Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)C)(=O)C.I([O-])(=O)(=O)=O.[Na+].[I:14]I.S(=O)(=O)(O)O.[Br:21][C:22]1[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=1>C(O)(=O)C>[CH3:28][C:25]1[CH:26]=[CH:27][C:22]([Br:21])=[CH:23][C:24]=1[I:14]
Reactant: II
Reactant: Cc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Product: Cc1ccc(Br)cc1I
Yield: 197.9 %

Procedure:
2-Methyl-5-bromo-iodobenzene was synthesized according to the method described by Lulinski, P., Skulski, L., Bull. Chem. Soc. Jpn. 2000 73:951-956. To a mixture of acetic acid (100 ml) and acetic anhydride (50 ml), cooled in an ice bath, was added sodium periodate (15.4 g, 72 mmol) and iodine (12.2 g, 48 mmol). While stirring vigorously, concentrated sulfuric acid (21 ml) was added slowly followed by 4-bromotoluene (23.1 g, 135 mmol). After stirring for 2 hours, the ice bath was removed and the mixture was protected from light. After stirring for 16 hours, the mixture was poured into a mixture of 10% aqueous sodium sulfite solution (250 ml) and ice (250 g), and extracted with dichloromethane (3×100 ml). The combined extracts were washed with water (100 ml), dried over sodium sulfate, and concentrated under reduced pressure. The residual oil was purified by distillation (87-92° C., 1 mm) to provide 2-methyl-5-bromo-iodobenzene (28.2 g, 70% yield) as colorless oil. 1H NMR (DMSO-d6) δ 7.99 (s, 1H), 7.50 (d, J=8.1 Hz, 1H), 7.28 (d, J=8.1 Hz, 1H), 2.33 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N+:11]([O-])=O)[CH:3]=1.[Cl:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1N>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([NH:11][C:16]2[CH:18]=[CH:19][CH:20]=[CH:21][C:15]=2[Cl:14])[CH:3]=1
Reactant: Nc1ccccc1Cl
Reactant: O=[N+]([O-])c1ccc(Cl)cc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccc(Cl)cc1Nc1ccccc1Cl
Yield: 5 %

Procedure:
A mixture of 101 g of 4-chloro-1,2-dinitrobenzene and 191 g of 2-chloroaniline in 750 ml of 95° EtOH is refluxed for 96 hours. The solvent is evaporated off under vacuum, the residue is extracted with DCM, washed with a 3 N solution of HCl and with water and dried over Na2SO4 and the solvent is evaporated off under vacuum. The residue is chromatographed on silica using a DCM/hexane mixture (50/50; v/v) as the eluent to give 7 g of the expected product after crystallization from EtOH. M.p.=97° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:37])[NH:19][C:20]2[CH:24]=[C:23]([C:25](=[O:32])[NH:26][CH2:27][CH2:28][C:29](=[NH:31])[NH2:30])[N:22]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:21]=2)=[CH:14][CH:13]=1)(C)(C)C.CCOCC>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>[NH2:7][CH2:8][CH2:9][NH:10][C:11](=[O:38])[C:12]1[CH:17]=[CH:16][C:15]([C:18]([NH:19][C:20]2[CH:24]=[C:23]([C:25](=[O:32])[NH:26][CH2:27][CH2:28][C:29](=[NH:30])[NH2:31])[N:22]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[CH:21]=2)=[O:37])=[CH:14][CH:13]=1
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ccc(C(=O)Nc2cc(C(=O)NCCC(=N)N)n(CC3CC3)c2)cc1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: N=C(N)CCNC(=O)c1cc(NC(=O)c2ccc(C(=O)NCCN)cc2)cn1CC1CC1
Reaction time: 0.5 h
Yield: 156 %

Procedure:
310 mg (0.55 mmol) 98 was dissolved in a mixture of 1 mL anisol and 4 mL trifluoroacetic acid and was agitated occasionally by swirling for 30 minutes at ambient temperature. 40 mL of cold ether was added, the precipitate was centrifuged, the ether phase was discarded, and the precipitate washed with ether (1×) then was re-precipitated from 5 mL methanol with 40 mL ether and dried to give 377 mg (96%) 99 as bis-TFA salt. MS: 220.61 (M+2H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH:21]1([C:24]2[NH:28][N:27]=[C:26]([NH2:29])[CH:25]=2)[CH2:23][CH2:22]1>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([NH:29][C:26]2[CH:25]=[C:24]([CH:21]3[CH2:23][CH2:22]3)[NH:28][N:27]=2)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Reactant: Nc1cc(C2CC2)[nH]n1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cnc(Cl)cc1Nc1cc(C2CC2)[nH]n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 88.6 %

Procedure:
To a solution of 2,4-dichloro-5-nitropyridine (Method 91, 0.42 g, 2.18 mmol) and DIEA (0.46 ml, 2.61 mmol) in THF (10 ml) was added a 5-cyclopropyl-1H-pyrazol-3-amine (0.31 g, 2.50 mmol) solution in THF (5 ml) drop wise at 0° C. After addition, the reaction mixture was stirred at 25° C. for 17 hours. The solvent was removed under reduced pressure and the resulted residue was purified by column chromatography (hexane:EtOAc=3:1) to give the title compound as a yellow solid (0.54 g, 89%). 1H NMR (400 MHz) 12.55 (s, 1H), 9.95 (s, 1H), 8.97 (s, 1H), 8.09 (s, 1H), 6.02 (d, J=2.0 Hz, 1H), 1.93 (m, 1H), 0.97 (m, 2H), 0.71 (m, 2H). MS: Calcd.: 279; Found: [M+H]+ 280.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.CN(C)C=O.C(Cl)(=O)C(Cl)=O.[CH3:24][NH:25][O:26][CH3:27].C(N(CC)CC)C>ClCCl.O>[CH3:27][O:26][N:25]([CH3:24])[C:7](=[O:9])[C:6]1[CH:10]=[CH:11][CH:12]=[C:4]([CH2:3][O:2][CH3:1])[CH:5]=1
Reactant: COCc1cccc(C(=O)O)c1
Reactant: CNOC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COCc1cccc(C(=O)N(C)OC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 63 %

Procedure:
To a stirred solution of 3-(methoxymethyl)benzoic acid (20.9 g, 125.8 mmol) in dichloromethane (250 mL), cooled to 0° C. with a brine/ice bath, was added N,N-dimethylformamide (0.48 mL, 6 mmol) followed by oxalyl chloride (13.2 mL, 150.9 mmol). The resulting mixture was stirred 4 h at room temperature, until gas evolution stopped and a clear solution was obtained. The mixture was cooled to 0° C. with a brine/ice bath, N,O-Dimethylhydroxylamine (17.2 g, 176 mmol) was added at once, followed by dropwise addition of triethylamine (70.1 mL, 503 mmol) through a dropping funnel, while keeping the internal temperature below 10° C. The resulting suspension was stirred overnight at room temperature, diluted with water (400 mL). The aqueous layer was extracted with dichloromethane (2×250 mL) and the organic layer was washed with water (2×150 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Purification over silica gel afforded N-methoxy-3-(methoxymethyl)-N-methylbenzamide as a yellow oil [19.4 g, yield 63%; HPLC/MS:m/z=210 (M+H); log P(HCOOH)=1.43].
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]2[CH3:11])=[CH:4][C:3]=1[OH:25].[CH3:26][N:27]([CH2:29]N(C)C)[CH3:28]>O>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:7]([CH2:12][S:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:8]2[CH3:11])=[C:4]([CH2:26][N:27]([CH3:29])[CH3:28])[C:3]=1[OH:25]
Reactant: CCOC(=O)c1c(CSc2ccccc2)n(C)c2cc(Br)c(O)cc12
Reactant: CN(C)CN(C)C
Solvent: O
Product: CCOC(=O)c1c(CSc2ccccc2)n(C)c2cc(Br)c(O)c(CN(C)C)c12
Yield: 69.9 %

Procedure:
To a solution containing ethyl 6-bromo-5-hydroxy-1-methyl-2-phenylthiomethylindole-3-carboxylate (76.4 g, 0.18 mole) in 470 ml of diowane was added bis-dimethylaminomethane (50 ml, 0.36 mole). The reaction mixture was refluxed for 3 hours, cooled, diluted with a 3-4-fold amount of water. The precipitated crystalls were removed, washed with water and dried to give 60.1 g (70%) of ethyl 6-bromo-5-hydroxy-4-dimethylaminomethyl-1-methyl-2-phenylthiomethylindole-3-carboxilate; m.p. 125°-126° C.
Reaction SMILES: C(O[C:6]([C:8]1[N:9]=[C:10]([O:22][C:23]2[CH:28]=[CH:27][C:26]([NH:29][C:30](=[O:32])[CH3:31])=[CH:25][CH:24]=2)[C:11]2[C:16]([C:17]=1[O:18]C(=O)C)=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:7])CCC.[NH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+].CO>>[C:30]([NH:29][C:26]1[CH:25]=[CH:24][C:23]([O:22][C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:17]([OH:18])=[C:8]([C:6]([NH:33][CH2:34][C:35]([OH:37])=[O:36])=[O:7])[N:9]=2)=[CH:28][CH:27]=1)(=[O:32])[CH3:31]
Reactant: CCCCOC(=O)c1nc(Oc2ccc(NC(C)=O)cc2)c2ccccc2c1OC(C)=O
Reactant: NCC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CC(=O)Nc1ccc(Oc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)cc1
Yield: 64 %

Procedure:
A mixture of 4-Acetoxy-1-(4-acetylamino-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (150 mg, 0.34 mmol), glycine (290 mg, 3.4 mmol), and 7.8 ml of a 0.5N solution of sodium methoxide in methanol (3.9 mmol) was refluxed over the weekend with stirring. Then the solvent was evaporated in vacuo and the residue dissolved in 25 ml of water. The pH of the solution was subsequently adjusted to about 2 and the resulting slurry was extracted with ethyl acetate (3×30 ml). The combined extracts were dried over MgSO4 and evaporated in vacuo. Recrystallization of the residue from methanol/CH2Cl2 gave 86 mg of the title compound; MS-(+)-ion: M+1=396.15.
Reaction SMILES: [F:1][CH:2]([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:5]=1[O:11][CH:12]([F:14])[F:13].[F:16][C:17]([F:28])([F:27])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][CH2:25][NH2:26])=[N:22][CH:23]=1>>[F:13][CH:12]([F:14])[O:11][C:5]1[CH:6]=[C:7]([NH:26][CH2:25][CH2:24][C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:28])([F:16])[F:27])=[CH:23][N:22]=2)[CH:8]=[CH:9][C:4]=1[O:3][CH:2]([F:15])[F:1]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: FC(F)Oc1ccc(I)cc1OC(F)F
Product: FC(F)Oc1ccc(NCCc2ccc(C(F)(F)F)cn2)cc1OC(F)F

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (3,4-bis-difluoromethoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 399.1 [M+H]+) was prepared from 1,2-bis-difluoromethoxy-4-iodo-benzene instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Ca+2]>CN(C)C=O>[CH2:16]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH:9]([OH:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CCOC(=O)C(O)Cc1ccc(O)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2 h
Yield: 96.9 %

Procedure:
To a solution of ethyl 3-(4-hydroxyphenyl)lactate (22.4 g) in N,N-dimethylformamide (220 ml) were added benzyl bromide (21.9 g) and calcium carbonate (35.3 g), and the reaction mixture was stirred at 50° C. for 2 hours. The reaction solution was partitioned between ethyl acetate and water, and then the separated ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant; hexane/ethyl acetate=7/3) to give the target compound (31.0 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:3](I)=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.CN(C)C(N(C)C)=N.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]#[CH:38])=[CH:32][CH:31]=1>CN(C)C=O.C(=O)([O-])O.[Na+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Cu]I>[F:14][C:13]1([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9][C@@:8]1([C:6]1[CH:7]=[C:2]2[C:3]([CH:38]=[C:37]([CH2:36][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:35][CH:34]=3)[NH:1]2)=[CH:4][C:5]=1[F:18])[CH3:17]
Reactant: C#CCc1ccc(OC)cc1
Reactant: C[C@]1(c2cc(N)c(I)cc2F)N=C(N)OCC1(F)F
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: COc1ccc(Cc2cc3cc(F)c([C@@]4(C)N=C(N)OCC4(F)F)cc3[nH]2)cc1
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 33.4 %

Procedure:
A solution of (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate B6.1) (100 mg, 260 μmol) N,N-dimethylformamide (0.5 ml) was purged with argon for 10 minutes. Thereafter, 1,1,3,3-tetramethylguanidine (74.8 mg, 81.3 μl, 649 μmol), bis-(triphenylphosphin)-palladium(II)dichlorid (9.11 mg, 13.0 μmol) and copper (I) iodide (7.42 mg, 38.9 μmol) were added. After 5 minutes at room temperature, a solution of 1-methoxy-4-prop-2-ynyl-benzene (CAS [13540-76-6]) (45.5 mg, 312 μmol) in N,N-dimethylformamide (0.2 ml) was added and the reaction mixture was stirred at 80° C. for 15 hours. For the workup, the reaction mixture was allowed to cool to room temperature, then it was diluted with a saturated solution of sodium hydrogencarbonate and extracted with ethyl acetate. The combined organic layers were dried over sodium sulphate and evaporated at reduced pressure. The crude product was purified by flash chromatography on a silica-NH2 phase using a gradient of heptane/ethyl acetate=100:0 to 0:100 as the eluent. The (R)-5,5-difluoro-4-[5-fluoro-2-(4-methoxy-benzyl)-1H-indol-6-yl]-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (35 mg, 33% yield) was obtained as a light green foam. MS (ISP): m/z=404.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]([CH3:25])=[CH2:24])=[CH:19][CH:18]=2)[N:3]=1.[H][H]>C(O)C.O1CCOCC1.[Pd]>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:22]=2)[N:3]=1
Reactant: C=C(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)c1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)cc1
Yield: 1 %

Procedure:
A solution of 200 mg (0.60 mmol) 2-amino-4-furan-2-yl-6-(4-isopropenyl-benzylamino)-pyrimidine-5-carbonitrile in 15 ml ethanol and 15 ml dioxane was stirred with a spatula end of 10% palladium on charcoal under 1 atm of hydrogen for 16 h at room temperature. After filtration to remove the catalyst, the reaction mixture was concentrated in vacuo. HPLC afforded 2 mg (1%) 2-amino-4-furan-2-yl-6-(4-isopropyl-benzylamino)-pyrimidine-5-carbonitrile as a white crystalline solid. ES-MS m/e (%): 334 (M+H+, 100).
Reaction SMILES: C([O:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:19])=[O:18])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:23])=[O:22])C1C=CC=CC=1>O1CCOCC1.CO.[H][H].[OH-].[Pd+2].[OH-]>[OH:8][CH2:9][C@H:10]1[C@H:15]([CH3:16])[N:14]([S:17]([CH3:20])(=[O:18])=[O:19])[CH2:13][CH2:12][N:11]1[S:21]([C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:22])=[O:23]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2COCc2ccccc2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)N2CCN(S(C)(=O)=O)[C@@H](C)[C@@H]2CO)cc1
Yield: 94.9 %

Procedure:
A mixture of (2R,3S)-2-benzyloxymethyl-4-methanesulfonyl-1-(4-methoxybenzenesulfonyl)-3-methylpiperazine (330 mg) and palladium hydroxide (40 mg) in dioxane (5 ml) and MeOH (5 ml) was hydrogenated in hydrogen at 3.5 atm and ambient temperature for 1 day. The catalyst was removed by filtration through a celite pad and the pad was washed with MeOH. The filtrate and combined washings were concentrated in vacuo. The residue was purified by SiO2 column chromatography (eluent: AcOEt/n-hexane 60%, then MeOH/AcOEt 1%) to give 253 mg of (2R,3S)-2-hydroxymethyl-4-methanesulfonyl-1-(4-methoxybenzene-sulfonyl)-3-methylpiperazine.
Reaction SMILES: C([O:5][C:6]([C:8]1[C:9]([C:14]2[CH:19]=[C:18]([C:20](=[O:37])[NH:21][C@H:22]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C@H:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[OH:24])[CH:17]=[CH:16][C:15]=2[F:38])=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.C1COCC1.[OH-].[Na+]>CCOC(C)=O>[CH2:30]([C@@H:22]([NH:21][C:20]([C:18]1[CH:17]=[CH:16][C:15]([F:38])=[C:14]([C:9]2[C:8]([C:6]([OH:7])=[O:5])=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:19]=1)=[O:37])[C@H:23]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[OH:24])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(-c2ccccc2C(=O)OC(C)(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@H](O)[C@@H](Cc1ccccc1)NC(=O)c1ccc(F)c(-c2ccccc2C(=O)O)c1
Reaction time: 1 h
Yield: 13 %

Procedure:
5′-((1R,2R)-1-benzyl-2-ethoxycarbonyl-2-hydroxy-ethylcarbamoyl)-2′-fluoro-biphenyl-2-carboxylic acid t-butyl ester (100 mg, 192 μmol, 1.0 eq.) was combined with 1:1 TFA/DCM (1 mL each) and stirred for 1 hour. The solvent was evaporated and THF (3 mL) and 1 M aqueous NaOH (577 μL, 3.0 eq.) were added. The mixture was stirred for 2 hours and EtOAc was added. The aqueous was extracted and the organic was washed with NaOH (0.2 mL), stirred, and the aqueous was extracted. The aqueous were acidified to pH ˜5 with concentrated HCl to yield a gummy solid. The aqueous was removed and the gummy solid was dissolved in AcOH and purified by preparative HPLC to yield the title compound (11.6 mg, 99% purity). MS m/z [M+H]+ calc'd for C26H24FNO6, 466.16. found 466.2.
Reaction SMILES: C1C=C2C=CC(O)=C(C3C4C(=CC=CC=4)C=CC=3O)C2=CC=1.[Cl:23][C:24]1[C:25]([F:35])=[C:26]([O:33][CH3:34])[C:27]([C:30](=[CH2:32])[CH3:31])=[CH:28][CH:29]=1.[F:36][C:37]([F:46])([F:45])[C:38](=[O:44])[C:39]([O:41][CH2:42][CH3:43])=[O:40]>C1(C)C=CC=CC=1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([C:30](=[CH2:31])[CH2:32][C:38]([OH:44])([C:37]([F:46])([F:45])[F:36])[C:39]([O:41][CH2:42][CH3:43])=[O:40])=[C:26]([O:33][CH3:34])[C:25]=1[F:35]
Reactant: CCOC(=O)C(=O)C(F)(F)F
Reactant: C=C(C)c1ccc(Cl)c(F)c1OC
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: Oc1ccc2ccccc2c1-c1c(O)ccc2ccccc12
Solvent: Cc1ccccc1
Product: C=C(CC(O)(C(=O)OCC)C(F)(F)F)c1ccc(Cl)c(F)c1OC
Temperature: 25 °C
Yield: 14.9 %

Procedure:
760 mg (2.67 mmol) of 1,1′-bi-2-naphthol are admixed with 2.68 ml (1.34 mmol) of a 0.5 M titanium tetraisopropoxide solution in toluene and the red solution is stirred at room temperature for an hour. 5.07 g (28.1 mmol) of 3-chloro-2-fluoro-6-(1-methyleneethyl)anisole and 3.25 ml (26.7 mmol) of ethyl trifluoropyruvate are added and the mixture is heated at 140° C. for 17 hours. After it has cooled it is immediately purified by column chromatography on silica gel (pentane/diethyl ether 25-40%) to give 1.47 g of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate. 1.47 g (3.97 mmol) of ethyl 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enoate in 40 ml of diethyl ether are cooled to −15° C. and over 10 minutes 300 mg (7.9 mmol) of lithium aluminum hydride in solid form are added in portions. The mixture is stirred for 1 hour, during which it warms to 0° C., and is poured into saturated ammonium chloride solution. Saturated tartaric acid solution is added and the mixture is stirred for 30 minutes. The phases are separated and subjected to repeated extraction with ethyl acetate. The extracts are washed with saturated sodium chloride solution and dried over sodium sulphate and the solvent is removed in vacuo. Separation by column chromatography on silica gel (hexane/ethyl acetate 0-50%) yields 0.38 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pent-4-enal and 0.15 g of alcohol. 0.27 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)-pent-4-enal is dissolved in 14 ml of methanol and 0.3 ml of acetic acid, and 27 mg of palladium on carbon (10%) are added. The suspension is shaken for 2 hours under a hydrogen atmosphere under atmospheric pressure until the hydrogen uptake is 46 ml. The mixture is filtered through Celite, the filter bed being rinsed thoroughly with ethyl acetate. Removal of the solvent gives 027 g of 4-(4-chloro-3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)pentanal as a mixture of the diastereomers.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH2:7]([N:14]([S:21](Cl)(=[O:23])=[O:22])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>C(Cl)Cl>[CH2:7]([N:14]([S:21]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)(=[O:22])=[O:23])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C1COCCN1
Reactant: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: CCOC(=O)CN(Cc1ccccc1)S(=O)(=O)N1CCOCC1
Temperature: 25 °C
Yield: 6 %

Procedure:
A solution of morpholine (1.05 ml, 12 mmol) and triethylanrine (1.84 ml, 12 mmol) in methylene chloride (10 ml) was added to a solution of ethyl 2-[benzyl-(chlorosulfonyl)-amino]acetate (2.3 g, 8.3 mmol), [prepared as described in Step 1 above], in methylene chloride (30 ml) at 0° C. The reaction mixture was slowly allowed to warm to RT and after 6h 1M HCl was added. The product was extracted into methylene chloride, washed with brine, and dried over MgSO4. The organics were removed in vacuo and the crude product was chromatographed (PTLC, SiO2, 25% ethyl acetate/hexane) to give ethyl 2-[benzyl-(morpholine-4-sulfonyl)amino]acetate as a colorless oil (6%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1.[C:19](Cl)(=[O:21])[CH3:20]>CN(C)C=O>[C:19]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8]3=[N:11][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:13][N:7]3[C:6]=2[CH:18]=1)(=[O:21])[CH3:20]
Reactant: COC(=O)c1cn2c(n1)COc1ccc(N)cc1-2
Reactant: CC(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)c1cn2c(n1)COc1ccc(NC(C)=O)cc1-2
Yield: 72 %

Procedure:
By the procedure of Step C in Example 1, methyl 8-amino-4H-imidazo[2,1-c][1,4]-benzoxazine-2-carboxylate and acetyl chloride were reacted in dimethylformamide as solvent to obtain a 72% yield of methyl 8-acetamido-4H-imidazo-[2,1-c][1,4]-benzoxazine-2-carboxylate with a melting point of 216-9° C.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[CH:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[O:30][CH3:31])[C:12]([C:18]([O:20][CH3:21])=[O:19])=[C:13]([CH3:17])[NH:14][C:15]=1[CH3:16])=[O:9].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[CH2:6][O:7][C:8]([C:10]1[C:11]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[C:23]=2[O:30][CH3:31])=[C:12]([C:18]([O:20][CH3:21])=[O:19])[C:13]([CH3:17])=[N:14][C:15]=1[CH3:16])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCC2CCCO2)C1c1cccc(OC)c1OC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Product: COC(=O)c1c(C)nc(C)c(C(=O)OCC2CCCO2)c1-c1cccc(OC)c1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 79 %

Procedure:
A mixture of 11 g (0,025 mol) of 2,6-dimethyl-4-(2,3-dimethoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid 3-methyl ester 5-(tetrahydrofuran-2-ylmethyl) ester and 92 g (0,076 mol) of pyridinium chlorochromate absorbed on alumina, was suspended on 250 ml of CH2C12, and the whole mixture was maintained on stirring at room temperature for 6 hours. The remaining solid was eliminated by filtration, and the liquid was washed with water (3×300 ml), dried over anh. Na2SO4, and concentrated at reduced pressure, to dryness. The product was obtained as an oil, which was purified by column chromatography (Silicagel, n-hexane:EtAcO, 8:2) with a yield of 79%.