Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:18][CH3:19])=[CH:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4].[C:20]1([CH3:27])[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][CH:21]=1.B(F)(F)F.O(CC)CC>CCOC(C)=O>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([CH2:18][CH3:19])([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([CH3:27])[CH:21]=3)[CH2:16][CH3:17])[CH:11]=2)[CH:6]=1)=[O:4]
Reactant: Cc1ccccc1O
Reactant: CC=C(CC)c1ccc2cc(C(=O)OC)ccc2c1
Agent: FB(F)F
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Yield: 87.3 %

Procedure:
Cool a solution of 6-(1-ethyl-propenyl)naphthalene-2-carboxylic acid methyl ester (0.74 g, 2.75 mmol) and o-cresol (2.0 mL, 19.4 mmol) in CH2CL2 (20 mL) to −78° C.; dropwise add BF3-OEt2 (1.22 mL, 9.6 mmol). Remove the cooling bath and stir the reaction at RT for 16 h. Quench the reaction with ice water; then dilute with EtOAc (200 mL). Wash the resulting mixture twice with brine, dry over Na2SO4, filter, and concentrate the filtrate. Purify the product using medium pressure silica gel chromatography (100% hex to 25:75 EtOAc:hex) to give the title compound as a white solid (0.87 g, 87%). MS (ES) in/e 363 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]=[C:12]([NH:27][C:28]([C:30]1[C:35]([NH2:36])=[N:34][C:33]([NH2:37])=[C:32]([Cl:38])[N:31]=1)=[O:29])[NH:13][CH:14]1[CH2:19][CH2:18][N:17](C(OC(C)(C)C)=O)[CH2:16][CH2:15]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1.CO>[NH2:36][C:35]1[C:30]([C:28]([NH:27][C:12](=[N:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[NH:13][CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:29])=[N:31][C:32]([Cl:38])=[C:33]([NH2:37])[N:34]=1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=NC(=O)OCc2ccccc2)NC(=O)c2nc(Cl)c(N)nc2N)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Nc1nc(N)c(C(=O)NC(=NC(=O)OCc2ccccc2)NC2CCNCC2)nc1Cl
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A suspension of tert-butyl 4-(2-(benzyloxycarbonyl)-3-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino)piperidine-1-carboxylate (Step 1) (6.3 g, 11.5 mmol) in dioxane (250 mL) and MeOH (small volume) is treated with 4 M HCl in dioxane (40 mL) and left to stir overnight at 40° C. The resulting suspension is filtered and the solid is partitioned between water (800 mL) and EtOAc (800 mL). 1 M NaOH is added to adjust the pH to pH 8 and the organic portion is separated, dried (MgSO4) and concentrated in vacuo to afford the title compound. [M+H]+ 447
Reaction SMILES: C([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:42])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C@@H:23]([N:31]3[CH2:36][C@@H:35]([CH3:37])[N:34]([CH2:38][CH:39]=[CH2:40])[CH2:33][C@@H:32]3[CH3:41])[C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=3)[CH:18]=2)[CH2:11][CH2:10]1)C.[OH-].[Na+].Cl>C1COCC1>[CH2:38]([N:34]1[C@H:35]([CH3:37])[CH2:36][N:31]([C@@H:23]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)[C:19]2[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=2)[C:16]([N:12]2[CH2:13][CH2:14][CH2:15][N:9]([CH2:8][CH2:7][CH2:6][CH2:5][C:4]([OH:43])=[O:3])[CH2:10][CH2:11]2)=[O:42])[C@@H:32]([CH3:41])[CH2:33]1)[CH:39]=[CH2:40]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCN(CCCCC(=O)OCC)CC3)c2)C[C@H]1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: C=CCN1C[C@H](C)N([C@@H](c2cccc(O)c2)c2cccc(C(=O)N3CCCN(CCCCC(=O)O)CC3)c2)C[C@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 68 %

Procedure:
To the compound of Example 9 (335 mg) in THF (4 mL) was added 1N NaOH solution (3.0 mL). The reaction was stirred at room temperature for overnight. The reaction solution was neutralized by the addition of 1 N HCl solution (3.0 mL). The mixture was put under rotary evaporator for the removal of THF. The remaining water layer was diluted by water (5 mL). The water layer was extracted by n-butanol (6 mL×3). The combined n-butanol layer was washed by water (5 mL×2) and concentrated to give crude product (225 mg), which was purified by silica gel chromatography conducted on CombiFlash™ Sq 16× (gradient: 100% CH2Cl2 to 30% MeOH in CH2Cl2) to give 5-(4-{3-[(R)-((2S,5R)-4-allyl-2,5-dimethyl-piperazin-1-yl)-(3-hydroxy-phenyl)-methyl]-benzoyl}-[1,4]diazepan-1-yl)-pentanoic acid (217 mg; 68%). 1H NMR (300 MHz, DMSO-d6) δ 9.36 (bs, 1H), 8.31 (s, 1H), 7.35 (m, 3H), 7.18 (m, 1H), 7.12 (dd, 1H, J=8.0, 8.0 Hz), 6.66 (m, 3H), 5.78 (m, 1H), 5.19-5.00 (m, 3H), 3.56 (m, 2H), 3.30 (m, 2H), 3.19 (m, 1H), 2.86 (m, 1H), 2.72 (m, 2H), 2.59-2.49 (m, 7H), 2.37 (m, 1H), 2.20 (m, 2H), 2.07 (m, 1H), 1.83 (m, 2H), 1.65 (m, 1H), 1.50-1.35 (m, 4H), 1.07 (d, 3H, J=6.0 Hz), 0.92 (d, 3H, J=5.5 Hz).
Reaction SMILES: [Si]([O:8][C@H:9]([C@H:39]1[CH2:43][C@@H:42]([O:44][CH2:45][CH2:46][CH3:47])[CH2:41][N:40]1C(OC(C)(C)C)=O)[C@@H:10]([NH:20][C:21](=[O:38])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]2[CH2:34][CH2:33][CH2:32][C@@H:31]2[CH2:35][O:36][CH3:37])=[O:29])[CH:23]=1)[CH2:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=1)(C(C)(C)C)(C)C.C(OC(N1C[C@H](OCCC)C[C@@H]1[C@@H](O[Si](C(C)(C)C)(C)C)[C@@H](NC(C1C=C(C=CC=1)C(O)=O)=O)CC1C=C(F)C=C(F)C=1)=O)(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.COC[C@H]1CCCN1>ClCCl.CN(C=O)C.C(OCC)(=O)C>[F:19][C:14]1[CH:13]=[C:12]([CH2:11][C@H:10]([NH:20][C:21](=[O:38])[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:30]3[CH2:34][CH2:33][CH2:32][C@@H:31]3[CH2:35][O:36][CH3:37])=[O:29])[CH:23]=2)[C@H:9]([OH:8])[C@H:39]2[CH2:43][C@@H:42]([O:44][CH2:45][CH2:46][CH3:47])[CH2:41][NH:40]2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N3CCC[C@@H]3COC)c2)N(C(=O)OC(C)(C)C)C1
Agent: CCCO[C@@H]1C[C@H]([C@@H](O[Si](C)(C)C(C)(C)C)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)O)c2)N(C(=O)OC(C)(C)C)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COC[C@H]1CCCN1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCCO[C@H]1CN[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)NC(=O)c2cccc(C(=O)N3CCC[C@@H]3COC)c2)C1
Reaction time: 0.33 h
Yield: 79 %

Procedure:
Step 1 (D): (2R,4R)-tert-butyl 2-((1S,2S)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)-2-(3-((R)-2-(methoxymethyl)pyrrolidine-1-carbonyl)benzamido)propyl)-4-propoxypyrrolidine-1-carboxylate. To a solution of 3-(((1S,2S)-1-((2R,4R)-1-(tert-butoxycarbonyl)-4-propoxypyrrolidin-2-yl)-1-(tert-butyldimethylsilyloxy)-3-(3,5-difluorophenyl)propan-2-yl)carbamoyl)benzoic acid (Step 1 (C), 50 mg, 0.074 mmol) in dichloromethane (2 mL) and DMF (5 mL) was added Hunig's base (28 mg, 0.222 mmol) to make a clear solution and HATU (36 mg, 0.0962 mmol) was then added. After stirring for 20 min, the reaction mixture was added (R)-2-(methoxymethyl)pyrrolidine (17 mg, 0.148 mmol) and the reaction mixture was stirred at rt overnight. Ethyl acetate (100 mL) was added and the mixture was washed with Brine, H2O, dried and concentrated to give 45 mg of the title compound (79% yield): 1H NMR (CDCl3, 500 MHz) δ 0.02 (3H, s), 0.05 (3H, s), 0.83 (9H, s), 0.86-0.89 (3H, m), 1.48-1.51 (11H, m), 1.72 (1H, m), 1.91-2.07 (4H, m), 2.18 (1H, d, J=15 Hz), 2.64 (1H, dd, J=10, 15 Hz), 2.90-2.94 (1H, m), 3.02 (1H, brd s), 3.28-3.38 (6H, m), 3.48 (1H, m), 3.55 (1H, m), 3.67 (1H, m), 3.74 (1H, m), 3.98 (1H, m), 4.04-4.12 (2H, m), 4.42 (1H, m), 4.59 (1H, m), 6.57-6.60 (1H, m), 6.76 (2H, d, J=5 Hz), 7.41-7.44 (1H, m), 7.60-7.62 (1H, m), 7.88 (1H, d, J=5 Hz), 7.96 (1H, s), 8.08 (1H, brd s). MS (ESI) (M+H)+ 774.40.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2].[CH3:21][C:22]1[S:26][C:25]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[N:24][C:23]=1[CH2:37][CH2:38]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[CH:5]([O:17][CH2:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:38][CH2:37][C:23]2[N:24]=[C:25]([C:27]3[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:34])[F:35])=[CH:29][CH:28]=3)[S:26][C:22]=2[CH3:21])=[CH:9][C:8]=1[O:14][CH2:15][CH3:16])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1OCC)OCC
Reactant: Cc1sc(-c2ccc(C(F)(F)F)cc2)nc1CCO
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OCCc2nc(-c3ccc(C(F)(F)F)cc3)sc2C)cc1OCC)OCC

Procedure:
In analogy to the procedure described in example 1 d], [rac]-2-ethoxy-3-(2-ethoxy-4-hydroxy-phenyl)-propionic acid ethyl ester (example 58 c]) was reacted with 2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethanol [PCT Int. Appl. (2001), WO 01/00603 A1] in tetrahydrofuran in the presence of triphenylphosphine and DBAD (di-tert-butyl azodicarboxylate) to yield [rac]-2-ethoxy-3-(2-ethoxy-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid ethyl ester, which was further saponified in analogy to the procedure described in example 1 e], to yield [rac]-2-ethoxy-3-(2-ethoxy-4-{2-[5-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-4-yl]-ethoxy}-phenyl)-propionic acid as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:7]2[N:11]([CH2:12][C:13]([F:16])([F:15])[F:14])[N:10]=[CH:9][N:8]=2)[S:5][CH:6]=1.[Br:17]Br>CC(O)=O>[Br:17][C:6]1[S:5][C:4]([C:7]2[N:11]([CH2:12][C:13]([F:14])([F:16])[F:15])[N:10]=[CH:9][N:8]=2)=[CH:3][C:2]=1[Cl:1]
Reactant: FC(F)(F)Cn1ncnc1-c1cc(Cl)cs1
Reactant: BrBr
Solvent: CC(=O)O
Product: FC(F)(F)Cn1ncnc1-c1cc(Cl)c(Br)s1
Temperature: 120 °C
Reaction time: 5 h
Yield: 71.1 %

Procedure:
To a solution of 5-(4-chloro-thiophen-2-yl)-1-(2,2,2-trifluoro-ethyl)-1H-[1,2,4]triazole (1.13 g, 4.22 mmol) and AcOH (10 mL) in a sealed tube, is added Br2 (0.23 mL, 4.43 mmol). The solution is heated at 120° C. for 2 hours, and 140° C. for 5 hours. The solution is concentrated, diluted with Et2O (150 mL), washed with sat NaHCO3 (75 mL), sat. Na2S2O3 (75 mL), brine (75 mL) dried over MgSO4, filtered and concentrated. The residue is purified by ISCO flash chromatography (5%-15% EtOAc gradient) furnish the title compound (1.04 g, 3.00 mmol, 71%). 1H NMR (CDCl3) δ 4.88 (q, J=16.0, 7.9 Hz, 2H), 7.22 (s, 1H), 7.99 (s, 1H). LC/MS (m/z): calcd. for C8H4BrClF3N3S (M+H)+: 345.9; found: 346.0.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[O:14]C.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C>ClCCCl>[Cl:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:16][C:17]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=2[F:27])=[O:18])[CH:11]=[CH:12][C:13]=1[OH:14]
Reactant: COc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Cl)cnn1C
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: CCOC(C)=O
Product: Cn1ncc(Cl)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75 %

Procedure:
A mixture of 1-[3-(4-Chloro-2-methyl-2H-pyrazol-3-yl)-4-methoxy-phenyl]-3-(2,4-difluoro-phenyl)urea (Compound 77, example 1.61) (0.270 g, 0.69 mmol) in anhydrous 1,2-dichloroethane (10 mL) was cooled to 0° C. on an ice bath and stirred for 10 minutes. Anhydrous aluminium chloride (0.368 g, 2.76 mmol) was added and the reaction mixture stirred at 0° C. for 20 minutes, then moved to an oil bath and stirred at 80° C. for 1 hour. Ethyl acetate was added and washed with potassium sodium tartrate (10%) twice. Organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated to give the crude product that was further purified via HPLC. The corresponding fractions were collected and lyophilized to afford Compound 120 as a white solid in 75.0% yield. LCMS m/z (%)=379 (M+H 35Cl, 100), 381 (M+H 37Cl, 40). 1H NMR (400 MHz. DMSO-d6) δ: 9.81 (s, 1H), 8.92 (s, 1H), 8.45 (s, 1H), 8.12-8.06 (m, 1H), 7.63 (s, 1H), 7.40-7.31 (m, 3H), 7.09-7.04 (m, 1H), 6.99 (d, =8.72 Hz, 1H), 3.69 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[I:17]N1C(=O)CCC1=O>CN(C=O)C.[O-]S([O-])(=S)=O.[Na+].[Na+].O.C(OCC)C>[C:1]([O:5][C:6](=[O:16])[NH:7][C:8]1([C:11]2[O:12][C:13]([I:17])=[CH:14][CH:15]=2)[CH2:9][CH2:10]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccco2)CC1
Reactant: O=C1CCC(=O)N1I
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)NC1(c2ccc(I)o2)CC1
Reaction time: 2.5 h

Procedure:
To a solution of (1-furan-2-yl-cyclopropyl)-carbamic acid tert-butyl ester (4.30 g, 19.3 mmol) (prepared according to the procedure described in patent application WO 2009/070485 A1) in anhydrous DMF (77 mL) at room temperature is added solid N-iodosuccinimide (4.77 g, 21.2 mmol) in one portion. After 2.5 hours, the reaction is diluted with a saturated aqueous solution of Na2S2O3 (75 mL), water (75 mL), and ethyl ether (100 mL). Phases are separated and the aqueous layer is extracted with ethyl ether (2×100 mL). The combined organic layers are dried over Na2SO4 and concentrated. The resultant solid is triturated with hexanes to afford the title compound as a powder (ES+ m/z 350.5).
Reaction SMILES: [O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[O:10][CH2:11][C:5]2=[N:4][N:3]1[CH3:24].C(Cl)(Cl)Cl.C(Cl)(=O)OCC>C(N(CC)CC)C>[O:1]=[C:2]1[N:6]2[C:7]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:8]=3[CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[O:10][CH2:11][C:5]2=[N:4][N:3]1[CH2:24][CH2:5][N:6]([CH3:7])[CH3:2]
Reactant: Cn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Agent: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)CCn1nc2n(c1=O)-c1ccc(Cl)cc1C(c1ccccc1Cl)OC2
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Compound 33 is mixed with chloroform (20 ml), triethylamine (0.708 g), and ethyl chlorocarbonate (0.76 g), and the mixture is stirred at room temperature for 20 minutes, then refluxed under heating for 3.5 hours, and washed with water. The chloroform layer is dried and concentrated to give crystalline Compound 34 (2.15 g), which is recrystallized from ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]([NH:11][C:12]2[CH:36]=[CH:35][C:15]([O:16][C:17]3[CH:22]=[CH:21][N:20]=[C:19]([C:23]4[NH:27][CH:26]=[C:25]([C:28]([NH:30][CH2:31][CH2:32][CH:33]=O)=[O:29])[CH:24]=4)[CH:18]=3)=[CH:14][CH:13]=2)=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH:37][CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O)(=O)C.C([BH3-])#N.[Na+].C1COCC1>CN(C=O)C.O>[OH:37][CH:38]1[CH2:43][CH2:42][N:41]([CH2:33][CH2:32][CH2:31][NH:30][C:28]([C:25]2[CH:24]=[C:23]([C:19]3[CH:18]=[C:17]([O:16][C:15]4[CH:14]=[CH:13][C:12]([NH:11][C:9]([NH:8][C:4]5[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[CH:3]=5)=[O:10])=[CH:36][CH:35]=4)[CH:22]=[CH:21][N:20]=3)[NH:27][CH:26]=2)=[O:29])[CH2:40][CH2:39]1
Reactant: OC1CCNCC1
Reactant: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCC=O)c[nH]4)c3)cc2)c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: Cc1cccc(NC(=O)Nc2ccc(Oc3ccnc(-c4cc(C(=O)NCCCN5CCC(O)CC5)c[nH]4)c3)cc2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-N-(3-oxopropyl)-1H-pyrrole-3-carboxamide (150 mg, 0.31 mmol) in 10 ml of anhydrous DMF were added 4-hydroxypiperidine (59 mg, 0.58 mmol) and acetic acid (10 mg, 0.17 mmol). The mixture was stirred at room temperature for 60 minutes, followed by addition of 1M sodium cyanoborohydride solution in THF (0.60 ml, 0.60 mmol). Stirring was continued for another 60 minutes and the mixture was poured into 50 ml of water. The precipitates were filtered, washed with water and dried to give the crude, which was purified by silica gel flash chromatography eluting with 20% of MeOH in CHCl3 to give N-[3-(4-hydroxypiperidin-1-yl)propyl]-5-{4-[4-({[(3-methylphenyl)amino]carbonyl}amino)phenoxy]pyridin-2-yl}-1H-pyrrole-3-carboxamide as off-white solid. Yield: 102 mg, 58%.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:13])([CH3:12])[CH2:10]O>C1(C)C=CC=CC=1>[CH3:10][C:9]1([CH3:13])[NH:8][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:12]1
Reactant: O=C1CCCCC1
Reactant: CC(C)(N)CO
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCCC2)N1
Temperature: 25 °C
Yield: 81.2 %

Procedure:
Into a solution of 45 g (460 mmol) of cyclohexanone in 300 mL of toluene is added 35.6 g (400 mmol) of 2-amino-2,2-dimethylethanol. The reaction mixture is then heated to reflux and the by-product water is collected by a Dean-Stark trap. After 16 hours of heating at reflux, the reaction mixture is allowed to cool to ambient temperature and is then concentrated under vacuum to give 55 g of a yellow liquid. The product, identified by mass spectroscopy (m/z=169) is obtained in an 81.4% yield. The structure is confirmed by 1Hnmr.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])#[N:2].[OH:16]O.[OH-].[Na+].Cl>>[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=[O:7])(=[O:16])[NH2:2]
Reactant: CC(C)Oc1ccc(C(=O)O)cc1C#N
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CC(C)Oc1ccc(C(=O)O)cc1C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
3-Cyano-4-isopropoxy-benzoic acid (50 mg, 0.24 mmol), hydrogen peroxide (280 μL of 30% w/v, 2.4 mmol), and 10% NaOH (240 μL of 10% w/v, 0.61 mmol) were combined and stirred at room temperature for 16 h. The mixture was acidified with 4M HCl and was extracted with ethyl acetate (2×7 mL). The combined organics were washed with brine, dried over sodium sulfate and evaporated to give 3-carbamoyl-4-isopropoxy-benzoic acid (45 mg, 83%). ESI-MS m/z talc. 223.1, found 224.3 (M+1)+; Retention time: 1.49 minutes (4 min run).
Reaction SMILES: [OH:1][C:2]1[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])=[CH:5][N:4]([CH3:12])[N:3]=1.Cl[CH2:14][C:15]1[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]2[N:23]=[C:24]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[O:25][C:26]=2[CH3:27])[CH:16]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:12][N:4]1[CH:5]=[C:6]([CH2:7][C:8]([O:10][CH3:11])=[O:9])[C:2]([O:1][CH2:14][C:15]2[O:19][N:18]=[C:17]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])[CH:16]=2)=[N:3]1
Reactant: Cc1oc(-c2ccccc2)nc1COc1cc(CCl)on1
Reactant: COC(=O)Cc1cn(C)nc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)Cc1cn(C)nc1OCc1cc(OCc2nc(-c3ccccc3)oc2C)no1
Temperature: 60 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A mixture of methyl (3-hydroxy-1-methyl-1H-pyrazol-4-yl)acetate (298 mg), 5-chloromethyl-3-(5-methyl-2-phenyl-4-oxazolylmethoxy)isoxazole (533 mg), potassium carbonate (484 mg) and N,N-dimethylformamide (10 ml) was stirred at 60° C. for 4 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography, and methyl [1-methyl-3-[3-(5-methyl-2-phenyl-4-oxazolylmethoxy)-5-isoxazolylmethoxy]-1H-pyrazol-4-yl]acetate (701 mg, yield 91%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (2:1, volume ratio).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O>[N:16]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[S:10]([N:13]([CH3:15])[CH3:14])(=[O:12])=[O:11])=[N+:17]=[N-:18]
Reactant: [N-]=[N+]=[N-]
Reactant: CN(C)S(=O)(=O)c1cc(F)ccc1CBr
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)S(=O)(=O)c1cc(F)ccc1CN=[N+]=[N-]
Temperature: 57.5 °C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of 2-bromomethyl-5-fluoro-N,N-dimethyl-benzenesulfonamide (880 mg, 2.97 mmol) and sodium azide (200 mg, 3 mmol) in dimethylformamide (4 mL) was stirred at 55-60° C. for 30 min after which the solvent was removed in vacuo. The residue was partitioned between CH2Cl2 and water, and the organic fraction was washed with water, dried (Na2SO4), filtered and concentrated to provide 670 mg (Yield 87%) of the title compound as a yellow oil; 1H NMR (500 MHz, CDCl3) δ ppm: 2.84 (6H, s) 4.78 (2H, s) 7.29-7.34 (1H, m) 7.59-7.64 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]I)[N:14]=1)=[O:8].[NH2:21][CH2:22][CH2:23][OH:24].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][NH:21][CH2:22][CH2:23][OH:24])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Reactant: NCCO
Solvent: C1CCOC1
Solvent: O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CNCCO)cs1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea (Intermediate XXII) was taken up in THF and an excess of the 2-Amino-ethanol (20 equiv.) was added. The reaction was allowed to stir overnight at room temperature. Reaction poured into water and extracted with ethyl acetate, partitioned with brine, dried over NaSO4, filtered, and volatiles were removed in vacuo. The resulting solid was triturated with ethyl acetate, followed by diethyl ether to give the title compound. 1H NMR (400 MHz, CD3OD): 7.50-7.45 (m, 2H), 7.26 (dd, 1H), 6.78 (s, 1H), 4.41 (s, 2H), 3.73 (s, 2H), 3.65 (t, 2H), 2.71 (t, 2H). MS (ES+): M/Z 375 and 377 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:11](I)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=1.C([Mg]Br)(C)C.[B:18](OC)([O:21]C)[O:19]C.Cl>C1COCC1>[Br:1][C:2]1[C:11]([B:18]([OH:21])[OH:19])=[CH:10][C:9]2[C:4]([CH:3]=1)=[CH:5][CH:6]=[CH:7][CH:8]=2
Reactant: Brc1cc2ccccc2cc1I
Reactant: COB(OC)OC
Agent: CC(C)[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Product: OB(O)c1cc2ccccc2cc1Br
Temperature: -65 °C
Reaction time: 0.5 h

Procedure:
On the other hand, to another 100 ml Schlenk reaction vessel were added under a nitrogen atmosphere 85 mg (0.255 mmol) of 2-bromo-3-iodonaphthalene synthesized in Synthetic Example 2 and 2.0 ml of THF. The solution was cooled to −65° C. and 0.34 ml (0.27 mmol) of a THF solution of isopropylmagnesium bromide (manufactured by Tokyo Chemical Industry Co. Ltd., 0.80M) was added dropwise. After 30 minutes of aging, 33 mg (0.32 mmol) of trimethyl borate (manufactured by Wako Pure Chemical Industries, Ltd.) was added dropwise at the temperature. After the temperature was gradually raised to room temperature, 3N hydrochloric acid was added and phase separation was conducted. The organic phase was concentrated under reduced pressure to obtain 3-bromo-2-naphthylboronic acid as a residue. To the resulting white solid were added the intermediate obtained in the above, 15 mg (0.013 mmol) of tetrakis(triphenylphosphine)palladium (manufactured by Tokyo Chemical Industry Co. Ltd.), 2.2 ml of toluene, and 0.5 ml of ethanol. A solution composed of 148 mg (1.39 mmol) of sodium carbonate and 0.7 ml of water was further added and the mixture was subjected to a reaction at 85° C. for 5 hours. After cooling to room temperature, toluene and an aqueous sodium chloride solution were added and phase separation was conducted. The organic phase was washed with aqueous sodium chloride solution. The organic phase was concentrated under reduced pressure and the solvent was removed by distillation, followed by further heating and drying under vacuum. The obtained residue was dissolved in toluene and a 70% tert-butyl hydroperoxide solution (manufactured by Wako Pure Chemical Industries, Ltd.) (0.04 ml) was added thereto, followed by 2 hours of stirring at room temperature. The solution was washed with water and then the organic phase was concentrated under reduced pressure. The residue was dissolved in hexane and chloroform and the solution was passed through a column packed with silica gel. The elute was concentrated under reduced pressure and the resulting crude solid was washed with hexane to obtain the objective compound (103 mg, yield 54.0%).