Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21](Cl)=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[OH-].[Na+].[C:39]1([CH3:45])[CH:44]=CC=CC=1>[Br-].C([N+](C)(C)C)CCCCCCCCCCCCCCC.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:13]([CH3:34])([CH3:33])[C:14]([N:16]([C:18]2[CH:19]=[N:20][C:21]([N:20]3[CH2:19][CH:18]([CH3:23])[NH:16][CH2:44][CH:39]3[CH3:45])=[CH:22][C:23]=2[C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][C:25]=2[CH3:31])[CH3:17])=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: Cc1ccccc1
Reactant: Cc1cc(F)ccc1-c1cc(Cl)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Product: Cc1cc(F)ccc1-c1cc(N2CC(C)NCC2C)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Temperature: 90 °C
Yield: 42 %

Procedure:
A mixture of 0.20 g (0.38 mmol) 2-(3,5-bis-trifluoromethyl-phenyl)-N-[6-chloro-4-(4-fluoro-2-methyl-phenyl)-pyridin-3-yl]-N-methyl-isobutyramide, 87 mg (0.75 mmol) (2RS,5SR)-dimethyl-piperazine, 0.01 g (0.03 mmol) cetyltrimethyl-ammonium bromide, 0.01 g (0.02 mmol) bis(tri-t-butylphosphine)palladium(0), 0.075 ml NaOH 50% and 3 ml toluene was degassed by two freeze-thaw cycles. The reaction mixture was heated under argon at 90° C. for 48 h. After cooling to room temperature the mixture was diluted with water and brine and extracted with three portions of tert-butyl methyl ether. The combined organic layers were dried over sodium sulphate and concentrated in vacuo. Flash column chromatography gave 96 mg (42%) of the title compound as a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[Br:32]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[C:13]([Br:32])[N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:24]=[CH:25][C:26]([O:29][CH3:30])=[CH:27][CH:28]=1)=[CH:8]2)=[O:4]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccc(OC)cc3)c(=O)n2Cc2ccccc2)c1O
Yield: 69.7 %

Procedure:
A mixture of 1-benzyl-5-hydroxy-3-(4-methoxy-phenyl)-2-oxo-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (93 mg, 0.22 mmol) and N-bromosuccinimide (44 mg, 0.25 mmol) in CH2Cl2 (0.8 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 76 mg of the title compound as a yellow solid. MS: (+) m/z 495.21, 497.10 (M+1, 79/81Br).
Reaction SMILES: C[Mg]Cl.[CH3:4][C:5](=[C:10]([CH3:12])[CH3:11])[C:6](=[CH2:9])[CH:7]=[O:8].[C:13](O)(=O)C>C1COCC1>[CH3:4][CH:5]([CH:10]([CH3:12])[CH3:11])[C:6](=[CH2:9])[CH:7]([OH:8])[CH3:13]
Reactant: C=C(C=O)C(C)=C(C)C
Reactant: CC(=O)O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: C=C(C(C)O)C(C)C(C)C
Temperature: 17.5 °C
Reaction time: 2 h
Yield: 84.2 %

Procedure:
Methylmagnesium chloride in THF (3 M, 2.65 L) was charged into a flame-dried 2-L reaction flask fitted with a mechanical stirrer, a thermocouple, a condenser, and a dropping funnel. The reaction flask was cooled with an external bath to about 15-20° C. 3,4-Dimethyl-2-methylene-pentenal (prepared as above) (834 g) was fed over about 2-3 hours to allow the exotherm temperature at about 30-35° C. After the feeding was completed, the reaction mass was aged for about 2 hours. GC analysis determined a conversion rate of about 95%. The reaction mixture was poured into a mixture of ice and acetic acid (500 g). The organic layer was separated and washed sequentially with brine (500 mL) and sodium carbonate (5%, 300 mL), and further fractional distilled to provide 4,5-dimethyl-3-methylene-hexan-2-ol (804 g) with a boiling point of 110° C. at 60 mmHg.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[CH3:21])[NH2:17]>>[CH3:13][C:14]1[CH:15]=[C:16]([NH:17][C:9]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:12][CH:11]=2)=[NH:10])[CH:18]=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1ccc(N)cc1C
Reactant: CS(=O)(=O)c1ccc(C#N)cc1
Product: Cc1ccc(NC(=N)c2ccc(S(C)(=O)=O)cc2)cc1C
Yield: 45 %

Procedure:
The title compound was prepared from 4-methylsulfonylbenzonitrile (5.0 g, 28 mmol) and 3,4-dimethylaniline (3.36 g, 28 mmol) by following the procedure described in preparation 1 (3.75 g, yield 45%, purity 97.1% by HPLC). 1H-NMR (CDCl3):δ 2.25-2.26 (d, 6H), 3.07 (s, 3H), 4.91 (bs, 2H, D2O exchangeable), 6.71-6.73 (m, 1H), 6.78 (s, 1H), 7.12-7.14 (d, 1H), 8-8.02 (d, 2H), 8.07-8.09 (d, 2H). MS m/z:303.2 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[NH:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:26]([C:33](O)=[O:34])=[N:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:33]([C:26]3[C:27]4[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=4)[NH:24][N:25]=3)=[O:34])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: O=C(O)c1n[nH]c2ccccc12
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3n[nH]c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with 1H-indazole-3-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=477.1.
Reaction SMILES: [NH2:1][C:2]1[C:3](/[CH:9]=[CH:10]/[C:11]([O:13]CC)=O)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.C[O-].[Na+].CO>CO>[F:8][C:6]1[CH:7]=[C:2]2[C:3]([CH:9]=[CH:10][C:11](=[O:13])[NH:1]2)=[N:4][CH:5]=1
Reactant: CCOC(=O)/C=C/c1ncc(F)cc1N
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=c1ccc2ncc(F)cc2[nH]1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 60.5 %

Procedure:
To a solution of 0.36 g of ethyl (2E)-3-(3-amino-5-fluoropyridin-2-yl)acrylate in 3 mL of methanol, 0.37 g of a 28% sodium methoxide/methanol solution was added at room temperature, and the mixture was heated under reflux while stirring for 2 hours 40 minutes. Thereto was added 72 mg of a 28% sodium methoxide/methanol solution, and the mixture was heated under reflux while stirring for 1 hour. The reaction mixture was cooled to room temperature, the solvent was then distilled off under reduced pressure, and the resultant residue was charged with ethyl acetate and water and adjusted to pH 6.7 with 1 mol/L hydrochloric acid. The solvent was distilled off under reduced pressure, the solid was filtered off and washed with water and diethyl ether to obtain 0.17 g of 7-fluoro-1,5-naphthyridin-2(1H)-one as a light brown solid.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:15]=[C:14]2[C:10]([C:11]([C:26](=[O:37])[NH:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=3)=[C:12]([CH:23]([CH3:25])[CH3:24])[N:13]2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:9][CH:8]=1)(=O)=O.[N:40]1[CH:45]=[CH:44][C:43](B(O)O)=[CH:42][CH:41]=1.C([O-])([O-])=O.[K+].[K+].[Li+].[Cl-]>C1(C)C=CC=CC=1.CO.CCOC(C)=O.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>[CH2:16]([N:13]1[C:14]2[C:10](=[CH:9][CH:8]=[C:7]([C:43]3[CH:44]=[CH:45][N:40]=[CH:41][CH:42]=3)[CH:15]=2)[C:11]([C:26]([NH:27][CH2:28][C:29]2[CH:34]=[CH:33][C:32]([F:35])=[C:31]([F:36])[CH:30]=2)=[O:37])=[C:12]1[CH:23]([CH3:25])[CH3:24])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: OB(O)c1ccncc1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2n1Cc1ccccc1
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: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(-c3ccncc3)cc2n1Cc1ccccc1
Temperature: 90 °C

Procedure:
General Procedure W. A mixture of 1-benzyl-3-(3,4-difluorobenzylcarbamoyl)-2-isopropyl-1H-indol-6-yl trifluoromethanesulfonate (Compound 160, 50 mg, 0.088 mmol), pyridin-4-ylboronic acid (22 mg, 0.18 mmol), Pd(PPh3)4 (5.0 mg, 0.0043 mmol), K2CO3 (61 mg, 0.44 mmol), and LiCl (19 mg, 0.44 mmol) in toluene (3 ml), MeOH (1 ml), and H2O (0.5 ml) was heated at 90° C. for 16 h. The reaction was then cooled to room temperature, diluted with EtOAc, washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].Br[CH:12]([CH2:16][CH2:17][CH2:18][Br:19])[C:13](Cl)=[O:14]>>[Br:19][CH2:18][CH2:17][CH2:16][CH:12]1[C:13](=[O:14])[NH:1][C:2]2[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=2[O:10]1
Reactant: O=C(Cl)C(Br)CCCBr
Reactant: COc1ccc(O)c(N)c1
Product: COc1ccc2c(c1)NC(=O)C(CCCBr)O2
Yield: 56.9 %

Procedure:
In a manner similar to that of Reference Example 16, 2-amino-4-methoxyphenol was allowed to react with 2,5-dibromovaleryl chloride, then cyclized to give 2-(3-bromopropyl)-6-methoxy-2H-1,4-benzoxazine-3(4H)-one as crystals. The yield was 56.9%. m.p. 102°-103° C. (recrystallization from ether).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[C:21]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:39]=3)[C:34]([F:45])=[CH:33][N:32]=2)=[N:22][CH:23]=[C:24]([F:30])[C:25]=1[Si](C)(C)C.C1COCC1>O>[F:19][C:20]1[C:21]([C:31]2[C:40]3[C:35](=[CH:36][CH:37]=[C:38]([C:41]([O:43][CH3:44])=[O:42])[CH:39]=3)[C:34]([F:45])=[CH:33][N:32]=2)=[N:22][CH:23]=[C:24]([F:30])[CH:25]=1
Reactant: COC(=O)c1ccc2c(F)cnc(-c3ncc(F)c([Si](C)(C)C)c3F)c2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(F)cnc(-c3ncc(F)cc3F)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrabutylammonium fluoride (1M THF solution, 0.35 mL) was added to a mixture of methyl 1-[3,5-difluoro-4-(trimethylsilyl)pyridin-2-yl]-4-fluoroisoquinoline-7-carboxylate and THF (1.8 mL), and stirred at room temperature overnight. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried, and concentrated under reduced pressure. The resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 1-(3,5-difluoropyridin-2-yl)-4-fluoroisoquinoline-7-carboxylate (55 mg).
Reaction SMILES: C[O:2][C:3]1[C:8]2[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][OH:24])=[CH:19][CH:18]=3)[CH2:12][CH2:13][C:7]=2[C:6]([O:25]C)=[C:5]([O:27][CH3:28])[C:4]=1[O:29][CH3:30].N1C(C(O)=O)=CC=CC=1C(O)=O.C1COCC1.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>O>[OH:24][CH2:23][C:20]1[CH:19]=[CH:18][C:17]([O:16][CH2:15][CH2:14][CH:11]2[CH2:12][CH2:13][C:7]3[C:6](=[O:25])[C:5]([O:27][CH3:28])=[C:4]([O:29][CH3:30])[C:3](=[O:2])[C:8]=3[CH2:9][CH2:10]2)=[CH:22][CH:21]=1
Reactant: COc1c2c(c(OC)c(OC)c1OC)CCC(CCOc1ccc(CO)cc1)CC2
Agent: O=C(O)c1cccc(C(=O)O)n1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: C1CCOC1
Solvent: O
Product: COC1=C(OC)C(=O)C2=C(CCC(CCOc3ccc(CO)cc3)CC2)C1=O
Reaction time: 0.25 h
Yield: 43.8 %

Procedure:
To a mixture of 4-[2-(1,2,3,4-tetramethoxy-6,7,8,9-tetrahydro-5H-benzo[a]cyclohepten-7-yl)ethoxy]phenylmethanol (261 mg), 2,6-pyridinedicarboxylic acid (314 mg), THF (6 ml), and water (3 ml) was dropwise added a solution of CAN (1.38 g) in water (3 ml) with cooling with ice. After the reaction mixture was stirred for 15 min, water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride and dried. The solvent was removed in vacuo The residue was purified by silica gel column chromatography (hexane to hexane:ethyl acetate=2:1) and then with recrystallization from hexane-ethyl acetate to yield the entitled compound (106 mg) as crystals.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[C:9](Cl)=[CH:8][C:6]([NH2:7])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1.Cl.[F:17][C:18]([F:26])([F:25])[CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C([O-])([O-])=O.[K+].[K+]>CN1C(=O)CCC1>[F:1][C:2]([F:15])([F:14])[C:3]1[C:9]([N:22]2[CH2:23][CH2:24][CH:19]([C:18]([F:26])([F:25])[F:17])[CH2:20][CH2:21]2)=[CH:8][C:6]([NH2:7])=[C:5]([N+:11]([O-:13])=[O:12])[CH:4]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Nc1cc(N2CCC(C(F)(F)F)CC2)c(C(F)(F)F)cc1[N+](=O)[O-]

Procedure:
The sub-title compound was prepared from 4-trifluoromethyl-5-chloro-2-nitro-aniline (100 mg, 0.42 mmol), 4-trifluoromethyl-piperidine hydrochloride (394 mg, 2.1 mmol) and K2CO3 (600 mg, 4.4 mmol) in NMP (2 mL) in analogy to example 3, step (a).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14](=[CH:15]N(C)C)[C:13](=[O:19])[C@@H:12]2[C@H:10]1[C@H:11]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[H-].C([Al+]CC(C)C)C(C)C.C(O)(=O)C.OP(O)(O)=O>O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C@@:9]1([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:14](=[CH2:15])[C:13](=[O:19])[C@@H:12]2[C@H:10]1[C@H:11]2[C:20]([O:22][C:23]([CH3:25])([CH3:24])[CH3:26])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Agent: CC(C)C[Al+]CC(C)C
Agent: O=P(O)(O)O
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=C1C(=O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]2[C@]1(NC(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Temperature: -47 °C
Yield: 99.1 %

Procedure:
To a solution of di-tert-butyl (1S,2R,5R,6R)-2-(tert-butoxycarbonylamino)-3-(dimethylaminomethylene)-4-oxo-bicyclo[3.1.0]hexane-2,6-dicarboxylate (620.4 g, 1.33 mol) in dry tetrahydrofuran (12 L), triethylamine (277.3 ml, 1.99 mol) is added at room temperature under nitrogen. The mixture is cooled to −47° C. and diisobutylaluminum hydride (1M in hexane, 2.06 L, 2.06 mol) is added dropwise over 2 hours. The resulting mixture is stirred at −47° C. After 1 hour 15 minutes, acetic acid (118 ml, 2.06 mol) is dropwise added at −47° C., warmed to room temperature, and then stirred overnight. Add 20% H3PO4 in water until pH=2. Separate the organic phase and extract the aqueous phase with ethyl acetate (2×1.7 L). The combined organic phases are washed successively with 10% aqueous HCl (1.5 L), water (1.5 L), and brine (1.5 L), dried over anhydrous sodium sulfate, filtered, and concentrated to yield a solid. The resulting solid is triturated with water (3.2 L), collected by filtration, and then dried to yield the title compound (558.2 g, yield 99%). HPLC-MS: 97.4%.
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:9][CH:8]([N:10]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH2:7][N:6]1[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:4].[Li+].[OH-]>CO>[CH2:27]([N:6]1[CH2:7][CH:8]([N:10]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:13]=2[F:19])[CH2:9][CH:5]1[C:3]([OH:4])=[O:2])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: COC(=O)C1CC(N(Cc2ccc(F)cc2F)C(=O)OC(C)(C)C)CN1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1F)C1CC(C(=O)O)N(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.3 %

Procedure:
To a solution of 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid methyl ester (109 g, 4.13 mmol) in CH3OH (10 ml) was added LiOH (0.826 g, 20.65 mmol), and the solution was stirred overnight at rt. After removal of solvent, the residue was dissolved in water, acidified until PH=5, and then extracted by EA. The organic phase was washed with water (2×50 mL) and brine (40 mL), dried over anhydrous Na2SO4, and concentrated to afford the product 1-benzyl-4-[tert-butoxycarbonyl-(2,4-difluoro-benzyl)-amino]-pyrrolidine-2-carboxylic acid 1.72 g (93%) as white solid. MS m/e=447.4 [M+H]+.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.S(Cl)(Cl)=O.[CH2:14](O)[CH3:15]>>[CH2:14]([O:8][C:7]([C@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][NH:5]1)=[O:9])[CH3:15]
Reactant: CCO
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Solvent: O=S(Cl)Cl
Product: CCOC(=O)[C@H]1C[C@@H](O)CN1
Temperature: 25 °C

Procedure:
To a stirred solution of cis-4-hydroxy-pyrrolidine-2-carboxylic acid (1 g, 7.6 mmol) in absolute ethanol (20 mL) is added dropwise thionyl chloride (0.67 mL, 9.15 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture is then refluxed under nitrogen for about 2 h. The mixture is cooled to room temperature, and all solvent is removed under reduced pressure. The white precipitate is filtered and washed with diethyl ether (1×25 mL), to obtain compound (1) as a white solid.
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@H:7]([C@@H:9](CO)[OH:10])[OH:8])[OH:6])[OH:4].C(O)C(N)(CO)CO.Cl.N[C@H](C(O)=O)CS.S(=O)(=O)(O)O.C1C2NC3C(=CC=CC=3)C=2C=CC=1.OCC([C@H]([C@H]([C@@H](CO)O)O)O)=O>>[O:1]=[CH:2][C@H:3]([C@@H:5]([C@@H:7]([CH2:9][OH:10])[OH:8])[OH:6])[OH:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Agent: Cl
Agent: NC(CO)(CO)CO
Agent: N[C@@H](CS)C(=O)O
Product: O=C[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 24 h

Procedure:
The recombinant strains Corynebacterium glutamicum CJ-1-TNAI and Corynebacterium glutamicum CJ-7-TNAI (Accession Nos: KCCM10786P and KCCM10787P) prepared in Example 1 were inoculated in MB medium (Bacto-trypton 10 g/L, Bacto-yeast extract 5 g/L, NaCl 10 g/L, Soytone 5 g/L) containing 10 μg/Ml of kanamycin at the concentration of OD600=0.1, followed by culture at 30° C. for 24 hours to induce expression of the recombinant arabinose isomerase. To measure the enzyme activity of the expressed arabinose isomerase, the culture solution was centrifuged at 8,000× g for 10 minutes and cells were recovered. The cells were resuspended in 50 mM Tris-HCl (pH 7.0) buffer, followed by ultrasonification to lyse the cells. The supernatant was obtained as a crude enzyme solution, with which galactose isomerization was performed. Particularly, for the isomerization, 100 μl of an enzyme solution containing 40 mM of galactose as a substrate was mixed with 1 ml of a reaction buffer (50 mM Tris-HCl, pH 7.0). At that time, 5 mM of MnCl2 and 1mM of CoCl2 were added to the reaction mixture. The crude enzyme reaction mixture was reacted at 60° C. for 20 minutes. The activity of the crude enzyme was measured by the cystein-carbazol-sulfuric acid method (Dische, Z., and E. Borenfreund., A New Spectrophotometric Method for the Detection and Determination of Keto Sugars and Trioses, J. Biol. Chem., 192:583-587, 1951). The protein contained in the crude enzyme solution was quantified with a Bradford assay kit (Biorad, U.S.A.). As a result, the isomerase activity was 2.050 (mg-tagatose/mg-protein·h), indicating that the product of galactose isomerization, tagatose, was successfully generated.
Reaction SMILES: [C:1](Cl)(=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Li]>COCCOCCOC>[CH:1](=[O:10])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCC/C=C/C(=O)Cl
Agent: [Li]
Solvent: COCCOCCOC
Product: CCCCCC/C=C/C=O
Temperature: -78 °C

Procedure:
Trans-2-nonenoyl chloride (170 g, 1 mole) is dissolved in 500 ml of diglyme and placed in a flask fitted with a mechanical stirrer, dripping funnel, low temperature thermometer and nitrogen inlet and outlet. The flask is flushed with nitrogen and cooled to -78°C in a dry ice acetone bath. To the flask, lithium tri-t-butoxyaluminohydried (254 g, 1 mole) in 1000 ml of diglyme is added over a period of 7 hours. The cooling bath is removed and the contents of the flask are allowed to warm to room temperature. The contents are poured onto crushed ice and the oily layer taken up in ether. The ether solution is dried over sodium sulfate, concentrated and vacuum distilled to give trans-2-nonenal.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](O)=[N:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[C:10]([Br:11])[C:5]2=[N:4][CH:3]=1.P(Cl)(Cl)([Cl:23])=O.C(=O)(O)[O-].[Na+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(OCC)(=O)C>[Br:1][C:2]1[N:6]2[C:7]([Cl:23])=[N:8][C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])=[C:10]([Br:11])[C:5]2=[N:4][CH:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Oc1nc(-c2ccc(Cl)cc2Cl)c(Br)c2ncc(Br)n12
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Clc1ccc(-c2nc(Cl)n3c(Br)cnc3c2Br)c(Cl)c1
Temperature: 120 °C
Reaction time: 12 h

Procedure:
575 mg (1.3 mmol) of 3,8-dibromo-7-(2,4-dichlorophenyl)imidazo[1,2-c]pyrimidin-5-ol (Example 123A) are introduced into phosphoryl chloride (5 ml), 900 mg (4 mmol) of benzyltriethylammonium chloride are added, and the reaction mixture is stirred at 120° C. for 12 h. The reaction mixture is slowly poured, while stirring vigorously, into saturated sodium bicarbonate solution, and solid sodium bicarbonate (approx. 3 g) is added until a pH of 10 is reached. The mixture is stirred for 10 min, ethyl acetate (100 ml) is added and shaken, and the organic phase is separated off, washed with water and dried over magnesium sulphate and concentrated in a rotary evaporator. The residue is purified by silica gel chromatography (cyclohexane/ethyl acetate 10:1). 480 mg (80% of theory) of the product are obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[CH:21]([C:27]([O:29][CH:30]([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH:22]([CH2:25][OH:26])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.O.C(OCC)(=O)C>CS(C)=O>[C:8]1([CH2:14][C:15]([NH:17][CH:18]2[C:43](=[O:44])[N:20]3[CH:21]([C:27]([O:29][CH:30]([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)=[O:28])[C:22](=[CH:25][O:26][C:1](=[O:3])[CH3:2])[CH2:23][S:24][C@H:19]23)=[O:16])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Reactant: CC(=O)OC(C)=O
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)OC=C1CS[C@@H]2C(NC(=O)Cc3ccccc3)C(=O)N2C1C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
Acetic anhydride (20 ml.) was added to a solution of diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (10.0 g.) in dimethylsulfoxide (20 ml.), and stirred at room temperature for 15 hours. The resultant solution was poured into a solution of water (400 ml.) and ethyl acetate (400 ml.). The organic layer was separated and adjusted to pH 7.5 with an aqueous solution of sodium bicarbonate. The organic layer was separated, washed with water and a saturated aqueous solution of sodium chloride in turn, and dried over magnesium sulfate. The solution was concentrated under reduced pressure to give diphenylmethyl 7-(2-phenylacetamido)-3-acetoxymethylenecepham-4-carboxylate (5.3 g.).