Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][O:10][C:11]2[N:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[CH:13][N:12]=2)[CH2:2]1.[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH:30]=O.C(N(C(C)C)CC)(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C>[Cl:26][C:27]1[CH:28]=[C:29]([CH:32]=[CH:33][C:34]=1[Cl:35])[CH2:30][N:1]1[CH2:5][CH2:4][CH:3]([CH2:6][NH:7][C:8](=[O:25])[CH2:9][O:10][C:11]2[N:12]=[CH:13][C:14]([C:17]3[CH:18]=[CH:19][C:20]([O:23][CH3:24])=[CH:21][CH:22]=3)=[CH:15][N:16]=2)[CH2:2]1
Reactant: COc1ccc(-c2cnc(OCC(=O)NCC3CCNC3)nc2)cc1
Reactant: O=Cc1ccc(Cl)c(Cl)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(-c2cnc(OCC(=O)NCC3CCN(Cc4ccc(Cl)c(Cl)c4)C3)nc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A stock solution containing N-(pyrrolidin-3-(RS)-ylmethyl)-2-(5-(4-methoxyphenyl)pyrimidin-2-yloxy)acetamide (0.44 mmol) in dichloroethane (10 mL) was added to a solution of 3,4-dichlorobenzaldehyde (85 mg, 0.48 mmol, 1.1 equiv.) and diisopropylethylamine (0.35 mL, 2.0 mmol, 4.5 equiv.) in dichloroethane (5 mL). Excess Na(OAc)3BH (140 mg, 0.66 mmol, 1.5 equiv.) was added and the reaction mixture was stirred rapidly at room temperature overnight. The reaction mixture was quenched with methanol, concentrated and diluted with 1:1 methanol/dimethyl sulfoxide. The solution was then purified directly using preparative reverse phase chromatography to give, after treatment with 4 M hydrochloric acid in dioxane (1 mL) and concentration, N-[1-(3,4-dichlorobenzyl)pyrrolidin-3-(RS)-ylmethyl]-2-[5-(4-methoxyphenyl)pyrimidin-2-yloxy]-acetamide HCl salt (96 mg).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1.[H-].[Na+].C[O:17][CH:18](OC)[CH2:19]Br>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[CH:6]=1)[CH2:19][CH:18]=[O:17]
Reactant: COC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32.6 %

Procedure:
A mixture of 25 g (114 mmol) (3,4-dichloro-phenyl)-acetic acid methyl ester (commercially available), 5.7 g (131 mmol) NaH (55%) and 23.1 g (137 mmol) bromoacetaldehyde dimethylacetal in 80 mL DMF was stirred at room temperature for 3 h. The mixture was poured onto ice/water and extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4 and evaporated to dryness. The residue was dissolved in 250 mL THF and treated with 300 mL 1N HCl at room temperature for 20 h. Water was added and the mixture was extracted with ethyl acetate. The combined organic phases were washed with NaCl aq., dried with Na2SO4, evaporated to dryness and subjected to column chromatography on silica eluting with a gradient formed from heptane and ethyl acetate. The product containing fractions were evaporated to yield 9.7 g (32%) of the title compound as light yellow oil.
Reaction SMILES: Br[C:2]1[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6](=[O:26])[N:5]([CH3:27])[C:4]=2[N:3]=1.[CH2:28]1[C@@H:32]2[CH2:33][NH:34][CH2:35][C@@H:31]2[CH2:30][N:29]1[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:27][N:5]1[C:4]2[N:3]=[C:2]([N:34]3[CH2:33][C@@H:32]4[CH2:28][N:29]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:30][C@@H:31]4[CH2:35]3)[N:10]([CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])[C:9]=2[C:8](=[O:16])[N:7]([CH2:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:6]1=[O:26]
Reactant: CC(C)=CCn1c(Br)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)=CCn1c(N2C[C@H]3CN(C(=O)OC(C)(C)C)C[C@H]3C2)nc2c1c(=O)n(CC(=O)c1ccccc1)c(=O)n2C
Temperature: 90 °C
Reaction time: 5 h

Procedure:
52 mg of 8-bromo-3-methyl-7-(3-methyl-but-2-enyl)-1-(2-oxo-2-phenyl-ethyl)-3,7-dihydro-purine-2,6-dione were dissolved in 1 ml of DMF, and 56 mg of tert-butyl cis-hexahydropyrrolo[3,4-c]pyrrole-2-carboxylate and 36.5 mg of potassium carbonate were added. The mixture was stirred at 90° C. for 5 hours, cooled and evaporated in a vacuum. The oily residue was purified by column chromatography (silica gel: mobile phase: methylene chloride: methanol=98:2).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]>[Pd].C(O)C>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[C:14]([S:21]([CH3:24])(=[O:23])=[O:22])[N:13]=2)[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2N)CC1
Reaction time: 8 h
Yield: 92.7 %

Procedure:
A mixture of 0.090 g (0.24 mmol) of (6′-methanesulfonyl-3′-nitro-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester and 0.015 g (0.014 mmol) of 10% palladium on carbon in ethanol (8 mL) is stirred overnight under an atmosphere of hydrogen. The mixture is passed through a pad of diatomaceous earth and concentrated under reduced pressure to provide 0.076 g (94%) of (3′-amino-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester as a black oil.
Reaction SMILES: [CH2:1]([O:8][C@H:9]([C:25]([F:28])([F:27])[F:26])[C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=1[CH3:24])[C:11](O)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]([C:31]1[CH:40]=[CH:39][C:34]([C:35]([NH:37][NH2:38])=[O:36])=[CH:33][CH:32]=1)#[N:30].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C@H:9]([C:25]([F:26])([F:28])[F:27])[C@@H:10]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[C:17]([Cl:23])[C:16]=1[CH3:24])[C:11]([NH:38][NH:37][C:35](=[O:36])[C:34]1[CH:33]=[CH:32][C:31]([C:29]#[N:30])=[CH:40][CH:39]=1)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@@H](C(=O)O)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1c(N[C@@H](C(=O)NNC(=O)c2ccc(C#N)cc2)[C@H](OCc2ccccc2)C(F)(F)F)ccc(C#N)c1Cl
Temperature: -20 °C
Reaction time: 0.5 h
Yield: 47.7 %

Procedure:
To a solution of (2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoic acid (280 mg) in THF (15 mL) were added 4-cyanobenzohydrazide (130 mg, 0.81 mmol), HOBt (109 mg, 0.81 mmol), EDC (232 mg, 1.21 mmol) and Et3N (0.25 mL, 1.79 mmol) at −20° C. sequentially. After addition, the mixture was stirred at −20° C. for 30 min., then room temperature overnight. The reaction was quenched by adding ice-water. After removal of the THF, the residue was extracted with EtOAc (200 mL). The EtOAc extracts were washed with water, brine and dried over Na2SO4. The filtrate was concentrated and purified by flash chromatography to give the title compound N′-((2R,3S)-3-(benzyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)-4,4,4-trifluorobutanoyl)-4-cyanobenzohydrazide (180 mg, 10%). 1H NMR (400 MHz, CDCl3, δ in ppm) 9.26 (b, 1H), 8.88 (b, 1H), 7.92 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.36˜7.39 (m, 5H), 7.28 (d, J=8.7 Hz, 1H), 6.44 (d, J=8.7 Hz, 1H), 5.22 (d, J=6.6 Hz, 1H), 4.93 (d, J=11.1 Hz, 1H), 4.80 (d, J=11.1 Hz, 1H), 4.66 (m, 1H), 4.33 (d, J=6.6 Hz, 1H), 2.27 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH:13]=O)=[CH:7]2.CO.O1CC[CH2:19][CH2:18]1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.C(OCC)(=O)C.[C].[Pd]>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][CH2:18][CH3:19])=[CH:7]2
Reactant: C1CCOC1
Reactant: O=Cc1cc2cc(F)ccc2[nH]1
Agent: [Pd]
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCCc1cc2cc(F)ccc2[nH]1
Temperature: 25 °C
Yield: 65 %

Procedure:
To a suspension of ethyltriphenylphosphonium bromide (0.86 g, 2.30 mmol) in tetrahydrofuran (20 mL) was added sodium hydride (60% in oil, 80 mg, 1.99 mmol) with stirring at room temperature, and the mixture was stirred at the same temperature for 20 min. To the solution was added 5-fluoro-1H-indole-2-carbaldehyde (0.25 g, 1.53 mmol) synthesized according to the method described in WO99/09025, and the mixture was stirred at 70° C. for 3 hr. After cooling, the reaction mixture was diluted with ethyl acetate, and the mixture washed with water and saturated brine, dried, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-hexane/ethyl acetate=4/1) to give a beige powder. A mixture of the obtained powder, 10% palladium-carbon (50% water-containing product, 0.1 g) and methanol (10 mL) was stirred under a hydrogen atmosphere for 3 hr. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1-hexane/ethyl acetate=4/1) to give the title compound (0.18 g, yield 65%) as a colorless oil. MS (ESI+): 178 (M+H).
Reaction SMILES: C[C:2]1([CH3:12])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[OH-].[Na+].OO>O1CCCC1.C(OCC)(=O)C>[CH:10]([C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:4]=1[NH:3][CH:2]=[CH:12]2)=[CH2:11]
Reactant: CC1(C)C=Cc2ccccc2N1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=Cc1cccc2cc[nH]c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.5 %

Procedure:
To a 0° C. solution of 7-vinylindole 1 (0.95 g, 6.6 mmol) in anhydrous tetrahydrofuran (60 mL) was added 1 M borane-tetrahydrofuran complex in tetrahydrofuran (9.95 mL, 9.95 mmol) and the reaction stirred overnight at room temperature. 1 N sodium hydroxide (25 mL) and 30% hydrogen peroxide (35 mL) were then added and the mixture stirred at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (50 mL) and saturated aqueous sodium chloride (2×50 mL), dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 50% ethyl acetate in hexanes. Fractions containing product were combined and concentrated under reduced pressure to provide 0.60 g (56%) of the desired compound as a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]2)[N:5]=[C:4]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[CH:3]=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.Cl>CN1CCCC1=O>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:4]2[CH:3]=[C:2]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[N:7]=[C:6]([N:8]3[C:12]([CH3:13])=[CH:11][C:10]([CH3:14])=[N:9]3)[N:5]=2)=[CH:17][CH:18]=1
Reactant: Cc1cc(C)n(-c2nc(Cl)cc(Nc3ccc(Cl)cc3)n2)n1
Reactant: C1COCCN1
Agent: Cl
Solvent: CN1CCCC1=O
Product: Cc1cc(C)n(-c2nc(Nc3ccc(Cl)cc3)cc(N3CCOCC3)n2)n1
Temperature: 110 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
A mixture of [6-chloro-2-(3,5-dimethyl-pyrazol-1-yl)-pyrimidin-4-yl]-(4-chlorophenyl)-amine (125 mg, 0.37 mmol) and morpholine (0.32 mL, 3.74 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was stirred for one hour at 110° C. The reaction mixture was allowed to cool down to room temperature, acidified with aqueous hydrochloric acid (1 M) and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over sodium sulphate, filtrated and concentrated in vacuo. The crude product was purified by flash chromatography (dichloromethane/methanol as eluent) to give (4-chloro-phenyl)-[2-(3,5-dimethyl-pyrazol-1-yl)-6-morpholin-4-yl-pyrimidin-4-yl]-amine (92 mg, 64%) as a white solid. Mp. 186-187° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[N:19](C3CCCCO3)[N:18]=2)=[O:16])[CH:9]=1.C([SiH](CC)CC)C>C(Cl)Cl>[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:15]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]4[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=4)[CH:24]=3)[NH:19][N:18]=2)=[O:16])[CH:9]=1
Reactant: O=C(Nc1cccnc1)c1nn(C2CCCCO2)c2ccc(-c3cccnc3)cc12
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1cccnc1)c1n[nH]c2ccc(-c3cccnc3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
TFA (5.0 mL) was added to a solution of N,5-di(pyridin-3-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxamide (CXXXIV) (0.36 g, 0.90 mmol) and triethylsilane (0.29 mL, 1.81 mmol) in DCM (5.0 mL). The solution was stirred overnight at room temperature. An additional 5.0 mL of TFA was added, and the solution was again stirred overnight. The solvents were removed, and the residue was treated with 7 N ammonia in MeOH. The solvents were again removed, and the product was purified by flash chromatography using a 12 g Thomson normal phase silica gel cartridge (100% CHCl3→5:95 MeOH[7N NH3]:CHCl3) to afford N,5-di(pyridin-3-yl)-1H-indazole-3-carboxamide (4) (0.23 g, 0.73 mmol, 82% yield) as a white solid. 1H NMR (DMSO-d6) δ ppm 14.00 (s, 1H), 10.69 (s, 1H), 9.08 (d, J=2.0 Hz, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.60 (dd, J=4.8, 1.3 Hz, 1H), 8.48-8.47 (m, 1H), 8.33-8.31 (m, 2H), 8.15-8.12 (m, 1H), 7.85-7.81 (m, 2H), 7.54-7.51 (m, 1H), 7.41-7.39 (m, 1H); ESIMS found for C18H13N5O m/z 316 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=2)[N:3]=1.CCN(CC)CC.[NH2:30][C@@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][C@@H:32]1[NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41].O>C1COCC1.CCOC(C)=O>[C:40]([O:39][C:38]([NH:37][C@H:32]1[CH2:33][CH2:34][CH2:35][CH2:36][C@H:31]1[NH:30][C:2]1[CH:11]=[C:10]([C:12]#[N:13])[C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17]([CH3:22])[CH:16]=2)[N:3]=1)=[O:44])([CH3:43])([CH3:41])[CH3:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1N
Reactant: COC(=O)c1c(C#N)cc(Cl)nc1Nc1ccc(F)c(C)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(C#N)cc(N[C@@H]2CCCC[C@@H]2NC(=O)OC(C)(C)C)nc1Nc1ccc(F)c(C)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 12.4 %

Procedure:
A mixture of methyl 6-chloro-4-cyano-2-(4-fluoro-3-methylphenylamino)nicotinate (390 mg, 1.220 mmol), Et3N (0.204 mL, 1.464 mmol) and tert-butyl (1S,2R)-2-aminocyclohexylcarbamate (392 mg, 1.830 mmol) in THF (5 mL) was stirred at 80° C. overnight. Water and EtOAc were subsequently added to the mixture and the aqueous phase was extracted with EtOAc. The organic phases were combined, washed with H2O and brine, dried over MgSO4, and evaporated. The residue was diluted with EtOAc and filtered to give the title compound as a yellow solid (75 mg, 12.36%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.03-1.71 (m, 17H), 2.22 (d, J=0.98 Hz, 3H), 3.80-3.82 (m, 3H), 3.83 (br s, 1H), 4.01-4.09 (m, 1H), 6.48 (s, 1H), 6.62 (d, J=7.81 Hz, 1H), 7.06 (t, J=9.03, 1H), 7.39 (d, J=4.39 Hz, 1H), 7.50-7.68 (m, 1H), 10.41 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]([CH3:15])([N:7]1[CH:11]=[C:10]([N+:12]([O-])=O)[N:9]=[CH:8]1)[CH3:6].[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[C:26]([F:28])[CH:27]=1)[CH2:24][CH:23]([NH:29][CH:30]([CH2:34][CH2:35][CH3:36])[C:31](O)=[O:32])[CH2:22][CH2:21]2>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]([N:7]1[CH:11]=[C:10]([NH:12][C:31](=[O:32])[CH:30]([NH:29][CH:23]2[CH2:22][CH2:21][C:20]3[C:25](=[C:26]([F:28])[CH:27]=[C:18]([F:17])[CH:19]=3)[CH2:24]2)[CH2:34][CH2:35][CH3:36])[N:9]=[CH:8]1)([CH3:15])[CH3:6]
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Reactant: COC(=O)CC(C)(C)n1cnc([N+](=O)[O-])c1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-Methyl-3-(4-nitro-imidazol-1-yl)-butyric acid methyl ester was reduced and coupled with 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid to afford the title compound; MS 463.5 m/z (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[NH2:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30]>>[Br:1][C:2]1[C:3]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[N:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([NH:23][C@@H:24]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:25]1[OH:30])=[O:9]
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: O=C(O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F
Product: O=C(N[C@@H]1CCCC[C@H]1O)c1cc(Br)c(OCc2ccccn2)nc1C(F)(F)F

Procedure:
The title compound was synthesized in analogy to Example 1c, using 5-bromo-6-(pyridin-2-ylmethoxy)-2-trifluoromethyl-nicotinic acid and (1R,2R)-2-amino-cyclohexanol as starting materials, MS (ISP) 476.1 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17]([OH:19])=[O:18])[CH:15]=3)[NH:10][N:9]=2)=[CH:4][CH:3]=1.[C:20](O)(=[O:22])[CH3:21].C(OC(=O)C)(=O)C>O>[C:20]([N:10]1[C:11]2[C:16](=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=2)[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[N:9]1)(=[O:22])[CH3:21]
Reactant: CC(=O)O
Reactant: O=C(O)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)n1nc(-c2ccc(F)cc2)c2cc(C(=O)O)ccc21
Temperature: 80 °C
Yield: 100 %

Procedure:
To a flask containing 3-(4-fluorophenyl)-1H-indazole-5-carboxylic acid (5.0 g, 0.02 mol) was added acetic acid (1100 mL). The flask was placed under nitrogen and to the flask was added acetic anhydride (5.6 mL, 0.06 mol). The reaction refluxed at 80° C. for three hours. The flask was cooled to room temperature and the reaction was diluted with water. The product was collected by vacuum filtration and rinsed with additional amounts of water to yield the title compound (5.96 g, 100% yield) 1H NMR (DMSO-d6) δ 8.6 (s, 1H), 8.45–8.5 (d, 1H), 8.2–8.25 (d, 1H), 8.1 (m, 2H), 7.5 (t, 2H), 2.8 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:26])=[O:25])=[CH:16][CH:15]=2)=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CO[C:38]1C=CC(C)=C[C:39]=1S(Cl)(=O)=O>>[CH2:38]([O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][CH2:20][N:21]3[S:24]([C:27]3[CH:32]=[C:31]([CH3:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])(=[O:25])=[O:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][C:2]=1[F:1])[CH3:39]
Reactant: COc1ccc(C)cc1S(=O)(=O)N1CCCc2ccc(C(=O)Nc3ccc(C(=O)O)c(F)c3)cc21
Reactant: COc1ccc(C)cc1S(=O)(=O)Cl
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(C)ccc2OC)CCC3)cc1F

Procedure:
2-Fluoro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}benzoic acid, m/z (ES+): 499.31 (M+H+.), was prepared in analogy to example 48, steps 1 to 5. Step 4 was performed using 2-methoxy-5-methyl-benzenesulfonyl chloride, yielding 2-fluoro-4-{[1-(2-methoxy-5-methyl-benzenesulfonyl)-1,2,3,4-tetrahydro-quinoline-7-carbonyl]-amino}-benzoic acid ethyl ester, which was hydrolyzed in step 5.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][CH:7]2[O:11][C:10]([CH3:13])([CH3:12])[O:9][C:8]2=[O:14])=[CH:4][CH:3]=1.[CH2:17]([SiH](CC)CC)[CH3:18].OS(O)(=O)=O>C(Cl)Cl.CCO.Cl[Ti](Cl)(Cl)Cl>[CH2:17]([O:9][C:8](=[O:14])[CH:7]([O:11][CH:10]([CH3:13])[CH3:12])[CH2:6][C:5]1[CH:15]=[CH:16][C:2]([OH:1])=[CH:3][CH:4]=1)[CH3:18]
Reactant: CC1(C)OC(=O)C(Cc2ccc(O)cc2)O1
Reactant: CC[SiH](CC)CC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C(Cc1ccc(O)cc1)OC(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 69.6 %

Procedure:
A 0° C. solution of 5-(4-hydroxy-benzyl)-2,2-dimethyl-[1,3]dioxolan-4-one (0.20 g, 0.900 mmol) and triethylsilane (1.05 g, 9.0 mmol) in dry CH2Cl2 (10 mL) was treated dropwise with a 1 molar solution of TiCl4 in CH2Cl2 (0.90 mL, 0.900 mmol) under N2. The resultant red slurry was stirred at 0° C. for 15 minutes and then warmed to room temperature for 45 minutes. The reaction mixture was quenched with water and extracted with EtOAc. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford 0.320 g of crude acid that was carried on as is. The oil was dissolved in EtOH (25 mL) and treated with conc. H2SO4 (1 mL) and then stirred at room temperature for 17 h under N2. The solvent was removed in vacuo and the oil extracted with EtOAc and water. The organic layer was dried (Na2SO4) and the solvent removed in vacuo to afford crude product that was purified by flash chromatography using 5:1 hexanes:acetone to give 0.158 g (70%) 3-(4-hydroxy-phenyl)-2-isopropoxy-propionic acid ethyl ester. Rf=0.48 (1:1 hexanes:acetone). 1H NMR (500 MHz, CDCl3) δ 7.10 (d, 2H, J=8.80 Hz), 6.73 (d, 2H, J=8.31 Hz), 4.79 (bs, 1H) 4.20-4.12 (m, 2H), 3.99 (dd, 1H, J=8.31 Hz, J=4.89 Hz), 3.49 (hp, 1H, J=5.87 Hz), 2.95-2.83 (m, 2H), 1.23 (t, 3H, J=6.85 Hz), 1.14 (d, 3H, J=6.36 Hz), 0.97 (d, 3H, J=6.36 Hz); MS (ES−) Calc'd for C14H19O4 (M−1) 251. Found m/z 251 (100%). 97.6% ee by chiral HPLC assay (Chiralcel OJ, 4.6×250 mm, 90/10 heptane/IPA eluent, 1 mL/min, 266 nm).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:43]=[CH:42][C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:36]([CH3:37])=[C:35]([CH3:38])[C:17]([C:18]([O:20][C:21]3[C:29]([CH3:30])=[C:28]([CH3:31])[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([O:32][CH3:33])[C:22]=3[CH3:34])=[O:19])=[C:16]([O:39][CH3:40])[C:15]=2[CH3:41])=[CH:7][CH:6]=1)=[O:4].[OH-].[K+]>CS(C)=O>[C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH2:10][CH2:11][CH2:12][O:13][C:14]2[C:36]([CH3:37])=[C:35]([CH3:38])[C:17]([C:18]([O:20][C:21]3[C:29]([CH3:30])=[C:28]([CH3:31])[C:24]([C:25]([NH2:27])=[O:26])=[C:23]([O:32][CH3:33])[C:22]=3[CH3:34])=[O:19])=[C:16]([O:39][CH3:40])[C:15]=2[CH3:41])=[CH:42][CH:43]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(OCCCOc2c(C)c(C)c(C(=O)Oc3c(C)c(C)c(C(N)=O)c(OC)c3C)c(OC)c2C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: COc1c(C)c(OC(=O)c2c(C)c(C)c(OCCCOc3ccc(C(=O)O)cc3)c(C)c2OC)c(C)c(C)c1C(N)=O
Yield: 88.8 %

Procedure:
To a solution of the amide-ester prepared in Example 46 (101, 694 mg, 1.17 mmol) in 30 ml of DMSO, was added 1N-KOH (3.5 ml, 3.5 mmol) with stirring, so that the amide-ester was subjected to hydrolysis to give 602 mg of the title compound 102 (89%).
Reaction SMILES: CO[C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30].N12CCCNC1=NCCC2.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:30][CH2:29][CH2:28][CH2:27][CH2:26][NH:25][C:3](=[O:24])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1
Reactant: NCCCCO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C)nc1
Agent: C1CN=C2NCCCN2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NCCCCO)cn1
Temperature: 25 °C
Reaction time: 6 h
Yield: 37.2 %

Procedure:
To a solution of 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester (180 mg, 0.55 mmol) and 4-amino-1-butanol (59 mg, 0.66 mmol) in toluene (1 mL) was added 1,5,7-triazabicyclo[4.4.0]dec-5-ene (23 mg, 0.17 mmol) and the reaction stirred under argon for 6 h at room temperature. Saturated aqueous sodium bicarbonate (1 mL) was then added and the resulting mixture was extracted with ethyl acetate (3×5 mL). The combined organic extracts were then dried over sodium sulfate and evaporated. Purification by chromatography (SiO2, dichloromethane:methanol=100:0 to 9:1) afforded the title compound (78 mg, 37%) which was obtained as a white solid. MS: m/e=382.2 [M+H]+.