Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](=[O:30])[C@@H:9]2[C@:26]3([CH3:27])[C@H:12]([C@H:13]4[C@H:23]([C:24](=[O:28])[CH2:25]3)[C@:21]3([CH3:22])[C@H:16]([CH2:17][C:18](=[O:29])[CH2:19][CH2:20]3)[CH2:15][CH2:14]4)[CH2:11][CH2:10]2)[CH2:3][CH2:2]1>O>[OH:29][C@@H:18]1[CH2:19][CH2:20][C@@:21]2([CH3:22])[C@@H:16]([CH2:15][CH2:14][C@@H:13]3[C@@H:23]2[C:24](=[O:28])[CH2:25][C@@:26]2([CH3:27])[C@H:12]3[CH2:11][CH2:10][C@@H:9]2[C:8](=[O:30])[CH2:7][N:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:17]1
Reactant: C[C@]12CCC(=O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)CN4CCOCC4)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 21-morpholino-5α-pregnane-3,11,20-trione (100 mg.) in the "stock" hloroiridic solution (see preparation 6 below) (10 ml.), was refluxed for 14 hours. The cooled mixture was poured into water and made just alkaline. The slight oily precipitate was extracted into ethyl acetate and the extracts were washed with water, dried (Na2SO4), and evaporated to give essentially the title compound, shown by n.m.r. spectroscopy and T.L.C. (Rf 0.16) on silica in ethyl acetate to be identical to the product of Example 38.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:27])[C@@H:4]([NH:9][CH2:10][C:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)=[CH:12][C:13](OCC)=[O:14])[CH2:5][CH:6]([CH3:8])[CH3:7]>O1CCCC1>[CH3:1][O:2][C:3](=[O:27])[C@@H:4]([N:9]1[CH2:10][C:11]([O:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[CH:12][C:13]1=[O:14])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CCOC(=O)C=C(CN[C@@H](CC(C)C)C(=O)OC)Oc1ccc(OC)cc1
Solvent: C1CCOC1
Product: COC(=O)[C@H](CC(C)C)N1CC(Oc2ccc(OC)cc2)=CC1=O
Temperature: 25 °C
Yield: 46.6 %

Procedure:
A solution of (S)-2-[3-ethoxycarbonyl-2-(4-methoxy-phenoxy)-allylamino]-4-methyl-pentanoic acid methyl ester (0.83 g, 2.51 mmol) in tetrahydrofuran (10 mL) was heated to 160° C. in a high pressure reaction vessel for 24 h. At this time, the reaction was cooled to 25° C. and was concentrated in vacuo. Purification by Analogix flash chromatography (40 g, 20-30% ethyl acetate/hexanes) afforded (S)-2-[4-(4-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-methyl-pentanoic acid methyl ester (0.39 g, 46%) as a yellow oil: HR-ES-MS m/z calculated for C18H23NO5 [M+H]+ 334.1649, observed 334.1649; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.87 (d, J=6.6 Hz, 3H), 0.92 (d, J=6.6 Hz, 3H), 1.39-1.53 (m, 1H), 1.53-1.68 (m, 1H), 1.68-1.87 (m, 1H), 3.65 (s, 3H), 3.77 (s, 3H), 4.13 (d, J=18.1 Hz, 1H), 4.20 (d, J=18.1 Hz, 1H), 4.72 (dd, J=11.3, 4.4 Hz, 1H), 4.77 (s, 1H), 7.00 (d, J=9.1 Hz, 2H), 7.23 (d, J=9.1 Hz, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:18][CH3:19].CS([C:23]1[N:28]=[CH:27][C:26]2=[CH:29][CH:30]=[C:31]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[S:38]([CH3:41])(=[O:40])=[O:39])[N:25]2[N:24]=1)=O>>[CH3:41][S:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:31]1[N:25]2[C:26]([CH:27]=[N:28][C:23]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([N:8]4[CH2:13][CH2:12][N:11]([CH2:14][C@@H:15]([OH:17])[CH3:16])[CH2:10][CH2:9]4)=[CH:4][C:3]=3[O:18][CH3:19])=[N:24]2)=[CH:29][CH:30]=1)(=[O:39])=[O:40]
Reactant: CS(=O)c1ncc2ccc(-c3ccccc3S(C)(=O)=O)n2n1
Reactant: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1N
Product: COc1cc(N2CCN(C[C@H](C)O)CC2)ccc1Nc1ncc2ccc(-c3ccccc3S(C)(=O)=O)n2n1
Temperature: 190 °C

Procedure:
Following the procedure of example 532 (c), (S)-1-[4-(4-Amino-3-methoxy-phenyl)-piperazin-1-yl]-propan-2-ol (0.087 g, 0.33 mmol) and 2-Methanesulfinyl-7-(2-methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (0.16 g, 0.48 mmol) were heated in the microwave at 190° C. for 4 hours. Purification by Gilson chromatography gave (S)-1-(4-{4-[7-(2-Methanesulfonyl-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-3-methoxy-phenyl}-piperazin-1-yl)-propan-2-ol as a tan solid. MP: 98-100° C.; LCMS (m/e) 537 (M+1); 1H-NMR (DMSO-d6, 400 MHz) δ 8.94 (s, 1H), 8.16-8.15 (d, 1H, J=6.84 Hz), 7.88-7.85 (t, 1H, J=6.24 Hz), 7.80-7.76 (t, 1H, J=7.73 Hz), 7.70-7.68 (d, 1H, J=7.56 Hz), 7.60 (s, 1H), 7.44-7.42 (d, 1H, J=8.77 Hz), 6.95-6.91 (q, 2H, J=4.64 Hz), 6.56 (s, 1H), 6.21-6.18 (dd, 1H, J=2.44 Hz), 4.30-4.29 (d, 1H), 3.77 (s, 3H), 3.29 (s, 1H), 3.05-3.03 (m, 3H), 2.87 (s, 3H), 2.55-2.52 (m, 2H), 2.28-2.21 (m, 6H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][N:6](C(OC(C)(C)C)=O)[C:5]=2[CH:4]=[N:3]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]1[C:10]2[CH2:9][CH2:8][CH2:7][NH:6][C:5]=2[CH:4]=[N:3]1
Reactant: Cn1ncc2c1CCCN2C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1ncc2c1CCCN2
Reaction time: 18 h
Yield: 69.1 %

Procedure:
To a stirred solution of tert-butyl 1-methyl-6,7-dihydro-1H-pyrazolo[4,3-b]pyridine-4(5H)-carboxylate (55 mg, 232 μmol) in CH2Cl2 (4 mL) was added TFA (740 mg, 500 μL, 6.49 mmol). After 18 h, the reaction mixture was concentrated in vacuo and the residue obtained purified by chromatography (40 g column, 50 m silica-gel from Analogix, 0 to 5% 9:1 methanol:ammonium hydroxide in CH2Cl2, 20 min) to give 1-methyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-b]pyridine (22 mg, 69%). 1H NMR (CHLOROFORM-d) δ: 7.05 (s, 1H), 3.70 (s, 3H), 3.08-3.21 (m, 2H), 2.88 (br. s., 1H), 2.64 (t, J=6.4 Hz, 2H), 1.84-2.01 (m, 2H). MS (EI/CI) m/z: 138.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F:11][C:12]([Si](C)(C)C)([F:14])[F:13].Cl>C1COCC1.C(Cl)(Cl)Cl.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]([OH:5])[C:12]([F:14])([F:13])[F:11]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: OC(c1ccc(F)cc1Br)C(F)(F)F
Temperature: 0 °C
Yield: 90 %

Procedure:
Charge 2-bromo-4-fluoro-benzaldehyde (6.1 g, 30.1 mmol) and trifluoromethyl trimethylsilane (5.4 g, 36.1 mmol) in THF (50 mL) in a 100-mL round bottom flask. Cool the solution to 0° C. under N2. Add Bu4NF (0.3 g, 1.20 mmol). Stir the mixture at 0° C. for another hour. Add hydrogen chloride (40 mL, 1 M, 40 mmol) to the mixture. Stir the mixture at RT overnight. Dilute the reaction mixture with chloroform. Wash the organic layer with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo to give the crude product. Purify by FCC (hexanes/ethyl acetate, 4/1) to give the title compound as a yellow oil (7.40 g, 90%). MS (ES) m/z 273/275 [M+1]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10](Cl)=[CH:9][N:8]=1)=[O:6].[NH4+].[Cl-].[CH3:17][OH:18]>>[CH3:3][O:4][C:5]([C:7]1[C:12]([NH2:13])=[N:11][C:10]([O:18][CH3:17])=[CH:9][N:8]=1)=[O:6]
Reactant: CO
Reactant: COC(=O)c1ncc(Cl)nc1N
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Product: COC(=O)c1ncc(OC)nc1N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
At 0° C. 75 mg (1.866 mmol) 60% sodium hydride in oil was added in portions to 5 ml MeOH and the mixture was stirred at room temperature for 30 min. After re-cooling to 0° C. 350 mg (1.866 mmol) 3-amino-5-chloro-pyrazine-2-carboxylic acid methyl ester (GB 1248146) was added and the mixture was allowed to warm to room temperature and stirred over night. Saturated aqueous NH4Cl was added and the mixture was extracted with DCM and EtOAc, the combined organic layers were washed with saturated aqueous sodium chloride, dried with Na2SO4 and evaporated. The residue was purified by chromatography on silica gel (cyclohexane to EtOAc) to provide the title compound as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[CH2:9]([NH:16][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: NCc1ccccc1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nccc(NCc2ccccc2)n1
Temperature: 25 °C

Procedure:
A solution of 2,4-dichloropyrimidine (0.500 g, 3.36 mmol) in isopropanol (10 mL) was cooled to 0° C., and benzylamine (0.360 g, 0.37 mL, 3.36 mmol) was added. N,N-Diisopropylethylamine (0.434 g, 0.58 mL, 3.4 mmol) was added and the mixture was allowed to warm to room temperature over 15 h. The resulting white suspension was concentrated to afford a white solid. This material was purified via column chromatography on silica gel (gradient elution with 0-50% ethyl acetate-hexane) to afford benzyl-(2-chloropyrimidin-4-yl)amine as a white solid. MS (MH+) 220.1; Calculated 219.68 for C11H10ClN3.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11](C=O)=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.[OH-].[K+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([OH:36])=[CH:10][C:9]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCOCOc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 2′-methoxyethoxymethoxy-[1,1′;3′,1″]terphenyl-5′-carboxaldehyde (0.836 g, 2.31 mmol) in CH2Cl2 (25 mL) at room temperature was added MCPBA (0.598 g, 3.46 mmol). The reaction mixture was refluxed for 48 h. After concentration, the residue was dissolved in EtOAc (300 mL). The organic layer 15 was washed with sat. aq. NaHCO3 until effervescence ceased followed brine (30 mL) and then dried (Na2SO4). After concentration, the residue was dissolved in THF:MeOH (3:2, 45 mL) followed by the dropwise addition of 1 N KOH (11.6 mL, 11.6 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. The residue was diluted with H2O (30 mL) and then acidified to pH 4 with 1 N HCl followed by extraction with EtOAc (300 mL). This organic layer was washed with brine (30 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (5 to 15% acetone/hexane gradient) to afford the product (0.490 g, 61%) as a solid; 1H NMR (CDCl3) δ 2.73-2.86 (m, 2H), 2.90-2.98 (m, 2H), 3.17 (s, 3H), 4.35 (s, 2H), 4.67 (s, 1H), 6.82 (s, 2H), 7.27-7.47 (m, 6H), 7.57 (d, J=9.3 Hz, 4H); mass spectrum [(+) ESI], m/z 373 (M+Na)+.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:34])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([OH:30])[C:22]=3[CH2:31][CH2:32][CH3:33])[CH:14]=2)[CH:7]=1.Cl>C(O)(C)C>[C:27]([C:24]1[CH:25]=[CH:26][C:21]([O:20][CH2:19][C:15]2[CH:14]=[C:13]([NH:12][C:8]3[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=3)[C:5]([OH:34])=[O:4])[CH:18]=[CH:17][CH:16]=2)=[C:22]([CH2:31][CH2:32][CH3:33])[C:23]=1[OH:30])(=[O:29])[CH3:28]
Reactant: CCCc1c(OCc2cccc(Nc3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CC(C)O
Product: CCCc1c(OCc2cccc(Nc3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
Add 1M aqueous lithium hydroxide (3.23 mL, 3.23 mmol) to a solution of 3-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenylamino]-benzoic acid methyl ester (280 mg, 0.646 mmol) in isopropanol (25 mL) and stir. Heat to 80° C. After 1 hour, pour reaction into 1N aqueous hydrochloric acid (50 mL) and extract with ethyl acetate. Combine organic layers, dry with sodium sulfate, filter and concentrate to dryness. Purify the resulting residue by trituration (ether:hexanes) to yield the title compound as a yellow solid (200 mg, 74%): 1H NMR (DMSO-d6) δ 0.81 (t, 3H), 1.46 (sextuplet, 2H), 2.58 (m, 5H), 5.23 (s, 2H), 6.71 (d, 1H), 6.94 (d, 1H), 7.02 (d, 1H), 7.19 (s, 1H), 7.29 (m, 3H), 7.40 (d, 1H), 7.65 (s, 1H), 7.81 (d, 1H), 8.44 (s, 1H), 12.73-12.92 (bs, 1H), 12.84 (s, 1H); MS (esi negative) m/z (rel intensity) 418 (100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20](=O)[CH2:21][C:22](=O)[CH2:23][O:24][CH2:25][CH3:26])=[CH:16][CH:15]=3.C(O)(=O)C(O)=O.[CH2:40]([NH:42][NH2:43])[CH3:41]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:31](=[O:32])[N:30]([CH3:33])[C:12]2[N:13]([CH3:29])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[N:42]([CH2:40][CH3:41])[N:43]=[C:22]([CH2:23][O:24][CH2:25][CH3:26])[CH:21]=1)=[CH:16][CH:15]=3
Reactant: CCNN
Reactant: CCOCC(=O)CC(=O)c1ccc2c(c1)c1cc(-c3ccc(Cl)cc3Cl)c(=O)n(C)c1n2C
Agent: O=C(O)C(=O)O
Product: CCOCc1cc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C)n(CC)n1

Procedure:
The process is carried out as in Example 37 above, with the compound from Example 80A, 1-[3-(2,4-dichlorophenyl)-1,9-dimethyl-2-oxo-2,9-dihydro-1H-pyrido[2,3-b]indol-6-yl]-4-ethoxybutane-1,3-dione and ethylhydrazine oxalate.
Reaction SMILES: [Si](O[CH2:9][C:10]1[C:15]([CH3:16])=[CH:14][CH:13]=[C:12]([O:17]COC)[C:11]=1[C:21]1([OH:25])[CH2:24][CH2:23][CH2:22]1)(C(C)(C)C)(C)C>C(OCC)(=O)C.S(=O)(=O)(O)O>[CH3:16][C:15]1[C:10]2[CH2:9][O:25][C:21]3([CH2:22][CH2:23][CH2:24]3)[C:11]=2[C:12]([OH:17])=[CH:13][CH:14]=1
Reactant: COCOc1ccc(C)c(CO[Si](C)(C)C(C)(C)C)c1C1(O)CCC1
Agent: O=S(=O)(O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(O)c2c1COC21CCC1
Reaction time: 2 h
Yield: 77.1 %

Procedure:
To a solution of 1-[2-[[tert-butyl(dimethyl)silyl]oxymethyl]-6-(methoxymethoxy)-3-methyl-phenyl]cyclobutanol (Intermediate 175, 0.05 g, 0.136 mmoli) in Ethyl Acetate (5 ml), Sulphuric Acid (96%, 2 drops) was added at room temperature and the reaction mixture was stirred for 2 h. Ethyl Acetate (20 ml) was added and the organic phase was washed with brine (2×50 ml), dried over sodium sulphate and evaporated. The residue was purified by flash chromatography (Biotage system) on silica gel using a 10 g SNAP column and cyclohexane to cyclohexane/ethyl acetate 7:3 as eluents affording the title compound (0.02 g) as a colourless oil.
Reaction SMILES: [CH:1]1([CH3:34])[CH2:6][CH2:5][CH:4]([CH:7]([CH3:9])[CH3:8])[CH:3]([O:10][C:11]([CH:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16](=[O:23])[N:15]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=3[F:32])[C:14]2=[O:33])=[O:12])[CH2:2]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:42][C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44].O>CN(C=O)C>[CH3:47][C:46]([O:45][C:43](=[O:44])[CH2:42][C:13]1([C:11]([O:10][CH:3]2[CH:4]([CH:7]([CH3:8])[CH3:9])[CH2:5][CH2:6][CH:1]([CH3:34])[CH2:2]2)=[O:12])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16](=[O:23])[N:15]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([Br:31])=[CH:27][C:26]=2[F:32])[C:14]1=[O:33])([CH3:49])[CH3:48]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC1CCC(C(C)C)C(OC(=O)C2C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1CCC(C(C)C)C(OC(=O)C2(CC(=O)OC(C)(C)C)C(=O)N(Cc3ccc(Br)cc3F)C(=O)c3ccccc32)C1
Temperature: 85 °C
Reaction time: 2 h
Yield: 25.9 %

Procedure:
To a mixture of 2-[(4-bromo-2-fluorophenyl)methyl]-1,2,3,4-tetrahydro-1,3-dioxo-4-isoquinoline carboxylic acid menthyl ester (7.62 g, 14.37 mmol), K2CO3 (3.96 g, 28.74 mmol) in DMF (100 mL) was added tert-butyl bromoacetate (4.64 mL, 28.74 mmol). The mixture was stirred at 85° C. for 2 hours, poured into H2O (1000 mL) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography (hexane/EtOAc:4/1) gave a clear oil (6.9 g, diastereomeric mixture). The two diastereomers were separated by preparative HPLC on prep. Pac silica column, (μ poraSi/125 Å, 15-20 μsilica) by elution with hexane/CH2Cl2 to give the less polar A-diastereomer as a white solid (2.4 g) and the more polar diastereomer B as a clear oil (2.2 g). The diastereomeric purity was determined by analytical HPLC, on Dynamax silica 25 cmx4.1 mm and was found to be greater than 99% for both diastereomers.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17]>C(O)(=O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: N=CN
Reactant: Nc1ccc(I)cc1C(=O)O
Solvent: CC(=O)O
Product: O=c1[nH]cnc2ccc(I)cc12
Temperature: 130 °C
Yield: 99.8 %

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (9.00 g, 34.2 mmol) and formamidine acetate (18.00 g, 173 mmol) in acetic acid (50 mL) was heated at 130° C. for 3 hours. After it was cooled down to room temperature, it was quenched with water, filtered, washed with water, and dried under vacuum with P2O5 to afford 6-iodoquinazolin-4(3H)-one as solid (9.289 g, 99.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.38 (d, 1H), 8.13 (s, 1H), 8.09 (dd, 1H), 7.46 (d, 1H); LC-MS (ESI) m/z 273 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6]([C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=O)=[CH:4][CH:3]=1.[NH2:35][OH:36]>C(O)C>[F:1][C:2]1[CH:34]=[CH:33][C:5]([C:6](=[N:35][OH:36])[C:8]2[CH:32]=[CH:31][C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][C@H:25]([O:29][CH3:30])[C:26]([OH:28])=[O:27])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=O)c3ccc(F)cc3)cc2)cc1)C(=O)O
Solvent: CCO
Product: CO[C@@H](Cc1ccc(C#CCCCOc2ccc(C(=NO)c3ccc(F)cc3)cc2)cc1)C(=O)O
Reaction time: 8 h

Procedure:
(2S)-3-(4-{5-[4-(4-Fluoro-benzoyl)-phenoxy]-pent-1-ynyl}-phenyl)-2-methoxy-propionic acid from Example 25 (1 eq) was mixed with Hydroxylamine chlorydrate (4 eq), pyrydine (10 eq) and Ethanol (2 ml) and the mixture reaction was stirred overnight. The ethanol was evaporated under vacuo and HCl 0.5% was added to the residue to pH=3. Extracted with Ethyl Acetate and concentrated to give the title product as a mixture of two oximes. MS(ES) for C28H26FNO5 [M+H]+: 476.2, [M−H]−: 474.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9]O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.N1C=CC=CC=1.S(Cl)([Cl:19])=O.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][Cl:19])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Cl)cc(Cl)c1
Solvent: c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Product: ClCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
Under a nitrogen atmosphere, a stirred solution of 25.0 grams (0.141 mole) of 3,5-dichlorophenylmethanol and 11.4 mL (0.141 mole) of pyridine in 200 mL of chloroform was cooled to 5° C., and 15.9 mL (0.218 mole) of thionyl chloride was added dropwise during a 10 minute period. Upon completion of addition, the reaction mixture was allowed to warm to ambient temperature where it was stirred for about 18 hours. After this time, the reaction mixture was poured into 300 mL of water, and the mixture was extracted with 600 mL of diethyl ether. The ether solution was washed with 70 mL of an aqueous 6N hydrochloric acid solution, and then it was concentrated under reduced pressure to a residual oil. The oil was distilled under reduced pressure, yielding 25.6 grams of 3,5-dichlorophenylmethyl chloride, bp 95°-100° C./0.1 mm Hg.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4]([NH2:6])=[O:5].OC1C=CC=CN=1.[CH3:16][C:17]1([CH3:55])[CH2:22][N:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[C:20](=[O:30])[CH2:19][N:18]1[CH2:31][C@H:32]([NH:42][S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53])(=[O:45])=[O:44])[C@@H:33]1[CH2:37][C@@H:36]([CH:38]([CH3:40])[CH3:39])[C:35](=[O:41])[O:34]1>C(N(CC)CC)C>[C:4]([C:3]([CH3:8])([CH3:7])[CH2:2][NH:1][C:35](=[O:41])[C@H:36]([CH:38]([CH3:39])[CH3:40])[CH2:37][C@H:33]([OH:34])[C@@H:32]([NH:42][S:43]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[N+:52]([O-:54])=[O:53])(=[O:44])=[O:45])[CH2:31][N:18]1[CH2:19][C:20](=[O:30])[N:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:29])[CH2:22][C:17]1([CH3:55])[CH3:16])(=[O:5])[NH2:6]
Reactant: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H]2C[C@@H](C(C)C)C(=O)O2)CC1=O
Reactant: CC(C)(CN)C(N)=O
Agent: Oc1ccccn1
Solvent: CCN(CC)CC
Product: Cc1ccccc1N1CC(C)(C)N(C[C@H](NS(=O)(=O)c2ccccc2[N+](=O)[O-])[C@@H](O)C[C@H](C(=O)NCC(C)(C)C(N)=O)C(C)C)CC1=O
Temperature: 80 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
223 mg of 3-amino-2,2-di(methyl)propionamide obtained in Reference Example 2 (1.92 mmol) and 61 mg of 2-hydroxypyridine (0.64 mmol) were added to a solution of 367 mg of N-{(S)-2-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-1-[(2S,4S)-4-isopropyl-5-oxotetrahydrofuran-2-yl]ethyl}-2-nitrobenzenesulfonamide obtained in the above reaction (0.64 mmol) in triethylamine (6 ml), and the mixture was stirred at 80° C. for one hour. The reaction mixture was cooled and then concentrated under reduced pressure and further stirred at 80° C. for 14 hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent:methylene chloride/methanol=20/1) to obtain 345 mg of (2S,4S,5S)-6-[2,2-dimethyl-4-(2-methylphenyl)-5-oxopiperazin-1-yl]-4-hydroxy-2-isopropyl-5-(2-nitrobenzenesulfonylamino)hexanoic acid (2-carbamoyl-2-methylpropyl)amide (yield: 78%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]#[N:15].C[Sn]([N:20]=[N+:21]=[N-:22])(C)C>C1(C)C(C)=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]12[CH2:13][CH:12]1[C:14]1[NH:22][N:21]=[N:20][N:15]=1
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#CC1CC12C(=O)Nc1ccc(Br)cc12
Solvent: Cc1ccccc1C
Product: O=C1Nc2ccc(Br)cc2C12CC2c1nnn[nH]1
Temperature: 5 °C
Yield: 68.6 %

Procedure:
A suspension containing 5′-bromo-2-cyano-spiro[cyclopropane-1,3′-[3H]indol]-2′(1′H)-one (263 mg, 1 mmol) and trimethyltin azide(384 mg, 2 mmol) in xylene (20 mL) was stirred and heated to reflux for 16 hours. After cooling the solution to 5° C., a white precipitate was obtained that gave 210 mg (yield: 69%) of the title compound. MS: m/z 206 [M+1]+; 1H NMR (DMSO-d6): δ 10.7 (br, 1H), 7.14 (m, 1H), 7.0 (m, 2H), 6.70 (d, 1H), 2.90 (m, 1H), 2.24 (m, 1H). 1.98 (m, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:36]=[CH:35][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22](C(OCC5C=CC=CC=5)=O)[CH2:21][CH2:20]4)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]>CO.O1CCCC1.[Pd]>[C:1]([C:3]1[CH:4]=[C:5]([CH:38]([CH3:40])[CH3:39])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)=[O:16])=[CH:35][CH:36]=3)=[N:8][C:7]=2[CH:37]=1)#[N:2]
Reactant: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCN(C(=O)OCc5ccccc5)CC4)cc3)oc12
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)NCC4CCNCC4)cc3)oc12
Temperature: 50 °C
Reaction time: 3 h
Yield: 103.5 %

Procedure:
To a solution of benzyl 4-({[4-(5-cyano-7-isopropyl-1,3-benzoxazol-2yl)benzoyl]amino}methyl)piperidine-1-carboxylate (2.19 g, EXAMPLE 35) in methanol (30 ml) and tetrahydrofuran (7 ml) was added 10% palladium on carbon (500 mg, 4.70 mmol). The mixture was flushed with nitrogen, then flushed with hydrogen, and then warmed to 50° C. and stirred for 3 h under a hydrogen balloon at this temperature, at which point LC/MS analysis showed no starting material. The mixture was filtered through a plug of Celite, washing liberally with methanol, and then concentrated to provide the title compound (1.7 g, 103%). Mass spectrum (ESI) 403.6 (M+1). 1H NMR (500 MHz, CDCl3): δ 8.32 (d, J=8 Hz, 2H), 7.94 (d, J=8.5 Hz, 2H), 7.93 (s, 1H), 7.51 (s, 1H), 6.33 (br s, 1H), 3.44-3.54 (m, 2H), 3.40 (m, 2H), 3.13 (br d, 2H), 2.63 (br t, 2H), 1.77 (m, 2H), 1.46 (d, J=6.5 Hz, 6H), 1.26 (m, 2H).