Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([F:11])([F:10])[F:9])=[N:4][NH:5][C:6]=1[CH3:7].C([O-])([O-])=O.[K+].[K+].Cl[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1)=[O:21].CN(C=O)C>CCCCCC.C(OCC)(=O)C>[F:34][C:31]1[CH:30]=[CH:29][C:28]([N:25]2[CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][N:5]3[C:6]([CH3:7])=[C:2]([Br:1])[C:3]([C:8]([F:9])([F:11])[F:10])=[N:4]3)[CH2:27][CH2:26]2)=[CH:33][CH:32]=1
Reactant: O=C(CCl)N1CCN(c2ccc(F)cc2)CC1
Reactant: Cc1[nH]nc(C(F)(F)F)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1c(Br)c(C(F)(F)F)nn1CC(=O)N1CCN(c2ccc(F)cc2)CC1

Procedure:
Protocol T was followed using 4-Bromo-5-methyl-3-trifluoromethyl-1H-pyrazole, K2CO3, 2-Chloro-1-[4-(4-fluoro-phenyl)-piperazin-1-yl]-ethanone and DMF. Column chromatography using a solvent mixture (hexane/ethyl acetate=2/3) afforded the title compound as white solid. 1H NMR (400 MHz, CDCl3): 6.96-7 (m, 2H), 6.84-6.9 (m, 2H), 5 (s, 2H), 3.6-3.8 (m, 4H), 3.02-3.16 (m, 4H), 2.3 (s, 3H). 13C NMR (400 MHz, CDCl3): 162.6, 146.5, 142, 118.5, 116, 52.2, 50.4, 46, 42.2, 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([NH2:13])=O)[CH:6]=[CH:5][C:4]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1.P(Cl)(Cl)(Cl)=O>>[CH3:1][O:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]#[N:13])[CH:6]=[CH:5][C:4]=1[N:14]1[CH:18]=[C:17]([CH3:19])[N:16]=[CH:15]1
Reactant: COc1nc(/C=C/C(N)=O)ccc1-n1cnc(C)c1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1nc(/C=C/C#N)ccc1-n1cnc(C)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (3.54 g) and phosphorus oxychloride (12 ml) was stirred at 90° C. for one hour. The reaction solution was concentrated under reduced pressure and then diluted with ice water, chloroform and aqueous ammonia, and the organic layer was separated. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was diluted with ether and the precipitated crystals were collected by filtration. The crystals were washed with ether and then air-dried to obtain 2.27 g of the title compound. The property value of the compound is as follows.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:10])[C@@H:5]1[CH2:9][CH2:8][CH2:7][NH:6]1.C(N(CC)CC)C.[S:18](Cl)([Cl:21])(=[O:20])=[O:19]>C1(C)C=CC=CC=1.ClCCl>[Cl:21][S:18]([N:6]1[CH2:7][CH2:8][CH2:9][C@H:5]1[C:4]([O:3][CH3:2])=[O:10])(=[O:20])=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: COC(=O)[C@@H]1CCCN1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCN1S(=O)(=O)Cl
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 87.8 %

Procedure:
A solution of L-proline methyl ester hydrochloride (0.33 g, 0.002 mole) in toluene (5 ml), dichloromethane (2 ml) and triethylamine (0.6 ml, 0.004 mole) was added dropwise over a period of 3 minutes to a cold (−20° C.) solution of sulfuryl chloride (0.32 ml, 0.0039 mole) in toluene. The mixture was stirred an additional 45 minutes at −20° C. The reaction was filtered and the solvent was removed under reduced pressure to give the title compound (0.40 g). 1H NMR (300 MHz, CDCl3) δ 2.13 (m, 2 H) 2.32 (m, 2 H) 3.58 (m, 1 H) 3.75 (m, 1 H) 3.79 (s, 3 H) 4.40 (dd, J=8.82, 4.04 Hz, 1 H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:31]=[CH:30][CH:29]=[CH:28]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:11]=2)[O:8][CH:9]=1)=O.CO.[BH4-].[Li+]>C1COCC1>[OH:2][CH2:3][C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[C:12]([C:16]3[CH2:17][C:18](=[O:32])[NH:19][C:20]4[CH:26]=[C:25]([N:27]5[CH:28]=[CH:29][CH:30]=[CH:31]5)[CH:24]=[CH:23][C:21]=4[N:22]=3)[CH:13]=[CH:14][CH:15]=2)[O:8][CH:9]=1
Reactant: COC(=O)c1coc(-c2cccc(C3=Nc4ccc(-n5cccc5)cc4NC(=O)C3)c2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=C1CC(c2cccc(-c3nc(CO)co3)c2)=Nc2ccc(-n3cccc3)cc2N1
Temperature: 40 °C
Reaction time: 1 h
Yield: 30.1 %

Procedure:
To a solution of 2-[3-(4-oxo-7-pyrrol-1-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-phenyl]-oxazole-4-carboxylic acid methyl ester (Example 25) (88 mg, 0.2 mmol) in THF (1.5 mL) were added successively MeOH (0.012 mL) and lithium borohydride (6.5 mg, 0.3 mmol). The mixture was stirred at 40° C. for 1 h and then partitioned between EtOAc and 1N HCl. The organic layer was washed with brine, dried and evaporated in vacuum. The residue was chromatographed on silica gel using EtOAc/hexane (1:2) as eluents to give the title compound (24 mg) as light-yellow solid.
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:23]=1)[C:8]([NH:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)=[O:9])(=O)C.C[O-].[Na+].Cl.C(=O)(O)[O-].[Na+]>C1COCC1.O.C(OCC)(=O)C.C(O)(=O)C>[OH:4][C:5]1[CH:6]=[C:7]([CH:21]=[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[CH3:32])[CH:23]=1)[C:8]([NH:10][C:11]1[N:16]=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=1)=[O:9]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3C)cc(OC(C)=O)c2)nc1
Agent: C[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3C)c2)nc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 91.5 %

Procedure:
Methyl 6-{[3-acetoxy-5-(2-methylbenzyloxy)benzoyl]amino}-3-pyridinecarboxylate (11.64 g, 26.8 mM) was dissolved in THF (150 ml) and sodium methoxide (25% in methanol) (11.6 ml, 53.6 mM) was added. The resulting yellow solution was stirred for 20 minutes at ambient temperature and was then added to dilute hydrochloric acid. The pH of the mixture was adjusted to pH=4 by the addition of sodium bicarbonate and acetic acid before ethyl acetate (50 ml) and water (25 ml) were added. This resulted in the precipitation of a colourless solid which was isolated by filtration and washed with water and ethyl acetate before being dried over magnesium sulphate, filtered, to give methyl 6-{[3-hydroxy-5-(2-methylbenzyloxy)benzoyl]amino}-3-pyridinecarboxylate as a colourless solid (9.62 g); H1 NMR δ (d6-DMSO) 2.33 (3H s) 3.85 (3H s) 5.11 (2H s) 6.61 (1H s) 7.01 (1H s) 7.18–7.29 (4H m) 7.40 (1H d) 8.32 (2H s) 8.90 (1H s) 9.77 (1H s) 11.04 (1H s).
Reaction SMILES: C[O-].[Na+].[NH2:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9].[CH:13](=O)[CH3:14].[BH4-].[Na+].[OH-].[Na+]>CO>[CH2:13]([NH:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])[CH3:14]
Reactant: N#Cc1cccc(N)c1
Reactant: CC=O
Agent: C[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCNc1cccc(C#N)c1
Yield: 70.2 %

Procedure:
Sodium methoxide (4.05 g, 75 mmol) is added into methanol (45 ml) and is dissolved under stirring, and to this solution is added a solution of 3-aminobenzonitrile (17.70 g, 150 mmol) in methanol (60 ml) dropwise and the resulting mixture is stirred at room temperature for 0.5 h. Then the reaction mixture is poured into a solution of acetaldehyde (8.8 g, 200 mmol) in methanol (100 ml) and is stirred at room temperature for 5.0 h. The mixture is added with NaBH4 (6.00 g, 150 mmol) in portions and is stirred at room temperature for 10 min, and then is refluxed at elevated temperature for 10 min. The reaction mixture is cooled under ice-water bath, added with 10% NaOH (aq) (90 ml) dropwise and is stirred for 5 min. Methanol is removed under reduced pressure, and the left aqueous solution is extracted with ethyl acetate (150 ml*2). The organic phases are combined, washed with saturated brine (100 ml) and separated, dried over anhydrous sodium sulfate, and concentrated to give a oily crude product (22.1 g). The crude product is purified by neutral alumina column chromatography (eluent: petroleum ether/CH2Cl2=2/1) to give a light yellow oily target product (15.4 g, yield: 70.2%).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([CH:8]([CH2:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=O)[CH:5]=[CH:4][N:3]=1.C([O-])(O)=[O:25].[Na+].CCOC(C)=O>C(O)(=O)C>[C:19]([C:18]1[O:23][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:8]([C:6]2[CH:5]=[CH:4][NH:3][C:2](=[O:25])[CH:7]=2)[CH:17]=1)([CH3:22])([CH3:20])[CH3:21]
Reactant: CC(C)(C)C(=O)CC(C(=O)c1ccccc1)c1ccnc(F)c1
Reactant: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(-c2cc[nH]c(=O)c2)c(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
A solution of 2-(2-fluoropyridin-4-yl)-5,5-dimethyl-1-phenylhexane-1,4-dione (200 mg, 0.6 mmol) in acetic acid (3 mL) was heated at reflux for 18 h. Upon cooling to RT the solution was slowly added to a mixture of sat'd aqueous NaHCO3 (40 mL) and EtOAc (40 mL). The mixture was stirred for 15 min. and the organic layer then collected. The aqueous layer was extracted with ethyl acetate (30 mL) and the organic layers combined, washed with sat'd aqueous NaHCO3, H2O and brine, dried (MgSO4) and concentrated. The product was purified by flash chromatography using EtOAc-MeOH (100:0→95:5) as eluant to give the pure product as a cream solid (146 mg, 78%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([N:15](CC1C=CC(OC)=CC=1OC)[C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2.C(=O)([O-])[O-].[K+].[K+].[C:38]([C:40]1[CH:45]=[C:44]([C:46]([F:49])([F:48])[F:47])[CH:43]=[CH:42][C:41]=1B(O)O)#[N:39].O1CCOCC1>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>[C:38]([C:40]1[CH:45]=[C:44]([C:46]([F:47])([F:48])[F:49])[CH:43]=[CH:42][C:41]=1[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([S:12]([NH:15][C:16]1[S:20][N:19]=[CH:18][N:17]=1)(=[O:14])=[O:13])=[CH:7]2)#[N:39]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(Br)cccc3c2)c(OC)c1
Reactant: N#Cc1cc(C(F)(F)F)ccc1B(O)O
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: N#Cc1cc(C(F)(F)F)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Yield: 1.4 %

Procedure:
A pressure vessel was charged with 5-bromo-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (Intermediate D) (150 mg, 0.288 mmol), potassium carbonate (199 mg, 1.441 mmol), (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.576 mmol), tetrakis(triphenylphosphine)palladium(0) (33.3 mg, 0.029 mmol), dioxane (1922 μl) and water (961 μl). The reaction was heated in a microwave to 100° C. for 60 min. Additional (2-cyano-4-(trifluoromethyl)phenyl)boronic acid (124 mg, 0.576 mmol) and tetrakis(triphenylphosphine)palladium(0) (33.3 mg, 0.029 mmol) were added and the resulting mixture was heated in a microwave at 100° C. for an additional hour. After heating the mixture was allowed to cool to room temperature, the organic layer was separated and the organic layer was concentrated. The resulting product was purified by MPLC (40 g silica gel column, eluting with 0% to 50% EtOAc in heptane) to afford a white solid that was further purified by reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% NH4OH in ACN and water). The fractions containing product were dried under a vacuum to afford 5-(2-cyano-4-(trifluoromethyl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (2.1 mg, 0.004 mmol) as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.58 (d, J=8.76 Hz, 1H) 7.69-7.74 (m, 1H) 7.75-7.83 (m, 2H) 7.87 (d, J=8.01 Hz, 1H) 8.16-8.24 (m, 2H) 8.34 (d, J=8.34 Hz, 1H) 8.52-8.57 (m, 2H); m/z (ESI) 461.0 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=[C:7]1[N:14]1[CH2:19][CH2:18][CH2:17][C@@H:16]([NH:20]C(=O)OC(C)(C)C)[CH2:15]1)#[N:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>ClCCl>[NH2:20][C@@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:7]2[N:6]([CH2:5][C:4]3[CH:28]=[C:29]([F:32])[CH:30]=[CH:31][C:3]=3[C:1]#[N:2])[C:11](=[O:12])[C:10]([CH3:13])=[N:9][N:8]=2)[CH2:15]1
Reactant: Cc1nnc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2cc(F)ccc2C#N)c1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nnc(N2CCC[C@@H](N)C2)n(Cc2cc(F)ccc2C#N)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 1-(4-(2-cyano-5-fluorobenzyl)-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)piperidin-3-ylcarbamate (20, 37 mg) in dichloromethane (1 mL) was added TFA (0.5 mL) and the mixture was stirred at RT for 1 h. The mixture was carefully neutralized with NaHCO3 (aq, saturated), and extracted with CH2Cl2 (10 mL×3). The combined extracts were dried over Na2SO4 and concentrated to give the crude product, which was purified by column chromatography on silica gel, and eluted with 92:6:2 dichloromethane-methanol-ammonia to provide (R)-2-((3-(3-aminopiperidin-1-yl)-6-methyl-5-oxo-1,2,4-triazin-4(5H)-yl)methyl)-4-fluorobenzonitrile (21). 1H NMR (400 MHz, DMSO, ppm): δ 7.96 (m, 1H), 7.36 (br, 1H), 7.29 (d, 1H), 5.23 (s, 2H), 3.15 (m, 3H), 2.72 (m, 2H), 2.23 (s, 3H), 1.78 (d, 1H), 1.64 (d, 1H), 1.47 (m, 1H), 1.12 (m, 1H). MS: m/z, 343 (100%, M+1);
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4].Cl.[NH2:25][CH2:26][CH2:27][S:28]([NH2:31])(=[O:30])=[O:29].C[O-].[Na+]>CCO>[S:28]([CH2:27][CH2:26][NH:25][C:3]([C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:23])[N:10]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=[CH:12][C:13]=2[C:14]=1[OH:15])=[O:4])(=[O:30])(=[O:29])[NH2:31]
Reactant: NCCS(N)(=O)=O
Reactant: COC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: NS(=O)(=O)CCNC(=O)c1ncc2c(=O)n(Cc3ccccc3)ccc2c1O
Temperature: 140 °C
Yield: 53.8 %

Procedure:
A mixture of 7-benzyl-4-hydroxy-8-oxo-7,8-dihydro-[2,7]naphthyridine-3-carboxylic acid methyl ester (30 mg, 0.097 mmol), 2-amino-ethanesulfonic acid amide HCl salt (24 mg, 0.19 mmol), and NaOMe (9.9 mg, 0.18 mmol) in EtOH (2 mL) was heated at 140° C. for 6 h in a microwave reactor. Solvent was evaporated in vacuo, and the residue was partitioned between 1 M HCl and EtOAc. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and dried over MgSO4. After evaporating the solvent, the crude product was purified by silica gel chromatography (0-10% MeOH/CH2Cl2) to give 21 mg of the title compound. MS: (+) m/z 403.25 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[CH:56]=[CH:55][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:51])([CH3:50])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[CH:26][C:25]=3[O:57][CH3:58])[N:14]=2)=[CH:4][CH:3]=1.BrC1N=C(C(=O)NC)C(NC2C(C(F)(F)F)=CN=C(NC3C(OC)=CC(CP(=O)(O)OCC)=C([Cl:97])C=3)N=2)=CC=1.CC1(C)C(C)(C)OB(C2C=NN(CC3(CO)COC3)C=2)O1>>[Br:1][C:2]1[N:7]=[C:6]([C:8](=[O:11])[NH:9][CH3:10])[C:5]([NH:12][C:13]2[C:18]([C:19]([F:21])([F:20])[F:22])=[CH:17][N:16]=[C:15]([NH:23][C:24]3[C:25]([O:57][CH3:58])=[CH:26][C:27]([CH2:28][P:29](=[O:54])([O:33][CH2:34][C:35]4([CH2:39][N:40]5[CH:44]=[C:43]([B:45]6[O:49][C:48]([CH3:50])([CH3:51])[C:47]([CH3:53])([CH3:52])[O:46]6)[CH:42]=[N:41]5)[CH2:38][O:37][CH2:36]4)[O:30][CH2:31][CH3:32])=[C:55]([Cl:97])[CH:56]=3)[N:14]=2)=[CH:4][CH:3]=1
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)c(OC)c1)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1
Reactant: CCOP(=O)(O)Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl
Agent: CC1(C)OB(c2cnn(CC3(CO)COC3)c2)OC1(C)C
Product: CCOP(=O)(Cc1cc(OC)c(Nc2ncc(C(F)(F)F)c(Nc3ccc(Br)nc3C(=O)NC)n2)cc1Cl)OCC1(Cn2cc(B3OC(C)(C)C(C)(C)O3)cn2)COC1

Procedure:
Prepared analogously to Compound 44A using ethyl hydrogen (4-{[4-{[6-bromo-2-(methylcarbamoyl)pyridin-3-yl]amino}-5-(trifluoromethyl)pyrimidin-2-yl]amino}-2-chloro-5-methoxybenzyl)phosphonate (Compound 56B, 200 mg, 0.306 mmol) and (3-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl]methyl}oxetan-3-yl)methanol (Compound 44B, 94.5 mg, 0.321 mmol) to afford 175 mg of the title compound as a racemic mixture (61%). MS (ESI): m/z=931.68/933.72 [M+H]+. UPLC: tR=1.72 min (UPLC-TOF: polar—2 min).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][CH:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].IC1C=CC2C3CCNCC=3OC=2C=1.C(OC1C=C(S)C=CC=1)C1C=CC=CC=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[C:14]3[CH:20]=[CH:19][C:18]([S:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:25]=4)(=[O:23])=[O:22])=[CH:17][C:15]=3[O:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC2c3ccc(S(=O)(=O)c4cccc(OCc5ccccc5)c4)cc3OC2C1
Agent: Ic1ccc2c3c(oc2c1)CNCC3
Agent: Sc1cccc(OCc2ccccc2)c1
Product: CC(C)(C)OC(=O)N1CCc2c(oc3cc(S(=O)(=O)c4cccc(OCc5ccccc5)c4)ccc23)C1

Procedure:
Prepared as described for 7-(3-benzyloxy-benzenesulfonyl)-3,4,4a,9a-tetrahydro-1H-benzo[4,5]furo[2,3-c]pyridine-2-carboxylic acid tert-butyl ester using 7-iodo-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine and 3-benzyloxy-thiophenol
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:19])=[O:18])[O:14][C:13]3=[O:20])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[F:22][CH2:23][CH2:24]N.Cl.C(N(CC)CC)C>CO>[F:22][CH2:23][CH2:24][NH:19][C:17]([C@@H:15]1[O:14][C:13](=[O:20])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:18]
Reactant: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Reactant: NCCF
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CN1C(=O)COc2cc(N3C[C@H](C(=O)NCCF)OC3=O)ccc21
Temperature: 55 °C
Reaction time: 16 h
Yield: 69.8 %

Procedure:
To a stirred suspension of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (7.5 mL) is added FCH2CH2NH2.HCl (325 mg, 3.25 mmol). To this resulting suspension is added triethylamine (453 μL, 3.25 mmol), and the solution is heated to 55° C. for 5 h followed by stirring for 16 h at room temperature. The reaction mixture is then concentrated to dryness under reduced pressure and the residue is purified by silica gel column chromatography (eluent: EtOAc) to give the title compound (153 mg, 63%); 1H NMR (300 MHz, DMSO) δ 8.68 (br t, 1H), 7.30 (d, 1H), 7.22–7.14 (m, 2H), 5.08 (dd, 1H), 4.65 (s, 2H), 4.54 (dd, 1H), 4.38 (t, 1H), 4.26 (t, 1H), 3.45 (s, 3H), 3.96 (dd, 1H), 3.50–3.35 (m, 5H); MS for C15H16FN3O5 m/z 338.5 (M+H)+.
Reaction SMILES: BrC1C=C(F)C2OC(C3CCN(C4N=CC(CCC)=CN=4)CC3)CC=2C=1.CC1(C)C(C)(C)OB(C2CCN(C(OC(C)(C)C)=O)CC=2)O1.[F:49][C:50]1[C:58]2[O:57][CH:56]([C:59]3(O)[CH2:64][CH2:63][N:62]([C:65]4[N:70]=[CH:69][C:68]([CH2:71][CH2:72][CH3:73])=[CH:67][N:66]=4)[CH2:61][CH2:60]3)[CH2:55][C:54]=2[CH:53]=[C:52]([C:75]2[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[CH2:77][CH:76]=2)[CH:51]=1>>[F:49][C:50]1[C:58]2[O:57][CH:56]([CH:59]3[CH2:60][CH2:61][N:62]([C:65]4[N:70]=[CH:69][C:68]([CH2:71][CH2:72][CH3:73])=[CH:67][N:66]=4)[CH2:63][CH2:64]3)[CH2:55][C:54]=2[CH:53]=[C:52]([C:75]2[CH2:80][CH2:79][N:78]([C:81]([O:83][C:84]([CH3:85])([CH3:87])[CH3:86])=[O:82])[CH2:77][CH:76]=2)[CH:51]=1
Reactant: CCCc1cnc(N2CCC(O)(C3Cc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc(F)c4O3)CC2)nc1
Agent: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: CCCc1cnc(N2CCC(C3Cc4cc(Br)cc(F)c4O3)CC2)nc1
Product: CCCc1cnc(N2CCC(C3Cc4cc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc(F)c4O3)CC2)nc1

Procedure:
Compound 3G was prepared from Compound 3F and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate in a similar manner to the procedure described for Compound 1I in Example 1. 1H NMR (500 MHz, CDCl3) δ ppm 8.15 (s, 2 H), 6.96 (s, 1 H), 6.92 (d, J=12.1 Hz, 1 H), 5.91 (br. s., 1 H), 4.81 (dd, J=13.3, 1.2 Hz, 2 H), 4.61-4.71 (m, 1 H), 4.04 (d, J=1.9 Hz, 2H), 3.61 (t, J=5.6 Hz, 2 H), 3.24 (dd, J=15.7, 9.1 Hz, 1 H), 3.04 (dd, J=15.7, 8.3 Hz, 1 H), 2.78-2.91 (m, J=12.8, 12.8, 6.1, 2.8 Hz, 2 H), 2.34-2.50 (m, 4 H), 2.01-2.09 (m, 1 H), 1.91-2.01 (m, 1 H), 1.70-1.79 (m, 1 H), 1.53-1.62 (m, 2 H), 1.49 (s, 9 H), 1.32-1.44 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H). 19F NMR (471 MHz, CDCl3) δ ppm −138.98. LC/MS (m/z)=523 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11]N.[Cl:13][C:14]1[CH:24]=[CH:23][C:17]([O:18][CH2:19][C:20](=O)[CH3:21])=[CH:16][CH:15]=1>CC#N.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]2[C:3]=1[NH:11][C:20]([CH3:21])=[C:19]2[O:18][C:17]1[CH:16]=[CH:15][C:14]([Cl:13])=[CH:24][CH:23]=1
Reactant: NNc1cc([N+](=O)[O-])ccc1Br
Reactant: CC(=O)COc1ccc(Cl)cc1
Solvent: O
Solvent: CC#N
Product: Cc1[nH]c2c(Br)ccc([N+](=O)[O-])c2c1Oc1ccc(Cl)cc1
Temperature: 75 °C
Reaction time: 16 h

Procedure:
A mixture of the compound from (i) (2.4 g) and 1-(4-Chloro-phenoxy)-propan-2-one (1.65 g) in MeCN (20 ml) and water (5 ml) was stirred for 16 h. The volatiles were removed in vacuo. AcOH (50 ml) was added and the reaction heated at 75° C. for 72 h. The volatiles were evaporated under reduced pressure and the residue was purified by chromatography on silica eluting with 5% ethylacetate/iso-hexane. Yield 0.34 g
Reaction SMILES: C(Cl)(=O)OC.C(N(CC)CC)C.[CH2:13]([C:15]1[C:20]([O:21]C(OC)=O)=[CH:19][C:18]([O:26]C(OC)=O)=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[C:16]=1[CH2:38][CH2:39][O:40][CH3:41])[CH3:14].[BH4-].[Na+].N>CO.O1CCCC1.O>[CH2:13]([C:15]1[C:20]([OH:21])=[CH:19][C:18]([OH:26])=[C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([CH3:37])[CH:32]=2)[C:16]=1[CH2:38][CH2:39][O:40][CH3:41])[CH3:14]
Reactant: CCc1c(OC(=O)OC)cc(OC(=O)OC)c(-c2cccc(C)c2)c1CCOC
Agent: COC(=O)Cl
Agent: N
Agent: [BH4-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CO
Product: CCc1c(O)cc(O)c(-c2cccc(C)c2)c1CCOC
Yield: 23 %

Procedure:
In the same manner as in Example 118, 1-[4,6-bis(methoxycarbonyloxy)-2-(2-methoxyethyl)-3-(3-methylphenyl)phenyl]ethanone was obtained from Compound 122 (320 mg, 1.1 mmol) obtained in Example 122, using methyl chlorocarbonate (0.21 mL, 2.7 mmol), triethylamine (0.37 mL, 2.7 mmol) and tetrahydrofuran (10 mL); and from the resulting compound, obtained was 4-ethyl-1,5-bis(methoxycarbonyloxy)-3-(2-methoxyethyl)-2-(3-methylphenyl)benzene, using sodium borohydride (160 mg, 4.3 mmol), water (5.0 mL) and tetrahydrofuran (10 mL). Then, the resulting compound was treated with methanol solution (10 mL) of 7 mmol/L ammonia to obtain Compound 130 (70 mg, 23%).