Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13]3=[N:14][NH:15][C:16](=[O:21])[C:17]4[CH:18]=[CH:19][CH:20]=[C:11]([C:12]=43)[NH:10][CH:9]2[C:22]2[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH:32]1[CH3:37]>C(Cl)Cl>[CH3:37][CH:32]1[N:31]([CH3:30])[CH2:36][CH2:35][N:34]([CH2:26][C:25]2[CH:24]=[CH:23][C:22]([CH:9]3[NH:10][C:11]4[C:12]5[C:13](=[N:14][NH:15][C:16](=[O:21])[C:17]=5[CH:18]=[CH:19][CH:20]=4)[CH:8]3[C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:29][CH:28]=2)[CH2:33]1
Reactant: O=Cc1ccc(C2Nc3cccc4c(=O)[nH]nc(c34)C2c2ccc(F)cc2)cc1
Reactant: CC1CNCCN1C
Solvent: ClCCl
Product: CC1CN(Cc2ccc(C3Nc4cccc5c(=O)[nH]nc(c45)C3c3ccc(F)cc3)cc2)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.8 %

Procedure:
A mixture of 4-(9-(4-fluorophenyl)-3-oxo-3,7,8,9-tetrahydro-2H-pyrido[4,3,2-de]phthalazin-8-yl)benzaldehyde (200 mg, 0.52 mmol), 1,2-dimethylpiperazine (311 mg, 1.56 mmol) in methylene chloride (10 mL) was stirred at room temperature overnight, then NaBCNH3 (129 mg, 2.08 mmole) was added and the mixture was stirred for another 5 hours. After removal of solvents, the residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=3:1 to 1:1) to give the title compound (70 mg, 26%). LC-MS (ESI) m/z: 484 (M+1)+. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.43 (d, J=5.2 Hz, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.33-3.44 (m, 6H), 4.03 (s, 2H), 4.22 (m, 1H), 4.65 (m, 1 H), 6.91 (m, 1H), 6.97 (m, 1H), 7.00 (d, J=8 Hz, 2H), 7.23-7.37 (m, 4H), 7.65 (m, 1H), 7.77 (d, J=7.2 Hz, 1H), 9.92 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30](=O)[CH:31]=[CH:32][N:33](C)C)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.O.[NH2:38]N.Cl>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:24]2[CH:29]=[CH:28][C:27]([C:30]3[NH:38][N:33]=[CH:32][CH:31]=3)=[CH:26][CH:25]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C=CC(=O)c1ccc(-c2nc3c(cnn3-c3ccccc3)c(=O)n2-c2ccc(Cl)cc2)cc1
Reactant: NN
Agent: Cl
Solvent: O
Solvent: CO
Product: O=c1c2cnn(-c3ccccc3)c2nc(-c2ccc(-c3ccn[nH]3)cc2)n1-c1ccc(Cl)cc1
Temperature: 80 °C

Procedure:
To a suspension of 5-(4-chloro-phenyl)-6-[4-(3-dimethylamino-acryloyl)-phenyl]-1-phenyl-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one (11 mg, 0.022 mmol) in MeOH (0.5 mL) is added hydrazine hydrate (2.0 mg, 0.04 mmol) and HCl (4 M in dioxane, 10 μL, 0.04 mmol), The mixture is heated to 80° C. for 2 h and cooled down to room temperature. The mixture is concentrated and purified by preparative LC/MS to provide the titled compound 5-(4-chloro-phenyl)-1-phenyl-6-[4-(2H-pyrazol-3-yl)-phenyl]-1,5-dihydro-pyrazolo[3,4-d]pyrimidin-4-one as white solid. HPLC-MS calculated for C26H17ClN6O (M+H1): 465.1. Found: 465.1.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(I)cc1
Product: O=C(Cl)c1ccc(I)cc1

Procedure:
A mixture of 4-iodobenzoic acid (5 g) and thionyl chloride (30 ml) was heated at 70°-80° C. for 2 hours. The reaction mixture was cooled, the thionyl chloride evaporated and the resulting oil was azeotroped with toluene to give 4-iodobenzoyl chloride (5.38 g) as a solid which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.Br[CH2:11][CH2:12][CH2:13][CH2:14][Cl:15]>>[Cl:15][CH2:14][CH2:13][CH2:12][CH2:11][O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: ClCCCCBr
Reactant: COc1ccc(O)cc1
Product: COc1ccc(OCCCCCl)cc1

Procedure:
Prepared by Procedure U and Scheme AK using 4-methoxyphenol and 1-bromo-4-chlorobutane.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]([O:10][C:11](=[O:26])[NH:12][C:13]1[C:14]([CH3:25])=[N:15][O:16][C:17]=1[C:18]1[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=1)[CH3:9].[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=1)[CH3:28]>>[CH2:27]([O:29][C:30](=[O:47])[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:21]2[CH:22]=[CH:23][C:18]([C:17]3[O:16][N:15]=[C:14]([CH3:25])[C:13]=3[NH:12][C:11]([O:10][C@H:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH3:9])=[O:26])=[CH:19][CH:20]=2)=[CH:34][CH:33]=1)[CH3:28]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)O[C@@H](C)c1ccccc1Cl
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)O[C@@H](C)c3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid (S)-1-(2-chloro-phenyl)-ethyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide (4′-{-4-[(S)-1-(2-chloro-phenyl)-ethoxycarbonylamino]-3-methyl-isoxazol-5-yl}-biphenyl-4-yl)-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 34, Step 2.
Reaction SMILES: C1C(O)=CC=CC=1C.C1C(O)=CC=C(C)C=1.C[O:18][CH3:19].[CH3:20][C:21]1[C:26](C)=[CH:25][CH:24]=[C:23]([CH3:28])[C:22]=1O>CO>[CH3:24][C:25]1[CH:26]=[C:21]([CH3:20])[CH:22]=[C:23]([CH3:28])[C:19]=1[OH:18]
Reactant: Cc1ccc(C)c(O)c1C
Reactant: COC
Agent: Cc1ccc(O)cc1
Solvent: Cc1cccc(O)c1
Solvent: CO
Product: Cc1cc(C)c(O)c(C)c1

Procedure:
methylating meta-cresol and para-cresol in the ortho position by reacting the meta-cresol and para-cresol with methanol, dimethyl ether or a mixture thereof at a temperature of 270° to 450° C., at a pressure of atmospheric to 100 bar and in the presence of a catalyst bed without a residence time of 0.01 to 10 seconds, whereby a mixture of 2,3,6-trimethylphenol and 2,4,6-trimethylphenol is produced;
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH3:44])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:45]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].O.C(=O)(O)[O-].[Na+]>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:11][CH:12]([CH3:15])[CH3:13])[CH2:23][CH2:22][C:21]([C:25]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]([OH:42])[C:35]5[CH:40]=[CH:39][CH:38]=[CH:37][N+:36]=5[O-:41])=[C:30]([O:43][CH3:44])[CH:29]=4)=[O:26])=[CH:20][C:19]=3[CH:45]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(OC)c2)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 183.1 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.3 g) and isobutylaldehyde (0.22 ml) were dissolved in 1,2-dichloroethane (15 ml), and to the solution, triacetoxy sodium borohydride (0.31 g) was added under ice-cooling and the mixture was stirred overnight at room temperature. The mixture was poured into water, neutralized with solution of sodium bicarbonate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then, dried over anhydrous magnesium sulfate. The solvent was distilled off, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-methoxyphenyl]-1-isobutyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (compound 4) (0.3 g) as yellow amorphous.
Reaction SMILES: [CH3:1][C@@H:2]1[NH2+:6][C@H:5]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:4][CH2:3]1.[CH3:12][O:13][C:14]([NH:16][C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18](O)=[O:19])=[O:15].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[CH3:12][O:13][C:14]([NH:16][C@@H:17]([CH:21]([CH3:23])[CH3:22])[C:18]([N:6]1[C@@H:2]([CH3:1])[CH2:3][CH2:4][C@H:5]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:19])=[O:15]
Reactant: CCOC(=O)[C@@H]1CC[C@H](C)[NH2+]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1CC[C@H](C)N1C(=O)[C@@H](NC(=O)OC)C(C)C
Reaction time: 20 h
Yield: 73 %

Procedure:
To a cold (0-4° C.) stirred solution of ethyl (2S,5S)-5-methylpyrrolidin-1-ium-2-carboxylate (7 g, 24.4 mmol) (J. Med. Chem. 2006, 49, 3520-3535), (2S)-2-(methoxycarbonylamino)-3-methyl-butanoic acid (4.5 g, 25.6 mmol), and HATU (9.7 g, 25.6 mmol) in DMF (66 ml) is added DIPEA (12.7 ml, 73.3 mmol). The resultant mixture is slowly warmed up to rt and stirred for 20 hours. The reaction mixture is diluted with water and extracted with ethyl acetate. The combined extracts are washed with sodium bicarbonate, brine, dried (Na2SO4) and concentrated. The residue is purified by flash column chromatography on silica gel using ethyl acetate-hexanes (3:7 to 4:6) as eluent to afford ethyl (2S,5S)-1-[(2S)-2-(methoxycarbonylamino)-3-methyl-butanoyl]-5-methyl-pyrrolidine-2-carboxylate (5.6 g, 73%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11](Br)=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1.[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][C:26]=1[F:34])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Li+].[Cl-].C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.O1CCOCC1>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][N:7]2[C:12](=[O:13])[C:11]([C:28]3[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)=[C:26]([F:34])[CH:27]=3)=[CH:10][N:9]=[CH:8]2)=[CH:4][CH:3]=1
Reactant: O=c1c(Br)cncn1Cc1ccc(Cl)cc1
Reactant: OB(O)c1ccc(OCc2ccccc2)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1c(-c2ccc(OCc3ccccc3)c(F)c2)cncn1Cc1ccc(Cl)cc1
Temperature: 10 °C
Reaction time: 1 h
Yield: 31.1 %

Procedure:
To a round bottom flask was added 3-(4-chlorobenzyl)-5-bromopyrimidin-4(3H)-one (0.388 g, 1.30 mmol), 4-benzyloxy-3-fluorophenylboronic acid (0.382 g, 1.55 mmol), Pd(PPh3)4 (0.0748 g, 0.0648 mmol), LiCl (0.275 g, 6.48 mmol), dioxane (10 mL) and 2 M aqueous sodium carbonate solution (5 mL). The reaction mixture was stirred at 10° C. for 1 hour, then quenched the reaction by pouring the mixture into water and diluting with ethyl acetate. The organic layer washed with brine, dried with Na2SO4, filtered and concentrated. The residue was purified by silica gel chromatography (Biotage 40S) to afford the title compound as white solid (0.17 g, 31.2% yield). LRMS (APCI pos) m/e 421.0 (M+1). 1H NMR (400 MHz, CDCl3): δ 8.15 (s, 1H), 8.02 (s, 1H), 7.49-7.54 (m, 1H), 7.42-7.46 (m, 2H), 7.36-7.41 (m, 3H), 7.32-7.35 (m, 5H), 5.18 (s, 2H), 5.12 (s, 2H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:34]O)[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:33])[CH:11]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=3[Cl:31])=[CH:19][C:18]2=[O:32])[CH2:12][C:13]([F:16])([CH3:15])[CH3:14])=[N:5]1.[CH3:36]N(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.Cl.O[C@@H](CO)CN1C=CC(NC(=O)[C@@H](N2CC(OC3C=CC=C(Cl)C=3Cl)=CC2=O)CC(C)C)=N1>ClCCl>[OH:1][C:2]([CH3:34])([CH3:36])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:33])[CH:11]([N:17]2[CH2:21][C:20]([O:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:24]=3[Cl:31])=[CH:19][C:18]2=[O:32])[CH2:12][C:13]([F:16])([CH3:14])[CH3:15])=[N:5]1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cccc(OC2=CC(=O)N(C(CC(C)(C)F)C(=O)Nc3ccn(C[C@@H](O)CO)n3)C2)c1Cl
Agent: CC(C)C[C@@H](C(=O)Nc1ccn(C[C@@H](O)CO)n1)N1CC(Oc2cccc(Cl)c2Cl)=CC1=O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: COc1cccc(OC2=CC(=O)N(C(CC(C)(C)F)C(=O)Nc3ccn(CC(C)(C)O)n3)C2)c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.8 %

Procedure:
A solution of 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-fluoro-4-methyl-pentanoic acid (prepared as in Example 170, 200 mg, 0.54 mmol) in dichloromethane (20 mL) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (92 mg, 0.59 mmol), 1-hydroxybenzotriazole (76 mg, 0.57 mmol) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared in U.S. Pat. Appl. US2008021032 Example 80, 100 mg, 0.65 mmol). The reaction mixture was stirred for 18 h at 25° C., under nitrogen and then diluted with dichloromethane, washed with 2N hydrochloric acid, saturated sodium bicarbonate solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product obtained after concentration, was purified by ISCO flash chromatography (Teledyne Isco RediSep Flash Column 12 g; 0% to 10% methanol/dichloromethane) to afford 2-[4-(2-chloro-3-methoxy-phenoxy)-2-oxo-2,5-dihydro-pyrrol-1-yl]-4-fluoro-4-methyl-pentanoic acid [1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-amide (156 mg, 57%) as a white powder: LR-ES-MS m/z calculated for C24H30ClFN4O5 [M]+ 508, observed 509 [M+H]+; 1H NMR (300 MHz, DMSO-d6) δ ppm 1.05 (br. s., 3H), 1.06 (br. s., 3H), 1.19, 1.32 (2×d, J=3.0 Hz, 3H), 1.26, 1.39 (2×d, J=3.0 Hz, 3H), 1.96-2.33 (m, 2H), 3.90 (br. s., 5H), 4.25 (d, J=18.4 Hz, 1H), 4.52 (d, J=18.4 Hz, 1H), 4.67 (s, 1H), 4.77, 4.80 (2×s, 1H), 5.01, 5.10 (2×dd, J=9.8, 4.4 Hz, 1H), 6.44 (d, J=1.8 Hz, 1H), 7.00, 7.06 (2×d, J=8.2 Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.41 (t, J=8.2 Hz, 1H), 7.54 (d, J=1.8 Hz, 1H), 10.71, 10.82 (2×s, 1H).
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=[O:5])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[CH2:12]([C:14]1[C:15]#[C:16][CH:17]=[CH:18][CH:19]=1)[CH3:13].B(F)(F)F>>[CH2:12]([C:14]1[CH:15]=[CH:16][C:17]([C:4]([C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[C:1]([OH:6])=[O:11])=[O:5])=[CH:18][CH:19]=1)[CH3:13]
Reactant: CCc1c#cccc1
Reactant: O=C1OC(=O)c2ccccc21
Agent: FB(F)F
Product: CCc1ccc(C(=O)c2ccccc2C(=O)O)cc1

Procedure:
A complex of ortho-(4-ethylbenzoyl)benzoic acid (OEBB acid) is prepared according to U.S. Pat. No. 4,379,092 by reacting 26.6 g phthalic anhydride, 19.07 g ethylbenzyne, 35.9 g HF, and 121.77 g BF3 for 30 minutes at -40° C. After reaction and degassing at -40° C., 144.4 g of a complex solution in HF is obtained. This solution is injected over a 20 minute period into the column described in Example 1. The same temperature and pressure conditions were used and methylene chloride was again selected as the solvent. The methylene chloride reflux rate was 3.8 kg/h. After introducing the complex solution, the solvent reflux was maintained for 20 minutes before evaporating the solvent in the boiler. 43.31 g of crude OEBB acid which contained 39.07 g of OEBB acid was recovered. Also, the recovery rates for BF3 and HF were 99.3% and 99.6%, respectively.
Reaction SMILES: Br[C:2]1[C:12]2[CH2:11][CH2:10][C:9](=O)[CH2:8][CH2:7][C:6]=2[C:5]([O:14][CH3:15])=[C:4]([N+:16]([O-:18])=[O:17])[CH:3]=1.[NH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]1.C(Cl)Cl.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH3:15][O:14][C:5]1[C:6]2[CH2:7][CH2:8][CH:9]([N:19]3[CH2:24][CH2:23][CH2:22][CH:21]([OH:25])[CH2:20]3)[CH2:10][CH2:11][C:12]=2[CH:2]=[CH:3][C:4]=1[N+:16]([O-:18])=[O:17]
Reactant: OC1CCCNC1
Reactant: COc1c([N+](=O)[O-])cc(Br)c2c1CCC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COc1c([N+](=O)[O-])ccc2c1CCC(N1CCCC(O)C1)CC2
Temperature: 40 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 4-bromo-1-methoxy-2-nitro-5,6,8,9-tetrahydro-benzocyclohepten-7-one (2.00 g, 0.00637 mol) and piperidin-3-ol (6 g, 0.06 mol) in methylene chloride (100 mL, 2 mol) at room temperature was added acetic acid (4 mL, 0.06 mol) dropwise. Molecular sieves (2 mass equiv) were added to the reaction mixture and the contents heated at 40° C. overnight. The reaction mixture was cooled to room temperature then at 0° C. in an ice bath. Sodium triacetoxyborohydride (7 g, 0.03 mol) was added in one portion as a solid. The reaction mixture continued to stirr at 0° C. for 1 h then warmed to room temperature for 4 h Workup involved quenching with water, adjusting the pH to 8-10 with 10 N NaOH (aq) and extracting with methylene chloride. The organic phase was dried over magnesium sulfate, filtered and concentrated in vacuo to a dark oil. Purification involved ISCO chromatography on silica gel (40 g column) using methylene chloride-methanol with 5% ammonium hydroxide. Fractions corresponding to product (polar fractions) were combined and concentration to give 1-(1-methoxy-2-nitro-6,7,8,9-tetrahydro-5H-benzocyclohepten-7-yl)-piperidin-3-ol as a brown oil. 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 3.86 (s, 4H), 3.47 (m, 3H), 2.88 (t, 1H, J=11 Hz), 2.60-2.70 (m, 4H), 2.48-2.41 (m, 2H), 2.21 (m, 2H), 1.86 (m, 2H), 1.59 (m, 3H), 1.26-1.39 (m, 2H).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([OH:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24].C1CCN2C(=NCCC2)CC1.[H-].[Na+]>CN(C=O)C>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH:32]([O:35][C:11]2[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:2][CH2:3]3)=[CH:9][C:10]=2[F:16])[CH2:31]1)=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(OC3CCN(C(=O)OC(C)(C)C)C3)c(F)cc2c1=O
Temperature: 25 °C
Yield: 58.6 %

Procedure:
To a mixture of 233 mg of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate, 168 mg of 1-t-butoxycarbonyl-3-hydroxypyrrolidine, 170 mg of DBU and 5 xl of DMF was added 36 mg of 55% sodium hydride while the former was stirred at room temperature. After the resultant mixture was stirred for 1 hour at room temperature, the reaction mixture was concentrated to dryness under reduced pressure. After chloroform and 10% citric acid were added to the residue and the resultant mixture was shaken thoroughly, the resulting chloroform layer was collected and then successively washed with a 5% aqueous solution of sodium hydrogencarbonate and saturated saline. The chloroform solution was dried over anhydrous sodium sulfate and then concentrated. The residue was purified by chromatography on silica gel (chloroform/methanol: 100:1), whereby 210 mg of ethyl 7-(1-t-butoxycarbonyl-3-pyrrolidinyloxy)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate was obtained.
Reaction SMILES: [CH:1]([C:3]1[S:4][CH:5]=[CH:6][N:7]=1)=O.C(O)(=O)[CH2:9][C:10]([OH:12])=[O:11]>N1C=CC=CC=1.N1CCCCC1.O>[S:4]1[CH:5]=[CH:6][N:7]=[C:3]1[CH:1]=[CH:9][C:10]([OH:12])=[O:11]
Reactant: O=C(O)CC(=O)O
Reactant: O=Cc1nccs1
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)C=Cc1nccs1
Temperature: 100 °C
Yield: 12.4 %

Procedure:
Mix 2-formyl thiazole (10.0 g, 88.4 mmol) and malonic acid (9.2 g, 88.4 mmol). Dissolve in pyridine (7.2 mL, 88.5 g) and add 3 drops of piperidine. Heat the mixture at 100° C. under nitrogen for 3 hours, cool, dilute with water, and filter the solids to afford 1.7 g of the title compound as a white solid. Concentrate the filtrate, acidify with 1N HCl, extract with ethyl acetate (2×100 mL), wash with brine (100 mL), dry (sodium sulfate), filter and concentrate to afford an additional 4.8 g of 3-thiazol-2-yl-acrylic acid MS: m/e=156 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([O:12][CH3:13])=[O:11])=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[CH3:14][NH:15][CH:16]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]1>CN(C=O)C>[C:25]([O:24][C:22]([N:19]1[CH2:18][CH2:17][CH:16]([N:15]([CH3:14])[C:7]2[CH:6]=[C:5]([Cl:9])[N:4]=[C:3]([C:10]([O:12][CH3:13])=[O:11])[C:2]=2[Cl:1])[CH2:21][CH2:20]1)=[O:23])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1nc(Cl)cc(Cl)c1Cl
Reactant: CNC1CCN(C(=O)OC(C)(C)C)CC1
Solvent: CN(C)C=O
Product: COC(=O)c1nc(Cl)cc(N(C)C2CCN(C(=O)OC(C)(C)C)CC2)c1Cl
Temperature: 100 °C
Yield: 17.6 %

Procedure:
To a stirred solution of methyl 3,4,6-trichloropyridine-2-carboxylate (310 mg, 1.29 mmol) in DMF (5 ml) was added TEA (359 μl, 2.58 mmol) followed by tert-butyl 4-(methylamino)piperidine-1-carboxylate (276 mg, 1.29 mmol) and the reaction mixture was heated at 100° C. for 4 h. The reaction mixture was then cooled to room temperature and poured onto water (50 ml), followed by extraction of the product into TBME (3×50 ml), washing of the combined organics with brine (50 ml), drying with Na2SO4 and evaporation. The crude product was then purified over a 10 g silica Isolute column eluting with a gradient of 0% to 50% EtOAc in heptane to afford the title compound as a white solid (95 mg, 18%). LC-MS 95%, 2.29 min (3.5 minute LC-MS method), m/z=418.1/419.8, 1H NMR (500 MHz, Chloroform-d) δ 6.87 (s, 1H) 4.12-4.34 (m, 2H) 3.99 (s, 3H) 3.69-3.80 (m, 1H) 2.79 (s, 3H) 2.64-2.77 (m, 2H) 1.75 (br. s., 4H) 1.48 (s, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][C:10]2=[O:13])=[CH:5][CH:4]=1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=[O:17].[H-].[Na+].O1CCCC1>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH:9]([C:16](=[O:17])[C:15]([F:22])([F:21])[F:14])[C:10]2=[O:13])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)C(=O)CCC2
Reactant: CCOC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(=O)C(C(=O)C(F)(F)F)CC2

Procedure:
A mixture of 7-methoxy-1-tetralone (7.8 g), ethyl trifluoroacetate (6 ml), sodium hydride (80% dispersion in mineral oil, 1.8 g) and tetrahydrofuran (75 ml) was stirred under reflux for 2 h under an atmosphere of argon. The cooled reaction mixture was treated with 20% acetic acid solution (250 ml) and the mixture was extracted twice with ethyl acetate. The extracts were combined, dried and evaporated to dryness under reduced pressure, and the residue was recrystallised from ethanol to give 7-methoxy-2-(2,2,2-trifluoracetyl)-1-tetralone, m.p. 89°-90°.
Reaction SMILES: CC1(C)[C@H]2CC[C@]1(CS(O)(=O)=O)C(=O)C2.[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH2:26])[CH2:20]2.C(=O)([O-])[O-].[K+].[K+].Cl[C:34]([O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:35]>CCOC(C)=O.O>[Br:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[CH2:22][C@H:21]([NH:26][C:34](=[O:35])[O:36][CH2:37][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:20]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: N[C@H]1Cc2ccc(Br)cc2C1
Agent: CC1(C)[C@H]2CC[C@]1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1Cc2ccc(Br)cc2C1)OCc1ccccc1
Reaction time: 8 h
Yield: 107.7 %

Procedure:
(S)-5-bromo-2,3-dihydro-1H-inden-2-amine((1R,4S)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonate (18.47 mmol, 8.21 g) was dissolved in EtOAc (30 mL)/water (30 mL) and potassium carbonate (55.4 mmol, 7.66 g) added. The mixture was cooled in an ice bath and benzyl chloroformate (20.32 mmol, 2.89 mL, 3.47 g) added dropwise. Stirring was continued overnight during which time the reaction came to room temperature. The crude reaction mixture was diluted with water and ethylacetate and the phases mixed and separated. The aqueous layer was further extracted with EtOAc (×2). Combined organics were dried and concentrated to give (S)-benzyl 5-bromo-2,3-dihydro-1H-inden-2-ylcarbamate as a colourless solid (6.89 g, 108%). 1H NMR (400 MHz, CDCl3) δ 2.79 (m, 2H) 3.26 (m, 2H) 4.53 (bm, 1H) 4.93 (bm, 1H) 5.10 (bs, 2H) 7.07 (m, 1H) 7.26-7.37 (m, 7H)