Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:27]=[CH:26][C:16]([CH2:17][CH2:18][CH:19]([PH:21](=[O:25])[O:22][CH2:23][CH3:24])[CH3:20])=[CH:15][C:14]=2[O:28][CH3:29])[N:3]=1.[NH2:30][C:31]1[C:32]([C:38]([NH:40][CH3:41])=[O:39])=[N:33][C:34]([Br:37])=[CH:35][CH:36]=1.C(O)(C(F)(F)F)=O>>[Br:37][C:34]1[N:33]=[C:32]([C:38](=[O:39])[NH:40][CH3:41])[C:31]([NH:30][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]3[CH:27]=[CH:26][C:16]([CH2:17][CH2:18][CH:19]([PH:21](=[O:25])[O:22][CH2:23][CH3:24])[CH3:20])=[CH:15][C:14]=3[O:28][CH3:29])[N:3]=2)=[CH:36][CH:35]=1
Reactant: CCO[PH](=O)C(C)CCc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1
Reactant: CNC(=O)c1nc(Br)ccc1N
Solvent: O=C(O)C(F)(F)F
Product: CCO[PH](=O)C(C)CCc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
A solution of ethyl (4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}-3-methoxybenzyl)propan-2-ylphosphinate (Compound 68D, 1.00 g, 2.21 mmol) and 3-amino-6-bromo-N-methylpyridine-2-carboxamide (Compound 6D, 0.516 g, 2.24 mmol) in TFE (11.71 mL) was charged with TFA (0.341 mL, 4.43 mmol). The reaction mixture was heated at 80° C. for 16 hours. The reaction mixture was concentrated under reduced pressure to a light yellow oil. The crude material was purified using a Teledyne ISCO Combiflash® Rf system using DCM/MeOH (100:0→95:5) as eluent to afford the desired product as a white solid (865 mg, 61%). 1H NMR (CDCl3, 400 MHz): δ 12.97 (br. s., 1H), 8.85 (d, J=9.3 Hz, 1H), 8.29 (s, 1H), 8.13 (q, J=4.4 Hz, 1H), 7.66 (br. s., 1H), 7.59 (d, J=9.1 Hz, 1H), 7.02 (t, J=1.6 Hz, 1H), 6.88 (td, J=1.8, 8.2 Hz, 1H), 3.92-4.10 (m, 2H), 3.87 (s, 3H), 3.19 (dd, J=2.8, 14.9 Hz, 2H), 3.04 (d, J=5.3 Hz, 3H), 1.87-2.00 (m, 1H), 1.18-1.27 (m, 9H). MS (ESI): m/z 645.55/647.54 [M+H]+. UPLC: tR=1.47 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11]O.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([Cl:10])=[CH:4][C:3]=1[CH2:11][Br:14]
Reactant: COc1cc(Cl)cc(CO)c1Cl
Reactant: BrP(Br)Br
Solvent: Cc1ccccc1
Product: COc1cc(Cl)cc(CBr)c1Cl
Yield: 86.6 %

Procedure:
By the method of Example 1, Step B, 13.95 grams (0.0674 mole) of 2,5-dichloro-3-methoxyphenylmethanol and 7.295 grams (0.270 mole) of phosphorus tribromide were reacted in toluene, yielding 15.76 grams of 2,5-dichloro-3-methoxyphenylmethyl bromide as an oil. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]4)[CH:16]=2)=[O:11])=[C:6]([CH3:29])[N:5]=[C:4]([NH:30]C(=O)OC(C)(C)C)[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:30][C:4]1[N:5]=[C:6]([CH3:29])[C:7]([CH2:8][NH:9][C:10]([C:12]2[N:13]=[N:14][N:15]([CH2:17][C:18]3[CH:19]=[C:20]4[C:25](=[CH:26][CH:27]=3)[N:24]=[C:23]([CH3:28])[CH:22]=[CH:21]4)[CH:16]=2)=[O:11])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(NC(=O)OC(C)(C)C)nc4C)nn3)ccc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc2cc(Cn3cc(C(=O)NCc4c(C)cc(N)nc4C)nn3)ccc2n1
Temperature: 23 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (4,6-dimethyl-5-((1-((2-methylquinolin-6-yl)methyl)-1H-1,2,3-triazole-4-carboxamido)methyl)pyridin-2-yl)carbamate (131.9 mg, 0.263 mmol) in DCM (1.2 ml) was added TFA (0.405 ml, 5.26 mmol). Reaction mixture was stirred overnight at 23° C. Reaction mixture was evaporated to afford the crude material, which was purified by preparative HPLC (Sunfire C18-ODB, 5 μm, 100×30 mm, elution with A=water+0.1% TFA and B=ACN+0.1% TFA, gradient from 5% to 100% B in 25 min, flow: 40 mL/min). Fractions were combined and acetonitrile was evaporated. Residual aqueous layer was frozen and lyophilized to afford the product as a TFA salt, which was dissolved in acetonitrile/methanol and eluted through a PL-HCO3 MP-resin column (Stratosphere SPE). The eluted solution was evaporated, and the residue was triturated in Et2O and filtered to afford the title compound as a free base. 1H-NMR (DMSO-d6, 400 MHz) δ 8.70 (s, 1H), 8.62 (broad s, 1H), 8.24 (d, 1H), 7.91 (d, 1H), 7.86 (s, 1H), 7.66 (d, 1H), 7.43 (d, 1H), 6.37 (broad s, 1H), 5.82 (s, 2H), 4.33 (d, 2H), 2.64 (s, 3H), 2.42 (s, 3H), 2.29 (s, 3H); HPLC (Method G) Rt=0.932 min; MS (Method F) [M+H]+=402.5.
Reaction SMILES: [CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][OH:25])=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1.[CH3:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1O.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1>[CH3:1][C:2]1[N:3]([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH2:24][O:25][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[CH3:26])=[C:10]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:11]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1nccn1-c1nc(-c2ccc(C(F)(F)F)cc2)c(CCCO)o1
Reactant: Cc1ccccc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cc1ccccc1OCCCc1oc(-n2ccnc2C)nc1-c1ccc(C(F)(F)F)cc1
Reaction time: 1 h

Procedure:
To a mixture of 2-(2-methyl-1-imidazolyl)-4-(4-trifluoromethylphenyl)-5-oxazolepropanol (700 mg), 2-methylphenol (432 mg), tributylphosphine (607 mg) and tetrahydrofuran (10 mL) was added 1,1′-(azodicarbonyl)dipiperidine (750 mg) at room temperature and the mixture was stirred for 1 h. The reaction mixture was concentrated and the residue was subjected to silica gel column chromatography. The title compound was obtained as crystals from an eluate from ethyl acetate-hexane (2:3, v/v). Recrystallization from acetone-isopropyl ether gave colorless prism crystals (591 mg, 67%). melting point: 101-102° C.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH:14]([NH:17][NH:18][C:19](=[O:31])[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:22][CH:21]=1)([CH3:16])[CH3:15].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:1][C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([N:17]([CH:14]([CH3:16])[CH3:15])[NH:18][C:19](=[O:31])[C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:24][CH:25]=1)=[O:8]
Reactant: O=C(O)COc1ccc(F)cc1Br
Reactant: COCCOc1ccc(C(=O)NNC(C)C)cc1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(C(=O)NN(C(=O)COc2ccc(F)cc2Br)C(C)C)cc1
Yield: 63.3 %

Procedure:
A solution of (2-bromo-4-fluoro-phenoxy)-acetic acid (164 mg, 0.66 mmol) and 4-(2-methoxy-ethoxy)-benzoic acid-N′-isopropyl hydrazide (200 mg, 0.79 mmol) in DMF (5 ml) was treated with diisopropylethyl amine (0.29 mL, 1.65 mmol) and PyBroP (462 mg, 0.99 mmol) at room temperature overnight. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with water and brine, then dried over sodium sulfate, filtered and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 45-60% ethyl acetate/hexanes gradient to afford the product as a solid (202 mg, 63%).
Reaction SMILES: [CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21]C)[C:18]([O:23]C)=[C:17]([O:25]C)[CH:16]=3)=[N:10][C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.B(Br)(Br)Br>>[CH:1]1([CH2:7][C:8]2[S:12][C:11]([NH:13][C:14](=[O:27])[C:15]3[CH:16]=[C:17]([OH:25])[C:18]([OH:23])=[C:19]([OH:21])[CH:20]=3)=[N:10][C:9]=2[C:28]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)Nc2nc(-c3ccc(O)cc3)c(CC3CCCCC3)s2)cc(OC)c1OC
Agent: BrB(Br)Br
Product: O=C(Nc1nc(-c2ccc(O)cc2)c(CC2CCCCC2)s1)c1cc(O)c(O)c(O)c1
Yield: 55.8 %

Procedure:
A procedure similar to that in Example 7 was used. N-[5-cyclohexylmethyl-4-(4-hydroxy-phenyl)-thiazol-2-yl]-3,4,5-trimethoxy-benzamide prepared in Example 50 and boron tribromide were used as starting materials. The obtained crude product was recrystallized with acetone to obtain a product as a white solid in a yield of 55.8%, mp: 238-239 └. 1H-NMR (DMSO-d6, 400 MHz) δ: 0.80˜0.90 (2H, m), 1.00˜1.23 (3H, m), 1.45˜1.75 (6H, m), 2.70 (2H, d, J=7.00 Hz, CHCH2Ar), 6.84 (2H, d, J=8.68 Hz, ArH), 7.09 (2H, s, ArH), 7.38 (2H, d, J=8.68 Hz, ArH), 9.17 (4H, br, 4×OH), 12.20 (1H, br, CONH); EI-MS m/e (%): 440.0 (M+, 6), 288.1 (38), 205.1 (100), 163.0 (28); HREI-MS Calcd. for C23H24N2O5S: 440.1406. found: 440.1406.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH2:21])[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22]1([N:28]=[C:29]=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]1[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:30])[CH2:14][CH2:15]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C=Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCCN)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC1CCN(CCCCCNC(=O)Nc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
5-(4-tert-Butoxycarbonylaminomethylpiperidin-1-yl)pentylamine (2.00 g) was dissolved in methylene chloride (80 ml) and phenyl isocyanate (0.80 ml) was dropwise added under ice-cooling. The mixture was stirred at room temperature for 15 hr, and the reaction mixture was concentrated under reduced pressure to give 4-tert-butoxycarbonylaminomethyl-1-(5-(3-phenylureido)pentyl)piperidine.
Reaction SMILES: ON=[C:3]([CH3:17])[C:4](=[N:12][NH:13][C:14]([NH2:16])=[S:15])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1.C(=O)([O-])[O-].[K+].[K+].C>O.CO>[CH3:17][C:3]1[C:4]([C:5]2[CH:6]=[C:7]([CH3:11])[CH:8]=[CH:9][CH:10]=2)=[N:12][NH:13][C:14](=[S:15])[N:16]=1
Reactant: CC(=NO)C(=NNC(N)=S)c1cccc(C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Cc1cccc(-c2n[nH]c(=S)nc2C)c1
Yield: 115.2 %

Procedure:
A mixture of 2-hydroxyimino-3'-methylpropiophenone thiosemicarbazone (5 g) and potassium carbonate (6.1 g) in water (44 ml) was refluxed for 4 hours under nitrogen atmosphere. The reaction mixture was treated with activated charcoal and filtered by suction. The filtrate was acidified with diluted hydrochloric acid, and the resultant precipitates were collected by filtration, washed with water and dried. The above obtained crude product was dissolved in methanol (150 ml), and the solution was filtered by suction. The filtrate was concentrated under reduced pressure, and the residue was crystallized from diisopropyl ether, collected by filtration, washed with a mixture of methanol and diisopropyl ether, and dried to give 5-methyl-6-(m-tolyl)-1,2,4-triazine-3(2H)-thione (5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][CH3:8])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:21]1[S:22][C:23]([CH:27]=[O:28])=[C:24]([Cl:26])[N:25]=1>O1CCCC1>[Cl:26][C:24]1[N:25]=[C:21]([N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH3:8])[S:22][C:23]=1[CH:27]=[O:28]
Reactant: O=Cc1sc(Cl)nc1Cl
Reactant: CNCc1ccc(Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CN(Cc1ccc(Cl)cc1)c1nc(Cl)c(C=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 119525.2 %

Procedure:
To a solution of (4-chloro-benzyl)-methyl-amine (550, 2 g, 0.01 mol) and N,N-diisopropylethylamine (4 mL, 0.03 mol) in tetrahydrofuran (50 mL) was added 2,4-dichloro-thiazole-5-carbaldehyde (93, 3 g, 0.01 mmol) in tetrahydrofuran (20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate, washed with brine, and dried over sodium sulfate. After removal of solvent, the residue was collected by filtration and washed with hexanes to provide the desired compound as a light-yellow solid (551, 3.6 g, 90%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:16])[C:7]3[N:8]([CH:13]=[CH:14][CH:15]=3)[N:9]([CH3:12])[C:10]=2[CH:11]=1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1.[Br:35]N1C(=O)CCC1=O.[Al]>C1COCC1>[Br:35][C:13]1[N:8]2[N:9]([CH3:12])[C:10]3[CH:11]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:6](=[O:16])[C:7]2=[CH:15][CH:14]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c2cc(Cl)ccc2c(=O)c2cccn21
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Agent: [Al]
Solvent: C1CCOC1
Product: Cn1c2cc(Cl)ccc2c(=O)c2ccc(Br)n21
Temperature: 25 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
To a solution of 7-chloro-5-methylpyrrolo[1,2-b]cinnolin-10(5H)-one (6.0 g) and a catalytic amount of dibenzoyl peroxide in 100 ml of THF was added portionwise N-bromosuccinimide (4.63 g) over 15 min. The flask was covered with aluminum foil and the solution was stirred at room temperature for 24 hrs. The solution was then concentrated and the residue was purified by HPLC (silica, dichloromethane) to give 7.10 g of a light green powder. This powder was recrystallized from ethanol to give 5.7 g of a yellow fibrous material, mp 133°-135°.
Reaction SMILES: [CH3:1][C:2]([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([C:21]2[CH:22]=[N:23][CH:24]=[N:25][CH:26]=2)[CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH:27]1[C:35]2[CH2:34][CH2:33][CH2:32][C:31](=[O:36])[C:30]=2[CH:29]=[CH:28]1.[O-]CC.[Na+]>C(O)C>[OH:5][C:4]([C:7]([F:10])([F:8])[F:9])([CH2:3][C:2]([CH3:1])([C:12]1[C:20]2[O:19][CH2:18][CH2:17][C:16]=2[CH:15]=[C:14]([C:21]2[CH:26]=[N:25][CH:24]=[N:23][CH:22]=2)[CH:13]=1)[CH3:11])[CH2:6][N:27]1[C:35]2[CH2:34][CH2:33][CH2:32][C:31](=[O:36])[C:30]=2[CH:29]=[CH:28]1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1cc(-c2cncnc2)cc2c1OCC2
Reactant: O=C1CCCc2[nH]ccc21
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(CC(O)(Cn1ccc2c1CCCC2=O)C(F)(F)F)c1cc(-c2cncnc2)cc2c1OCC2
Temperature: 85 °C
Yield: 56.1 %

Procedure:
To a suspension of 5-{7-[1,1-dimethyl-2-(2-trifluoromethyloxiranyl)ethyl]-2,3-dihydrobenzofuran-5-yl}pyrimidine (56.0 mg, 0.15 mmol) and 1,5,6,7-tetrahydroindol-4-one (41.6 mg, 0.31 mmol) in 1.0 mL of anhydrous ethanol was added sodium ethoxide solution (0.057 mL, 21 wt. % in ethanol). The reaction mixture was heated at 85° C. for 15 hours. After cooling to room temperature, the reaction mixture was concentrated onto silica gel (for dry loading) and purified by silica gel chromatography (eluted with 40% to 70% ethyl acetate-hexanes) to give 42.0 mg (55% yield) of the title compound as a white solid, m.p. 213° C.-214° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:33]([O-])=O)=[C:6]([C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=3[CH:25]=2)=[O:12])[CH:7]=1.O1CCCC1>C(O)(=O)C.[Fe]>[NH2:33][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][C:6]=1[C:8]([CH3:32])([CH3:31])[CH2:9][C:10]([OH:30])([C:26]([F:29])([F:28])[F:27])[C:11]([NH:13][C:14]1[CH:15]=[CH:16][C:17]2[C:22](=[O:23])[O:21][N:20]=[C:19]([CH3:24])[C:18]=2[CH:25]=1)=[O:12]
Reactant: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3[N+](=O)[O-])C(F)(F)F)cc12
Agent: [Fe]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Cc1noc(=O)c2ccc(NC(=O)C(O)(CC(C)(C)c3cc(F)ccc3N)C(F)(F)F)cc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 25.3 %

Procedure:
42 mg of 6-[4-(5-fluoro-2-nitrophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is dissolved in 1 ml of acetic acid and 1 ml of tetrahydrofuran b, mixed with 22.5 mg of iron powder and stirred for 16 hours at room temperature. It is suctioned off on diatomaceous earth, concentrated by evaporation, the residue is taken up in ethyl acetate and washed with a saturated sodium hydrogen carbon solution. After chromatography on silica gel with hexane/ethyl acetate (1.5+1) and recrystallization from diisopropyl ether, 10 mg of 6-[4-(2-amino-5-fluorophenyl)-2-hydroxy-4-methyl-2-trifluoromethylvaleroylamino]-4-methyl-2,3-benzoxazin-1-one is obtained, flash point 208° C.
Reaction SMILES: O=[C:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OC(=O)C)(=O)C>C1C=CC=CC=1.[Zn]>[CH2:3]([C:2]([C:15]1[CH:16]=[C:17]([Si:20]([CH3:23])([CH3:22])[CH3:21])[O:18][CH:19]=1)=[CH:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCOC(=O)CBr
Reactant: CCCCCCCCCCCCC(=O)c1coc([Si](C)(C)C)c1
Agent: [Zn]
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CCCCCCCCCCCCC(=CC(=O)OCC)c1coc([Si](C)(C)C)c1
Reaction time: 14 h

Procedure:
A mixture of 4-(1-ketotridecyl)-2-trimethylsilylfuran (Compound 26, 84.5 mg, 0.25 mmol), zinc (100 mg, 1.53 mmol) and ethyl bromoacetate (105 mg, 0.63 mmol) in benzene (6 ml) was refluxed for 2 hours. After cooling to 0°, acetic anhydride (83 ul, 0.88 mmol) was added. Stirring was continued for 14 hours while the cooling bath attained room temperature. The mixture was washed with 5% sodium bicarbonate and water. Evaporation of the dried (magnesium sulfate) organic phase gave a residue which was purified by a silica column using 2% ethyl ether/hexane to give the title ester.
Reaction SMILES: [CH:1]1([O:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:12]SCl>>[CH:1]1([O:7][CH2:8][C:9]([Cl:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)COC1CCCCC1
Reactant: ClSCl
Product: O=C(Cl)COC1CCCCC1
Temperature: 25 °C

Procedure:
A mixture of 2-(cyclohexyloxy)acetic acid (0.90 g, 5.69 mmol) and dichlorosulfane (10 mL) was refluxed for 2 h. The mixture was cooled to rt and concentrated in vacuo to give the title compound as yellow oil, which was used for next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:4]([CH:9]=[CH:10][C:11]=1[Cl:12])[C:5]([O:7][CH3:8])=[O:6].[N:18]([C:21]1[C:22]([CH3:30])=[CH:23][C:24]([N:27]([CH3:29])[CH3:28])=[N:25][CH:26]=1)=[C:19]=[S:20]>O1CCCC1>[Cl:12][C:11]1[CH:10]=[CH:9][C:4]([C:5]([O:7][CH3:8])=[O:6])=[C:3]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])[C:2]=1[NH:1][C:19](=[S:20])[NH:18][C:21]1[CH:26]=[N:25][C:24]([N:27]([CH3:29])[CH3:28])=[CH:23][C:22]=1[CH3:30]
Reactant: Cc1cc(N(C)C)ncc1N=C=S
Reactant: COC(=O)c1ccc(Cl)c(N)c1NCCCO
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Cl)c(NC(=S)Nc2cnc(N(C)C)cc2C)c1NCCCO
Temperature: 70 °C
Reaction time: 7 h

Procedure:
A mixture of methyl 3-amino-4-chloro-2-[(3-hydroxypropyl)amino]benzoate (4.00 g, 15.5 mmol) and 5-isothiocyanato-N,N,4-trimethylpyridin-2-amine (8.96 g, 46.4 mmol) in tetrahydrofuran (30 mL) was stirred at 70° C. for 7 hr. The mixture was concentrated in vacuo, and the residue was purified by flash column chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give methyl 4-chloro-3-({[6-(dimethylamino)-4-methylpyridin-3-yl]carbamothioyl}amino)-2-[(3-hydroxypropyl)amino]benzoate as a brown amorphous (3.01 g).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH2:41](O)[CH2:42][CH2:43][CH2:44]C>O>[Cl:1][C:2]1[CH:20]=[C:19]([F:21])[C:18]([N:22]2[C:27](=[O:28])[CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[N:24]([CH3:33])[C:23]2=[O:34])=[CH:17][C:3]=1[O:4][C:5]1[C:6]([O:11][CH2:12][C:13]([O:15][CH2:16][CH2:41][CH2:42][CH2:43][CH3:44])=[O:14])=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: COC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Reactant: CCCCCO
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCCCCOC(=O)COc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1Cl
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.30 g of methyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-6), 0.06 g of sodium carbonate, and 3.0 ml of n-pentanol was stirred at 100° C. for 1.5 hours. After cooling to room temperature, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.07 g of pentyl [3-{2-chloro-4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]phenoxy}-2-pyridyloxy]acetate (compound a-20).
Reaction SMILES: C(OC([NH:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:21]=1)[C:16]([OH:18])=O)=O)(C)(C)C.[Cl:37][C:38]1[CH:39]=[C:40]([CH:44]([NH2:46])[CH3:45])[CH:41]=[CH:42][CH:43]=1>>[NH2:8][C:9]([CH3:36])([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:10][O:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:19]=[C:20]([C:22]2([C:27]#[N:28])[CH2:23][CH2:24][CH2:25][CH2:26]2)[CH:21]=1)[C:16]([NH:46][CH:44]([C:40]1[CH:41]=[CH:42][CH:43]=[C:38]([Cl:37])[CH:39]=1)[CH3:45])=[O:18]
Reactant: CC(COCc1cc(C(=O)O)cc(C2(C#N)CCCC2)c1)(Cc1ccccc1)NC(=O)OC(C)(C)C
Reactant: CC(N)c1cccc(Cl)c1
Product: CC(NC(=O)c1cc(COCC(C)(N)Cc2ccccc2)cc(C2(C#N)CCCC2)c1)c1cccc(Cl)c1

Procedure:
Prepared from 3-((2-tert-butoxycarbonylamino-2-methyl-3-phenylpropoxy)methyl)-5-(1-cyanocyclopentyl)benzoic acid and 1-(3-chlorophenyl)ethanamine using a similar procedure as described for the preparation of Example 20. HRMS ES calculated for C32H36ClN3O2: 530.2569, found: 530.2565.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([N+:12]([O-])=O)[CH:9]=[CH:8][C:7]=1[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=[C:17]2[C:16]1=[O:26])(=[O:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Rh]>[C:1]([O:4][CH2:5][C:6]1[CH:11]=[C:10]([NH2:12])[CH:9]=[CH:8][C:7]=1[N:15]1[C:19](=[O:20])[C:18]2=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=[C:17]2[C:16]1=[O:26])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)OCc1cc([N+](=O)[O-])ccc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: [Rh]
Solvent: CCOC(C)=O
Product: CC(=O)OCc1cc(N)ccc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The solution of 300 mg of N-(2-acetoxymethyl-4-nitrophenyl)-4-chlorophthalimide in 35 ml of ethyl acetate is hydrogenated with 200 mg of 5% rhodium on carbon at 2.5 atmospheres of hydrogen pressure for 3 hours. After filtration from the catalyst, the residue is crystallized from ethyl acetate-hexane to give the N-(2-acetoxymethyl-4-aminophenyl)-4-chlorophthalimide melting at 136°-138°.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH:22]=O)=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:13][CH:14]([CH2:16][CH:10]([CH2:11]3)[CH2:9]1)[CH2:15]2)=[O:5].[NH2:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:21]=[CH:20][C:19]([CH2:22][NH:24][CH2:25][CH2:26][S:27][CH2:28][CH2:29][OH:30])=[CH:18][C:3]=1[C:4]([NH:6][CH2:7][C:8]12[CH2:17][CH:12]3[CH2:11][CH:10]([CH2:16][CH:14]([CH2:13]3)[CH2:15]1)[CH2:9]2)=[O:5]
Reactant: O=Cc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCSCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CNCCSCCO)ccc1Cl
Yield: 50.9 %

Procedure:
Prepared according to the method described in Example 2 from 2-chloro-5-formyl-N-(tricyclo [3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.800 g, Example 1b), 2-(2-aminoethylthio)ethanol (0.584 g) and sodium triacetoxyborohydride (0.715 g) in 1,2-dichloroethane (15 ml). After work-up, the residue was purified by NPHPLC eluting with a gradient of 0-10% ethanol in dichloromethane to give the title compound as a white powder (0.536 g).