Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:14]=2[C:15]([O:17]CC)=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([C:13]2[N:23]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:21]=[CH:20][C:14]=2[C:15]([OH:17])=[O:16])[CH:8]=[CH:9][C:10]=1[O:11][CH3:12]
Reactant: CCOC(=O)c1ccc(-c2ccccc2)nc1-c1ccc(OC)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Product: COc1ccc(-c2nc(-c3ccccc3)ccc2C(=O)O)cc1OC
Yield: 75 %

Procedure:
30% strength sodium hydroxide (2 ml) is added to a solution of ethyl 2-(3,4-dimethoxyphenyl)-6-phenylnicotinate (compound no. 309; 3.6 g; 0.01 mole) in 95% strength alcohol (100 ml). The reaction medium is heated for 2 h to 60°-70° C. The medium is concentrated under reduced pressure and the residue is dissolved in water (100 ml). The medium is acidified with concentrated hydrochloric acid (2 ml): a gum is released. The mixture is extracted with ethyl acetate (100 ml). The solution is washed with water (2×100 ml), dried over anhydrous magnesium sulphate and then concentrated under reduced pressure. A foam is obtained which is crystallized by trituration in ether (50 ml). After filtration and drying, a beige poser (2.6 g; yield=75%) is obtained, m.p. 178° C. Working in the same manner, the compounds of formula (IV"') in which Z3 is the hydroxyl group and R371 has the meanings indicated below, is obtained.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:39])([F:38])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.CN(C)C=O.[C:45]([OH:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([OH:50])=[O:49]>CC(O)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:21]([NH:23][C:24]2[CH:25]=[C:26]([C:36]([F:38])([F:39])[F:37])[CH:27]=[C:28]([N:30]3[CH:34]=[N:33][C:32]([CH3:35])=[CH:31]3)[CH:29]=2)=[O:22])=[CH:6][C:7]=1[NH:8][C:9]1[N:10]=[CH:11][CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][CH:18]=[N:19][CH:20]=2)[N:14]=1.[C:45]([O-:52])(=[O:51])/[CH:46]=[CH:47]\[C:48]([O-:50])=[O:49]
Reactant: O=C(O)/C=C\C(=O)O
Agent: Cc1cn(-c2cc(NC(=O)c3ccc(C)c(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1
Solvent: CN(C)C=O
Solvent: CC(C)O
Product: O=C([O-])/C=C\C(=O)[O-]
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
Nilotinib base form A (4.00 g, 7.55 mmol) was stirred with IPA (40 mL, 10V) and the suspension was heated to 80° C. Stirring was continued at the same temperature for 30 min. To the stirred suspension was added a solution of maleic acid (0.96 g, 8.31 mol. 1.1 eq) in IPA (10 mL, 2.5V) in one portion. The resulting mixture was stirred at 80° C. for 1 h and then cooled to room temperature and stirred over night. The solids were isolated by filtration to give Nilotinib maleate form V. The obtained Nilotinib maleate form V was dried in a vacuum oven (35 mmHg) at 60° C. for 32 hours. The dried product was analyzed by PXRD and was found to be Nilotinib maleate form V. Mono maleate was obtained as confirmed by assay determination.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]([CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:11]([CH3:15])[C:12](O)=[O:13])=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:34][NH2:35]>C(Cl)Cl>[OH:34][NH:35][C:12](=[O:13])[CH:11]([CH3:15])[CH:10]([S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH2:16][CH2:17][CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: C[Si](C)(C)ON
Reactant: COc1ccc(SC(CCCCc2ccccc2)C(C)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(SC(CCCCc2ccccc2)C(C)C(=O)NO)cc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
(±)-3-(4-Methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.38 g, 1.1 mmol) is dissolved in CH2Cl2 (1 mL) and cooled to 0° C. A solution of oxalyl chloride in CH2Cl2 (0.7 mL, 1.4 mmol) is added dropwise, the bath removed and the reaction allowed to warm and stir at 23° C. for 3 hours. The reaction is then concentrated in vacuo and azeotroped with CHCl3. The resulting oil is dissolved in CH2Cl2 (3 mL), cooled to 0° C. and O-(trimethylsilyl)hydroxylamine (0.4 mL, 3.4 mmol) is added dropwise. The bath is removed and the reaction is allowed to warm to 20° C. The reaction is then partitioned between CH2Cl2 (20 mL) and 1 N HCl (10 mL). The organic layer is then separated and washed with water (10 mL), dried (MgSO4) and concentrated in vacuo to yield (±)-3-(4-methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid hydroxyamide (0.37 g, 90%) which is used without further purification: 1H NMR (300 MHz, CDCl3) δ 7.30-7.18 (m, 4H), 7.14-7.07 (m, 3H), 7.80-7.73 (m, 2H), 3.73 (s, 1.5H), 3.72 (s, 1.5H), 3.12-3.06 (m, 0.5H), 2.97-2.90 (m, 0.5H), 2.53 (m, 2H), 2.32-2.19 (m, 1H), 1.68-1.25 (m, 6H) 1.16 (d, J=7.0 Hz, 1.5H), 1.11 (d, J=7.0 Hz, 1.5H); MS (FAB) m/e 374 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)([O-:3])=[O:2].[C:16]([NH:23][CH2:24][C:25](O)=[O:26])([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[N:10]1[CH2:15][CH2:14][N:13]([C:25](=[O:26])[CH2:24][NH:23][C:16](=[O:17])[O:18][C:19]([CH3:20])([CH3:21])[CH3:22])[CH2:12][CH2:11]1)([O-:3])=[O:2]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: O=[N+]([O-])c1cnccc1N1CCNCC1
Product: CC(C)(C)OC(=O)NCC(=O)N1CCN(c2ccncc2[N+](=O)[O-])CC1
Yield: 99 %

Procedure:
Following the method of Example 84 (Method 3), 1-(3-nitropyridin-4-yl)piperazine was coupled to N-Boc-glycine yielding tert-butyl 2-(4-(3-nitropyridin-4-yl)piperazin-1-yl)-2-oxoethylcarbamate (99% yield). LCMS (m/z): 365.8 (MH+); LC Rt=1.81 min.
Reaction SMILES: [C:1]([CH2:3][CH:4]([CH:27]1[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]1)[N:5]1[CH:9]=[C:8]([C:10]2[C:11]3[CH:18]=[CH:17][N:16](COCC[Si](C)(C)C)[C:12]=3[N:13]=[CH:14][N:15]=2)[CH:7]=[N:6]1)#[N:2].ClCCCl.FC(F)(F)C(O)=O.CO.C(N)CN>>[NH:30]1[CH2:29][CH2:28][CH:27]([CH:4]([N:5]2[CH:9]=[C:8]([C:10]3[C:11]4[CH:18]=[CH:17][NH:16][C:12]=4[N:13]=[CH:14][N:15]=3)[CH:7]=[N:6]2)[CH2:3][C:1]#[N:2])[CH2:32][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCC(C(CC#N)n2cc(-c3ncnc4c3ccn4COCC[Si](C)(C)C)cn2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: NCCN
Solvent: ClCCCl
Product: N#CCC(C1CCNCC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Reaction time: 1.1 h
Yield: 82.1 %

Procedure:
A solution of tert-butyl 4-{2-cyano-1-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]ethyl}piperidine-1-carboxylate (2.0 g, 0.0036 mol) in 1,2-dichloroethane (20 mL, 0.2 mol) and trifluoroacetic acid (20 mL, 0.2 mol) was stirred for 1.1 hour, then the solvent was removed by rotary evaporation to give a colorless oil. The thick oil was dissolved in methanol (15 mL, 0.37 mol) and ethylenediamine (1.0 mL, 0.015 mol) was added. After 1.1 hours, the reaction was purified by preparative-LCMS (pH 10) to give 0.95 g white solid (82% yield). LCMS (M+1): 322.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([CH:11]([OH:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=1.I[CH3:20].[Cl-].[NH4+]>O1CCCC1>[CH3:3][S:4][C:5]1[N:10]=[CH:9][N:8]=[C:7]([CH:11]([O:18][CH3:20])[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=1
Reactant: CI
Reactant: CSc1cc(C(O)c2ccccc2)ncn1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COC(c1ccccc1)c1cc(SC)ncn1
Reaction time: 0.5 h

Procedure:
In 3 ml of tetrahydrofuran was suspended 0.08 g of sodium hydride (60% in oil), to which 6-methylthio-4-(α-hydroxylbenzyl)pyrimidine dissolved in 0.3 ml of tetrahydrofuran was added. The mixture was stirred at 0° C. for 15 minutes, to which 0.28 g of iodomethane was added dropwise at room temperature, followed by stirring at the same temperature for 30 minutes. The reaction mixture was then poured into a saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.17 g of 6-methylthio-4-(α-methoxybenzyl)pyrimidine.
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH2:3][CH2:2]1.Cl[C:17]1[C:18]([O:23][C@H:24]2[CH2:29][CH2:28][C@H:27]([NH:30][C:31]3[S:32][C:33]4[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=4[N:35]=3)[CH2:26][CH2:25]2)=[N:19][CH:20]=[CH:21][N:22]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC>[O:1]1[CH2:6][CH:5]=[C:4]([C:17]2[C:18]([O:23][C@H:24]3[CH2:25][CH2:26][C@H:27]([NH:30][C:31]4[S:32][C:33]5[CH:39]=[CH:38][CH:37]=[CH:36][C:34]=5[N:35]=4)[CH2:28][CH2:29]3)=[N:19][CH:20]=[CH:21][N:22]=2)[CH2:3][CH2:2]1
Reactant: Clc1nccnc1O[C@H]1CC[C@H](Nc2nc3ccccc3s2)CC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: C1=C(c2nccnc2O[C@H]2CC[C@H](Nc3nc4ccccc4s3)CC2)CCOC1
Temperature: 80 °C

Procedure:
A mixture of 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.10 g, 0.49 mmol) and N-(trans-4-(3-chloropyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.14 g, 0.39 mmol), prepared as in step 1 of example 9a, in 1,2-dimethoxyethane (2 mL) and aqueous sodium carbonate (2 M, 0.58 mL, 1.16 mmol) was placed under nitrogen atmosphere using 3 evacuation/backfill cycles. Tetrakis triphenylphosphine(palladium) (0.022 g, 0.019 mmol) was added and one more evacuation/backfill cycle was executed. The mixture was then heated to 80° C. After 4 h the mixture was cooled to RT and partitioned between ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate twice. The combined extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. The resulting oil was purified by silica gel chromatography to give N-(trans-4-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yloxy)cyclohexyl)benzo[d]thiazol-2-amine (0.13 g, 0.32 mmol, 83% yield). [M+1] 409.2. IC50 (uM): 0.03702.
Reaction SMILES: O1CCCC1.[CH3:6][C:7]([NH:10][C:11]1[O:12][C:13]([C:20]([O:22]CC)=[O:21])=[C:14]([C:16]([F:19])([F:18])[F:17])[N:15]=1)([CH3:9])[CH3:8].[OH-].[Na+].Cl>O>[CH3:9][C:7]([NH:10][C:11]1[O:12][C:13]([C:20]([OH:22])=[O:21])=[C:14]([C:16]([F:17])([F:19])[F:18])[N:15]=1)([CH3:6])[CH3:8]
Reactant: CCOC(=O)c1oc(NC(C)(C)C)nc1C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)Nc1nc(C(F)(F)F)c(C(=O)O)o1
Temperature: 25 °C
Yield: 9.5 %

Procedure:
A reaction vessel was charged with 200 ml tetrahydrofuran and 28 g (100 mmol) of ethyl 2-[(1,1dimethylethyl)amino]-4-trifluoromethyl-5-oxazolecarboxylate (prepared by Example 6). With this mixture stirred at ambient temperature, 50% aqueous sodium hydroxide (16 g; 200 mmol) was added followed by 50 ml water as a rinse. The reaction mixture was stirred at ambient temperature for 16 hours. The mixture was then poured into 500 ml of 5% hydrochloric acid. After cooling with an ice bath, the mixture was filtered, washed with water, and then dried to yield 2.4 g of a white powder which was recrystallized from ethyl acetate to a crystalline product (m.p.=256°-258° C.) identified in Table I.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[OH:14])(=O)[CH3:2].CCO.Cl.[NH2:19][OH:20]>[OH-].[Na+]>[OH:14][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:4]=1[C:1](=[N:19][OH:20])[CH3:2])[C:8]([O:10][CH3:11])=[O:9]
Reactant: NO
Reactant: COC(=O)c1ccc(C(C)=O)c(O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COC(=O)c1ccc(C(C)=NO)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.1 %

Procedure:
Methyl 4-acetyl-3-hydroxybenzoate (350 mg, 1.8 mmole) is combined with 5 ml absolute EtOH. The solution is treated with hydroxylamine hydrochloride (125 mg, 1.8 mmole) dissolved in 0.9 ml 2N aqueous NaOH, and the reaction is stirred overnight at rt. The volatiles are removed in vacuo and the residue is washed with H2O, collected, and dried to give 294 mg (78%) of methyl 3-hydroxy-4-[N-hydroxyethanimidoyl]benzoate as a tan solid. MS (EI) m/z: 209 (M+).
Reaction SMILES: [H-].[Na+].[C:3]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[CH2:16]([O:23][C:24]1[CH:29]=[C:28](F)[CH:27]=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[CH2:8]([O:7][C:5](=[O:6])[CH:4]([C:28]1[CH:27]=[CH:26][C:25]([N+:31]([O-:33])=[O:32])=[C:24]([O:23][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:29]=1)[C:3]([O:11][C:12]([CH3:14])([CH3:13])[CH3:15])=[O:10])[CH3:9]
Reactant: CCOC(=O)CC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc(F)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)OC(C)(C)C)c1ccc([N+](=O)[O-])c(OCc2ccccc2)c1
Temperature: 50 °C
Reaction time: 1.5 h

Procedure:
To a suspension of NaH (60%, 9.38 g, 235 mmol) in DMF (200 mL) at 0° C. under N2 is added tert-butyl ethyl malonate (45.7 mL, 243 mmol) over 30 min. The reaction is stirred for 1.5 h in an ice bath. 2-Benzyloxy-4-fluoro-1-nitrobenzene (20.0 g, 80.9 mmol) is added and the reaction heated to 50° C. for 7.5 h. The reaction is quenched with H2O (600 mL) and extracted with EtOAc (2 L). The organic phase is concentrated to ˜1 L, washed with H2O (2×500 mL) and brine (300 mL), and dried over Na2SO4. Evaporation yields a yellow oil. The oil is azeotroped with DCM and the resulting solid is triturated with a hexanes/Et2O solution, affording a yellow solid. Two additional crops of the solid are obtained from the filtrate upon standing. The solids are combined to afford 2-(3-benzyloxy-4-nitrophenyl) -malonic acid tert-butyl ester ethyl ester: MS (M−H)−=414.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46]
Reactant: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
To a solution of 1-[3-(4-chloro-2-methyl-2H-pyrazol-3-yl)-4-hydroxy-phenyl]-3-(2,4-difluoro-phenyl)urea (see above) (0.035 g, 0.09 mmol) in THF (3 mL), triphenyl phosphine (0.071 g, 0.27 mmol) and 2-dimethylamino ethanol (27.1 μL, 0.27 mmol) were added followed by dropwise addition of diisopropyl azodicarboxylate (DIAD) (52.3 μL, 0.27 mmol). The reaction mixture was stirred at room temperature for 2 hours, concentrated to give a crude product that was purified via preparative HPLC. The corresponding fractions were collected, neutralized with 1N NaOH and extracted with EtOAc. A second purification by flash chromatography (SiO2, CH2Cl2/MeOH gradient elution) afforded Compound 132 as an off-white solid in 45.9% yield. LCMS m/z (%)=450 (M+H 35Cl, 100), 452 (M+H 37Cl, 32). 1H NMR (400 MHz. DMSO-d6) δ: 9.11 (s, 1H), 8.56 (s, 1H), 8.06-8.00 (m, 1H), 7.60 (s, 1H), 7.52 (d, J=8.95 Hz, 1H), 7.38 (s, 1H), 7.33-7.27 (m, 1H), 7.17 (d, J=9.04 Hz, 1H), 7.05-6.98 (m, 1H), 4.12-3.95 (m, 2H), 3.65 (s, 3H), 2.55-2.51 (m, 2H), 2.10 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[C:15]([CH2:16][CH:17]=[CH2:18])=[C:14]([OH:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]>C(OCC)(=O)C.[Pd]>[OH:1][C:2]1[C:15]([CH2:16][CH2:17][CH3:18])=[C:14]([OH:19])[CH:13]=[CH:12][C:3]=1[C:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:5]
Reactant: C=CCc1c(O)ccc(C(=O)c2ccccc2)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCc1c(O)ccc(C(=O)c2ccccc2)c1O

Procedure:
A solution of 2,4-dihydroxy-3-(2-propenyl)benzophenone (3 g) was reduced under ˜1 atm H2 in ethyl acetate (100 mL) over 10% Pd/C catalyst (0.3 grams) for 3 hours. The product was purified by crystallization from methanol/water. The product is obtained as small yellow plates.
Reaction SMILES: [F:1][C:2]([F:49])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[CH:31]=[C:32]([C:37]4[CH:42]=[CH:41][C:40]([C:43](O)=[O:44])=[CH:39][C:38]=4[CH3:46])[CH:33]=[CH:34][C:35]=3[Cl:36])[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.B.CCOC(C)=O.CCCCCC.O>C1COCC1>[F:49][C:2]([F:1])([F:48])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:27])([F:29])[F:28])[CH:23]=[CH:22][C:21]=3[C:30]3[C:35]([Cl:36])=[CH:34][CH:33]=[C:32]([C:37]4[CH:42]=[CH:41][C:40]([CH2:43][OH:44])=[CH:39][C:38]=4[CH3:46])[CH:31]=3)[C@H:14]2[CH3:47])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1cc(C(=O)O)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Agent: B
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cc(CO)ccc1-c1ccc(Cl)c(-c2ccc(C(F)(F)F)cc2CN2C(=O)O[C@H](c3cc(C(F)(F)F)cc(C(F)(F)F)c3)[C@@H]2C)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of acid from Example 34 (1.0 g, 1.40 mmol) in THF (15 ml) at −78° C., Borane (2.79 ml, 2.79 mmol, 1M solution in THF) was added. The solution was stirred at −78° C. for 30 min and slowly warmed to room temperature for 2 h. TLC showed no more starting material (EtOAc/hexane 3:7). Water (10 ml) was added. The mixture was extracted with EtOAc (3×20 ml). The combined EtOAc layers were washed with saturated sodium bicarbonate, brine and dried over sodium sulfate. The solvent was removed and the residue was purified by flash column on silica gel, eluting with EtOAc/hexane (30:70) to give the title compound as a colorless solid. 1H NMR (CDCl3, 500 MHz): δ a mixture of 1:1 atopoisomers 7.89 (s, 1H), 7.73 (s, 1H), 7.72 (s, 2H), 7.70 (m, 1H), 7.59 (d, J=8.0 Hz, 1H), 7.49 (d, J=8.5 Hz, 0.5H), 7.47 (d, J=8.0 Hz, 0.5H), 7.39-7.36 (m, 2H), 7.32 (s, 1H), 7.25 (m 1.5H), 7.20 (d, J=2.0 Hz, 0.5H), 5.62 (d, J=8.0 Hz, 1H), 4.99 (d, J=15.0 Hz, 0.5H), 4.83 (d, J=16.0 Hz, 0.5H), 4.73 (s, 2H), 4.15 (s, 1H), 4.10 (d, J=16.0 Hz, 0.5H), 4.01 (d, J=15.5 Hz, 0.5H), 3.96 (m, 0.5H), 3.86(m, 0.5H), 2.34 (s, 1.5H), 2.33 (s, 1.5H), 0.61 (d, J=6.5 Hz, 1.5H), 0.58 (d, J=6.5 Hz, 1.5H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([O:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:7]=1.[OH-:16].[Na+].O>O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2].CO>[O:13]1[CH2:14][CH2:15][CH:10]([CH2:9][O:8][C:6]2[CH:7]=[C:2]([OH:16])[CH:3]=[N:4][CH:5]=2)[CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: Brc1cncc(OCC2CCOCC2)c1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1cncc(OCC2CCOCC2)c1
Temperature: 210 °C
Reaction time: 6 h
Yield: 59.4 %

Procedure:
A mixture of 3-bromo-5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridine (300 mg), copper(II) sulfate pentahydrate (130 mg), bronze (100 mg), sodium hydroxide (700 mg), and water (5 mL) was stirred in an autoclave at 210° C. for 6 hours. The reaction mixture was cooled to room temperature, followed by addition of methanol, and insolubles were removed by filtration. The filtrate was concentrated under reduced pressure and extracted with chloroform. The aqueous layer was neutralized by addition of 1M hydrochloric acid (3.5 mL), followed by extraction with ethyl acetate. The organic layers were combined and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 5-(tetrahydro-2H-pyran-4-ylmethoxy)pyridin-3-ol (137 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]3[NH:9][CH:10]([C:16]4[N:17]=[C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[S:19][CH:20]=4)[CH2:11][C:12](=[O:15])[C:13]=3[O:14][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH3:28]>C1COCC1.O=[Mn]=O>[OH:15][C:12]1[CH:11]=[C:10]([C:16]2[N:17]=[C:18]([NH:21][C:22](=[O:26])[CH:23]([CH3:25])[CH3:24])[S:19][CH:20]=2)[N:9]=[C:8]2[C:7]3[C:2]([Cl:1])=[C:3]([O:27][CH3:28])[CH:4]=[CH:5][C:6]=3[O:14][C:13]=12
Reactant: COc1ccc2oc3c(c2c1Cl)NC(c1csc(NC(=O)C(C)C)n1)CC3=O
Agent: O=[Mn]=O
Solvent: C1CCOC1
Product: COc1ccc2oc3c(O)cc(-c4csc(NC(=O)C(C)C)n4)nc3c2c1Cl
Yield: 60.3 %

Procedure:
11F (500 mg, 1.19 mmol) was dissolved in THF (tetrahydrofuran, 30 mL). To the solution was added activated MnO2 (600 mg, 6 eq, 6.9 mmol). The mixture was refluxed for 48 hours. After reaction completed, the mixture was cooled and filtered. The cake was washed well with THF and MeOH. The filtrate was concentrated and purified by column chromatography on silica gel to give 300 mg of pure product (11G).
Reaction SMILES: [NH2:1][NH:2][C:3]([NH2:5])=[S:4].O=[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]1[CH2:13][CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18].Cl.O>CO>[NH2:5][C:3]([NH:2][N:1]=[C:13]([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:7]=1)[CH2:14][NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])=[S:4]
Reactant: NNC(N)=S
Reactant: CC(C)C(=O)NCCC1C=CC=CC1=O
Agent: Cl
Solvent: CO
Solvent: O
Product: CC(C)C(=O)NCC(=NNC(N)=S)c1ccccc1
Yield: 60.7 %

Procedure:
Thiosemicarbazide (2.22 g, 24.4 mmol) was added to a solution of N-(2-oxo-phenyl-ethyl)-2-methyl-propanamide (5.0 g, 24.4 mmol), prepared in the previous step, in 70 ml of methanol plus 6.75 ml of 1N HCl plus 6.25 ml of water and the reaction stirred at room temperature overnight. The solid formed was collected by filtration, rinsed with isopropyl alcohol and hexane, and then dried to give 4.12 g of a white solid. Recrystallization of this solid from isopropyl alcohol gave the title compound (3.15 g, 46%) as a white solid, mp 183-185° C.
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([F:10])[C:7]([CH3:11])=[N:6][CH:5]=1.CO.[OH-].[Na+]>O>[F:10][C:8]1[C:7]([CH3:11])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:12])=[O:2]
Reactant: COC(=O)c1cnc(C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1ncc(C(=O)O)cc1F
Temperature: 50 °C
Yield: 88.4 %

Procedure:
To a suspension of 5-fluoro-6-methyl-nicotinic acid methyl ester (0.21 g, 1.24 mmol) in a 1:1 mixture of MeOH:water (20 mL) is added sodium hydroxide as a 10% aqueous solution (1.0 mL, 2.5 mmol). The mixture is heated to 50° C. for 1 h then cooled to room temperature and concentrated under reduced pressure to remove volatile organics. The pH of the resulting solution is adjusted to slightly acidic (approximately pH 5) by the addition of a 2N solution of HCl. The mixture is extracted with EtOAc and the combined organic phase is dried over anhydrous sodium sulfate and concentrated to provide 0.170 g of 5-fluoro-6-methyl-nicotinic acid as a solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20](=O)[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1.[CH3:28][N:29]([CH3:34])[CH2:30][CH:31]([NH2:33])[CH3:32].C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]([NH:33][CH:31]([CH3:32])[CH2:30][N:29]([CH3:34])[CH3:28])[CH3:21])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:23]=[CH:24][C:25]([CH3:27])=[CH:26][C:4]=2[N:3]=1
Reactant: CC(N)CN(C)C
Reactant: CC(=O)c1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(C(C)NC(C)CN(C)C)cc3)cc12

Procedure:
N2-(1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethyl)-N1,N1-dimethylpropane-1,2-diamine was prepared from 1-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenyl)ethanone (from Example 171) and N1,N1-dimethylpropane-1,2-diamine (commercially available) following the procedures described for Example 182. 1H NMR (Acetone-d6) TFA Salt: δ 8.83 (m, 2H), 8.40 (d, 1H), 7.46-7.51 (m, 3H), 7.43 (m, 1H), 7.37 (d, 2H), 4.54 (m, 1H), 3.74 (m, 1H), 3.19 (m, 4H), 2.90 (s, 3H), 2.77 (s, 3H), 2.55 (s, 3H), 2.41 (d, 2H), 1.66 (d, 3H), 1.39 (d, 3H). LRMS [M+H]=442.2.