Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][C@H:16]([CH3:31])[C:17]([N:19]2[CH2:23][CH2:22][CH2:21][C@H:20]2[C:24](=[O:30])[NH:25][CH:26]2[CH2:29][CH2:28][CH2:27]2)=[O:18])[C:12]2[C:7](=[CH:8][C:9]([CH3:32])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[CH:26]1([NH:25][C:24]([C@@H:20]2[CH2:21][CH2:22][CH2:23][N:19]2[C:17](=[O:18])[C@@H:16]([CH3:31])[O:15][C:13]2[C:12]3[C:7](=[CH:8][C:9]([CH3:32])=[CH:10][CH:11]=3)[N:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=2)=[O:30])[CH2:27][CH2:28][CH2:29]1
Reactant: COC(=O)c1cc(O[C@H](C)C(=O)N2CCC[C@H]2C(=O)NC2CCC2)c2ccc(C)cc2n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc2c(O[C@H](C)C(=O)N3CCC[C@H]3C(=O)NC3CCC3)cc(C(=O)O)nc2c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6.30 g 4-[(R)-2-((S)-2-Cyclobutylcarbamoyl-pyrrolidin-1-yl)-1-methyl-2-oxo-ethoxy]-7-methyl-quinoline-2-carboxylic acid methyl ester in 14 ml THF were added 14.3 ml aqueous NaOH (1 M) and the reaction mixture was stirred for 4 h at RT. The reaction mixture was acidified with 15 ml 1 M HCl, concentrated to a volume of 25 ml and extracted with DCM to give the crude product after evaporation of the solvent. Yield: 5.00 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[O:7][C:6]2[CH:8]=[CH:9][C:10]([C@H:12]3[O:16][C:15](=[O:17])[N:14]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][OH:27])[CH2:13]3)=[CH:11][C:5]=2[CH2:4][O:3]1.[H-].[Na+].[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1.P([O-])([O-])([O-])=O>CN(C=O)C.O>[Br:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:27][CH2:26][CH2:25][O:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][N:14]2[CH2:13][C@@H:12]([C:10]3[CH:9]=[CH:8][C:6]4[O:7][C:2]([CH3:28])([CH3:1])[O:3][CH2:4][C:5]=4[CH:11]=3)[O:16][C:15]2=[O:17])=[CH:34][CH:33]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCO)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4ccc(Br)cc4)C(=O)O3)ccc2O1
Reaction time: 0.25 h
Yield: 74.3 %

Procedure:
A solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-3-{6-[(2-hydroxyethyl)oxy]hexyl}-1,3-oxazolidin-2-one (2.00 g) in DMF (25 ml) under nitrogen was treated with sodium hydride (244 mg, 60% in oil) and the mixture was stirred at 20° for 15 min. 4-Bromobenzyl bromide (1.40 g) was added and the mixture was stirred at 20° for 18 h. Phosphate buffer solution (50 ml, pH6.5) and water (50 ml) were added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (40 mm diameter column). Elution with EtOAc-PE (1:1) gave the title compound (2.125 g). LCMS RT=3.77 min.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]([C:10]1[CH:37]=[CH:36][C:13]([CH2:14][CH2:15][N:16]([C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH3:17])=[CH:12][CH:11]=1)(=O)[NH2:8]>O1CCCC1>[NH2:8][CH2:7][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][CH2:15][N:16]([C:18]([CH3:35])([CH3:34])[CH2:19][O:20][CH:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH3:17])=[CH:36][CH:37]=1
Reactant: CN(CCc1ccc(C(N)=O)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CN(CCc1ccc(CN)cc1)C(C)(C)COC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 52.3 %

Procedure:
Lithium aluminium hydride (57 mg) was added to a solution of 2-[N-(4-carbamoylphenethyl)-N-methylamino]-1-diphenylmethoxy-2-methylpropane (170 mg -- see Example 42) in tetrahydrofuran (12 ml) and the mixture was stirred at room temperature for 17 hours, heated under reflux for 2 hours, quenched by the sequential dropwise addition with stirring of a solution of water (57 mg) in tetrahydrofuran (1 ml), 15% aqueous sodium hydroxide solution (57 mg) and water (156 mg), stirred at room temperature for 30 minutes and filtered. The filtrate was evaporated and the residue was partitioned between methylene chloride and 5% aqueous sodium carbonate solution. The organic layer was washed with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on silica (17 g) using hexane:ether:diethylamine (90:5:5) as the eluant. Appropriate fractions were combined and evaporated to give the title compound as a colourless oil (86 mg, 52%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][CH:10]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:33])[F:32])(=[O:29])=[O:28])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2].C(=O)([O-])[O-].[K+].[K+].CC1C=CC(S([CH2:51][N+:52]#[C-:53])(=O)=O)=CC=1.[N+](CS(C1C=CC(C)=CC=1)(=O)=O)#[C-]>CO.O>[CH2:1]([N:3]1[C:7]([O:8][C:9]2[CH:10]=[CH:11][C:12]([C:15]3[O:16][CH:53]=[N:52][CH:51]=3)=[CH:13][CH:14]=2)=[CH:6][C:5]([C:17]2[CH:18]=[C:19]([C:23]([NH:26][S:27]([CH2:30][C:31]([F:34])([F:32])[F:33])(=[O:28])=[O:29])([CH3:25])[CH3:24])[CH:20]=[CH:21][CH:22]=2)=[N:4]1)[CH3:2]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(-c2cnco2)cc1
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 3 %

Procedure:
N-(2-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}propan-2-yl)-2,2,2-trifluoroethanesulfonamide (340 mg, 0.69 mmol, 1 equiv) was added to a suspension of potassium carbonate (237 mg, 1.72 mmol, 2.5 equiv) stirring in MeOH (3.4 mL) at 22° C. 1-[(isocyanomethyl)sulfonyl]-4-methylbenzene isocyanomethyl 4-methylphenyl sulfone (161 mg, 0.82 mmol, 1.2 equiv) was added and the resulting mixture was stirred at 22° C. for 30 minutes. The reaction was diluted with water and extracted with ethyl acetate. The organic layer was washed with saturated aqueous ammonium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (0-40% EtOAc:Hex). Fractions were identified, combined and concentrated in vacuo but the isolated material was not pure. The residue was then purified by reversed phase HPLC (0-95% acetonitrile:water with 0.025% TFA). Pure fractions were identified, combined, basified with saturated aqueous sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (3% yield). Calc'd (M+1)+: 535.1. Found: 535.1.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH:2]=1.[O:10]1CC[CH2:12][CH2:11]1.[H-].[Na+].ICCO>CO.C(OCC)(=O)C>[N:1]1([CH2:12][CH2:11][OH:10])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: C1CCOC1
Agent: OCCI
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: OCCn1cnc2ccccc21
Temperature: 5 °C
Reaction time: 0.33 h

Procedure:
To a flask were added 2.3 g benzimidazole and 40 ml tetrahydrofuran and the mixture was cooled to 10 C under nitrogen. 1.0 g Sodium hydride were added in portions and the reaction mixture was stirred for 20 minutes. 4.0 g 2-Iodoethanol were added and the mixture was heated to 5° C. for 16 hours. The mixture was quenched slowly with 50 ml water, extracted twice with ethyl acetate and dried over sodium sulfate. Following filtration and solvent removal, the product was purified by silica gel chromatography using 25% methanol in ethyl acetate. A solid was obtained that was dissolved in a hot mixture of 10% methanol in ethyl acetate, cooled, filtered and dried giving 1.4 g white solid.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]2([CH:25]([CH3:27])[CH3:26])[O:22][C:21](=[O:23])[CH:20]=[C:19]([OH:24])[CH2:18]2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C>[Pd].C1COCC1>[OH:24][C:19]1[CH2:18][C:17]([CH2:16][CH2:15][C:12]2[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=2)([CH:25]([CH3:27])[CH3:26])[O:22][C:21](=[O:23])[CH:20]=1
Reactant: CC(C)C1(CCc2ccc(OCc3ccccc3)cc2)CC(O)=CC(=O)O1
Agent: [Pd]
Solvent: C1CCOC1
Product: CC(C)C1(CCc2ccc(O)cc2)CC(O)=CC(=O)O1

Procedure:
The title compound was prepared as described in General Method 4 using 30 g of 6-[2-(4-benzyloxy-phenyl)-ethyl]-4-hydroxy-6-isopropyl-5,6-dihydro-pyran-2-one (prepared in the paragraph above), 3 g of 20% Pd over charcoal and 600 mL of THF. The crude compound was purified by silica gel filtration. 1H NMR (DMSO-d6) δ 0.83 (d, 3 H), 0.86 (d, 3 H), 1.78 (m, 2 H), 2.06 (m, 1 H), 2.25 (d of ABX q, 1 H), 2.39 (m, 2 H), 2.53 (d of ABX q, 1 H), 4.89 (s, 1 H), 6.6 (d, 2 H), 6.89 (d, 2 H), 9.1 (br s, 1 H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:16]=2)[C:11]([OH:13])=O)=[N:6][CH:7]=1.[Cl-].[K+].[O-:23][N+:24]1[C:29]([C:30]([F:33])([F:32])[F:31])=[CH:28][CH:27]=[C:26]([C@H:34]([NH2:36])[CH3:35])[CH:25]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NC(C)C)(C)C>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:14]=[C:15]([C:17]([OH:20])([CH3:19])[CH3:18])[CH:16]=2)[C:11]([NH:36][C@@H:34]([C:26]2[CH:25]=[N+:24]([O-:23])[C:29]([C:30]([F:31])([F:32])[F:33])=[CH:28][CH:27]=2)[CH3:35])=[O:13])=[N:6][CH:7]=1
Reactant: C[C@@H](N)c1ccc(C(F)(F)F)[n+]([O-])c1
Reactant: CC(C)(O)c1cc(C(=O)O)cc(-c2ccc(Cl)cn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: C[C@@H](NC(=O)c1cc(-c2ccc(Cl)cn2)cc(C(C)(C)O)c1)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
To a solution of 3-(5-chloropyridin-2-yl)-5-(1-hydroxy-1-methylethyl)benzoic acid (20 mg, 0.07 mmol) in DMF (0.7 mL) were added the potassium chloride salt of (1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethanamine (33.6 mg, 0.09 mmol), HATU (0.05 M in DMA; 0.21 mL, 0.10 mmol) and diisopropylamine (60 μL, 0.34 mmol). The mixture was stirred at ambient temperature. After 30 min, the mixture was filtered and the filtrate was purified by reverse phase chromatography (C-18, 95% water/acetonitrile→25% water/acetonitrile with 0.1% trifluoroacetic acid) gave the title compound (25 mg). FIRMS 480.1302 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.58 (s, 1H); 8.36 (s, 1H); 8.20 (d, J=4.9 Hz, 2H); 8.04 (s, 1H); 7.78-7.61 (m, 3H); 7.42-7.30 (m, 2H); 5.33-5.23 (m, 1H); 1.69 (s, 6H), 1.63 (d, J=7.1 Hz, 3H).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)=[N:14][O:15][C:16]=2[C:17]([F:20])([F:19])[F:18])=[N:6][CH:5]=1.COC(=O)C1C=CC(OCC2C(C3C=CC=CC=3)=NOC=2C(F)(F)F)=[N:34][CH:33]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:34][CH3:33])=[O:28])=[CH:5][N:6]=3)=[C:16]([C:17]([F:18])([F:20])[F:19])[O:15][N:14]=2)=[CH:22][CH:23]=1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Reactant: COC(=O)c1ccc(OCc2c(-c3ccccc3)noc2C(F)(F)F)nc1
Product: CNC(=O)c1ccc(OCc2c(-c3ccc(F)cc3)noc2C(F)(F)F)nc1
Yield: 66 %

Procedure:
As described for example 129, 6-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (100 mg, 0.25 mmol), instead of 6-(3-phenyl-5-trifluoromethyl-isoxazol-4-ylmethoxy)-nicotinic acid methyl ester, was converted to the title compound (66 mg, 66%) which was obtained as an off white solid. MS: m/e=396.1 [M+H]+.
Reaction SMILES: [CH:1]1[N:9]2[C:4]([NH:5][NH:6][C:7]3[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=32)=[N:3][N:2]=1.[C:14](Cl)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[C:14]([N:5]1[C:4]2=[N:3][N:2]=[CH:1][N:9]2[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[N:6]1[C:14](=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:23])[CH:15]=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: c1ccc2c(c1)NNc1nncn1-2
Reactant: O=C(Cl)C=Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C(C=Cc1ccccc1)N1c2ccccc2-n2cnnc2N1C(=O)C=Cc1ccccc1
Yield: 75 %

Procedure:
A mixture of 4.0 g (0.023 mole) of 4,5-dihydro-s-triazolo[3,4-c]benzo-as-triazine, 7.66 g (0.046 mole) of cinnamoyl chloride and 70 ml of dimethyl formamide is refluxed for 4 hours, and the mixture is processed in the usual way. 7.48 g (75%) of the title compound are obtained; m.p.: 220°-221° C.
Reaction SMILES: [CH3:1][C:2]([O:4][C@H:5]1[C:14]2[C@@:15]3([CH3:30])[C@@H:26]([CH2:27][O:28][CH3:29])[O:25][C:23](=[O:24])[C:17]4=[CH:18][O:19][C:20]([C:21](=[O:22])[C:13]=2[C@@H:8]2[CH2:9][CH2:10][C@H:11]([OH:12])[C@@:7]2([CH3:31])[CH2:6]1)=[C:16]34)=[O:3].[NH:32]([CH2:36][CH2:37][OH:38])[CH2:33][CH2:34][OH:35]>C(Cl)Cl>[OH:35][CH2:34][CH2:33][N:32]([CH:18]=[C:17]1[C:16]2[C:15]([CH3:30])([C:14]3[CH:5]([O:4][C:2](=[O:3])[CH3:1])[CH2:6][C:7]4([CH3:31])[CH:8]([C:13]=3[C:21](=[O:22])[C:20]=2[OH:19])[CH2:9][CH2:10][CH:11]4[OH:12])[CH:26]([CH2:27][O:28][CH3:29])[O:25][C:23]1=[O:24])[CH2:36][CH2:37][OH:38]
Reactant: COC[C@H]1OC(=O)c2coc3c2[C@@]1(C)C1=C(C3=O)[C@@H]2CC[C@H](O)[C@@]2(C)C[C@H]1OC(C)=O
Reactant: OCCNCCO
Solvent: ClCCl
Product: COCC1OC(=O)C(=CN(CCO)CCO)C2=C(O)C(=O)C3=C(C(OC(C)=O)CC4(C)C(O)CCC34)C21C
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 100 mg (0.23 mmol) 17-hydroxywortmannin in 2 mL CH2Cl2 is added diethanolamine (45 μL, 0.46 mmol). The reaction mixture is stirred at room temperature for 12 hours and then concentrated in vacuo. The residue is dissolved in EtOAc and precipitated with hexane. The precipitate is washed two times with hexane to give the product as a yellow solid. MS (ESI) m/z 537 (M+H).
Reaction SMILES: Cl.[C:2]1([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:15]1[CH:20]=[CH:19][C:18]([S:21]([NH:24][C@@H:25]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:26]([OH:28])=[O:27])(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[CH3:31][CH:30]([CH3:32])[CH2:29][C@H:25]([NH:24][S:21]([C:18]1[CH:17]=[CH:16][C:15]([N:11]2[CH2:10][CH2:9][CH:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)=[CH:20][CH:19]=1)(=[O:23])=[O:22])[C:26]([OH:28])=[O:27]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)C[C@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Agent: Cl
Product: CC(C)C[C@H](NS(=O)(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1)C(=O)O

Procedure:
In a manner similar to Example 3(b), 4-phenyl-piperidin hydrochloride was condensed with (S)-2-(4-fluoro-benzenesulfonylamino)-4-methyl-pentanoic acid to give the title compound, % C,H,N found: 63.96, 6.96, 6.44.
Reaction SMILES: [OH2:1].[CH2:2]([OH:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]>OS(O)(=O)=O.CC(O)=O>[C:2]([OH:1])(=[O:16])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][CH2:14][CH3:15]
Reactant: CCOCCCCCOCCCCCO
Reactant: O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCOCCCCCOCCCCC(=O)O
Temperature: 25 °C
Reaction time: 7 h
Yield: 54.8 %

Procedure:
Kiliani reagent [Chem. Ber. 34, 3562 (1901)]was prepared in situ by dissolving Na2Cr2O7 2H2O(3 g) in a cold solution of H2SO4 (4 g) and water (13.5 g). To a solution of compound 6 (1.2 g, 5.5 mmol ) in AcOH (28 mL ) was added Kiliani reagent (20 g) at 0° C. The reaction mixture was stirred for 7 h at room temperature. Water (120 mL) was added to the mixture and then extracted with EtOAc (2×100 mL). The organic phase was washed with water (2×30 mL) and dried (Na2SO4). The residual oil was purified by column chromatography on silica gel with CHCl3 : MeOH (7:1) and subsequent Kugelrohr distillation to give the title product (1) (0.7 g, 52%); bp 128°-132° C. / 0.1 torr); IR(neat): 3000 (broad) and 1730 cm-1 ; 1H NMR: 1.23 (t, 3H, J=7.4 Hz), 1.3-1.8 (m, 10H), 2.38 (t, 2H, J=5.4 Hz), 3.3-3.6 (m 8H), and 9.98 ppm (b s, 1H); Anal. Calcd for C12H24O4 : C, 62.04; H, 10.41%. Found: C, 61.95; H, 10.43%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:17]=O)=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1.CCN(C(C)C)C(C)C.Cl.[NH2:29][OH:30]>C(Cl)Cl>[Cl:1][C:2]1[C:3](/[CH:17]=[N:29]/[OH:30])=[C:4]2[N:10]([CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])[C:9]([OH:16])=[N:8][C:5]2=[N:6][CH:7]=1
Reactant: CCC(CC)n1c(O)nc2ncc(Cl)c(C=O)c21
Reactant: NO
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)n1c(O)nc2ncc(Cl)c(/C=N/O)c21
Temperature: 60 °C
Reaction time: 2 h
Yield: 71 %

Procedure:
6-Chloro-2-hydroxy-1-(pentan-3-yl)-1H-imidazo[4,5-b]pyridine-7-carbaldehyde (20 mg) was dissolved in 3 mL of CH2Cl2. DIEA (130 uL, 10 eq.) and hydroxylamine hydrochloride (51.5 mg, 10 eq.) were added, and the resulting solution was stirred at 60° C. for 2 h. The solvent was evaporated, and the crude was purified by reversed phase HPLC using an acetonitrile/water gradient to give 15 mg of the desired product in 71.4% yield. m/z=283.20 [M+H]+
Reaction SMILES: [F:1][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:11])=[O:10]>C(O)C.[Pd]>[F:1][C:2]1([C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[NH:8][S:9]([CH:12]([CH3:14])[CH3:13])(=[O:10])=[O:11]
Reactant: CC(C)S(=O)(=O)NC1CCCCC1(F)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)S(=O)(=O)NC1CCCCC1(F)c1ccc(N)cc1
Reaction time: 18 h

Procedure:
[2-Fluoro-2-(4-nitrophenyl)cyclohexyl][(methylethyl)sulfonyl]amine (prepared in example 6) is diluted with ethanol and was transferred to a Parr bottle containing 1.25 g of 5% Pd on C (rinsed in with 5 mL of THF) under nitrogen (total ethanol=45 mL). The reaction mixture is then hydrogenated for 16-20 hours at 20-25° C. The reaction mixture is then filtered and the filtrate concentrated under vacuum. The residue can then be purified by flash chromatography on silica gel with ethyl acetate/hexanes to provide the final title compound.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17]C)=[CH:14][CH:15]=3)[N:10]([CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1.B(Br)(Br)Br.C(Cl)Cl>>[CH:1]1([CH2:4][NH:5][C:6]([C:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:17])=[CH:14][CH:15]=3)[N:10]([CH3:19])[C:9]=2[CH3:20])=[O:7])[CH2:3][CH2:2]1
Reactant: COc1ccc2c(C(=O)NCC3CC3)c(C)n(C)c2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1c(C(=O)NCC2CC2)c2ccc(O)cc2n1C
Yield: 76.9 %

Procedure:
This material was prepared by reaction of N-(cyclopropylmethyl)-6-methoxy-1,2-dimethyl-1H-indole-3-carboxamide 55a (0.38 g, 1.4 mmole) with 1.0 M BBr3 in CH2Cl2 (4.19 ml, 4.19 mmole) in a manner as previously described for example 1d to give a pale yellow solid (0.278 g, 77%). 1H NMR (400 MHz, CD3OD) δ 7.55 (1H, d, J=8.5 Hz), 6.77 (1H, s), 6.71 (1H, d, J=8.5 Hz), 3.63 (3H, s), 3.28 (2H, m), 2.61 (3H, s), 1.18 (1H, m), 0.56 (2H, m); ESIMS (MH+): 259.10.
Reaction SMILES: C(OC([NH:8][C@@H:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:22][CH:21]=1)[C:10]([NH:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1)=[O:11])=O)(C)(C)C.FC(F)(F)C(O)=O>>[NH2:8][C@@H:9]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH3:40])=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:22][CH:21]=1)[C:10]([NH:12][C:13]1[S:14][C:15]([CH3:19])=[C:16]([CH3:18])[N:17]=1)=[O:11]
Reactant: COc1cc2ncnc(Oc3ccc([C@H](NC(=O)OC(C)(C)C)C(=O)Nc4nc(C)c(C)s4)cc3)c2cc1OC
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2ncnc(Oc3ccc([C@H](N)C(=O)Nc4nc(C)c(C)s4)cc3)c2cc1OC
Yield: 34 %

Procedure:
Using an analogous procedure to that described in the second paragraph of Example 21, (2S)-2-(N-tert-butoxycarbonylamino)-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]-N-(4,5-dimethylthiazol-2-yl)acetamide was reacted with trifluoroacetic acid to give the title compound in 34% yield; 1H NMR: (DMSOd6) 2.13 (s, 3H), 2.21 (s, 3H), 3.97 (s, 3H), 3.98 (s, 3H), 4.64 (s, 1H), 7.25 (d, 2H), 7.38 (s, 1H), 7.54 (m, 3H), 8.53 (s, 1H); Mass Spectrum: M+H+466.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.S(Cl)(Cl)=O.C(N(CC)CC)C.[CH:22]([NH2:25])([CH3:24])[CH3:23]>C(#N)C.CN(C=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([NH:25][CH:22]([CH3:24])[CH3:23])=[O:7]
Reactant: CC(C)N
Reactant: O=C(O)c1ccnc(Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)NC(=O)c1ccnc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.5 %

Procedure:
To a stirred suspension of 20.00 g 2-chloroisonicotinic acid (123.2 mmol) in 200 mL acetonitrile were added 11.77 mL thionyl chloride (160.2 mmol, 1.3 eq) and 762 μL DMF (9.86 mmol, 0.08 eq). The mixture was heated to reflux and was monitored by HPLC. After 60 min (<1% of 2-chloroisonicotinic acid), the reaction mixture was cooled to room temperature and all volatiles were removed in a rotary evaporator (40° C./10 mbar). The residual oil was dissolved in 200 mL dichloromethane and the solution was cooled to 0° C. 20.6 mL triethylamine (147.8 mmol, 1.20 eq) and 11.7 mL isopropylamine (135.5 mmol, 1.10 eq) were subsequently added and stirring was continued for 2 h at 0° C. until the solution turned almost black. The mixture was poured on 200 mL water and phases were separated. The organic phase was washed with 200 mL brine, dried over 15 g sodium sulfate and filtered. The filter cake was washed with 30 mL dichloromethane. After removal of solvent in a rotary evaporator (40° C., 20 mbar), the crude product (24.83 g, 102% w/w) was obtained as a brown solid (HPLC purity 98.6% area).
Reaction SMILES: [N:1]1[N:2]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([O:30]C)=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][C:11]=2[CH3:36])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2.C(=O)=O>>[N:1]1[N:2]([C:10]2[CH:35]=[CH:34][C:13]([O:14][CH:15]([C:19]3[CH:33]=[CH:32][C:22]([C:23]([NH:25][CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[O:24])=[CH:21][CH:20]=3)[CH2:16][CH2:17][CH3:18])=[CH:12][C:11]=2[CH3:36])[CH:3]=[C:4]2[C:9]=1[CH:8]=[CH:7][CH:6]=[CH:5]2
Reactant: CCCC(Oc1ccc(-n2cc3ccccc3n2)c(C)c1)c1ccc(C(=O)NCCC(=O)OC)cc1
Agent: O=C=O
Product: CCCC(Oc1ccc(-n2cc3ccccc3n2)c(C)c1)c1ccc(C(=O)NCCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Step D of Example 82, using Isomer 2 of methyl 3-(4-(1-(4-(2H-indazol-2-yl)-3-methylphenoxy)butyl)benzamido)propanoate. 1H NMR (400 MHz, CD3OD, δ): 8.25 (s, 1H), 7.78 (d, J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.62 (d, J=8.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 2H), 7.30-7.35 (m, 1H), 7.23 (d, J=8.4 Hz, 1H), 7.09-7.13 (m, 1H), 6.92 (d, J=2.4 Hz, 1H), 6.83 (dd, J=8.4, 2.8 Hz, 1H), 5.37-5.40 (m, 1H), 3.60 (t, J=6.4 Hz, 2H), 2.61 (t, J=6.8 Hz, 2H), 1.96-2.02 (m, 4H), 1.80-1.86 (m, 1H), 1.44-1.57 (m, 2H), 1.00 (t, J=6.4 Hz, 3H). MS (M+1) 472.3. Chiral SFC: Chiralpak AD-3, 4.6×50 mm, 3 μm. Modifier: 0.05% DEA. Gradient: 95% CO2/5% methanol linear to 60% CO2/40% methanol over 3 minutes. Flow rate: 4 mL/min. Retention time: 1.94 minutes, 96.1% ee (Isomer 2).