Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([CH3:11])[C:5]2=[N:4][C:3]=1[NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16].[H-].[Na+].Cl[S:23]([C:26]1[CH:35]=[CH:34][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:28][CH:27]=1)(=[O:25])=[O:24]>CN(C=O)C.CCOC(C)=O>[C:15]([O:14][C:13]([N:12]([C:3]1[N:4]=[C:5]2[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][N:6]2[C:2]=1[CH3:1])[S:23]([C:26]1[CH:27]=[CH:28][C:29]([C:30]([O:32][CH3:33])=[O:31])=[CH:34][CH:35]=1)(=[O:25])=[O:24])=[O:19])([CH3:16])([CH3:18])[CH3:17]
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Cc1cccn2c(C)c(NC(=O)OC(C)(C)C)nc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(S(=O)(=O)N(C(=O)OC(C)(C)C)c2nc3c(C)cccn3c2C)cc1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a solution of compound 2-B (0.799 g, 3.06 mmol) in DMF (22 mL), cooled to 0° C., was added 60% NaH (0.147 g, 3.67 mmol) and the reaction mixture was stirred at 0° C. for 20 min. Methyl 4-(chlorosulfonyl)benzoate (2.15 g, 9.17 mmol) was added in small portions and the reaction mixture was stirred at ambient temperature for 18 h. The reaction mixture was diluted with EtOAc, washed with H2O (2×), brine, dried over Na2SO4, filtered, and the solvent evaporated under reduced pressure to afford a crude solid. The crude material was purified by flash column chromatography (SiO2) eluting with a heptanes-EtOAc gradient to afford compound 2-C as a white solid (0.693 g, 49%). 1H-NMR (CDCl3): δ 8.38-8.40 (dd, 2H), 8.23-8.25 (dd, 2H), 7.75-7.77 (d, 1H), 7.00-7.02 (d, 1H), 6.79-6.83 (m, 1H), 3.98 (s, 3H), 2.51 (s, 3H), 1.59 (s, 3H), 1.34 (s, 9H); MS: m/z 460.2 (MH+).
Reaction SMILES: N[C:2]1[C:3]([C:14]2[C:15]([Cl:34])=[C:16]([NH:21][C:22](=[O:33])[C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[CH:17]=[CH:18][C:19]=2[Cl:20])=[CH:4][C:5]2[CH:10]=[N:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[N:13]=1.N([O-])=[O:36].[Na+]>C(O)(C(F)(F)F)=O>[Cl:34][C:15]1[C:14]([C:3]2[C:2](=[O:36])[NH:13][C:6]3[N:7]=[C:8]([S:11][CH3:12])[N:9]=[CH:10][C:5]=3[CH:4]=2)=[C:19]([Cl:20])[CH:18]=[CH:17][C:16]=1[NH:21][C:22](=[O:33])[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:31])[F:32])[CH:24]=1
Reactant: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(N)nc2n1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc2cc(-c3c(Cl)ccc(NC(=O)c4cccc(C(F)(F)F)c4)c3Cl)c(=O)[nH]c2n1
Reaction time: 0.33 h
Yield: 96.4 %

Procedure:
To a solution of N-[3-(7-amino-2-methylsulfanyl-pyrido[2,3-d]pyrimidin-6-yl)-2,4-dichloro-phenyl]-3-trifluoromethyl-benzamide (1.7 g, 3.24 mmol) in TFA (15 mL) is slowly added NaNO2 (783 mg, 11.35 mmol) at 0° C. with stirring for 20 minutes. The solvents are evaporated and diluted with EtOAc and washed with saturated K2CO3, brine and water. The organic layer is dried, filtered and concentrated to give the crude product. The crude product is purified by flash silica gel column, eluting with CH2Cl2 (100%) gradient to CH2Cl2/MeOH(NH3, 2N)(93/7%), to give the title intermediate as a solid (1.64 g, 96.5%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=1)(=O)C.[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[O:7]([C:8]1[CH:9]=[CH:10][C:11]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:36])=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: Cc1noc(C)c1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(I)cc1
Product: Cc1noc(C)c1-c1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cc1
Yield: 63 %

Procedure:
By carrying out the operation analogously to example 29, starting from 4-iodophenyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation II, and 3,5-dimethyl-4-isoxazoleboronic acid, the expected compound is obtained in the form of a white solid with a yield of 63%.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:16](OC)[N:17]([CH3:19])[CH3:18]>CO>[CH3:16][N:17]([CH3:19])/[CH:18]=[CH:2]/[C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1ccc(C(C)=O)cc1
Solvent: CO
Product: COC(=O)c1ccc(C(=O)/C=C/N(C)C)cc1
Temperature: 0 °C
Yield: 84 %

Procedure:
A mixture of methyl 4-acetylbenzoate (25 g, 140 mmol) and N,N-dimethylformamide dimethyl acetal (100 mL) was heated to reflux for 2 days, diluted with MeOH (100 mL) and cooled to 0° C. The precipitate was collected by filtration and washed with MeOH to give (E)-methyl 4-(3-(dimethylamino)acryloyl)benzoate as a brown solid (27.65 g, 84% yield). MS (ES+) m/z: 234 (M+H); LC retention time: 2.91 min (analytical HPLC Method A).
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][C:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][C:12]=3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2].C(O)(C(F)(F)F)=O.[BH3-]C#N.[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([NH:6][C:7]1[C:15]2[NH:14][CH:13]3[CH2:16][CH2:17][N:18]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH:12]3[C:11]=2[CH:10]=[CH:9][CH:8]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Nc1cccc2c3c([nH]c12)CCN(C(=O)OCC)C3
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)Nc1cccc2c1NC1CCN(C(=O)OCC)CC21
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.4 %

Procedure:
To a solution of ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,5-tetrahydro-2H-pyrido[4,3-b] indole-2-carboxylate (4.5 g, 13.6 mmol) in CH2Cl2 (40 mL) at 0° C. was added TFA (20 mL) followed by NaCNBH3 (1.8 g, 27 mmol) and stirred at rt for 3 hours before the solvent was removed by the nitrogen stream. To the resulting residue were added CH2Cl2 (40 mL) and 6N HCl (20 mL) and stirred for 0.5 hour. The solution was diluted with water (20 mL), 1N NaOH (30 mL) and extracted with CH2Cl2 (2×30 mL). The combined extracts were dried over magnesium sulfate, concentrated, and purified by flash chromatography to afford ethyl 6-[(ethoxycarbonyl)amino]-1,3,4,4a,5,9b-hexahydro-2H-pyrido[4,3-b]indole-2-carboxylate (3.6 g, 80%) as a clear oil. MS [M+H]+334. 1H NMR (CDCl3, 300 MHz): δ 6.97 (d, 1H, J=7.3 Hz), 6.85 (d, 1H, J=7.3 Hz), 6.72 (t, 1H, J=7.3 Hz), 4.05 (m, 4H), 3.41 (m, 4H), 1.92 (m, 2H), 1.20-1.24 (m, 6H) ppm.
Reaction SMILES: [NH3:1].[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH:14]=[CH:15][C:16](OCC)=[O:17])=[C:9]([OH:21])[CH:8]=[CH:7]2)#[N:3]>>[C:2]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH:14]=[CH:15][C:16](=[O:17])[NH2:1])=[C:9]([OH:21])[CH:8]=[CH:7]2)#[N:3]
Reactant: CCOC(=O)C=Cc1c(O)ccc2cc(C#N)ccc12
Reactant: N
Product: N#Cc1ccc2c(C=CC(N)=O)c(O)ccc2c1
Reaction time: 32 h

Procedure:
2.0 Liters of 25% aqueous ammonia was added to 25.2 g of 6-cyano-1-(2-ethoxycarbonylvinyl)-2-naphthol, followed by stirring at 40°-45° C. for 32 hours. After cooling, the reaction mixture was concentrated to 300 ml under reduced pressure, and the residue was stirred for 30 minutes under cooling with water. The precipitate was collected by filtration and washed with a small amount of water and acetone to obtain 9.55 g of the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:24](N)=[O:25])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl.[OH-:28].[Na+]>O1CCOCC1>[NH2:1][C:2]1[C:3]([C:24]([OH:25])=[O:28])=[N:4][C:5]([C:14]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH3:23])[CH3:22])[N:15]=2)=[C:6]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: [OH-]
Reactant: CC(C)n1nc(-c2nc(C(N)=O)c(N)nc2-c2ccccc2)ccc1=O
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)n1nc(-c2nc(C(=O)O)c(N)nc2-c2ccccc2)ccc1=O
Temperature: 92.5 °C

Procedure:
A suspension of 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxamide (1.02 g) in a mixture of conc. HCl (40 ml) and dioxane (10 ml) was heated at 90-95° C. for 20 hours. Under ice-cooling, the reaction mixture was adjusted to pH 4 with 4N aq. NaOH solution to yield a precipitate. The precipitate was collected by filtration and dried at 60° C. under reduced pressure to give 3-amino-6-(1-isopropyl-6-oxo-1,6-dihydro-3-pyridazinyl)-5-phenyl-2-pyrazinecarboxylic acid as a solid (878 mg).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1.[Na].[CH2:18]([OH:21])[CH:19]=[CH2:20]>O1CCCC1>[Cl:1][C:2]1[N:7]=[C:6]([O:21][CH2:18][CH:19]=[CH2:20])[C:5]([CH2:9][C:10]2[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=2)=[CH:4][N:3]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2Cl)cn1
Reactant: C=CCO
Agent: [Na]
Solvent: C1CCOC1
Product: C=CCOc1nc(Cl)ncc1Cc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a stirred solution of 118.0 g (0.465 mol) of 2,4-dichloro-5-[(6-methyl-3-pyridinyl)methyl]pyrimidine from Example 1 in 200 ml of allyl alcohol and 300 ml of tetrahydrofuran at 0°-5° was added dropwise over 2 hours a solution of the sodium salt of allyl alcohol [generated from 22.4 g (0.465) of sodium hydride (50% oil dispersion) and 200 ml of allyl alcohol]. The mixture was stirred 30 minutes at 5°, warmed to room temperature and concentrated. The resulting oil was dissolved in 1 L of methylene chloride, washed with water, dried over sodium sulfate, filtered, and concentrated to give 112.0 g (0.0409 mol, 88%) of 2-chloro-4-allyloxy-5[(6-methyl-3-pyridinyl)methyl]pyrimidine as crystals: IR(Nujol) 2850, 2650, 1655, 1580, 1560 cm-1 ; 1H NMR(D6 -DMSO/CDCl3) δ 2.45 (s, 3H), 3.85 (s, 2H), 4.90 (dd, 2H), 5.25 (dd, 1H), 5.34 (dd, 1H), 6.00 (m, 1H), 7.10 (d, 1H), 7.48 (dd, 1H), 8.30 (s, 1H), 8.35 (d, 1H).
Reaction SMILES: N1C=CC=CC=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[N:29]1([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH2:43][OH:44])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1>C(Cl)Cl>[N:29]1([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([CH2:41][CH2:42][CH:43]=[O:44])=[CH:37][CH:36]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: OCCCc1ccc(CN2CCCC2)cc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=CCCc1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2.87 mL (35.56 mmol) pyridine and 2.11 g (4.98 mmol) Dess-Martin periodinane are added to a solution of 780 mg (3.56 mmol) 3-(4-pyrrolidin-1-ylmethyl-phenyl)-propan-1-ol in 30 mL DCM. The reaction mixture is stirred for 4 h at RT, then added to 100 mL saturated, aqueous NaHCO3 solution, exhaustively extracted with tert-butylmethylether, the organic phase is washed with saturated, aqueous NaCl solution and dried over Na2SO4. After the desiccant and solvent have been eliminated the crude product is further reacted without purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:41]=[C:42]([F:44])[CH:43]=1)[CH2:5][C@H:6]([C:26](N1[C@@H](CC2C=CC=CC=2)COC1=O)=[O:27])[C@@H:7]([C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[OH:8].[Li+].[OH-].OO.C(OCC)(=[O:51])C>C1COCC1.O>[F:44][C:42]1[CH:41]=[C:4]([CH:3]=[C:2]([F:1])[CH:43]=1)[CH2:5][C@@H:6]([C@@H:7]([C@H:9]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][N:10]1[C:19]([O:21][C:22]([CH3:23])([CH3:24])[CH3:25])=[O:20])[OH:8])[C:26]([OH:51])=[O:27]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: OO
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@@H]1[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (R)-tert-butyl 3-((1S,2S)-2-(3,5-difluorobenzyl)-3-((S)-4-benzyl-2-oxooxazolidin-3-yl)-1-hydroxy-3-oxopropyl)-3,4-dihydroisoquinoline-2(1H)-carboxylate (Step A (4), 13.0 g, 21.5 mmol) in THF (500 mL) was added a solution of LiOH (1.03 g, 43 mmol) in H2O (100 mL), then 30% H2O2 (24.4 g) was added at 0° C. This reaction mixture was warmed up to rt over 1 h and stirred at rt for 4 h. Ethyl acetate (1000 mL) was added and washed with 1N HCl, and H2O, dried (Na2SO4), and concentrated in vacuo to give the crude product which was ready for next step without purification. MS (ESI) (M−H)− 446.07.
Reaction SMILES: [F:1][C:2]1[CH2:11][CH2:10][C:9]2[CH2:8][CH2:7][N:6]3[C:12]([C@@H:15]([NH2:17])[CH3:16])=[N:13][CH:14]=[C:4]([C:5]=23)[CH:3]=1.[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23](Cl)[N:22]=[CH:21][N:20]=1.CCN(C(C)C)C(C)C>C(O)(C)C>[NH2:18][C:19]1[C:24]([C:25]#[N:26])=[C:23]([NH:17][C@H:15]([C:12]2[N:6]3[CH2:7][CH2:8][C:9]4[CH2:10][CH2:11][C:2]([F:1])=[CH:3][C:4]([C:5]=43)=[CH:14][N:13]=2)[CH3:16])[N:22]=[CH:21][N:20]=1
Reactant: C[C@H](N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Reactant: N#Cc1c(N)ncnc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc(N)c1C#N)C1=NC=C2C=C(F)CCC3=C2N1CC3
Temperature: 90 °C
Reaction time: 3 h
Yield: 41 %

Procedure:
A mixture of (S)-1-(5-fluoro-6,7,8,9-tetrahydro-2,9a-diazabenzo[cd]azulen-1-yl)ethylamine (70 mg, 0.30 mmol), 4-amino-6-chloropyrimidine-5-carbonitrile (46.4 mg, 0.30 mmol), and DIPEA (102 μL, 0.60 mmol) in isopropanol (1.5 mL) was stirred at 90° C. for 3 h. After cooling to RT, volatiles were removed under reduced pressure and the resulting residue was purified by column chromatography (Si—PCC, gradient 2-7% 2M NH3/MeOH in DCM). Crystallisation from MeOH (5 mL) afforded 406 as a white solid (43.2 mg, 41%). LCMS (Method K): RT 2.91 min [M+H]+ 352.1. 1H NMR ((CD3)2SO, 400 MHz): 8.07 (1H, s), 7.69 (1H, d, J=7.5 Hz), 7.45 (1H, dd, J=8.8, 4.8 Hz), 7.31 (2H, bs), 7.00 (1H, dd, J=10.8, 8.7 Hz), 5.67 (1H, quintet, J=6.9 Hz), 4.25-4.14 (2H, m), 3.05-3.01 (2H, m), 2.08-1.93 (4H, m), 1.58 (3H, d, J=6.7 Hz)
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([OH:27])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.I[CH2:47][Cl:48]>O1CCOCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:16]([O:18][CH:19]1[CH2:24][CH2:23][CH:22]([C:25]([O:27][CH2:47][Cl:48])=[O:26])[CH2:21][CH2:20]1)=[O:17])[CH:13]([CH3:15])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClCI
Reactant: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)O)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCC(C(=O)OCCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-(N-benzyloxycarbonyl-L-valyloxy)cyclohexanoic acid (6.6 g, 20 mmole) in 1,4-dioxane (70 ml) was added a 40% solution of tetrabutylammonium hydroxide (11.34 g, 17.5 mmole) and the mixture was stirred 2 hours at room temperature. The mixture was evaporated under reduced pressure and co-evaporated two times with 1,4-dioxane and two times with toluene. The dried product was dissolved in 60 ml dichloromethane and iodochloromethane (30.9 g, 175 mmole) was added. The solution was stirred for two days at room temperature and evaporated under reduced pressure. About 100 ml ethyl actate was added and the organic phase washed twice with water, dried with sodium sulfate and evaporated under reduced pressure. The product was isolated by silica gel column chromatography with toluene/acetone. Yield: 4.1 g=55%.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([OH:22])([C:18]([F:21])([F:20])[F:19])[C:14]([F:17])([F:16])[F:15])=[CH:9][C:8]=1[CH2:23][CH2:24][CH3:25].[N+:26]([O-])([OH:28])=[O:27]>>[OH:6][C:7]1[C:8]([CH2:23][CH2:24][CH3:25])=[CH:9][C:10]([C:13]([OH:22])([C:14]([F:15])([F:16])[F:17])[C:18]([F:19])([F:20])[F:21])=[CH:11][C:12]=1[N+:26]([O-:28])=[O:27]
Reactant: O=[N+]([O-])O
Reactant: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)ccc1O
Agent: O=S(=O)(O)O
Product: CCCc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc([N+](=O)[O-])c1O
Temperature: 40 °C
Reaction time: 3 h
Yield: 16 %

Procedure:
Concentrated sulfuric acid (1.2 mL) was added to 2-(4-hydroxy-3-propylphenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (500 mg, 1.65 mmol) under ice-cooling. Then, a mixed solution of nitric acid (109 μL) and concentrated sulfuric acid (219 μL) was added dropwise at 30 to 35° C., followed by stirring at 40° C. for three hours. The reaction solution was cooled and then added dropwise to ice water. After neutralization to pH 7 with a sodium hydroxide solution (1 mol/L), the neutralized solution was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 94.3 mg of the title compound (yield: 16%) as a red orange oil.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[C:4]([OH:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[I:12]N1C(=O)CCC1=O.C([O-])(O)=O.[Na+]>CC#N.CN(C=O)C>[I:12][C:7]1[CH:8]=[C:3]([C:2]([F:1])([F:10])[F:11])[C:4]([OH:9])=[N:5][CH:6]=1
Reactant: O=C1CCC(=O)N1I
Reactant: Oc1ncccc1C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: Oc1ncc(I)cc1C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h
Yield: 81.9 %

Procedure:
3-trifluoromethyl-2-pyridinol (25 g, 153.3 mmol) is dissolved in anhydrous CH3CN (150 mL) and DMF (150 mL). N-iodosuccinimide (34.5 g, 153 mmol) is then added. The reaction mixture is stirred at 80° C. for 2 hours and cooled to room temperature. Aqueous 1 M NaHCO3 (150 mL) is then added to the cooled mixture. After stirring for 5 min, the solvents are evaporated to dryness. Water is added and the aqueous phase is extracted (×2) with dichloromethane. The organic phase is then evaporated and the desired product is recrystallized in water to afford 36.2 g (81%) of a white powder.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([NH2:6])=[O:5].[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([N:14]=[C:15]=[S:16])[CH:11]=[CH:12][CH:13]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:9]([CH3:17])=[C:10]([NH:14][C:15](=[S:16])[NH:2][CH2:3][C:4]([NH2:6])=[O:5])[CH:11]=[CH:12][CH:13]=1
Reactant: Cc1c(Cl)cccc1N=C=S
Reactant: NCC(N)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cccc1NC(=S)NCC(N)=O
Temperature: 25 °C
Yield: 88.2 %

Procedure:
A mixture of glycinamide hydrochloride (6.1 g), 3-chloro-2-methylphenylisothiocyanate (10.1 g), triethyl amine (5.6 g), and chloroform (200 mL) was heated at reflux for 3 hours then cooled to ambient temperature. The precipitate was collected by filtration, washed with chloroform and air dried to give 2-[3-(3-chloro-2-methylphenyl)-thioureido]-acetamide (12.5 g), m.p. 162°-164° C. (dec.). This compound was used without further purification for the preparation of the title compound of step 2.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:15]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>>[C:18]([O:17][C:15]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: Ic1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 75.4 %

Procedure:
The title compound (3.5 g, 75.5%) was prepared from 1-iodo-4-phenoxy-benzene (3.9 g, 13.1 mmol) and 1-Boc-piperazine (2.5 g, 13.1 mmol) by the procedure described in step 1 of Example 4: MS (ESI) m/z 355 (M+H); 1H NMR (400 MHz, CDCl3) δ 1.49 (s, 9H), 3.08 (t, J=4.8 Hz, 4H), 3.59 (t, J=4.8 Hz, 4H), 6.90-7.09 (m, 7H), 7.27-7.32 (m, 2H).
Reaction SMILES: [NH:1]([CH2:8][C:9]([O:11][C:12]1([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30](O)=[O:31])[CH:23]=[CH:24][CH:25]=1.S(Cl)(Cl)=O>>[CH3:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[NH:28][CH2:29][C:30]([N:1]([CH2:8][C:9]([O:11][C:12]2([CH3:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:10])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:31])[CH:23]=[CH:24][CH:25]=1
Reactant: CC1(OC(=O)CNc2ccccc2)CCCCC1
Reactant: Cc1cccc(NC(=O)NCC(=O)O)c1
Solvent: O=S(Cl)Cl
Product: Cc1cccc(NC(=O)NCC(=O)N(CC(=O)OC2(C)CCCCC2)c2ccccc2)c1
Yield: 11.4 %

Procedure:
The procedure is carried out in a manner analogous to that described in Example 1, but using 3.0 g of 1-methylcyclohexyl 2-anilinoacetate, 2.5 g of 2-[3-(3-methylphenyl)ureido]acetic acid and 0.9 cm3 of thionyl chloride as starting materials. The product obtained is purified by chromatography on 40 g of silica (0.063-0.200 mm) contained in a column 1.5 cm in diameter [eluent: cyclohexane/ethyl acetate (70/30 by volume)], collecting 20-cm3 fractions. Fractions 3 to 8 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After-recrystallization from an acetonitrile/diisopropyl ether mixture (50/50 by volume), 0.6 g of 1-methylcyclohexyl 2-{2-[3-(3-methylphenyl)ureido]-N-phenylacetamido}acetate melting at 192° C. is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[N:24](C)[CH:23]=[C:22]4[CH:27]=O)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[NH2:29][CH:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:18]=[CH:19][CH:20]=[C:21]4[C:25]=3[NH:24][CH:23]=[C:22]4[CH2:27][NH:29][CH:30]([CH3:35])[CH2:31][C:32]([OH:34])=[O:33])[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CC(N)CC(=O)O
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c(C=O)cn(C)c34)no2)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(CC(=O)O)NCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cccc12
Temperature: 40 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
To a stirred solution of 7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1-methyl-1H-indole-3-carbaldehyde (D61) (200 mg), 3-aminobutanoic acid (103 mg) and acetic acid (32 mg) in DCM (10 mL) was added NaBH(OAc)3 (223 mg). The reaction was stirred at 40° C. for 24 h. After cooled to room temperature, the mixture was diluted with DCM (10 mL), washed with water (20 mL) and aqueous saturated sodium bicarbonate (20 mL). The organic phase was dried over anhydrous sodium sulphate, evaporated to give the crude product, which was purified by Mass Directed Auto Prep to afford 3-({[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1H-indol-3-yl]methyl}amino)butanoic acid (E51) (55 mg, as TFA salt). δH (DMSO-d6, 400 MHz): 1.36 (9H, m), 2.57 (1H, m), 2.91 (1H, dd), 3.57 (1H, m), 4.46 (2H, s), 4.91 (1H, m), 7.33 (1H, t), 7.47 (1H, d), 7.72 (1H, d), 8.03 (1H, d), 8.05 (1H, d), 8.22 (1H, dd), 8.39 (1H, d), 11.37 (1H, s), 12.81 (1H, br s). MS (ES): C24H26ClN4O4 requires 468; found 366.1 (M—C4H8NO2+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]O.C[CH2:12][N:13](CC)CC.CS(Cl)(=O)=O.[C-]#N.[K+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:12]#[N:13]
Reactant: OCCc1ccccc1F
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Agent: [C-]#N
Agent: [K+]
Solvent: ClCCl
Product: N#CCCc1ccccc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-(2-fluoro-phenyl)-ethanol (10.00 g, 71.50 mmol) in CH2Cl2 at 0° C. was added Et3N (20.00 mL, 0.14 mol) followed by MsCl (19.00 mL, 0.25 mol). The resulting mixture was stirred for 1 hour, then washed with H2O (3×100 mL) and brine (1×150 mL), dried over MgSO4 and concentrated. The residue was dissolved in DMF and KCN (9.30 g, 0.14 mol) was added. The resulting mixture was stirred at 75° C. for 14 hours. After cooling to room temperature, the reaction mixture was quenched into water and extracted with Et2O (3×300 mL). The combined organic extracts were washed with H2O (2×200 mL), brine (1×200 mL), dried over MgSO4 and concentrated to give the title compound.