Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26](O)=[O:27])#[N:2].C(Cl)(=O)C(Cl)=O.[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([NH2:43])=[CH:39][CH:38]=1.N1C=CC=CC=1>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:43][C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=1)=[O:27])#[N:2]
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Reactant: COc1ccc(N)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: COc1ccc(NC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of p-anisidine (199 mg, 1.62 mmol), pyridine (0.262 ml, 3.24 mmol) and THF (3 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=5:1) to give the objective product as a solid material. The resultant material was recrystallized from hexane and ethyl acetate.
Reaction SMILES: [C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[C:28](Cl)(=[O:30])[CH3:29]>CN(C=O)C>[C:1]([Si:5]([CH3:25])([CH3:24])[O:6][C:7]1[CH:8]=[C:9]2[C:17](=[CH:18][CH:19]=1)[N:16]([C:28](=[O:30])[CH3:29])[C:15]1[C:14]3[CH:20]=[CH:21][CH:22]=[CH:23][C:13]=3[S:12][CH2:11][C:10]2=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]c3c(c2c1)CSc1ccccc1-3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)n1c2c(c3cc(O[Si](C)(C)C(C)(C)C)ccc31)CSc1ccccc1-2
Temperature: 25 °C

Procedure:
8-(tert-Butyl-dimethyl-silanyloxy)-6,11-dihydro-5-thia-11-aza-benzo[a]fluorene (170 mg, 0.462 mmoL) in DMF (2 mL) was treated with NaH (60%, 37 mg, 0.925 mmoL) at 0° C. Acetyl chloride (52 mg, 0.693 mmoL) was added dropwise into the reaction 30 minutes later. The reaction mixture was than slowly warmed to room temperature over 2 hours. The reaction was quenched with saturated NH4Cl. The residue was partitioned between CH2Cl2 and saturated NaHCO3. The aqueous phase was extracted two times with CH2Cl2. The organic layer from each extraction was combined, washed with water, brine, dried over anhydrous Na2SO4, filtered and concentrated to yield a brown oil. The oil was then purified by column chromatography (silica gel, hexanes:EtOAc 5:1 as eluent) to yield the title compound as a pale solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5]([O:23][CH2:24][CH3:25])=[CH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:26])[CH:5]([O:23][CH2:24][CH3:25])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:9]([O:21][CH3:22])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)c(OC)c1)OCC
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)c(OC)c1)OCC
Yield: 72.5 %

Procedure:
3-(4-Benzyloxy-3-methoxyphenyl)-2-ethoxyacrylic acid ethyl ester (5.5 g, 15.4 mmole) was dissolved in ethyl acetate and hydrogenated using Pd/C (dry, 5%). The reaction mixture was filtered through celite. Evaporation of the filtrate gave 4 g (97% yield) of 3-(4-benzyloxy-3-methoxyphenyl)-2-ethoxypropanoic acid ethyl ester.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C([O:9][C:10]([CH2:12][C:13]1[C:14]([C:32](OCC)=[O:33])=[N:15][C:16]2[C:21]([C:22]=1[C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[CH:20][C:19]([O:30][CH3:31])=[CH:18][CH:17]=2)=O)C.O>C1COCC1>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([O:30][CH3:31])[CH:20]=3)[N:15]=[C:14]([CH2:32][OH:33])[C:13]=2[CH2:12][CH2:10][OH:9])=[CH:24][CH:25]=1
Reactant: CCOC(=O)Cc1c(C(=O)OCC)nc2ccc(OC)cc2c1-c1ccc(F)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2nc(CO)c(CCO)c(-c3ccc(F)cc3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 125.7 %

Procedure:
To a suspension of lithium aluminum hydride (180 mg) in THF (15 ml), ethyl 3-ethoxycarbonylmethyl-4-(4-fluorophenyl)-6-methoxyquinoline-2-carboxylate (1.0 g) was added, followed by stirring at 0° C. for 30 minutes. Water was added to the reaction mixture to stop the reaction; after the insoluble substances were filtered off, the product was extracted with ethyl acetate. After being washed with water, the extract was dried over magnesium sulfate and concentrated under reduced pressure to yield a crude crystal (1 g) of the title compound. The crude crystal obtained was used for the next reaction without further purification.
Reaction SMILES: CO[C:3]([C:5]1[C:14](=[O:15])[N:13]([CH3:16])[C:8]2=[N:9][CH:10]=[CH:11][N:12]=[C:7]2[C:6]=1[O:17]C(=O)C(C)C)=[O:4].O[NH:24][C:25](=[NH:27])[CH3:26]>C1(C)C=CC=CC=1>[OH:17][C:6]1[C:7]2[C:8](=[N:9][CH:10]=[CH:11][N:12]=2)[N:13]([CH3:16])[C:14](=[O:15])[C:5]=1[C:3]1[O:4][N:27]=[C:25]([CH3:26])[N:24]=1
Reactant: COC(=O)c1c(OC(=O)C(C)C)c2nccnc2n(C)c1=O
Reactant: CC(=N)NO
Solvent: Cc1ccccc1
Product: Cc1noc(-c2c(O)c3nccnc3n(C)c2=O)n1
Temperature: 25 °C

Procedure:
To a solution of 8-isobutyryloxy-5-methyl-6-oxo-5,6-dihydro-pyrido[2,3-b]pyrazine-7-carboxylic acid methyl ester (Example 7.3) (0.10 g) in toluene (4 ml) was added N-hydroxy-acetamidine (0.025 g). The reaction mixture was heated to reflux for 16 hours. The reaction mixture was cooled to ambient temperature and the solid was isolated by filtration and dried to give Compound No. B5 of Table 5 (0.050 g).
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[CH2:7][CH:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][CH:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[NH:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[CH2:5][C:4]([CH3:27])([CH3:26])[NH:3]1.[N:29]1[C:36]([Cl:37])=[N:35][C:33]([Cl:34])=[N:32][C:30]=1Cl.[OH-].[Na+]>ClCCCl>[Cl:34][C:33]1[N:35]=[C:36]([Cl:37])[N:29]=[C:30]([N:8]([CH:6]2[CH2:7][C:2]([CH3:28])([CH3:1])[NH:3][C:4]([CH3:27])([CH3:26])[CH2:5]2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][N:15]([C:30]2[N:29]=[C:36]([Cl:37])[N:35]=[C:33]([Cl:34])[N:32]=2)[CH:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[NH:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[N:32]=1
Reactant: CC1(C)CC(NCCCCCCNC2CC(C)(C)NC(C)(C)C2)CC(C)(C)N1
Reactant: Clc1nc(Cl)nc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC1(C)CC(N(CCCCCCN(c2nc(Cl)nc(Cl)n2)C2CC(C)(C)NC(C)(C)C2)c2nc(Cl)nc(Cl)n2)CC(C)(C)N1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 118.20 g (0.30 mol) of N,N'-bis(2,2,6,6-tetramethyl-4-piperidyl)-1,6-diaminohexane in 150 ml of 1,2-dichloroethane is added slowly in the course of 2 hours to a solution, maintained at 0° C., containing 110.70 g (0.60 mol) of cyanuric chloride in 800 ml of 1,2-dichloroethane. 250 ml of an aqueous solution containing 25.20 g (0.63 mol) of sodium hydroxide are then added in 30 minutes at 0° C., and stirring is continued for 2 hours at 0° C. The aqueous phase is then separated off, the organic phase is washed repeatedly with water and dehydrated by means of anhydrous sodium sulfate, and a white solid of melting point 161°-163° C. is precipitated by evaporation of the solvent.
Reaction SMILES: [C:1]([CH:6]([NH:20][C@H:21]([C:23]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]([C:35]([OH:37])=[O:36])[NH:26]1)=[O:24])[CH3:22])[CH2:7][CH2:8][NH:9]C(OCC1C=CC=CC=1)=O)([O:3][CH2:4][CH3:5])=[O:2]>CO.[Pd]>[C:1]([CH:6]([NH:20][C@H:21]([C:23]([CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:28][CH:27]([C:35]([OH:37])=[O:36])[NH:26]1)=[O:24])[CH3:22])[CH2:7][CH2:8][NH2:9])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCOC(=O)C(CCNC(=O)OCc1ccccc1)N[C@@H](C)C(=O)C1NC(C(=O)O)Cc2ccccc21
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)C(CCN)N[C@@H](C)C(=O)C1NC(C(=O)O)Cc2ccccc21

Procedure:
1.1 g of N-(1-carboethoxy-3-benzoxycarbonylaminopropyl)-L-alanyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid are dissolved in 150 ml of methanol and are hydrogenated in the presence of 100 mg of palladium/active charcoal (10% strength) at 40° C. under normal pressure. After the end of the reaction, the solution is filtered off from the catalyst and the solvent is stripped off in vacuo.
Reaction SMILES: O[N:2]=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12].[CH2:13]([OH:15])[CH3:14]>[Rh]>[CH3:3][C:11]1[CH:6]=[CH:7][C:8]([CH2:14][C:13]([NH:2][CH:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]2=[O:12])=[O:15])=[CH:9][CH:10]=1
Reactant: CCO
Reactant: O=C1Nc2ccccc2C1=NO
Agent: [Rh]
Product: Cc1ccc(CC(=O)NC2C(=O)Nc3ccccc32)cc1
Reaction time: 12 h
Yield: 18 %

Procedure:
A solution of 4.86 g of 3-(hydroxyimino)indolin-2-one and 100 mg of 5% Rh/C in 300 ml of ethanol was stirred at room temperature under a hydrogen atmosphere for 1 day. The reaction mixture was filtered through Cerite, and the filtrate was concentrated. The concentrate was dissolved in 50 ml of N,N-dimethylformamide, and 5.15 g of dicyclohexylcarbodiimide, 3.83 g of 1-hydroxybenzotriazole, and 3.75 g of p-tolylacetic acid were added thereto successively. The mixture was stirred at the same temperature for 12 hours, whereupon a precipitate formed. The precipitate was filtered off, and the filtrate was concentrated. The concentrate was diluted with ethyl acetate and washed successively with dilute hydrochloric acid and saturated aqueous sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography (chloroform/methanol=40/1) to afford 1.01 g (18%) of the title compound.
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[F:15][C:16]([F:38])([F:37])[CH2:17][CH2:18][CH:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)O.[C:39]([O:43][C:44]([NH:46][C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:48]=1)=[O:45])([CH3:42])([CH3:41])[CH3:40].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[C:39]([O:43][C:44]([N:46]([CH:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)[CH2:18][CH2:17][C:16]([F:38])([F:37])[F:15])[C:47]1[CH:56]=[CH:55][C:50]([C:51]([O:53][CH3:54])=[O:52])=[CH:49][N:48]=1)=[O:45])([CH3:42])([CH3:40])[CH3:41]
Reactant: OC(CCC(F)(F)F)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1
Reactant: COC(=O)c1ccc(NC(=O)OC(C)(C)C)nc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(N(C(=O)OC(C)(C)C)C(CCC(F)(F)F)c2ccc(-c3ccc(C(F)(F)F)cc3)cc2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.5 %

Procedure:
Diisopropyl azodicarboxylate (50 μL, 0.25 mmol) was added to a room temperature solution of 4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butan-1-ol (84 mg, 0.24 mmol), methyl 6-(tert-butoxycarbonylamino)nicotinate (74 mg, 0.29 mmol), and triphenylphosphine (65 mg, 0.25 mmol) in 1.5 mL THF. The resulting solution was stirred overnight at room temperature. The solution was partitioned between dichloromethane and water. The organic layer was dried over MgSO4 and concentrated to give a colorless solid. Purification by silica gel chromatography provided methyl 6-(tert-butoxycarbonyl(4,4,4-trifluoro-1-(4′-(trifluoromethyl)biphenyl-4-yl)butyl)amino)nicotinate (30 mg, 21%) as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 8.99-9.01 (m, 1H), 8.17-8.21 (m, 1H), 7.63-7.69 (m, 4H), 7.49-7.54 (m, 3H), 7.39-7.44 (m, 2H), 5.98-6.08 (m, 1H), 3.92 (s, 3H), 2.61-2.74 (m, 1H), 2.39-2.54 (m, 1H), 2.17-2.36 (m, 2H), 1.31 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]3[CH:26]=[CH:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[N:18]=3)=[CH:14][C:9]=2[N:8]=[C:7]1[C@@H:27]1[C@H:29]([C:30]([O:32]CC)=[O:31])[C:28]1([CH3:36])[CH3:35].[F:40][C:41]1[CH:42]=[C:43](B(O)O)[CH:44]=[CH:45][C:46]=1[F:47]>>[F:40][C:41]1[CH:42]=[C:43]([C:2]2[CH:39]=[CH:38][CH:37]=[C:4]([CH2:5][N:6]3[C:10]4[CH:11]=[CH:12][C:13]([O:15][CH2:16][C:17]5[CH:26]=[CH:25][C:24]6[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=6)[N:18]=5)=[CH:14][C:9]=4[N:8]=[C:7]3[C@@H:27]3[C@H:29]([C:30]([OH:32])=[O:31])[C:28]3([CH3:36])[CH3:35])[CH:3]=2)[CH:44]=[CH:45][C:46]=1[F:47]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CCOC(=O)[C@H]1[C@@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(Br)c2)C1(C)C
Product: CC1(C)[C@H](c2nc3cc(OCc4ccc5ccccc5n4)ccc3n2Cc2cccc(-c3ccc(F)c(F)c3)c2)[C@@H]1C(=O)O

Procedure:
The title compound was prepared using similar methods to those in Example 110 using racemic cis-ethyl 3-(1-(3-bromobenzyl)-5-(quinolin-2-ylmethoxy)-1H-benzo[d]imidazol-2-yl)-2,2-dimethylcyclopropanecarboxylate and 3,4-difluorophenylboronic acid in Step A. MS (ESI): mass calcd. for C36H29F2N3O3, 589.22; m/z found, 590.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J=8.5, 1H), 8.11 (d, J=8.4, 1H), 7.87-7.83 (m, 1H), 7.79-7.73 (m, 1H), 7.70 (d, J=8.5, 1H), 7.60-7.54 (m, 1H), 7.51-7.47 (m, 1H), 7.45-7.40 (m, 1H), 7.34-7.29 (m, 2H), 7.27-7.25 (m, 2H), 7.24-7.18 (m, 2H), 7.16-7.11 (m, 1H), 7.02-6.97 (m, 1H), 5.52-5.35 (m, 4H), 2.29 (d, J=8.2, 1H), 2.11 (d, J=8.2, 1H), 1.17 (s, 3H), 0.98 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].C([Sn](CCCC)(CCCC)[C:36]1[S:37][CH:38]=[CH:39][N:40]=1)CCC.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([C:36]3[S:37][CH:38]=[CH:39][N:40]=3)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1nccs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nc(-c2nccs2)c2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Temperature: 120 °C
Yield: 46.9 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (70 mg, 0.15 mmol), 2-tributylstannanyl-thiazole (84 mg, 0.23 mmol) and PdCl2(PPh3)2 (21 mg, 0.030 mmol) in 4 mL of DMF was heated at 120° C. for 2 h under nitrogen atmosphere. After the mixture was cooled to r.t., EtOAc and brine were added. 1 M HCl was added with stirring until pH was about 3-4. The aqueous layer was extracted with additional EtOAc, and the combined organic layer was washed with water and brine, and dried over MgSO4. After evaporating the solvent in vacuo, the crude product was purified by silica gel chromatography (5-30% EtOAc/hexanes+1% AcOH) to give 33 mg of the title compound. MS: (+) m/z 470.33 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][CH2:6][CH2:7]OS(C)(=O)=O.[CH3:17][NH2:18]>C1COCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([F:16])[CH:15]=1)[O:5][CH2:6][CH2:7][NH:18][CH3:17]
Reactant: CN
Reactant: CS(=O)(=O)OCCOc1cc(F)cc(F)c1
Solvent: C1CCOC1
Product: CNCCOc1cc(F)cc(F)c1
Yield: 71 %

Procedure:
A mixture of methanesulfonic acid 2-(3,5-difluoro-phenoxy)-ethyl ester (1.2 g, 4.76 mmol), THF (30 ml) and 40% aqueous monomethylamine (30 ml) was heated under reflux for 8 hours. The reaction mixture was poured on water and extracted 3 times with diethyl ether (3×20 ml). The orghanic phase was washed with water, dried over magnesium sulfate and concentrated to dryness. The residue was chromatographed on silicagel eluting with methylene chloride-methanol (9-1) to give [2-(3,5-difluoro-phenoxy)-ethyl]-methyl-amine (0.63 g, 71%).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:10]([Br:20])=[CH:9][N:8]=1)(=O)=O.C(O)(=O)C.[OH:27][C@H:28]1[C@H:32]([OH:33])[CH2:31][NH:30][CH2:29]1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH2:13]([C:11]1[C:10]([Br:20])=[CH:9][N:8]=[C:7]([N:30]2[CH2:31][C@@H:32]([OH:33])[C@H:28]([OH:27])[CH2:29]2)[CH:12]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O[C@@H]1CNC[C@H]1O
Reactant: O=S(=O)(Oc1cc(Cc2ccccc2)c(Br)cn1)C(F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O[C@@H]1CN(c2cc(Cc3ccccc3)c(Br)cn2)C[C@H]1O
Reaction time: 3 h
Yield: 47.4 %

Procedure:
A mixture of 4.0 g of 4-benzyl-5-bromo-2-pyridyl trifluoromethanesulfonate, 1.8 g of (3R,4R)-3,4-dihydroxypyrrolidine acetate, 3 ml of 1,8-diazabicyclo[5.4.0]-7-undecene and 5 ml of tetrahydrofuran was heated under stirring for 3 hours in an oil bath kept at 70° C. in a nitrogen atmosphere. After cooling as it was, the reaction mixture was extracted with ethyl acetate-water. The organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. The residue was subjected to silica gel column chromatography and eluted with 10% methanol/ethyl acetate, to give 1.67 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH:10](O)[C:6]=2[C:5]([F:13])=[C:4]([Cl:14])[N:3]=1.C(Cl)Cl.C(O)(C(F)(F)F)=O.[SiH](CC)(CC)CC>C(OC)(C)(C)C>[Cl:1][C:2]1[C:7]2[C:8](=[O:12])[NH:9][CH2:10][C:6]=2[C:5]([F:13])=[C:4]([Cl:14])[N:3]=1
Reactant: O=C1NC(O)c2c(F)c(Cl)nc(Cl)c21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: COC(C)(C)C
Product: O=C1NCc2c(F)c(Cl)nc(Cl)c21
Temperature: 25 °C
Yield: 94.7 %

Procedure:
A 22-L 3-neck RBF equipped with overhead stirrer, refluxing condenser, and N2 inlet/outlet, and having all glass or PTFE-coated parts, was sequentially charged with 4,6-dichloro-7-fluoro-1-hydroxy-1H-pyrrolo[3,4-c]pyridin-3(2H)-one (908 g), DCM (4.55 L), and TFA (3.46 L, 11.76 eq). Agitation was started and Et3SiH (3.05 L, 4.97 eq) was added. The cloudy mixture was heated to reflux, resulting in a clear solution that was stirred at refluxing conditions for 24 h. The mixture was cooled to RT and stirred overnight. The orange solution was cooled to <10° C. using an ice bath. Methyl tert-butyl ether (14.0 L) was added via a peristaltic pump within a 1 h period. The resultant slurry was stirred at <10° C. for 1 h and then filtered through a coarse fitted glass funnel. The filter cake was washed with MTBE (2×4 L). The solid was dried under high vacuum at RT for 19 h to afford the title compound (802 g, 94%). 1H NMR (500 MHz, DMSO-d6) δ ppm 4.55 (s, 2H), 9.15 (s, 1H). [M+H] calc'd for C7H3Cl2FN2O, 221. found, 221.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:15]=[C:14]([O:16]C(=O)C)[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>C(O)C.O>[OH:16][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH:7]=[C:6]([C:4]([OH:5])=[O:3])[CH:15]=1
Reactant: CCOC(=O)c1cc(OC(C)=O)c2ccccc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cc(O)c2ccccc2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 18.5 g of 4-Acetoxy-naphthalene-2-carboxylic acid ethyl ester in 100 ml ethanol/water (9:1), 240 ml of a 1M NaOH was added and stirred for 2 days at RT. Then, the reaction mixture was acidified to pH 2 with diluted hydrochloric acid to precipitate the product. The product was then collected by filtration and dried reduced pressure. Yield: 13.7 g.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][S:9]([C:12]2[C:13](C)=[CH:14][CH:15]=[CH:16][CH:17]=2)(=[O:11])=[O:10])=[C:6]([Br:19])[C:5]([Br:20])=[C:4]([Br:21])[C:3]=1[Br:22].[C:23]1(C)C(S(Cl)(=O)=O)=CC=CC=1>>[Br:1][C:2]1[C:7]([O:8][S:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:23])=[CH:16][CH:17]=2)(=[O:10])=[O:11])=[C:6]([Br:19])[C:5]([Br:20])=[C:4]([Br:21])[C:3]=1[Br:22]
Reactant: Cc1ccccc1S(=O)(=O)Oc1c(Br)c(Br)c(Br)c(Br)c1Br
Reactant: Cc1ccccc1S(=O)(=O)Cl
Product: Cc1ccc(S(=O)(=O)Oc2c(Br)c(Br)c(Br)c(Br)c2Br)cc1

Procedure:
The o-toluenesulfonic acid pentabromophenyl ester can be prepared in the same manner by using the same molar amount of o-toluenesulfonyl chloride instead of the para compound.
Reaction SMILES: C([O:8][C@H:9]1[C@H:15]([O:16]CC2C=CC=CC=2)[C@@H:14]([O:24]CC2C=CC=CC=2)[C@:13]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH3:49])=[CH:43][CH:42]=4)[CH:34]=3)[O:32][C@@:10]1([C:50]([OH:53])([CH3:52])[CH3:51])[CH2:11][O:12]2)C1C=CC=CC=1.ClC1C=CC=CC=1Cl>[Pd].CO.O1CCCC1>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([C@@:13]23[O:32][C@@:10]([C:50]([OH:53])([CH3:52])[CH3:51])([CH2:11][O:12]2)[C@@H:9]([OH:8])[C@H:15]([OH:16])[C@H:14]3[OH:24])=[CH:34][C:35]=1[CH2:40][C:41]1[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH3:49])=[CH:45][CH:46]=1
Reactant: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]4OCc3ccccc3)ccc2Cl)cc1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: Clc1ccccc1Cl
Product: CCOc1ccc(Cc2cc([C@]34OC[C@](C(C)(C)O)(O3)[C@@H](O)[C@H](O)[C@H]4O)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
To a solution of 2-[(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]propan-2-ol 2c (155 mg, 0.21 mmol) in a methanol/tetrahydrofuran mixture (v/v=4/1, 5 mL) were added o-dichlorobenzene (155 mg, 1.06 mmol) and 10% Pd/C (22 mg, 0.02 mmol) in turn at room temperature. The mixture was stirred at room temperature under H2 for 1 hour and filtered. The filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography eluted with PE/EtOAc(v/v)=1/2 to give the title compound 2 as a white solid (90 mg, 91.8%, HPLC: 96.8%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 509[M+HCOO]−; and 1H NMR (400 MHz, DMSO-d6) δ(ppm): 7.35 (s, 2H), 7.30 (dd, 1H), 7.08 (d, 2H), 6.81 (d, 2H), 5.46 (t, 1H), 5.01 (d, 1H), 4.95 (d, 1H), 4.21 (s, 1H), 3.95 (d, 5H), 3.78 (d, 1H), 3.68 (dd, 1H), 3.43 (dd, 1H), 3.35 (m, 1H), 1.28 (t, 3H), 1.18 (s, 3H), 1.13 (s, 3H).