOH (0.370 g, 9.24 mmol) in three portions, followed by the addition of KMnO4 (1.461 g, 9.24 mmol) in five portions and the reaction was heated to 90° C. for 5 h. After cooling, the solvent was removed under reduced pressure. The residue was taken up in EtOAc (50 mL) and MeOH (50 mL) and stirred for 10 min. The reaction mixture was then passed through diatomaceous earth (Celite®), eluting with EtOAc. The filtrate was concentrated to yield (8-chloro-9-fluoro-6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-4-yl)carbamic acid (2.35 g, 2.082 mmol, 90% crude yield) as a yellow solid which was taken to the next step without purification. LC/MS (ESI) m/e 322.1 [(M+H)+, calcd for C14H10ClFN3O3 322.0] LC/MS retention time (method E): tR=1.05 min.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])[C:5]([Cl:19])=[CH:4][N:3]=1.[NH2:20][C:21]1[C:22]([O:34][CH3:35])=[CH:23][C:24]2[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=2[CH:33]=1>>[Cl:19][C:5]1[C:6]([NH:8][C:9]2[CH:18]=[CH:17][CH:16]=[CH:15][C:10]=2[C:11]([NH:13][CH3:14])=[O:12])=[N:7][C:2]([NH:20][C:21]2[C:22]([O:34][CH3:35])=[CH:23][C:24]3[N:30]([CH3:31])[C:29](=[O:32])[O:28][CH2:27][CH2:26][C:25]=3[CH:33]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: CNC(=O)c1ccccc1Nc1nc(Cl)ncc1Cl
Product: CNC(=O)c1ccccc1Nc1nc(Nc2cc3c(cc2OC)N(C)C(=O)OCC3)ncc1Cl
Yield: 26 %

Procedure:
In and analogous manner to Example 1503, the product was prepared from 2-(2,5-Dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as a yellow powder (25 mg, 26%). mp: 235-237° C., MS (ESI+): 483 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 11.06 (s, 1H), 8.64 (d, J=8 Hz, 1H), 8.28 (s, 1H), 8.15 (s, 1H), 7.53 (d, 2H), 7.46 (t, J=8 Hz, 1H), 7.11 (t, J=7 Hz, 1H), 6.70 (s, 1H), 6.23 (br s, 1H), 4.47 (t, J=6 Hz, 2H), 3.93 (s, 3H), 3.41 (s, 3H), 3.06 (d, J=5 Hz, 3H), 2.85 (t, J=6 Hz, 2H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[C:5]2[S:10][C:9](S(C)(=O)=O)=[N:8][C:6]=2[N:7]=1.[CH3:21][S:22]([CH2:25][CH2:26][NH2:27])(=[O:24])=[O:23].C(N(CC)CC)C>>[Cl:1][C:2]1[N:3]=[C:4]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)[C:5]2[S:10][C:9]([NH:27][CH2:26][CH2:25][S:22]([CH3:21])(=[O:24])=[O:23])=[N:8][C:6]=2[N:7]=1
Reactant: CS(=O)(=O)CCN
Reactant: CS(=O)(=O)c1nc2nc(Cl)nc(N3CCOCC3)c2s1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)CCNc1nc2nc(Cl)nc(N3CCOCC3)c2s1

Procedure:
5-Chloro-2-(methylsulfonyl)-7-morpholinothiazolo[4,5-d]pyrimidine was reacted with 2-(methylsulfonyl)ethanamine (HCl salt), using 2.8 equiv of triethylamine, via General Procedure C, to give crude 5-chloro-N-(2-(methylsulfonyl)ethyl)-7-morpholinothiazolo[4,5-d]pyrimidin-2-amine, which was then reacted with 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidin-2-amine via General Procedure C again to give 133 after purification by reverse HPLC. MS (Q1) 437 (M+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH2:9][N:10]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[N:11]1.CC(C)([O-])C.[K+].Br[CH2:33][CH2:34][CH2:35][CH3:36]>CS(C)=O>[CH2:33]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH2:9][N:10]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:25])[C:17]3[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=3[F:23])=[N:11]2)[CH:4]=1)[CH2:34][CH2:35][CH3:36]
Reactant: O=C(Nc1ccn(Cc2cc(O)ccc2Cl)n1)c1c(F)cccc1F
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCCOc1ccc(Cl)c(Cn2ccc(NC(=O)c3c(F)cccc3F)n2)c1
Reaction time: 0.08 h
Yield: 27.8 %

Procedure:
To a solution of N-{1-[(2-chloro-5-hydroxyphenyl)methyl]-1H-pyrazol-3-yl}-2,6-difluorobenzamide(for as preparation see Intermediate 13) (35 mg, 0.096 mmol) in DMSO (0.5 ml) was added potassium t-butoxide (10.80 mg, 0.096 mmol). The reaction was stirred for 5 min before adding 1-bromobutane (0.012 ml, 0.115 mmol, Acros). The reaction mixture was stirred under nitrogen for 72 h at ambient temperature. The reaction mixture was filtered through a hydrophobic frit and the filtrate diluted with methanol (0.5 ml) and the sample purified by MDAP on Sunfire C18 column using Acetonitrile-Water with a Formic acid modifier (Method B). The solvent was evaporated in vacuo to give the title compound as a brown gum (11.2 mg); LCMS: (System 4) MH+=420, tRET=3.41 min.
Reaction SMILES: [C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11]Br)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:19]12[CH2:27][CH2:26][CH2:25][CH:24]1[CH2:23][NH:22][CH2:21][CH2:20]2.O.[OH-].[K+]>C(OCC)C>[C:1]1([C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([CH2:10][CH2:11][N:22]2[CH2:23][CH:24]3[N:19]([CH2:27][CH2:26][CH2:25]3)[CH2:20][CH2:21]2)[C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#CC(CCBr)(c1ccccc1)c1ccccc1
Reactant: C1CC2CNCCN2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Product: N#CC(CCN1CCN2CCCC2C1)(c1ccccc1)c1ccccc1
Temperature: 30 °C
Yield: 86 %

Procedure:
To 70.6 parts of 2,2-diphenyl-4-bromobutyronitrile is added 27 parts of 1,4-diazabicyclo[4.3.0]nonane, 63 parts of demineralized water and 15.5 parts of potassium hydroxide. The mixture is stirred and heated to 75° - 80° C. and then further heated to reflux. After 3.5 hours at reflux, the mixture is cooled to about 30° C. and 180 parts of ethyl ether is added. The aqueous layer is separated and discarded. The remaining ether layer is extracted three times with 100 parts by volume portions of 1% acetic acid in water, twice with 30% solutions of hydrochloric acid in water, and twice with 50% solutions of hydrochloric acid in water. The hydrochloric acid solution extracts are combined and basified to pH 11.0 with a 50% solution of potassium hydroxide in water. The resulting oil is extracted with three 150 part portions of chloroform. The chloroform extracts are combined, washed with 100 parts of a saturated sodium chloride solution, dried over anhydrous potassium carbonate, and stripped of solvent under reduced pressure. The resulting product, 2,2-diphenyl-4-(1,4-diazabicyclo[4.3.0]non-4-yl)butyronitrile, identical to the product of Example 7, is obtained in 86% yield. Correction of this yield to reflect the purity of the 1,4-diazabicyclo[4.3.0]-nonane (86.4%) results in a yield of 99.5% for this reaction.
Reaction SMILES: C[O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1.O.Cl>[OH-].[K+].CO>[CH3:17][N:14]1[CH2:13][CH2:12][N:11]([CH2:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:18])=[O:2])=[CH:5][CH:6]=2)[CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(CN2CCN(C)CC2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Temperature: 25 °C

Procedure:
HCl-salt of 4-(4-methylpiperazin-1-ylmethyl)benzoic acid methyl ester (1.25 g) was dissolved in potassium hydroxide-methanol solution (0.93 g KOH in 15 ml methanol). Water (0.75 ml) was added and the mixture was refluxed for 1 hour. The reaction mixture was allowed to cool into room temperature and the pH was tuned to 6 with 2 M HCl. The solvent was evaporated and the residue was dried under vacuum. The residue contained 4-(4-methylpiperazin-1-ylmethyl)benzoic acid and inorganic salts. It was used further without purification and the yield of title compound was assumed to be 100%. 1H NMR (400 MHz, d6-DMSO) δ: 2.27 (s, 3H), 2.44 (bs, 2H), 3.18-3.95 (m, 8H), 7.41 (d, 2H, J 8.0 Hz), 7.89 (d, 2H, J 8.1 Hz).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[N:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([F:36])([F:35])[F:34])=[C:25]=[O:26]>>[CH:17]1([N:16]2[C:15]3[C:14]4[CH:13]=[CH:12][CH:11]=[C:10]([O:22][CH3:23])[C:9]=4[N:8]=[CH:7][C:6]=3[C:4](=[O:3])[N:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[C:33]([F:34])([F:35])[F:36])[C:25]2=[O:26])[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C=Nc1ccccc1C(F)(F)F
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Product: COc1cccc2c1ncc1c(=O)n(-c3ccccc3C(F)(F)F)c(=O)n(C3CCCC3)c12
Yield: 46.1 %

Procedure:
1-Cyclopentyl-7-methoxy-3-(2-trifluoromethyl-phenyl)-1H-pyrimido[5,4-c]quinoline-2,4-dione (21 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.1 mmol) and 1-isocyanato-2-trifluoromethyl-benzene (0.5 mmol) following general procedure C. LCMS: m/z 456 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([CH3:13])[N:5]=[C:4]([CH3:14])[CH:3]=1.[C:15]1([CH:21]2[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:13][C:6]1[N:5]=[C:4]([CH3:14])[CH:3]=[C:2]([NH:27][CH:24]2[CH2:23][CH2:22][CH:21]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:26][CH2:25]2)[C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)c1c(Cl)cc(C)nc1C
Reactant: NC1CCC(c2ccccc2)CC1
Product: CCOC(=O)c1c(NC2CCC(c3ccccc3)CC2)cc(C)nc1C

Procedure:
was prepared analogously to Example 8 using ethyl 4-chloro-2,6-dimethylnicotinate and 4-phenylcyclohexylamine. nD23 :1.5389.
Reaction SMILES: C(Cl)(=O)C([Cl:4])=O.CN(C)C=O.O[C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[N:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>C(#N)C>[Cl:4][C:13]1[C:22]2[C:17](=[C:18]([O:25][CH3:26])[N:19]=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][C:14]=1[C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1O
Reactant: O=C(Cl)C(=O)Cl
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2c(OC)nc(OC)cc2c1Cl
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 3.5 g of oxalyl chloride in 5 ml of dry acetonitrile is added dropwise to anhydrous dimethylformamide at -30°. After 20 minutes, 7.0 g of ethyl 4-hydroxy-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate is added at -30°. Reaction temperature is kept between -20° and -30° for 30 minutes, then allowed to warm up to room temperature and evaporated to dryness. Residue is taken up in chloroform, washed with cold sodium bicarbonate aqueous solution, dried over magnesium sulfate, treated with decolorizing charcoal and evaporated to dryness to yield ethyl 4-chloro-6,8-dimethoxy-1,7-naphthyridine-3-carboxylate, m.p. 200°-210°.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH2:13][CH2:14][CH3:15])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCCOc1ccc2ncc(C(=O)OCC)c(O)c2c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCCOc1ccc2ncc(C(=O)OCC)c(Cl)c2c1

Procedure:
Prepared as in Example 1b from ethyl 4-hydroxy-6-propoxyquinoline-3-carboxylate (Example 14c) and POCl3 as a pale yellow solid. MS 294, 296 (MH+).
Reaction SMILES: [CH3:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[CH:3]=[CH2:4].C1C[O:12]CC1>>[CH3:1][C:2]([CH3:8])([CH:5]([CH3:7])[CH3:6])[CH2:3][CH2:4][OH:12]
Reactant: C=CC(C)(C)C(C)C
Reactant: C1CCOC1
Product: CC(C)C(C)(C)CCO
Temperature: 25 °C

Procedure:
3,3,4-Trimethylpentene (1 equiv) is dissolved in dry THF under Ar. The reaction mixture is cooled to −78° C. at which time a 1 M solution of borane/dimethylsulfide complex in THF (0.4 equiv) is added dropwise. The cold bath is removed and the reaction mixture is allowed to warm to ambient temperature. The reaction mixture is carefully diluted with a solution of sodium acetate in aqueous hydrogen peroxide (large exess). The reaction mixture is stirred at ambient temperature and then diluted with diethyl ether and the layers are separated. The organic layer is dried over Na2SO4, decanted and concentrated. The crude material is purified by fractional distillation to yield 3,3,4-trimethylpentanol.
Reaction SMILES: CS(C)=O.[H-].[Na+].[I-].[CH3:8][S+](C)C.[CH:12]1([C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:16])[CH2:14][CH2:13]1>C1COCC1>[CH:12]1([C:15]2([C:17]3[CH:18]=[CH:19][C:20]([F:23])=[CH:21][CH:22]=3)[CH2:8][O:16]2)[CH2:13][CH2:14]1
Reactant: O=C(c1ccc(F)cc1)C1CC1
Reactant: C[S+](C)C
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: Fc1ccc(C2(C3CC3)CO2)cc1
Temperature: 65 °C
Reaction time: 0.17 h

Procedure:
DMSO is added to NaH (1-1.8 equiv.) and heated to 65° C. for 1 h. THF is added at the same temperature and heated for another 10 min. After 10 min., the reaction mixture is cooled to 0° C. Trimethylsulfonium iodide (1-1.2 equiv.) is added and the contents are stirred for 10 min. after which the solution of cyclopropyl(4-fluorophenyl)methanone (1 equiv.) in THF is added dropwise. After complete addition, the reaction mixture is stirred at RT for 2 h; the reaction is monitored by LCMS. After completion, the reaction mixture is poured in ice water, extracted in diethyl ether, dried over sodium sulfate and concentrated at 25° C. to get the crude product.
Reaction SMILES: [C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([OH:18])=O)=[CH:11][CH:10]=2)[CH:6]=[N:5][CH:4]=1)#[N:2].[O:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH:26]([NH2:28])[CH3:27]>>[C:1]([C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[CH:11][C:12]([C:15]([CH3:20])([CH3:19])[C:16]([NH:28][CH:26]([C:22]3[O:21][CH:25]=[CH:24][CH:23]=3)[CH3:27])=[O:18])=[CH:13][CH:14]=2)[CH:6]=[N:5][CH:4]=1)#[N:2]
Reactant: CC(C)(C(=O)O)c1ccc(-c2cncc(C#N)n2)cc1
Reactant: CC(N)c1ccco1
Product: CC(NC(=O)C(C)(C)c1ccc(-c2cncc(C#N)n2)cc1)c1ccco1
Yield: 35 %

Procedure:
Prepared in a similar manner to Example 20 from 2-(4-(6-Cyanopyrazin-2-yl)phenyl)-2-methylpropanoic acid (example 20a) and 1-(furan-2-yl)ethanamine. Yield 35%. 1H NMR (400 MHz, dMSO): δ 1.32-1.33 (d, 3H), 1.49-1.52 (d, 6H), 5.09 (m, 1H), 6.06 (d, 1H), 6.33-6.35 (dd, 1H), 7.49-7.51 (d, 2H), 7.54 (d, 1H), 8.12-8.14 (d, 2H), 9.16 (s, 1H), 9.56 (s, 1H); MS+H (361).
Reaction SMILES: C(O[C:6]([N:8]([C:11]1[CH:38]=[CH:37][C:14]([CH2:15][N:16]2[C:20]3=[N:21][C:22]([C:25](=[O:35])[NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])=[O:28])=[CH:23][CH:24]=[C:19]3[N:18]=[C:17]2[CH3:36])=[C:13]([Cl:39])[CH:12]=1)CC)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:39][C:13]1[CH:12]=[C:11]([NH:8][CH3:6])[CH:38]=[CH:37][C:14]=1[CH2:15][N:16]1[C:20]2=[N:21][C:22]([C:25](=[O:35])[NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])(=[O:29])=[O:28])=[CH:23][CH:24]=[C:19]2[N:18]=[C:17]1[CH3:36]
Reactant: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(N(CC)C(=O)OC(C)(C)C)cc3Cl)c2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCS(=O)(=O)NC(=O)c1ccc2nc(C)n(Cc3ccc(NC)cc3Cl)c2n1
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of 3-(4-(N-(tert-butoxycarbonyl)-N-ethylamino)-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.91 g) in dichloromethane (19 ml) was added trifluoroacetic acid (14.5 ml) under ice-cooling, and the mixture was stirred for 1 hr. The solvent was evaporated and methanol (19 ml) was added to the residue for re-dissolution. Water (9.5 ml) was added and 1N aqueous sodium hydroxide solution was added dropwise under ice-cooling to adjust to about pH 4. The resulting precipitate was collected by filtration and dried under reduced pressure to give 3-(2-chloro-4-(methylamino)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (1.53 g) as a white powder.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Br[CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31]>>[CH2:25]([O:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[C:17]([NH:16][CH2:15][C:13]1[N:14]=[C:10]([C:4]2[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([O:1][CH:29]([CH2:32][CH3:33])[CH2:30][CH3:31])[CH:3]=2)[O:11][CH:12]=1)=[O:27])[CH3:26]
Reactant: CCC(Br)CC
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(O)c2)n1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC)c(OC(CC)CC)c2)n1

Procedure:
Using the compound obtained in Example 2 and 3-bromopentane, white powdery 2-ethoxy-N-{2-[3-(1-ethylpropoxy)-4-methoxyphenyl]oxazol-4-ylmethyl}benzamide was obtained following the procedure of Example 3.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[S:7][CH:8]=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.[NH+]1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>ClCCl>[O:17]1[CH2:22][CH2:21][CH:20]([O:1][CH2:2][CH2:3][C:4]2[N:5]=[C:6]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[S:7][CH:8]=2)[CH2:19][CH2:18]1
Reactant: C1=COCCC1
Reactant: CC(C)(C)OC(=O)Nc1nc(CCO)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1nc(CCOC2CCOCC2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.2 %

Procedure:
To a solution of Example 3B (6.3 g, 27.4 mmol) in dichloromethane (100 mL) were added commercially available 3,4-dihydro-2H-pyran (purchased from Aldrich) (21 g, 250 mmol) and pyridinium-p-toluenesulfonic acid (purchased from Aldrich) (3.5 g, 14.0 mmol). The reaction mixture was stirred overnight at room temperature and then diluted with dichloromethane, washed with water, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography using an Analogix® IT280™ (SiO2, 0-100% ethyl acetate in hexanes) to afford 7.4 g (82%) of the title compound. MS (ESI+) m/z 329 (M+H)+
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[N:15]=1)=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=3)=O.Cl.[NH2:19][OH:20].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[N:19](=[CH:1][C:3]1[CH:4]=[CH:5][C:6]2[C:7](=[O:17])[C:8]3[C:13]([C:14]=2[N:15]=1)=[CH:12][CH:11]=[C:10]([Br:16])[CH:9]=3)[OH:20]
Reactant: O=Cc1ccc2c(n1)-c1ccc(Br)cc1C2=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1c2cc(Br)ccc2-c2nc(C=NO)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 286 mg (1 mmole) of 3-formyl-7-bromo-4-aza-9-fluorenone (prepared as described in Example 42), 85 mg (1.2 mmole) of hydroxylamine hydrochloride in ~2 mL of pyridine is stirred overnight at R.T. Ethyl acetate and excess sodium bicarbonate solution are then added and the precipitated solid precipitate is filtered and dried to give 3-oximinomethyl-7-bromo-4-aza-9-fluorenone.
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:16]=[N:17][N:18]([C:20]2[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=2)[CH:19]=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1.[BH4-].[Na+]>CC(N(C)C)=O>[CH3:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][N:10]=[C:9]2[C:15]1[N:16]=[N:17][N:18]([C:20]2[CH:27]=[CH:26][C:23]([CH2:24][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)=[CH:22][CH:21]=2)[CH:19]=1
Reactant: C1CCNC1
Reactant: Cc1ccc2[nH]nc(-c3cn(-c4ccc(C=O)cc4)nn3)c2c1
Agent: [BH3-]C#N
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1ccc2[nH]nc(-c3cn(-c4ccc(CN5CCCC5)cc4)nn3)c2c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Sodium cyanoborohydride (166 mg; 2.64 mmol; 4.0 eq.) was added to a solution of 4-[4-(5-methyl-1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]benzaldehyde (200 mg; 0.66 mmol; 1.0 eq.) and pyrrolidine (1.64 mL; 19.8 mmol; 30 eq.) in DMA (4 mL) and the reaction mixture was stirred at RT. After 12 h, as no product was detected, sodium borohydride was added (100 mg; 2.64 mmol; 4.0 eq.) and the reaction mixture was stirred at RT for 1 hour. Reaction was quenched with water and extracted with EtOAc (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by preparative HPLC afforded the title compound as a formic acid salt. It was dissolved in MeOH and passed through a SPE-NH2 cartridge. The fractions containing the desired compound were concentrated to dryness affording a yellow gum, which was twice sonicated in 3 mL of Et2O. The suspension obtained was concentrated then dried overnight under high vacuum to afford the title compound as a beige solid. 1H NMR (300 Mz, DMSO-d6) δ: 13.245 (brs, 1H), 9.26 (s, 1H), 8.14-8.13 (m, 1H), 7.99 (d, J=8.5 Hz, 2H), 7.55 (d, J=8.5 Hz, 2H), 7.50 (d, J=8.5 Hz, 1H), 7.27 (dd, J=8.5 Hz, 1.5 Hz, 1H), 3.67 (s, 2H), 2.49-2.45 (m, 7H), 1.74-1.70 (m, 4H). HPLC (Condition A): Rt 2.63 min (purity 99.5%). MS (ESI+): 359.2, MS (ESI−): 357.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH2:13][C:10]2([CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14](OC)=[O:15])[CH:8]=2)[O:3]1.CC(C[AlH]CC(C)C)C.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C1(C)C=CC=CC=1.ClCCl>[CH3:1][C:2]1([CH3:18])[CH2:13][C:10]2([CH2:11][CH2:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:14]=[O:15])[CH:8]=2)[O:3]1
Reactant: COC(=O)c1ccc2c(c1)C1(CC1)CC(C)(C)O2
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC1(C)CC2(CC2)c2cc(C=O)ccc2O1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
Methyl 2,2-dimethyl-2,3-dihydrospiro[chromene-4,1′-cyclopropane]-6-carboxylate (33.0 mg, 0.13 mmol) was dissolved in dry toluene (1.34 mL), and cooled to −78° C. DIBAL-H (536 μL, 0.54 mmol) was added dropwise via a syringe. The reaction mixture was stirred for 2 hours at −78° C. It was then quenched with methanol (500 μL) at the same temperature, and diluted with EtOAc (15.0 mL). The organic layer was washed with water (10.0 mL), dried over Na2SO4, filtered and concentrated under vacuum to afford the crude alcohol, which was used directly to the next step. The crude alcohol was dissolved in dichloromethane (4.00 mL) and Dess-Martin periodinane (114 mg, 0.27 mmol) was added in one portion at room temperature. The resulting mixture was stirred at room temperature for 1 hour and concentrated under vacuum on silica gel. It was then purified by silica gel chromatography eluting with 0-15% EtOAc/hexanes to give the desired product as a colorless oil.