Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=2)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.Cl.[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH2:31])[CH3:30])=[N:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CCCCO.C(OCC)(=O)C>[F:22][C:23]1[CH:24]=[N:25][C:26]([C@@H:29]([NH:31][C:2]2[N:7]=[C:6]([NH:8][C:9]3[CH:13]=[C:12]([O:14][CH:15]([CH3:17])[CH3:16])[NH:11][N:10]=3)[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=2)[CH3:30])=[N:27][CH:28]=1
Reactant: C[C@H](N)c1ncc(F)cn1
Reactant: CC(C)Oc1cc(Nc2nc(Cl)ccc2[N+](=O)[O-])n[nH]1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(Nc2nc(N[C@@H](C)c3ncc(F)cn3)ccc2[N+](=O)[O-])n[nH]1
Temperature: 70 °C
Reaction time: 4 h
Yield: 101.7 %

Procedure:
A mixture of 6-chloro-N-(5-isopropoxy-1H-pyrazol-3-yl)-3-nitropyridin-2-amine (Intermediate 7, 0.4 g) and [(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]amine hydrochloride (Intermediate 15, 0.25 g) in n-BuOH (5 mL) with diisopropylethylamine (1.5 mL) was stirred at 70° C. for 4 hours. The resulting mixture was diluted with ethyl acetate (20 mL), and washed with brine (10 mL×3). The organic layer was dried and concentrated. The resulting residue was separated by silica gel column (Hexane/Ethyl acetate) to yield 0.55 g of desired product. MS (electrospray): 403 (M+1) for C17H19FN8O3. 1H NMR (300 MHz, CD3OD) δ ppm 8.40 (s, 2H) 8.10 (d, 1H) 6.15 (d, 1H) 5.60 (s, 1H) 5.35 (m, 1H), 4.60 (m, 1H) 1.50 (d, 3H) 1.20 (d, 6H).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:9][CH:8]=[N:7][C:6]=1[CH3:10].[C:11](OCC)(=[O:13])[CH3:12]>>[C:11]([C:8]1[S:9][C:5]([CH2:4][CH2:3][O:2][CH3:1])=[C:6]([CH3:10])[N:7]=1)(=[O:13])[CH3:12]
Reactant: COCCc1scnc1C
Reactant: CCOC(C)=O
Product: COCCc1sc(C(C)=O)nc1C

Procedure:
From 5-(2-methoxyethyl)-4-methylthiazole and ethyl acetate, following the procedure of Preparation 1. 13C Nmr (CDCl3) 15.1, 25.6, 27.6, 58.7, 71.9, 137.9, 151.6, 163.0 and 191.5 ppm.
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5]([NH:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]3)=[CH:15][CH:14]=2)=[N:10][O:11][N:12]=1)=[O:6].O[CH:35]([CH2:40][CH:41]([CH3:43])[CH3:42])[C:36]([O:38][CH3:39])=[O:37].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>CN(C=O)C.O>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH2:20][N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:9]3[C:8]([N:7]([C:5]([O:4][CH2:3][C:2]([Cl:32])([Cl:1])[Cl:33])=[O:6])[C@H:35]([C:36]([O:38][CH3:39])=[O:37])[CH2:40][CH:41]([CH3:43])[CH3:42])=[N:12][O:11][N:10]=3)=[CH:14][CH:15]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:30])([CH3:29])[CH3:31]
Reactant: COC(=O)C(O)CC(C)C
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nonc3NC(=O)OCC(Cl)(Cl)Cl)cc2)CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1nonc1-c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To tert-butyl 4-[4-(4-{[(2,2,2-trichloroethoxy)carbonyl]amino}-1,2,5-oxadiazol-3-yl)phenyl]piperazine-1-carboxylate (485 mg, 0.932 mmol), methyl 2-hydroxy-4-methylpentanoate (275 mg, 1.87 mmol) and triphenyl phosphine (490 mg, 1.87 mmol) in dry DMF (15 mL) at 0° C. under dry nitrogen was added diisopropyl azodicarboxylate (0.375 mL, 1.87 mmol) dropwise over ½ hour and the reaction mixture stirred overnight at rt. The reaction was poured into water and the product extracted with Et2O (2×), dried over Na2SO4, concentrated in vacuo and purified by flash chromatography over silica gel (EtOAc/Hex, 2/8) to afford methyl N-(4-{4-[4-(tert-butoxycarbonyl)piperazin-1-yl]phenyl}-1,2,5-oxadiazol-3-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]leucinate.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])[C:5]([Cl:22])=[CH:4][N:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]2[N:33]([CH3:34])[C:32](=[O:35])[O:31][CH2:30][CH2:29][C:28]=2[CH:36]=1>>[Cl:22][C:5]1[C:6]([O:8][C:9]2[C:14]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[CH:13][CH:12]=[CH:11][C:10]=2[F:21])=[N:7][C:2]([NH:23][C:24]2[CH:25]=[CH:26][C:27]3[N:33]([CH3:34])[C:32](=[O:35])[O:31][CH2:30][CH2:29][C:28]=3[CH:36]=2)=[N:3][CH:4]=1
Reactant: Fc1cccc(OC2CCOC2)c1Oc1nc(Cl)ncc1Cl
Reactant: CN1C(=O)OCCc2cc(N)ccc21
Product: CN1C(=O)OCCc2cc(Nc3ncc(Cl)c(Oc4c(F)cccc4OC4CCOC4)n3)ccc21

Procedure:
2-{5-Chloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenoxy]-pyrimidin-2-ylamino}-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one was prepared from 2,5-Dichloro-4-[2-fluoro-6-(tetrahydro-furan-3-yloxy)-phenoxy]-pyrimidine and 2-Amino-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one in an analogous manner to Example 1221d. Title compound was isolated as a white solid HPLC purity=99%, LCMS 503.21 (M+H), 1H-NMR (DMSO-d6, 400 MHz) δ 9.88 (s, 1H), 8.52 (s, 1H), 7.30-7.18 (m, 5H), 7.02 (d, J=8.7 Hz, 1H), 4.87 (s, 1H), 4.26-4.23 (m, 2H), 3.69-3.65 (m, 4H), 3.19 (s, 3H), 2.65 (m, 2H), 1.94-1.90 (m, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25]([OH:27])=O)[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:23])[CH3:22])[CH:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=1)[CH3:29]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]([CH3:22])[CH3:23])[CH:16]=2)[CH2:24][C:25]([N:30]([CH2:28][CH3:29])[CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([CH3:38])[N:33]=2)=[O:27])(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CN(C)c1cccc(N(CC(=O)O)S(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Reactant: CCNCc1cccc(C)n1
Product: CCN(Cc1cccc(C)n1)C(=O)CN(c1cccc(N(C)C)c1)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(3-dimethylamino-phenyl)-amino]-acetic acid with ethyl-(6-methyl-pyridin-2-ylmethyl)-amine
Reaction SMILES: C([S:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[C:22]([O:24]C)=[O:23])(=O)C.[OH-].[K+]>O1CCOCC1.O>[SH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[N:9]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:8]=1[C:22]([OH:24])=[O:23]
Reactant: COC(=O)c1c(CCSC(C)=O)c2ccccc2n1-c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1c(CCS)c2ccccc2n1-c1ccccc1
Reaction time: 8 h
Yield: 93 %

Procedure:
To a deoxygenated solution of 3-(2-acetylthioethyl)-1-phenyl-1H-indole-2-carboxylic acid, methyl ester in dioxane (5 mL) was added a deoxygenated solution of potassium hydroxide (0.168 g, 3.0 mmol) in water (5 mL). The reaction mixture was stirred overnight. Volatile solvent was removed under reduced pressure and the remaining mixture was poured into 1 N HCl (25 mL) containing ice chips. The resulting white precipitate was washed with H2O and dried under vacuum to give 0.110 g of 3-(2-mercaptoethyl)-1-phenyl-1H-indole-2-carboxylic acid (93% yield) as a white solid: 1H NMR (CDCl3) δ 1.52 (t, J=8.1 Hz, 1H), 2.91 (q, J=7.7 Hz, 2H), 3.49 (t, J=7.6 Hz, 2H), 7.08 (d, J=8.2 Hz, 1H), 7.21 (t, J=7.5 Hz, 1H), 7.27–7.33 (m, 3H), 7.42–7.53 (m, 3H), 7.78 (d, J=8.0 Hz, 1H). Anal. Calcd. for C17H15N2O2S.0.25 H2O: C, 67.64, H, 5.18, N, 4.64, S, 10.62. Found: C, 67.77, H, 5.15, N, 4.69, S, 10.62.
Reaction SMILES: O=[O+][O-].[O:4]=O.[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=C)=[O:12])([CH3:9])([CH3:8])[CH3:7].O=O.S(C)C>C(Cl)Cl>[C:6]([O:10][C:11]([NH:13][C@@H:14]([CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C@@H:15]([O:18][C:19](=[O:21])[CH3:20])[CH:16]=[O:4])=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: C=C[C@H](OC(C)=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: O=O
Agent: O=[O+][O-]
Solvent: ClCCl
Solvent: CSC
Product: CC(=O)O[C@@H](C=O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
Ozone/oxygen was bubbled at -70° C. into a solution of (3S,4S)-N-[(tert-Butyloxy)carbonyl]-4-amino-3-acetoxy-5-phenylpentene (2.55g, 8.0 mmol) [prepared by the method of Hanson et al., J. Ora. Chem., 50, 5399 (1985)] in 100 mL of methylene chloride until a deep blue color persisted. Oxygen was introduced until the blue color completely faded, then 3.0 mL of Me2S was added and the solution was allowed to warm to 0°-5° C. and stand overnight. The solvent was removed at 0° C. under vacuum yielding the title compound as a thick yellow oil which was used without further purification.
Reaction SMILES: [ClH:1].C([O:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[CH2:23][CH2:22]1)=[O:20])=[O:11])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[ClH:1].[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][C:19]([C@H:21]1[CH2:22][CH2:23][C@H:24]([CH2:27][NH:28][C:29]([NH2:31])=[NH:30])[CH2:25][CH2:26]1)=[O:20])([OH:11])=[O:9]
Reactant: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: N=C(N)NC[C@H]1CC[C@H](C(=O)Nc2ccccc2C(=O)O)CC1

Procedure:
The above N-(o-benzyloxycarbonylphenyl)-trans-4-guanidinomethylcyclohexylcarboxamide hydrochloride (1.09 g, 0.0024 mole) is dissolved in methanol (50 ml), and thereto is added 10% palladium-carbon (0.23 g), and the mixture is stirred with blowing hydrogen gas under atmospheric pressure at 30° C. for one hour. After the completion of the reaction, palladium-carbon is filtered off, and the filtrate is concentrated under reduced pressure. The resulting residue is recrystallized from a mixture of methanol-water to give N-(o-carboxyphenyl)-trans-4-guanidinomethylcyclohexanecarboxamide hydrochloride (0.76 g) as white crystals, melting at around 135°-145° C. and after being solidified, decomposing at 215°-220° C.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH2:31])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1.C(N(CC)CC)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43].C([O-])(O)=O.[Na+]>ClCCl>[F:33][C:2]([F:1])([F:32])[C:3]1[CH:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:6]=[C:5]([C:19]2[CH:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][S:42]([CH3:41])(=[O:44])=[O:43])[CH:26]=3)[CH:22]=[CH:23][CH:24]=2)[N:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)Nc1cccc(-c2cccc(-c3nc(-c4ccc(C(F)(F)F)cc4)cc(C(F)(F)F)n3)c2)c1
Yield: 59.5 %

Procedure:
To a stirred and cooled (ice bath) solution of 3′-[4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidin-2-yl]-biphenyl-3-ylamine (example 220) (0.23 g, 0.5 mmol) in dichloromethane (5 mL) was added triethylamine (0.21 mL) and methanesulfonyl chloride (0.06 g, 0.52 mmol), the reaction mixture was allowed to stir at room temperature for 1 h, poured into sat. NaHCO3 solution (20 mL) and extracted with ethyl acetate (2×30 mL). The combined organic layers were washed with brine (30 mL), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (ethyl acetate/heptane) and crystallization (dichloromethane/MeOH/hexane) yielded the title compound (0.16 g, 72%) as a white solid. MS (ISP) 538.0 [(M+H)+]; mp 191° C.
Reaction SMILES: [C:1]1([C@@H:7]([NH2:9])[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:10][C:11]1[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[N:12]=1>C1COCC1>[C:1]1([C@@H:7]([NH:9][C:11]2[N:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[N:12]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:1]1([C@@H:7]([NH:9][C:15]2[CH:14]=[C:13]([Cl:18])[N:12]=[C:11]([Cl:10])[N:16]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: Clc1cc(Cl)nc(Cl)n1
Solvent: C1CCOC1
Product: C[C@H](Nc1cc(Cl)nc(Cl)n1)c1ccccc1
Product: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccccc1
Reaction time: 2 h

Procedure:
To a solution of (S)-1-phenylethylamine (2.6 mL) in THF (20 mL) at room temperature was added 2,4,6-trichloropyrimidine (1.83 g) dissolved in THF (10 mL) dropwise. The reaction mixture was stirred for 2 h, and then the solid was filtered and washed thoroughly with EtOAc. Combined filtrate was concentrated under reduced pressure, and the crude product was purified by flash chromatography (silica, 1:2), followed by 1:6 EtOAc:hexanes) to give 2-[(S)-1-phenylethylamino]-4,6-dichloropyrimidine (1.2 g) and 4-[(S)-1-phenylethylamino]-2,6-dichloropyrimidine (1.5 g). 2-[(S)-1-phenylethylamino]-4,6-dichloropyrimidine 1H NMR (500 MHz, CDCl3): δ 7.4-7.25 (m, 5H); 6.6 (s, 1H); 5.65 (br s, 1H); 5.2 (m, 1H); 1.58 (d, J=7.1 Hz, 3H). Mass spectrum (CI) 268.2 (M+1). 4-[(S)-1-phenylethylamino]-2,6-dichloropyrimidine 1H NMR (500 MHz, CDCl3): δ 7.41-7.3 (m, 5H); 6.1 (br s, 1H); 5.8 (br s, 1H); 4.6 (br s, 1H); 1.6 (d, J=7.1 Hz, 3H). Mass spectrum (CI) 268.2 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:17][CH2:18][CH2:19][CH2:20]Br>CC(=O)CC>[Cl:17][CH2:18][CH2:19][CH2:20][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1
Reactant: ClCCCBr
Reactant: NC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: NC(=O)c1ccc(OCCCCl)cc1
Yield: 87.2 %

Procedure:
A mixture of 4-hydroxybenzamide (5 g, 36.5 mmol, 1 eq), potassium carbonate (10.08 g, 72.9 mmol, 2 eq), 3-chloro-1-bromopropane (4.7 ml, 47.4 mmol, 1.3 eq) in butanone is stirred at reflux for 48 h. The solvent is then removed under vacuum and the residue is triturated in hexane and filtered. The solid is taken up in ethyl acetate and washed with a saturated solution of sodium hydrogencarbonate. The organic layer is dried over magnesium sulfate and concentrated to give 4-(3-chloropropoxy)benzamide ax54 (6.8 g) as a white solid.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([C:13]([O:15][CH3:16])=[O:14])[CH:6]=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9])=[O:2].[N+:17]([CH3:20])([O-:19])=[O:18].C(N(CC)CC)C>CO>[OH:2][CH:1]([C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[CH:6]=[C:5]([CH:4]=1)[C:13]([O:15][CH3:16])=[O:14])[CH2:20][N+:17]([O-:19])=[O:18]
Reactant: C[N+](=O)[O-]
Reactant: COC(=O)c1cc(C=O)cc(C(=O)OC)c1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1cc(C(=O)OC)cc(C(O)C[N+](=O)[O-])c1
Temperature: 22 °C
Reaction time: 16 h

Procedure:
To a solution of 2.45 g (11.0 mmol) of dimethyl 5-formylisophthalate in 30 mL of methanol was added 1.48 mL (27.6 mmol) of nitromethane and 1.53 mL (11.0 mmol) of triethylamine (TEA). The solution was stirred at 22° C. for about 16 h, evaporated then coevaporated with xylenes. The residue was purified by flash chromatography on silica gel, eluting first with 5% ethyl acetate/hexane and then gradually increasing to 20% ethyl acetate/hexane which gave dimethyl 5-(1-hydroxy-2-nitroethyl)isophthalate as a solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[C:5]([Cl:22])=[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)[CH:7]=[N:8][CH:9]=1.[C:23](Cl)(=[O:26])[CH2:24][CH3:25]>>[Cl:22][C:5]1[C:6]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]([CH3:20])[C:15](=[O:21])[CH2:14][CH2:13]3)=[CH:7][N:8]=[CH:9][C:4]=1[CH2:3][NH:2][C:23](=[O:26])[CH2:24][CH3:25]
Reactant: CCC(=O)Cl
Reactant: CN1C(=O)CCc2cc(-c3cncc(CN)c3Cl)ccc21
Agent: Cl
Product: CCC(=O)NCc1cncc(-c2ccc3c(c2)CCC(=O)N3C)c1Cl

Procedure:
In analogy to the procedure described in example 76, 6-(5-aminomethyl-4-chloro-pyridin-3-yl)-1-methyl-3,4-dihydro-1H-quinolin-2-one hydrochloride (example 218) has been reacted with propionyl chloride to give the title compound as an off-white solid. MS: 358.4 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([OH:33])[C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][C@H:6]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:13][CH:12]=1)[CH:7]([CH3:9])[CH3:8].[CH3:34][C:35]([CH3:43])([CH2:39][CH2:40][CH2:41][CH3:42])[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:34][C:35]([CH3:43])([CH2:39][CH2:40][CH2:41][CH3:42])[C:36]([NH:1][CH2:2][C@H:3]([OH:33])[C@@H:4]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:5][C@H:6]([CH2:10][C:11]1[CH:19]=[C:18]2[C:14]([CH:15]=[N:16][N:17]2[CH2:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:13][CH:12]=1)[CH:7]([CH3:8])[CH3:9])=[O:37]
Reactant: CCCCC(C)(C)C(=O)O
Reactant: COCCCn1ncc2ccc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)CN)C(C)C)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCC(C)(C)C(=O)NC[C@H](O)[C@H](C[C@H](Cc1ccc2cnn(CCCOC)c2c1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 5 h
Yield: 74.9 %

Procedure:
To a solution of tert-butyl (2S,3S,5S)-1-amino-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (350 mg, 0.76 mmol) in CH2Cl2 (15 mL), 2,2-dimethylhexanoic acid (176 mg, 1.22 mmol), HOBt (290 mg, 2.1 mmol) and EDCl (400 mg, 2.1 mmol) were added. The mixture cooled to 0° C. and DIEA (700 mg, 5.4 mmol) was added. The resulting mixture was allowed to warm to rt and stirred for 5 h. The reaction mixture was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo to give tert-butyl (2S,3S,5S)-1-(2,2-dimethylhexanamido)-2-hydroxy-5-((1-(3-methoxypropyl)-1H-indazol-6-yl)methyl)-6-methylheptan-3-ylcarbamate (335 mg, 75%). 1H NMR (400 MHz, CDCl3): 0.86 (m, 3H), 0.92 (m, 3H), 0.99 (m, 3H), 1.13 (s, 6H), 1.16 (m, 2H), 1.27 (m, 3H), 1.49 (m, 2H), 1.70 (m, 3H), 1.88 (m, 1H), 2.11 (m, 2H), 2.62 (m, 1H), 2.85 (m, 1H), 2.97 (m, 1H), 3.10 (m, 1H), 3.28 (s, 3H), 3.36 (m, 1H), 3.62 (m, 1H), 4.48 (m, 2H), 7.06 (m, 1H), 7.39 (s, 1H), 7.67 (m, 1H), 7.99 (s, 1H); MS: 588 (M++1)
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([O:15][C:16]1[N:17]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([C:37]3[C:38]([C:43]#[N:44])=[CH:39][CH:40]=[CH:41][CH:42]=3)=[CH:33][CH:32]=2)[C:18](=[O:29])[C:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]>O>[CH2:13]([O:15][C:16]1[N:17]([CH2:30][C:31]2[CH:32]=[CH:33][C:34]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[C:43]3[NH:3][C:4](=[O:7])[O:5][N:44]=3)=[CH:35][CH:36]=2)[C:18](=[O:29])[C:19]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:20]([CH3:22])[N:21]=1)[CH3:14]
Reactant: CCOc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [NH3+]O
Reactant: O=C([O-])O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOc1nc(C)c(-c2ccccc2)c(=O)n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 23.9 %

Procedure:
A mixture of hydroxylammonium chloride (1.08 g), sodium hydrogen carbonate (1.53 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-[(2-ethoxy-4-methyl-6-oxo-5-phenylpyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (0.77 g) was added, and the mixture was stirred at 90° C. for 5 hr. The mixture was allowed to cool to room temperature. Water was added to the reaction mixture, and the precipitate was collected by filtration. The obtained solid was dissolved in ethyl acetate. The solution was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated. The residue was dissolved in tetrahydrofuran (5 mL), N,N′-carbonyldiimidazole (0.44 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.41 mL) were added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was diluted with ethyl acetate, washed with 1 M hydrochloric acid and then with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.21 g, 24%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[O:10][C:11]3[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=3[N:13]=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1([CH3:44])[C:24]([CH3:26])([CH3:25])[O:23][B:22](C2C=CC(NC3OC4C=CC(Cl)=CC=4N=3)=CC=2)[O:21]1>>[CH3:19][C:20]1([CH3:44])[C:24]([CH3:26])([CH3:25])[O:23][B:22]([C:2]2[CH:7]=[CH:6][C:5]([NH:8][C:9]3[O:10][C:11]4[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:12]=4[N:13]=3)=[CH:4][CH:3]=2)[O:21]1
Reactant: CC1(C)OB(c2ccc(Nc3nc4cc(Cl)ccc4o3)cc2)OC1(C)C
Reactant: Cc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Product: Cc1ccc2oc(Nc3ccc(B4OC(C)(C)C(C)(C)O4)cc3)nc2c1

Procedure:
N2-[4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-methyl-1,3-benzoxazol-2-amine was prepared from N2-(4-bromophenyl)-5-methyl-1,3-benzoxazol-2-amine (1.5 g, 4.95 mmol) using the method described for the preparation of N2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-5-chloro-1,3-benzoxazol-2-amine. The product was formed as white floculent solid (0.79 g, 46%); RP-HPLC Rt 17.382 min, 98% purity (5% to 85% acetonitrile/0.1M aqueous ammonium acetate, buffered to pH 4.5, over 20 min at 1 mL/min; λ=254 nm; Deltapak C18, 300 Å, 5 μm, 150×3.9 mm column); 1H NMR (400 MHz, d6-DMSO) 1.29 (121H, s), 2.38 (3H, s), 6.94 (1H, d, J=8.1 Hz), 7.30 (1H, s), 7.36 (1H, d, J=8.1 Hz), 7.67 (2H, d, J=8.5 Hz), 7.75 (2H, d, J=8.5 Hz), and 10.74 (1H, s).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1OS(C(F)(F)F)(=O)=O)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1.[C:51]1(B(O)O)[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>O1CCOCC1.C(OCC)(=O)C>[F:31][C:30]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:32])([F:31])[F:33])[CH:27]=[CH:26][C:25]=1[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:10][N:9]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OS(=O)(=O)C(F)(F)F)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2-c2ccccc2)nc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 212.2 %

Procedure:
Ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(2-trifluoromethanesulfonyloxy-5-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate (200 mg) is dissolved in 1,4-dioxane (3 ml), and thereto are added phenyl boronic acid (64 mg), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (22 mg) and cesium carbonate (172 mg), and the mixture is stirred under nitrogen atmosphere at 80° C. overnight. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by NH-silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give ethyl 4-{2-[(3,5-bis-trifluoromethyl-benzyl)-(4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyrimidin-5-yloxy}-butyrate (192 mg). MS (m/z): 686 [M+H]+