Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][CH2:15][CH2:16][N:17]2[CH:21]=[CH:20][N:19]=[N:18]2)=[CH:9][CH:8]=1)(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[N:17]1([CH2:16][CH2:15][C:14]#[C:13][C:10]2[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=2)[CH:21]=[CH:20][N:19]=[N:18]1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(C#CCCn2ccnn2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Oc1ccc(C#CCCn2ccnn2)cc1
Reaction time: 3 h
Yield: 94.1 %

Procedure:
A mixture of 1.00 g (3.05 mmol) 1-{4-[4-(tert-butyl-dimethyl-silanyloxy)-phenyl]-but-3-ynyl}-1H-[1,2,3]triazole and 3.05 ml 1M tetrabutylammonium fluoride solution in THF was stirred for 3 h. After evaporation the residue was dissolved in dichloromethane and washed with water that was acidified by acetic acid. The organic phase was dried, evaporated and purified by chromatography on silica gel (ethyl acetate) to give 612 mg (94%) of the title compound.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].[O-]CC.[K+].I[CH2:14][CH2:15][CH2:16][Si:17]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])[O:18][CH2:19][CH3:20]>C(O)C>[C:1]([NH:4][CH2:5][C:6]([CH2:14][CH2:15][CH2:16][Si:17]([O:18][CH2:19][CH3:20])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])=[O:8])(=[O:3])[CH3:2]
Reactant: CCO[Si](CCCI)(OCC)OCC
Reactant: CC(=O)NCC(=O)O
Agent: CC[O-]
Agent: [K+]
Solvent: CCO
Product: CCO[Si](CCCC(=O)CNC(C)=O)(OCC)OCC
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
A 5 L, 4-neck flask equipped with a heating mantle, a mechanical stirrer, a pot thermometer, an addition funnel, and a short Vigreux column with a distillation head connected to a nitrogen bubbler was charged with 2500 g of ethanol and 146.4 g of N-acetylglycine. This mixture was stirred at room temperature for 15 minutes. 110.5 g of potassium ethoxide were added while maintaining the pot temperature below 50° C. The mixture was heated to a pot temperature of 80° and 362.7 g of 3-iodopropyltriethoxysilane was added. Ethanol was removed by distillation until the pot temperature rose to 90° C. to 95° C. The reaction was followed by GC and heating continued for ˜100 hours until less than 10% of the 3-iodopropyltriethoxysilane remained. The flask and the contents were allowed to cool to room temperature and then filtered to give a clear to slightly hazy solution with 25-30% solids. A sample of solution was stripped of solvent at 120° C. and 1 mm vacuum to remove all solvents and unreacted starting materials. The product was purified by wiped film distillation at 190° C. at 0.5 mm. IR and NMR results were consistent with the target structure.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4](C(OC)=O)[CH:3]=1.[NH2:16]N>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:5]=[C:4]([NH2:16])[CH:3]=1
Reactant: NN
Reactant: COC(=O)c1cc(Cl)cc(C(=O)OC)n1
Product: COC(=O)c1cc(Cl)cc(N)n1

Procedure:
4-Chloropyridine-2,6-dicarboxylic acid, dimethyl ester (230 mg, 1 mmol) was converted to the monoacyl hydrazide by adding one-half equivalent of anyhydrous hydrazine. The monohydrazide was converted to the monoacyl azide by the methodology described in step B of Example 35. The title compound was obtained by applying the methodology described in step C of Example 35.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([CH2:9][O:10][CH2:11][C:12]([N:14]2[CH2:18][CH2:17][C@H:16]([NH2:19])[CH2:15]2)=[O:13])[CH:4]=1.[OH:22][C:23]1([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[N:41]=[CH:40][CH:39]=[CH:38][N:37]=3)=[CH:32][N:31]=2)[CH2:28][CH2:27][C:26](=O)[CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCOC(C)=O>CO.C(O)(C)C>[N:37]1[CH:38]=[CH:39][CH:40]=[N:41][C:36]=1[C:33]1[CH:34]=[CH:35][C:30]([C:23]2([OH:22])[CH2:28][CH2:27][CH:26]([NH:19][C@H:16]3[CH2:17][CH2:18][N:14]([C:12](=[O:13])[CH2:11][O:10][CH2:9][C:5]4[CH:4]=[C:3]([C:2]([F:1])([F:20])[F:21])[CH:8]=[CH:7][N:6]=4)[CH2:15]3)[CH2:25][CH2:24]2)=[N:31][CH:32]=1
Reactant: O=C1CCC(O)(c2ccc(-c3ncccn3)cn2)CC1
Reactant: N[C@H]1CCN(C(=O)COCc2cc(C(F)(F)F)ccn2)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CO
Product: O=C(COCc1cc(C(F)(F)F)ccn1)N1CC[C@H](NC2CCC(O)(c3ccc(-c4ncccn4)cn3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (3S)-1-({[4-(trifluoromethyl)pyridin-2-yl]methoxy}acetyl)pyrrolidin-3-amine (47 mg, 0.15 mmol) and 4-hydroxy-4-(5-pyrimidin-2-ylpyridin-2-yl)cyclohexanone (41 mg, 0.15 mmol) in methanol (2 mL) and isopropanol (2 mL) was added sodium triacetoxyborohydride (36 mg, 0.17 mmol). After being stirred at room temperature overnight, EtOAc was added. The solution was washed with NaHCO3 solution and water, dried (MgSO4) and concentrated. Purification by HPLC provided two isomers of the title compound. MS (M+H) 557.2 for both isomers.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[F:9].[Li+].CC([N-]C(C)C)C.C1C[O:21]CC1.CCCCCCC.C(C1C=CC=CC=1)C.B(OC)(OC)OC.C(OO)(=O)C>O1CCCC1>[Br:1][C:2]1[C:3]([F:9])=[C:4]([OH:21])[C:5]([Cl:8])=[CH:6][CH:7]=1
Reactant: Fc1cc(Cl)ccc1Br
Reactant: C1CCOC1
Agent: CC(=O)OO
Agent: CC(C)[N-]C(C)C
Agent: COB(OC)OC
Solvent: CCc1ccccc1
Solvent: CCCCCCC
Product: Oc1c(Cl)ccc(Br)c1F
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a stirred solution of 1-bromo-4-chloro-2-fluorobenzene (5 g, 23.87 mmol) in tetrahydrofuran (40 mL) was cooled to −78° C. was added LDA, 2M in THF/heptane/ethylbenzene (14.92 mL, 29.8 mmol) dropwise and the reaction mixture was stirred at this temperature for 30 min. The solution was allowed to warm to −20° C. and stirred for 30 min. The reaction was cooled to −78° C. and trimethyl borate (3.47 mL, 31.0 mmol) dissolved in THF (5 mL) was added dropwise and the reaction mixture was warmed to −20° C. and stirred for 1 h. The reaction mixture was cooled to −78° C. and peracetic acid (16 mL, 84 mmol) was added dropwise and the mixture allowed to warm to rt and stirred for 12 h. The reaction mixture was cooled to 0° C. and quenched with 5% aqueous ammonium chloride and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL). The organic layer was dried over sodium sulphate and concentrated under reduced pressure to yield 3-bromo-6-chloro-2-fluorophenol (4.99 g, 18.25 mmol, 76% yield) as yellow oil. LCMS (ESI) m/e 225.1 [(M+H)+, calcd for C6H4BrClFO 224.9]; LC/MS retention time (method G): tR=0.87 min.
Reaction SMILES: [CH:1]1([S:7]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19](N(CC)CC)=[O:20])=[CH:18][C:13]3=[N:12][C:11]=2[CH:26]([CH3:28])[CH3:27])(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].C([O:33]CC)C>C(O)C(C)C>[CH:1]1([S:7]([C:10]2[N:14]3[CH:15]=[CH:16][C:17]([C:19]([OH:20])=[O:33])=[CH:18][C:13]3=[N:12][C:11]=2[CH:26]([CH3:27])[CH3:28])(=[O:8])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOCC
Reactant: CCN(CC)C(=O)c1ccn2c(S(=O)(=O)C3CCCCC3)c(C(C)C)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)CO
Product: CC(C)c1nc2cc(C(=O)O)ccn2c1S(=O)(=O)C1CCCCC1
Reaction time: 8 h
Yield: 42 %

Procedure:
Compound 13 (237 mg, 0.584 mmol) was dissolved in isobutyl alcohol (1.2 mL), and the solution was stirred overnight under heat and reflux after adding a 5 mol/L sodium hydroxide aqueous solution (1.2 mL). The reaction mixture was stirred after adding diethyl ether, and the aqueous layer was removed. Then, 3 mol/L hydrochloric acid (2.0 mL) was added to the aqueous layer, and the mixture was stirred. The precipitated crystals were collected by filteration to give 3-cyclohexylsulfonyl-2-isopropylimidazo[1,2-a]pyridine-7-carboxylic acid (86.2 mg, yield 42%).
Reaction SMILES: [NH3:1].[CH3:2][N:3]([CH3:13])[C:4]([C@H:6]1[CH2:12][CH2:11][C@@H:10]2[C@@H:8]([O:9]2)[CH2:7]1)=[O:5]>>[NH2:1][C@H:8]1[C@H:10]([OH:9])[CH2:11][CH2:12][C@H:6]([C:4]([N:3]([CH3:13])[CH3:2])=[O:5])[CH2:7]1
Reactant: N
Reactant: CN(C)C(=O)[C@H]1CC[C@H]2O[C@H]2C1
Product: CN(C)C(=O)[C@H]1CC[C@@H](O)[C@H](N)C1
Temperature: 40 °C

Procedure:
A 28% aqueous ammonia solution (5 ml) was added to (1S,3S,6R)—N,N-dimethyl-7-oxabicyclo[4.1.0]heptane-3-carboxamide (5) (1 g) at room temperature. The mixed solution was stirred at 40° C. for hours, and then, the solvent was concentrated under reduced pressure to obtain (1S,3R,4R)-3-amino-4-hydroxy-N,N-dimethylcyclohexanecarboxamide (1.18 g).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:17])=[O:16])[C:9]([OH:11])=[O:10].C=O.[BH4-].[Na+].F[C:25](F)(F)C(O)=O.OS(O)(=O)=O>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH3:25])[C:6]1[C:7]([CH3:19])=[C:8]([CH:12]=[CH:13][C:14]=1[S:15]([CH3:18])(=[O:16])=[O:17])[C:9]([OH:11])=[O:10]
Reactant: O=C(O)C(F)(F)F
Reactant: COCCNc1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Agent: C=O
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: COCCN(C)c1c(S(C)(=O)=O)ccc(C(=O)O)c1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under nitrogen, 1.0 g (3 mmol) of 3-[(2-methoxyethyl)amino]-2-methyl-4-(methylsulfonyl)benzoic acid was dissolved in 150 ml of THF, and 10 g of paraformaldehyde and then, a little at a time, 0.7 g (20 mmol) of NaBH4 were added. 15 ml of trifluoroacetic acid were then slowly added dropwise. The mixture was stirred at RT for another 3 days. For work-up, 10% strength H2SO4 was added, and the mixture was extracted repeatedly with EA and then dried over MgSO4 and concentrated. This gave a brownish oil.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[Cl:20])[C:8]=2[CH:21]=1)([OH:3])=O.[C:22]1([S:28]([NH2:31])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1>CN(C)C=O>[C:22]1([S:28]([NH:31][C:1]([C:4]2[CH:5]=[CH:6][C:7]3[N:11]=[C:10]([CH3:12])[N:9]([CH2:13][C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=4[Cl:20])[C:8]=3[CH:21]=2)=[O:3])(=[O:30])=[O:29])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NS(=O)(=O)c1ccccc1
Reactant: Cc1nc2ccc(C(=O)O)cc2n1Cc1ccccc1Cl
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: Cc1nc2ccc(C(=O)NS(=O)(=O)c3ccccc3)cc2n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
N,N'-carbonyldiimidazole (0.973 g) was added to a solution of 0.902 g of 6-carboxy-1-(2-chlorobenzyl)-2-methylbenzimidazole in 20 ml of N,N-dimethylformamide, and the mixture was stirred at room temperature for 1 hour. Subsequently, a solution of 0.943 g of benzenesulfonamide and 0.913 g of diazabicycloundecene in 5 ml of N,N-dimethylformamide was added thereto, and the mixture was stirred at 100° C. for 70 hours. The reaction solution was cooled, and the solvent was distilled off under reduced pressure. Water and chloroform were added to the residue, and 10% hydrochloric acid was added thereto while being stirred until the aqueous layer was acidified. The mixed solution was extracted twice with chloroform. The resulting organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate, and the solvent was distilled off under reduced pressure. The residue was dissolved in a small amount of chloroform, and ethyl acetate was added to the solution for crystallization. The crystals were separated through filtration, and were dried to give 0.667 g of 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole (163).
Reaction SMILES: [C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([O:21]CC3C=CC=CC=3)[C:8]2=[O:29])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C(Cl)Cl.CCOC(C)=O.CO.[Pd]>[C:1]1([N:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]3[N:17]=[N:18][NH:19][CH:20]=3)=[C:9]([OH:21])[C:8]2=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [H][H]
Reactant: O=c1c(OCc2ccccc2)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: ClCCl
Product: O=c1c(O)c(CCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 63.5 %

Procedure:
To a solution of 158b (0.29 g, 1.01 mmol) in CH2Cl2:EtOAc:MeOH (2:2:1, 10 mL) was added 10% Pd on carbon (15 mg). Reaction was stirred under balloon hydrogen pressure for 5 h. Reaction mixture was filtered and solvent was evaporated. Column chromatography using gradient CH2Cl2:Acetone (max 20%) gave pure 159b (0.19 g, 64%) as a slightly brownish solid. 1H NMR (400 MHz, DMSO) δ 9.03 (s, 1H), 8.62 (s, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.38 (m, 3H), 7.15 (d, J=6.6 Hz, 1H), 6.68 (d, J=6.4 Hz, 1H), 6.11 (t, J=6.7 Hz, 1H), 4.43 (t, J=6.4 Hz, 2H), 3.99 (m, 2H), 2.27 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 147.49, 129.71, 128.52, 127.99, 125.29, 120.42, 107.98, 66.61, 47.10, 29.27. (expected aromatic carbons=11; quaternary carbons can't be seen even after repeated cycles) HRMS (EI) calcd for C16H16N4O2 [M]+ 296.1273. found 296.1274.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26](OCC)=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)[CH:10]=2)=[N:6][CH:7]=1.[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1>>[F:1][C:2]1[C:3]([NH:23][C:24]2[CH:34]=[CH:33][CH:32]=[CH:31][C:25]=2[C:26]([N:35]2[CH2:40][CH2:39][S:38][CH2:37][CH2:36]2)=[O:27])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F
Reactant: C1CSCCN1
Product: O=C(c1ccccc1Nc1nc(Nc2cccc(CCN3CCOCC3)c2)ncc1F)N1CCSCC1

Procedure:
Ethyl 2-{[5-fluoro-2-({3-[2-(4-morpholinyl)ethyl]phenyl}amino)-4-pyrimidinyl]amino}benzoate (200 mg, 0.51 mmoles) and thiomorpholine (2 mL) were heated at 120° C. for 48 h. The reaction mixture was concentrated to dryness under vacuum and the title compound was purified by flash chromatography on silica gel (using ethyl acetate containing 0.1% triethylamine). MS: M(C27H31FN6O2S)=522.2, (M+H)+=523.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:30][C:11]=2[O:12][C@@H:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:14][CH2:15][C:16]([O:18]C(C)(C)C)=[O:17])[CH:6]=1)=[O:4]>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3]([C:5]1[NH:9][N:8]=[C:7]([C:10]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:30][C:11]=2[O:12][C@@H:13]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)OC(C)(C)C)c2ccccc2C)n[nH]1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cc(-c2ccc(OCc3cccnc3)cc2O[C@H](CCC(=O)O)c2ccccc2C)n[nH]1
Reaction time: 0.03 h
Yield: 22.2 %

Procedure:
tert-Butyl (R)-4-[2-(5-methoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoate (2 g) is dissolved in trifluoroacetic acid (10 mL) and allowed to stand at room temperature for 2 minutes. The solution is quenched with saturated aqueous sodium hydrogen carbonate solution (100 mL) and the product extracted into ethyl acetate (100 mL). This solution is washed with water, dried, and evaporated. The residue is purified by flash chromatography on silica eluting initially with a mixture of ethyl acetate and cyclohexane (3:2 v/v) to remove trace high running impurities, and then eluting with a mixture of methanol and dichloromethane (1:4 v/v). Fractions heterogeneous in the required product are combined and evaporated. The residue is recrystallised from a mixture ethyl acetate and cyclohexane to give (R)-4-[2-(5-methoxycarbonylpyrazol-3-yl)-5-(3-pyridylmethoxy)phenoxy]-4-(2-methylphenyl)butanoic acid (0.4 g) as a white solid, m.p. 155-156° C. [Elemental analysis:- C,66.90; H,5.49; N,8.11%. Calculated:- C,67.00; H,5.43; N,8.43%].
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([OH:30])=[O:29])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[CH3:32][N+:33]([CH2:36][CH2:37][OH:38])([CH3:35])[CH3:34]>CO.O>[CH3:32][N+:33]([CH3:35])([CH3:34])[CH2:36][CH2:37][OH:38].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:26])=[C:11]([N:15]4[CH2:19][CH2:18][CH:17]([N:20]5[CH:24]=[C:23]([CH3:25])[N:22]=[N:21]5)[CH2:16]4)[C:12]=3[F:14])[C:7](=[O:27])[C:6]([C:28]([O-:30])=[O:29])=[CH:5]2)[CH2:2][CH2:3]1
Reactant: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)O)cn(C5CC5)c4c3F)C2)nn1
Agent: C[N+](C)(C)CCO
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1cn(C2CCN(c3c(F)cc4c(=O)c(C(=O)[O-])cn(C5CC5)c4c3F)C2)nn1
Temperature: 25 °C

Procedure:
To a suspension of 1-cyclopropyl-6,8-difluoro-7-[3-(4-Methyl-1,2,3-triazol-1-yl)pyrrolidine-1-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (415.5 mg, 1 mmol) in 2.5 ml of methanol and 0.8 ml water at room temperature was added slowly 0.31 ml Of 45% N,N,N-trimethyl-2-hydroxyethyl-ammonium hydroxide in methanol (1 mmol). The solution was stirred at room temperature for an additional hour. This was filtered and the supernatant was evaporated under reduced pressure at 30° C. The residue was crystallized from acetone-methanol to yield after drying 420 mg of off-white solid, m.p. 188.7°-190.7° C. 1H NMR (D20) δ: 8.44 (s, 1H), 7.84 (bs, 1H), 7.62 (bd, 13.9Hz, 1H), 5.43-5.22 (m, 1H), 4.35-3.62 (m, 7H), 3.52 (t, 2H), 3.21 (s, 9H), 2.73-2.16 (m, 2H) 2.29 (s, 3H), 1.74-0.9 (m, 4H). Anal. calcd. for C25H32F2N6O4 . 1/2 H2O: C, 56.98; H, 6.31; N, 15.94. Found: C, 56.76; H, 6.26; N, 15.43.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1/[N:19]=[C:20](\[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)/[CH3:21])([CH3:9])[CH3:8].[O-]S([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16]([CH3:18])[CH3:17])[C:11]=1[NH:19][CH:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)[CH:23]=1)[CH3:21])([CH3:8])[CH3:9]
Reactant: C/C(=N/c1c(C(C)C)cccc1C(C)C)c1cccc(-c2ccccn2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: CC(C)c1cccc(C(C)C)c1NC(C)c1cccc(-c2ccccn2)c1
Yield: 91 %

Procedure:
To a suspension of 2.70 g (71.0 mmol) of LiAlH4 in 250 mL of THF, 8.03 g (22.6 mmol) of 14 was added. This mixture was refluxed for 3 hr, and then saturated aqueous Na2SO4 was added. The organic layer was separated, and the aqueous layer was additionally washed with 2×100 ml, of diethyl ether. The combined organic extract was evaporated to dryness, and the product was isolated using flash chromatography on silica gel 60 (40-63 um, eluent: hexanes-diethyl ether from 100:1 to 10:1, vol.) to yield 7.37 g (91%) of C1.
Reaction SMILES: Cl.[N+:2]([C:5]1[CH:14]=[C:13]2[C:8]([CH2:9][CH2:10][NH:11][CH2:12]2)=[CH:7][CH:6]=1)([O-])=O>CO.[Pd]>[CH2:12]1[C:13]2[C:8](=[CH:7][CH:6]=[C:5]([NH2:2])[CH:14]=2)[CH2:9][CH2:10][NH:11]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CNCC2
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc2c(c1)CNCC2
Reaction time: 2 h
Yield: 68.6 %

Procedure:
10% Pd/C (1.9 g) was added to a solution of 7-nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (19 g; 1 equiv.) in 300 ml of methanol, and the reaction mixture was hydrogenated for 2 hours at 60 PSI. When the conversion was complete, filtration over Celite was carried out, the filter cake was then washed 4 times with methanol, the filtrate was concentrated under reduced pressure, and the residue was taken up in 100 ml of water. The aqueous solution was adjusted to a pH value of 8-9 with potassium hydroxide solution and extracted 3× with chloroform. The combined organic phases were dried over sodium sulfate and reduced under reduced pressure. 1,2,3,4-Tetrahydroisoquinoline-7-amine (9 g; 69.2%) was obtained in the form of a pale-brown solid.
Reaction SMILES: C(O)=O.C1(C)C=CC=CC=1.C1CO[C:13]2([CH2:18][CH2:17][CH:16]([C:19]3[CH:24]=[C:23]([F:25])[C:22]([F:26])=[C:21]([F:27])[CH:20]=3)[CH2:15][CH2:14]2)[O:12]1>O>[F:25][C:23]1[CH:24]=[C:19]([CH:16]2[CH2:15][CH2:14][C:13](=[O:12])[CH2:18][CH2:17]2)[CH:20]=[C:21]([F:27])[C:22]=1[F:26]
Reactant: Fc1cc(C2CCC3(CC2)OCCO3)cc(F)c1F
Solvent: Cc1ccccc1
Solvent: O=CO
Solvent: O
Product: O=C1CCC(c2cc(F)c(F)c(F)c2)CC1
Reaction time: 2 h
Yield: 79.2 %

Procedure:
Formic acid (82.7 g) and toluene (20 ml) were added to 1,1-ethylenedioxy-4-(3',4', 5'-trifluorophenyl)cyclohexane (95.02 g), followed by heating the mixture under reflux with stirring for 2 hours, adding the reaction solution to water (500 ml), extracting with ethyl acetate (1 l), drying the organic layer over anhydrous magnesium sulfate, distilling off the solvent under reduced pressure, and recrystallizing from ethanol, to obtain 4-(3',4',5'-trifluorophenyl)cyclohexanone (63.1 g). m.p. 123.5° C.
Reaction SMILES: FC(F)(F)C([NH:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1)=O.[OH-].[Na+].Cl>CO>[NH2:5][C@@H:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C@H:9]([OH:16])[CH2:8][CH2:7]1
Reactant: O=C(N[C@H]1CC[C@@H](O)c2ccccc21)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N[C@H]1CC[C@@H](O)c2ccccc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 69 %

Procedure:
To a stirred solution of Intermediate 1c (117 g, 451 mmol) in methanol (0.7 L), 6N aqueous sodium hydroxide solution (190 mL, 1.14 mol) was added and stirred at RT for 20 h. The mixture was concentrated in vacuo and the residue was diluted with ethyl acetate (1 L) and water (0.5 L). Concentrated HCl solution (95 mL, 1.14 mol) was added slowly with stirring. Additional HCl was used to adjust the pH of the aqueous layer to pH=2. The mixture was then separated and the organic layer was extracted with HCl solution (2M aqueous, 3×500 mL). The combined aqueous layers were basified to pH˜12, by addition of concentrated aqueous NH4OH solution, and then extracted in to ethyl acetate (5×750 mL). The combined organic extracts were washed with brine (200 mL), dried (Na2SO4), filtered and concentrated in vacuo to give a solid (50.8 g). This material was recrystallized (cyclohexane/ethyl acetate[2:1], 350 mL) to provide Intermediate 1. (44.4 g, 60%). 1H NMR (400 MHz, d6-DMSO): 1.66-1.90 (4H, m), 3.71-3.77 (1H, t, J=5.4 Hz), 4.46-4.54 (1H, t, J=5.4 Hz), 7.14-7.22 (2H, m), 7.32-7.38 (1H, m), 7.40-7.46 (1H, m).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:11](B2OC(C)(C)C(C)(C)O2)=[CH:10][CH:9]=[CH:8][C:7]=1[N:21]1[CH2:26][CH2:25][C:24]2[C:27]3[CH2:33][CH2:32][CH2:31][CH2:30][C:28]=3[S:29][C:23]=2[C:22]1=[O:34])(=[O:3])[CH3:2].Br[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1>>[C:1]([O:4][CH2:5][C:6]1[C:7]([N:21]2[C:22](=[O:34])[C:23]3[S:29][C:28]4[CH2:30][CH2:31][CH2:32][CH2:33][C:27]=4[C:24]=3[CH2:25][CH2:26]2)=[CH:8][CH:9]=[CH:10][C:11]=1[C:36]1[CH:37]=[C:38]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([N:51]3[CH2:56][CH2:55][N:54]([CH:57]4[CH2:60][O:59][CH2:58]4)[CH2:53][CH2:52]3)=[CH:47][N:46]=2)[C:39](=[O:43])[N:40]([CH3:42])[CH:41]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(N3CCN(C4COC4)CC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)CC4)cn3)c(=O)n(C)c2)cccc1N1CCc2c(sc3c2CCCC3)C1=O
Yield: 50 %

Procedure:
Following Example 148c, 481 mg of 111a and 420 mg of 5-bromo-1-methyl-3-(5-(4-(oxetan-3-yl)piperazin-1-yl)pyridine-2-ylamino)pyridin-2(1H)-one 188e were reacted to give 209a as a yellow solid (347 mg, 50%). MS: [M+H]+ 695