Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[CH2:14][OH:15])[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34](O)=[C:33]([CH3:38])[CH:32]=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[CH3:28][O:29][C:30](=[O:39])[C:31]1[CH:36]=[CH:35][C:34]([O:15][CH2:14][CH:13]([N:12]2[C:11]3[CH:22]=[C:23]([F:27])[C:24]([F:26])=[CH:25][C:10]=3[N:9]=[C:8]2[C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:33]([CH3:38])[CH:32]=1
Reactant: COC(=O)c1ccc(O)c(C)c1
Reactant: OCC(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Product: COC(=O)c1ccc(OCC(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(C)c1

Procedure:
The title compound was prepared in analogy to Example 4, intermediate, from 2-[2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-2-cyclohexyl-ethanol (Ex. 1, int. c) and 4-hydroxy-3-methyl-benzoic acid methyl ester (commercially available) and replacing di-ethyl azodicarboxylate by di-tert-butyl azodicarboxylate. Colorless oil (60%). MS (Turbo Spray): m/z=539.2 [M+H].
Reaction SMILES: N(C(OCC1C=CC=CC=1)=O)[C@H](C(O[C:11]([CH3:14])([CH3:13])[CH3:12])=O)CCC(=O)O.[Li+].[BH4-].[NH:27]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[C@H:28]([C:34]([O:36]C(C)(C)C)=O)[CH2:29][CH2:30][C:31](=[O:33])[OH:32]>>[C:11]([O:32][C:31](=[O:33])[CH2:30][CH2:29][CH:28]([CH2:34][OH:36])[NH:27][C:41]([O:43][C:44]([CH3:45])([CH3:46])[CH3:47])=[O:42])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCC(=O)O)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@H](CCC(=O)O)NC(=O)OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Product: CC(C)(C)OC(=O)CCC(CO)NC(=O)OC(C)(C)C

Procedure:
Cbz-Glu-OtBu 51 is converted to 52 via the methyl ester followed by LiBH4 reduction according to the procedure of Y. Hamada, M. Shibata, T. Sugiura, S. Kato and T. Shioiri, J. Org. Chem. 52:1242, 1987 used for the conversion of t-Boc-Glu-OtBu to the corresponding alcohol.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:8]=[CH:7][S:6][CH:5]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]#[C:12][CH3:13]>>[CH2:16]([O:15][C:10]([C:11]1[C:3]([C:4]2[CH:8]=[CH:7][S:6][CH:5]=2)=[N:2][O:1][C:12]=1[CH3:13])=[O:14])[CH3:17]
Reactant: ON=C(Cl)c1ccsc1
Reactant: CC#CC(=O)OCC
Product: CCOC(=O)c1c(-c2ccsc2)noc1C
Yield: 91 %

Procedure:
As described for example 69a, N-hydroxy-thiophene-3-carboximidoyl chloride (Organic Letters, 8(17), 3679-3680, 2006, 11.4 g, 69.6 mmol) instead of N-hydroxybenzenecarboximidoyl chloride using ethyl 2-butynoate instead of cyclopropyl-propynoic acid ethyl ester was converted to the title compound (15.0 g, 91%) which was obtained as a dark brown liquid. MS: m/e=238.0 [M+H]+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][C:20]=2[O:19]1>>[CH2:18]1[O:27][C:26]2[CH:25]=[CH:24][C:22]([NH:23][C:2]3[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=4)[N:3]=3)=[CH:21][C:20]=2[O:19]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Product: FC(F)(F)c1cc(Nc2ccc3c(c2)OCO3)nc(-c2ccccn2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 3,4-methylenedioxyaniline (53 mg, 0.386 mmol) similar to Example 58 and isolated as a purple solid (24 mg, 35%). 1H NMR (CDCl3): 8.85–8.83 (m, 1H), 8.57–8.54 (m, 1H), 7.90–7.84 (m, 1H), 7.45–7.41 (m, 1H), 7.39 (s, 1H), 6.87 (d, J=8.1 Hz, 1H), 6.84 (s, 1H), 6.80 (s, 1H), 6.77 (dd, J=2.1, 8.1 Hz, 1H), 6.05 (s, 2H).
Reaction SMILES: [CH:1]([NH:3][C:4]1[CH:5]=[C:6]([CH:11]([OH:37])[CH2:12][NH:13][C@H:14]([CH3:36])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][NH:25]C(=O)OCC2C=CC=CC=2)[CH:7]=[CH:8][C:9]=1[OH:10])=[O:2].[H][H]>CO.[Pd]>[NH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH:14]([NH:13][CH2:12][C@@H:11]([C:6]1[CH:7]=[CH:8][C:9]([OH:10])=[C:4]([NH:3][CH:1]=[O:2])[CH:5]=1)[OH:37])[CH3:36]
Reactant: [H][H]
Reactant: C[C@H](CCCCCCCCCCNC(=O)OCc1ccccc1)NCC(O)c1ccc(O)c(NC=O)c1
Agent: [Pd]
Solvent: CO
Product: CC(CCCCCCCCCCN)NC[C@H](O)c1ccc(O)c(NC=O)c1
Yield: 100.4 %

Procedure:
A mixture of compound 23 (0.54 g, 1.05 mmol) dissolved in methanol (30 mL) and palladium catalyst (0.15 g, 10% Pd on carbon, 50% we) was stirred overnight at room temperature under one atmospheric hydrogen pressure. The catalyst was removed by filtration and washed with methanol (3×10 mL). The filtrate and washings were combined and concentrated under vacuum to complete dryness, affording the desired product 24 (0.40 g, 91% yield) as an off-white solid: 1H NMR (300 MHz, CD3OD) δ 1.31 (m, 15H), 1.48-1.58 (m, 4H), 1.75 (m, 2H), 260-2.80 (m, 5H), 4.66 (m, 1H), 5.09 (s, 2H), 6.82 (d, 1H), 7.00 (d, 1H), 8.02 (s, 1H), 8.30 (s, 1H); m/z (ESI) 380 [M+H]+.
Reaction SMILES: [OH-].[Na+].[O:3]=[S:4]1(=[O:36])[C:10]2[CH:11]=[C:12]([O:16][CH:17](C(OCC)=O)C)[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1.[CH3:37][C:38]([OH:40])=[O:39]>CCO>[O:36]=[S:4]1(=[O:3])[C:10]2[CH:11]=[C:12]([O:16][CH2:17][CH2:37][C:38]([OH:40])=[O:39])[C:13]([Br:15])=[CH:14][C:9]=2[N:8]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:7][C:6]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:30][CH3:31])[CH2:5]1
Reactant: CC(=O)O
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OC(C)C(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCCC(=O)O)cc2S(=O)(=O)C1
Yield: 65 %

Procedure:
Sodium hydroxide (0.045 g, 1.13 mmol) was added to a solution of 1,1-dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-(1-ethoxycarbonylethoxy)-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 39; 0.050 g, 0.090 mmol) in EtOH (4 ml, 95%) and heated under reflux. After 1.5 hours AcOH (0.2 ml) was added and most of the solvent was removed under reduced pressure. The crude product was extracted (DCM/H2), dried (MgSO4) and evaporated to give the title compound 0.031 g (65%) as white solid. NMR (500 MHz, CD3OD) 0.70-0.85 (m, 6H), 0.95-1.25 (m, 4H), 1.35-1.70 (m, 4H), 2.65 (d, 3H), 3.10-3.35 (m, 2H), 3.45-3.95 (m, 2H), 4.70 (q, 1H), 6.90-7.35 (m, 6H), 7.45 (s, 1H).
Reaction SMILES: [F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C:16](=[CH:17][CH2:18]3)[CH2:15][C@@H:14]([OH:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2.[H][H]>C(O)C.[Pd]>[F:1][C@:2]12[C@H:19]3[C@@H:10]([C@:11]4([CH3:21])[C@@H:16]([CH2:17][CH2:18]3)[CH2:15][C:14](=[O:20])[CH2:13][CH2:12]4)[CH2:9][CH2:8][C@:6]1([CH3:7])[C:5](=[O:22])[CH2:4][CH2:3]2
Reactant: [H][H]
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F
Agent: [Pd]
Solvent: CCO
Product: C[C@]12CCC(=O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@]12F

Procedure:
14α-Fluoro-3β-hydroxyandrost-5(6)-en-17-one (400mg) in ethanol (70 ml) was hydrogenated over palladium-charcoal (5%; 250 mg) until uptake of hydrogen ceased (72 hr). The solvent was evaporated in vacuo and the crude product was recrystallised from acetone: hexane to give prisms of
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9]C)=[CH:4][C:3]=1[C:11]1[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:20])([F:19])[F:18])=[CH:15][N:16]=1.Br.O>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([OH:9])=[CH:4][C:3]=1[C:11]1[C:12](=[O:22])[N:13]([CH3:21])[C:14]([C:17]([F:18])([F:20])[F:19])=[CH:15][N:16]=1
Reactant: COc1cc(-c2ncc(C(F)(F)F)n(C)c2=O)c(Cl)cc1Cl
Agent: Br
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(C(F)(F)F)cnc(-c2cc(O)c(Cl)cc2Cl)c1=O
Temperature: 140 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
A mixture of 1.00 g of 3-(2,4-dichloro-5-methoxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-358) and 16 ml of 48% hydrobromic acid was dissolved in 5.7 ml of acetic acid, and the solution was stirred at 140° C. for 1 hour. After completion of the reaction, the reaction mixture was poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated sodium hydrogencarbonate, water, and then saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography, which afforded 0.74 g (yield, 77%) of 3-(2,4-dichloro-5-hydroxyphenyl)-1-methyl-6-trifluoromethyl-2-oxo-1,2-dihydropyrazine (present compound 1-357; m.p., 173.5° C.).
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([OH:17])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH3:18][Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO>[C:1]([NH:8][C:9]1[CH:14]=[CH:13][N:12]=[CH:11][C:10]=1[C:15]([O:17][CH3:18])=[O:16])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)Nc1ccncc1C(=O)O
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1cnccc1NC(=O)OC(C)(C)C
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a stirring suspension of 4-(Boc-amino)pyridine-3-carboxylic acid (1.04 g, 4.37 mmol) in methanol (3.5 mL) was added a 2 M solution of (trimethylsilyl)diazomethane in hexanes (3.5 mL, 7 mmol). After 15 min, acetic acid was added and the solvents were removed in vacuo. The residue was chromatographed over silica gel, eluting with a step gradient of 20% ethyl acetate in hexanes through 70% ethyl acetate in hexanes. The product containing fractions were combined and concentrated in vacuo to give the title compound (0.894 g, 81%) as a white solid.
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C@@H:10]1[C@@H:17]2[C@@H:13]([O:14][C:15]([CH3:19])([CH3:18])[O:16]2)[CH:12]=[CH:11]1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C(C(OO)=[O:28])C=1>ClCCl>[C:1]([Si:5]([O:8][CH2:9][C@@H:10]1[C@H:17]2[O:16][C:15]([CH3:19])([CH3:18])[O:14][C@H:13]2[C@@H:12]2[O:28][C@H:11]12)([CH3:7])[CH3:6])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)O[C@@H]2[C@@H](CO[Si](C)(C)C(C)(C)C)C=C[C@@H]2O1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC1(C)O[C@H]2[C@@H]3O[C@@H]3[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]2O1
Temperature: 25 °C
Reaction time: 6 h
Yield: 66.6 %

Procedure:
To a stirred solution of compound 9 (5.0 g, 17.5 mmol) in dichloromethane (40 mL) at room temperature was added portion wise m-CPBA (13.6 g, 78.9 mmol). Mixture was stirred at room temperature for 6 h, quenched with saturated NaHCO3 solution and the mixture was extracted with DCM (50 mL×2). The combined organic layers were washed with brine (40 mL×2) dried over Na2SO4. The solvent was removed under reduced pressure and residue was purified by silica gel column chromatography (3% EtOAc/Hexane) to give epoxide 10 (3.5 g, 66%) as an oil. [α]24D +58.19° (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3) δ 4.54-4.52 (m, 1H), 3.91-3.90 (m, 1H,), 3.73-3.69 (m, 1H), 3.59-3.55 (m, 3H), 2.316-2.311 (m, 1H), 1.38 (s, 3H), 1.22 (s, 3H), 0.83-0.82 (m, 9H), 0.006-0.000 (m, 6H); HR-MS Calcd. For (C15H28O4Si+H)+ 301.1757, found 301.1895.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[S:12][C:13]([C:17]([N:19]4[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]4)=[O:18])=[C:14]([CH3:16])[N:15]=3)[S:10][C:3]=12.[OH:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][C:31]([CH3:36])=[C:30]2[C:37]#[N:38]>>[CH3:36][C:31]1[NH:32][C:33]2[C:29]([C:30]=1[C:37]#[N:38])=[CH:28][C:27]([O:26][C:2]1[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[C:9]([C:11]4[S:12][C:13]([C:17]([N:19]5[CH2:24][CH2:23][N:22]([CH3:25])[CH2:21][CH2:20]5)=[O:18])=[C:14]([CH3:16])[N:15]=4)[S:10][C:3]=13)=[CH:35][CH:34]=2
Reactant: Cc1[nH]c2ccc(O)cc2c1C#N
Reactant: Cc1nc(-c2cc3nccc(Cl)c3s2)sc1C(=O)N1CCN(C)CC1
Product: Cc1nc(-c2cc3nccc(Oc4ccc5[nH]c(C)c(C#N)c5c4)c3s2)sc1C(=O)N1CCN(C)CC1
Yield: 41 %

Procedure:
The title compound (61 mg, 41%) was prepared from [2-(7-Chloro-thieno[3,2-b]pyridin-2-yl)-4-methyl-thiazol-5-yl]-(4-methyl-piperazin-1-yl)-methanone and 5-Hydroxy-2-methyl-1 H-indole-3-carbonitrile by a procedure analogous to Example 16 using and in a 41% yield. C27H25N6O2S2: APCI m/z 529.4 (pos.); 1H NMR (CD3OD): δ 8.72 (d, 1H, J=6.6 Hz), 8.17 (s, 1H), 7.60 (d, 1H, J=8.7 Hz), 7.58 (s, 1H), 7.23 (d, 1H, J=8.7 Hz), 7.07 (d, 1H, J=6.6 Hz), 3.65–3.15 (bm, 8H), 2.96 (s, 3H), 2.63 (s, 3H), 2.52 (s, 3H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[N:12]1([C:17]2[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=2)[CH:16]=[N:15][CH:14]=[N:13]1.[OH-].[Na+]>C(O)C.O>[N:12]1([C:17]2[CH:24]=[CH:23][C:20](/[CH:21]=[CH:10]/[C:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)=[O:11])=[CH:19][CH:18]=2)[CH:16]=[N:15][CH:14]=[N:13]1
Reactant: O=Cc1ccc(-n2cncn2)cc1
Reactant: CC(=O)c1cc(Cl)cc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(/C=C/c1ccc(-n2cncn2)cc1)c1cc(Cl)cc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 16.6 %

Procedure:
To a solution of 1-(3,5-dichlorophenyl)ethanone (0.5 g, 2.6 mmol) in ethanol (20 mL) was added 4-(1H-1,2,4-triazol-1-yl)benzaldehyde (0.46 g, 2.65 mmol) and the reaction was cooled to 0° C. Sodium hydroxide (0.22 g, 5.29 mmol) in water (10 mL) was then added and the reaction was allowed to stir for 2 h at 0° C. The reaction was extracted with EtOAc and the combined organic layers were dried over Na2SO4 and concentrated under reduced pressure to afford the title compound (0.149 g, 17%):); ESIMS m/z 430.05 ([M+H]+) 344.08
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15])[CH:6]=O.[S:16]1[CH2:22][C:20](=[O:21])[NH:19][C:17]1=[S:18].CC([O-])=O.[Na+].CC(O)=O>O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[C:22]2[S:16][C:17](=[S:18])[NH:19][C:20]2=[O:21])[CH:8]=[CH:9][C:10]=1[O:11][CH2:12][CH2:13][O:14][CH3:15]
Reactant: O=C1CSC(=S)N1
Reactant: COCCOc1ccc(C=O)cc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COCCOc1ccc(C=C2SC(=S)NC2=O)cc1OC
Temperature: 90 °C
Yield: 71.1 %

Procedure:
To a N2-purged flask was added 3-methoxy-4-(2-methoxy-ethoxy)-benzaldehyde from Step A (162 mg, 771 mmol), rhodanine (103 mg, 1 equiv), NaOAc (190 mg, 2.31 mmol) and HOAc (3 mL). The mixture was stirred and heated at 90° C. for 14 h under a condenser, resulting in a yellow precipitate. The reaction mixture was diluted with water (100 mL) and the solid precipitate was filtered in a Buchner funnel. The solid was washed with water, washed with hexane, and dried under high vacuum to yield the intermediate compound (179 mg, 72% yield).
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:27][C:26]([CH3:28])=[N:25][C:24]=2[C:29](O)=[O:30])=[CH:19][CH:18]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:29]([C:24]2[N:25]=[C:26]([CH3:28])[O:27][C:23]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)=[O:30])[CH:9]=[N:8]1
Reactant: COc1ccc(-c2oc(C)nc2C(=O)O)cc1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: COc1ccc(-c2oc(C)nc2C(=O)Nc2cnn(CCCCC(C)(F)F)c2)cc1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 5-(4-methoxy-phenyl)-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=419.26.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](=O)[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[NH2:16][C:17]([NH2:19])=[O:18].Cl>C(O)C>[OH:18][C:17]1[N:19]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[C:3]([C:2]([F:15])([F:14])[F:1])[N:16]=1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: Oc1nc(-c2ccccc2)cc(C(F)(F)F)n1
Yield: 41.9 %

Procedure:
4,4,4-Trifluoro-1-phenyl-1,3-butanedione (10.8 g) and urea (6.01 g) were dissolved in ethanol (25 mL) and concentrated hydrochloric acid (5 mL) was added. The mixture was heated under reflux for 2.5 hr. The reaction solution was concentrated under reduced pressure, and water was added. The mixture washed with chloroform. A saturated a aqueous sodium hydrogen carbonate solution was added to the a aqueous layer and the precipitate was collected by filtration to give 2-hydroxy-4-phenyl-6-trifluoromethylpyrimidine (5.03 g) as a pale-pink crystalline powder.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:28])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH2:24])[C:11]=1[N+:25]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)C>[CH2:1]([O:8][C:9](=[O:28])[C:10]1[CH:15]=[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:13]=[C:12]([NH2:24])[C:11]=1[NH2:25])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cc(OCc2ccccc2)cc(C(=O)OCc2ccccc2)c1N

Procedure:
3.0 g (7.9 mmol) of 3-amino-5-benzyloxy-2-nitro-benzoic acid benzyl ester was reduced by 5.4 g (23.7 mmol) of 5 nCl2.2H2O in 30 mL of ethanol at 80° C. for 3 h to produce 2,3-diamino-5-benzyloxy-benzoic acid benzyl ester. LCMS: 350 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C@H:7]([C:17]([OH:19])=O)[O:8][C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[NH2:26][CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C@H:7]([C:17]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:19])[O:8][C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]=2[CH:3]=1
Reactant: CC(C)N
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2F)O1
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2F)O1
Reaction time: 16 h

Procedure:
A solution of 3.38 g (10.9 mmoles) of trans-6-chloro-4-(2-fluorophenyl)-1,3-benzodioxan-2-carboxylic acid, 10.0 ml (16.4 g, 137 mmoles) of thionyl chloride, and 5 drops of anhydrous DMF in 200 ml of anhydrous Ch2Cl2 was refluxed for 2 hours; the solvent and excess SOCl2 were removed under reduced pressure and the residue was flashed down with 3 portions of anhydrous benzene to remove traces of SOCl2. The acid chloride was redissolved in 100 ml of anhydrous CH2Cl2 and 5.57 ml (3.86 g, 65.4 mmoles) of 2-aminopropane was added all at once; heat was evolved. The reaction mixture stood in a stoppered flask for 16 hours.
Reaction SMILES: CO[C:3](=[O:12])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[CH:5]=1.[OH-].[Na+].Cl.[CH3:16][C@H:17]1[CH2:21][O:20][C:19](=[O:22])[CH2:18]1>>[CH3:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([CH3:11])[CH:7]=1)[C:3]([C@H:18]1[CH:17]([CH3:16])[CH2:21][O:20][C:19]1=[O:22])=[O:12]
Reactant: COC(=O)c1cc(C)cc(C)c1
Reactant: C[C@H]1COC(=O)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(C)cc(C(=O)[C@@H]2C(=O)OCC2C)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 62.1 %

Procedure:
To a solution of (R)-4-methyldihydrofuran-2-one (1.68 g in 40 mL dioxane) were added 5.51 g 3,5-dimethylbenzoic acid methyl ester followed by 1.82 g sodium hydroxide and the mixture heated to reflux on an oil bath. After 3 hours, the mixture was cooled to room temperature and the pH neutralized by the addition of 0.5N hydrochloric acid. The mixture was then extracted with ethyl acetate and the organic portion washed with brine and dried over sodium sulfate. Purification of the concentrate by flash chromatography on silica gel (hexane:ethyl acetate, 9:1) gave the title compound (2.42 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH3:23][S:24]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)(=[O:26])=[O:25]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:31]=[CH:32][C:27]([S:24]([CH3:23])(=[O:26])=[O:25])=[CH:28][CH:29]=4)[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CS(=O)(=O)c1ccc(B(O)O)cc1
Product: CC(C)(O)c1ccn2c(-c3ccc(F)c(-c4ccc(S(C)(=O)=O)cc4)c3)cnc2c1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 4-methanesulfonylbenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-4′-methanesulfonylbiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 443 [MH+].
Reaction SMILES: [N:1]1([C:8]([NH:10][C@@H:11]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:12]([OH:14])=O)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:19][O:20][C:21](=[O:33])[C@@H:22]([NH2:32])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1>C(OCC)(=O)C>[CH3:19][O:20][C:21](=[O:33])[CH:22]([NH:32][C:12](=[O:14])[CH:11]([NH:10][C:8]([N:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)=[O:9])[CH2:15][CH:16]([CH3:18])[CH3:17])[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:26][CH:25]=1
Reactant: CC(C)C[C@H](NC(=O)N1CCCCCC1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1ccc(OC)cc1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCc2ccccc2)cc1)NC(=O)C(CC(C)C)NC(=O)N1CCCCCC1
Yield: 151 %

Procedure:
A solution of the product from Example Z (2(S)-[(azepane-1-carbonyl)-amino]-4-methyl-pentanoic acid) (0.20 g, 0.78 mmol) and 2(S)-amino-3-(4-methoxy-phenyl)-propionic acid methyl ester (Bachem, 0.277 g, 0.86 mmol) were coupled according to the procedure described in Example 3. The residue was passed through a plug of silica gel eluting with ethyl acetate. The material obtained was purified by crystallization from hot hexane/ethyl acetate to give the title compound as a white solid (0.34 g, 83%), mp=72-74° C.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6].N([O-])=[O:18].[Na+].O>Cl.CO>[OH:18][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=N[O-]
Reactant: Nc1cc(C(=O)O)cc(N2CCCC2=O)c1
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: O=C(O)c1cc(O)cc(N2CCCC2=O)c1
Temperature: 90 °C

Procedure:
This amine (1.10 g, 5.0 mmol) in 2N HCl (10 ml) and methanol (approx 15 ml, to aid solubility) was cooled in an ice bath and treated portionwise with sodium nitrite (0.76 g, 11.0 mmol) at such a rate to keep the temperature below 5° C. After completion of the addition, water (20 ml) was added and the mixture was heated at approx 90° C. for 1 hr. After cooling the product was extracted into ethyl acetate and the combined extracts were washed with brine and then dried over sodium sulfate and evaporated to give the title compound, 0.93 g.
Reaction SMILES: [C:1]([OH:8])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].O[N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16].C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:8][N:10]1[C:14](=[O:15])[CH2:13][CH2:12][C:11]1=[O:16])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: O=C1CCC(=O)N1O
Reactant: CCCCCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CCCCCC(=O)ON1C(=O)CCC1=O
Reaction time: 5 h
Yield: 74.3 %

Procedure:
To a solution of 4.64 g (0.04 mol) of hexanoic acid and 5.75 g (0.05 mol) of N-hydroxy succinimide in 100 mL distilled DMF, 10.3 g (0.05 mol) of DCCI was added. The mixture was cooled with an ice-water bath and stirred for 5 h. The dicyclohexyl urea (DCU) precipitate was removed by filtration, and the DMF solvent was removed by vacuum rotary evaporation. The yellow oil residue was washed with water and hexane to yield a white solid, which was vacuum dried at 78° C. to give 6.34 g (74%) of N-hexanoyloxy succinimide. IR (KBr): 1816 cm−1 (ν(C═O) of ester), 1745-1786 cm−1 (ν(C═O) of imide). 1H-NMR (DMSO-d6, ppm): 0.86 (3H, —CH3), 1.31 (4H, —(CH2)2CH3), 1.62 (2H, CH2CH2COO—), 2.64 (2H, —CH2COO—), 2.80 (4H, —COCH2CH2CO—).