Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][NH:7][C:8](=[O:23])[C:9]2[CH:14]=[C:13]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:12]([F:21])=[CH:11][C:10]=2[OH:22])=[C:4]([F:26])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36].Cl>CC(C)=O>[CH2:38]([O:37][C:35](=[O:36])[CH2:34][O:22][C:10]1[CH:11]=[C:12]([F:21])[C:13]([N:15]2[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:14][C:9]=1[C:8](=[O:23])[NH:7][CH2:6][C:5]1[CH:24]=[CH:25][C:2]([Br:1])=[CH:3][C:4]=1[F:26])[CH3:39]
Reactant: CCOC(=O)CBr
Reactant: O=C(NCc1ccc(Br)cc1F)c1cc(N2CCOCC2)c(F)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1cc(F)c(N2CCOCC2)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 73.2 %

Procedure:
A solution of N-(4-bromo-2-fluoro-benzyl)-4-fluoro-2-hydroxy-5-morpholin-4-yl-benzamide (0.8 g, 2.13 mmol) in acetone (11 mL), was treated with aq 2 N K2CO3 (1.6 mL, 3.20 mmol) and ethyl bromoacetate (0.35 mL, 3.20 mmol), and heated to 50° C. After stirring for 30 min, the reaction was cooled to room temperature and acidified to pH 7 with aq 2 N HCl. The resulting solution was extracted with ethyl acetate and washed with saturated NaCl. The organic layer was dried over MgSO4, filtered and concentrated to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-fluoro-4-morpholin-4-yl-phenoxy]-acetic acid ethyl ester (0.8 g, 81%): 1H NMR (DMSO-d6 300 MHz) δ 9.05 (t, J=6 Hz, 1 H), 8.18 (d, J=2.1 Hz, 1 H), 8.09 (ddd, J, =8.4 Hz, J2=2.4 Hz, J3=0.9 Hz, 1 H), 7.79 (d, J=7.8 Hz, 1 H), 7.61 (t, J=8.0 Hz, 1 H), 7.54 (d, J=10.2 Hz, 1 H), 7.15 (d, J=14.1 Hz, 1 H), 4.94 (s, 2 H), 4.63 (d, J=6 Hz, 2 H), 4.14 (q, J=7.2 Hz, 2 H), 3.71 (t, J=4.7 Hz, 4 H), 2.92 (t, J=4.7 Hz, 4 H), 1.16 (t, J=7.2 Hz, 3 H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])[CH2:7][C:8](=[O:10])[CH3:9].[CH:15]([O-])([O-])OC.N1C2C(=CC=CC=2)C=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6](=[O:11])/[CH:7]=[C:8](\[O:10][CH3:15])/[CH3:9]
Reactant: CC(=O)CC(=O)Nc1cccc(Br)c1
Reactant: COC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: CO/C(C)=C\C(=O)Nc1cccc(Br)c1
Temperature: 20 °C
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A mixture of 68.5 g of m-bromo-acetylacetanilide, 39.6 g of methyl orthoformate, 160 ml of methanol and 0.5 g of p-toluene sulfonic acid was stirred for 2 hours at 20° C and after the addition of 1 ml of quinoline, the mixture was evaporated to dryness under reduced pressure. The 83 g of colorless oil residue was taken up in 400 ml of toluene and the mixture was heated at 140° C for 4 hours while distilling the toluene-methanol azeotrope formed. After cooling, the toluene was evaporated under reduced pressure and the residue was chromatographed over silica gel. The product was eluted with a 9-1 mixture of methylene chloride and ethyl acetate and the fraction with an Rf = 0.65 was taken up in isopropyl ether to obtain 44 g of m-bromo-3-methoxy-crotonanilide melting at 110° C.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1.[CH2:21]([NH2:25])[CH:22]([CH3:24])[CH3:23].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:21]([NH:25][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:8]([C:12]([F:15])([F:14])[F:13])[O:9]2)=[CH:4][CH:3]=1)[CH:22]([CH3:24])[CH3:23]
Reactant: CCOC(=O)C1=Cc2ccc(F)cc2OC1C(F)(F)F
Reactant: CC(C)CN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=Cc2ccc(NCC(C)C)cc2OC1C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of ethyl 7-fluoro-2-(trifluoromethyl)-2H-chromene-3-carboxylate (0.45 g, 1.54 mmole) and isobutylamine (0.11 g, 1.54 mmole) was dissolved in anhydrous DMF (5 mL), warmed to 90° C. and treated with K2CO3 (0.25 g, 1.84 mmole). The mixture was maintained at 90° C. for 24 hrs, cooled to room temperature, filtered through celite and condensed to a viscous oil (0.53g, 98%). No further purification was performed. LCMS m/z 344.00 (M+H).
Reaction SMILES: C[Si](C)(C)[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1.C(O[C@@H:18]1[O:40][C@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[C@@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@H:19]1[O:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=O)C.ClCCCl>C1C=CC=CC=1>[C:21]([O:20][C@@H:19]1[C@H:29]([O:30][C:31](=[O:38])[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C@@H:39]([CH2:41][O:42][C:43](=[O:50])[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[O:40][C@H:18]1[N:3]1[CH:7]=[N:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[N:4]1)(=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[Si](C)(C)n1cnc(CC(=O)O)n1
Reactant: CC(=O)O[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1
Solvent: ClCCCl
Solvent: c1ccccc1
Product: O=C(O)Cc1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC(=O)c2ccccc2)n1
Yield: 85.5 %

Procedure:
55 mmoles of 1-trimethylsilyl-3-carboxymethyl-1,2,4-triazole and 55 mmoles of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose were combined, in 100 ml. of 1,2-dichloroethane, with 5 mmoles of (CH3)3Si--O--SO2CF3 in 20 ml. of C6H6 and refluxed for 4 hours at a bath temperature of 100° C. After working up the mixture as usual, 24 g. (85.5%) of 1-(2,3,5-tri-O-benzoyl-β-D-ribofuranosyl)-3-carboxymethyl-1,2,4-triazole was produced.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([CH2:14][N:15]1[CH:19]=[C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]1)[CH:8]=[CH:7]2.Cl[CH2:34][C:35]1[C:36]([CH3:41])=[N:37][CH:38]=[CH:39][CH:40]=1.O>CN(C)C=O>[CH3:41][C:36]1[C:35]([CH2:34][O:3][C:4]2[CH:5]=[C:6]3[C:11](=[CH:12][CH:13]=2)[CH:10]=[C:9]([CH2:14][N:15]2[CH:19]=[C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:17]([CH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:16]2)[CH:8]=[CH:7]3)=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: CCOC(=O)CCc1cn(Cc2ccc3cc(O)ccc3c2)cc1-c1ccccc1
Reactant: Cc1ncccc1CCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cn(Cc2ccc3cc(OCc4cccnc4C)ccc3c2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 95.1 %

Procedure:
Sodium hydride (60%, oily, 80.0 mg) was added to a solution of ethyl 3-[1-(6-hydroxy-2-naphthylmethyl)-4-phenyl-3-pyrrolyl]propionate (799 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 3-Chloromethyl-2-methylpyridine (283 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[1-[6-(2-methyl-3-pyridylmethoxy)-2-naphthylmethyl]-4-phenyl-3-pyrrolyl]propionate (959 mg, yield: 95%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][CH2:4][C:3]=1[CH:7]=O.[CH2:9]([O:11][C:12](=[O:22])[CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:10]>C1(C)C=CC=CC=1>[CH2:15]([N:14]1[C:13]([C:12]([O:11][CH2:9][CH3:10])=[O:22])=[CH:7][C:3]2[CH2:4][CH2:5][CH2:6][C:2]1=2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=CC1=C(Cl)CCC1
Reactant: CCOC(=O)CNCc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2c(n1Cc1ccccc1)CCC2

Procedure:
46.7 g (0.358 mol) of 2-chloro-1-formylcyclopent-1-ene are dissolved in 400 ml of toluene. 138 g (0.716 mol) of N-benzylglycine ethyl ester are added. The mixture is refluxed for one hour, the ester of reaction being separated off via a water separator. After cooling, any precipitate formed is filtered off with suction and the toluene solution is washed with water, dried and concentrated. The residue is taken up in 300 ml of ethanol, 600 ml of 2N hydrochloric acid are added and the mixture is extracted 3x with petroleum ether. The petroleum ether phase is washed with 2×175 ml of ethanol/2N hydrochloric acid 1:2 and then with 100 ml of saturated NaHCO3 solution, the organic phase is dried over MgSO4, stirred with active charcoal and filtered with suction, and the filtrate is evaporated in vacuo.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[NH2:10].[Br:11][C:12]1[S:16][C:15]([CH:17]=O)=[CH:14][CH:13]=1.[BH4-].[Na+]>CCO.CO>[Br:11][C:12]1[S:16][C:15]([CH2:17][NH:10][C:3]2[CH:4]=[C:5]([F:9])[C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:14][CH:13]=1
Reactant: O=Cc1ccc(Br)s1
Reactant: Nc1cc(F)c(F)cc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CO
Product: Fc1cc(F)c(NCc2ccc(Br)s2)cc1F
Temperature: 25 °C
Yield: 73 %

Procedure:
To a solution of 2 g (13.6 mmol) of 2,4,5-trifluorophenylamine and 2.66 g (13.9 mmol) of 5-bromothiophene-2-carbaldehyde in 30 ml of EtOH, 9.4 g of molecular sieves (0.3 nm) were added and the mixture was refluxed for 20 hours. After this time the reaction mixture was cooled to room temperature, filtered and the solvent was evaporated in vacuo. The oil obtained was dissolved in 30 ml of MeOH and 0.51 g (13.6 mmol) of NaBH4 were added in small portions, maintaining the temperature of the reaction at room temperature. The mixture was stirred at this temperature for 20 more hours. After this time the solvent was evaporated in vacuo and the residue was treated with 100 ml of water and extracted twice with ether. The organic layers were combined, washed with brine, dried over anhydrous MgSO4, filtered and evaporated to dryness to give 3.2 g of an oil. This 3.2 g were combined with 3.5 g obtained in a subsequent preparation and the total product obtained (6.7 g) was purified by chromatography on silica gel using mixtures of hexane/AcOEt 5:1→1:1 as eluent Appropriate fractions were combined to give 0.95 g of the title product as an oil. (global yield 8.2%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[NH2:22][C:23]12[CH2:31][CH:30]1[CH2:29][CH:28]1[CH:24]2[CH2:25][NH:26][CH2:27]1.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:26]2[CH2:27][CH:28]3[CH:24]([C:23]4([NH2:22])[CH:30]([CH2:29]3)[CH2:31]4)[CH2:25]2)[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: NC12CC1CC1CNCC12
Reactant: Nc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Nc1c(F)c(N2CC3CC4CC4(N)C3C2)c(F)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 25 °C
Yield: 5 %

Procedure:
5-Amino-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (298 mg, 1.0 mmol) was added to a solution of 1-amino-4-azatricyclo[6.1.0.02,6]nonane (206 mg, 1.36 mmol) and triethylamine (418 μl, 3.0 mmol) in acetonitrile (10 ml) at room temperature, and the mixture was heated under reflux for 16 hours. After cooling to room temperature, the acetonitrile was evaporated. To the residue was added an aqueous hydrochloric acid solution, followed by washing with chloroform. The aqueous layer was made alkaline with an aqueous sodium hydroxide solution and washed with chloroform. The aqueous layer was adjusted to pH 7.5 with an aqueous hydrochloric acid solution and extracted with chloroform. The extract was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation. The residue was recrystallized from ethanol. Recrystallization from 2-propanol gave 21 mg of the title compound as yellow crystals.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].S(Cl)([Cl:17])=O>C1(C)C=CC=CC=1>[Br:1][C:2]1[C:3]([O:13][CH3:14])=[CH:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:17])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: COc1cc(OC)c(C(=O)O)cc1Br
Solvent: Cc1ccccc1
Product: COc1cc(OC)c(C(=O)Cl)cc1Br
Temperature: 75 °C
Reaction time: 1 h

Procedure:
Under a nitrogen atmosphere, 5-bromo-2,4-dimethoxybenzoic acid (40.0 g) was suspended in toluene solution (DMF concentration: 300 ppm, 200 mL). To the suspension was added dropwise thionyl chloride (21.9 g) at 75° C. After stirring at 75° C. for 1 hr, completion of the reaction was confirmed by HPLC. Toluene and excess thionyl chloride were evaporated under reduced pressure. Toluene (100 mL) was added to the concentrated residue, and the mixture was concentrated again under reduced pressure. THF (100 mL) was added to the obtained 5-bromo-2,4-dimethoxybenzoic acid chloride, which was directly used in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Br[CH:10]1[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:10]2[C:16](=[O:17])[CH2:15][CH2:14][N:13]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CCC(=O)C(Br)CC1
Reactant: Sc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)N1CCC(=O)C(Sc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60.5 g (320 mmol) 4-bromothiophenol in 300 mL chloroform are added to a solution of 84.5 g (320 mmol) ethyl 4-bromo-5-oxo-azepan-1-carboxylate and 32.4 g (320 mmol) triethylamine in 80 mL chloroform over 45 min, so that the internal temperature does not exceed 40° C. The reaction solution is stirred for 1.5 h at RT. The reaction mixture is washed twice with dilute ammonia solution and twice with water. The organic phase is dried over Na2SO4 and K2CO3 and the solvent is eliminated i.vac. The purification is carried out by repeated column chromatography on silica gel.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5](Cl)=[O:6].[BH4-].[Na+]>C1COCC1.CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[CH2:5][OH:6]
Reactant: O=C(Cl)c1cc(Cl)cc(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
To a stirred solution of 3,5-dichlorobenzoyl chloride (712 mg, 3.40 mmole) in THF (6 ml) at 0° C. is added dropwise a solution of sodium borohydride (227 mg, 6.0 mmole), in N-methyl pyrrolidinone (1.5 ml) maintaining the temperature at ≤18° C. The reaction mixture is stirred for 2 hours at ambient temperature and then partitioned with 0.5 N aqueous HCl (60 ml) and EtOAc (60 ml). The layers are separated and the aqueous layer is washed with EtOAc (20 ml). The combined organic layer is washed with H2O (60 ml) and brine (40 ml), dried (Na2SO4), filtered, and concentrated to give crude product as a crystalline solid. One recrystallization from hot cyclohexane (7.5 ml) gives 2, i.e., 3,5-dichlorobenzyl alcohol (451 mg, 2.55 mmole, 75%, m.p. 77°-77.5° C.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH2:14][CH2:15][C:16](OCC)=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.CC(C[AlH]CC(C)C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([CH3:13])[CH:9]1[CH:14]=[CH:15][CH2:16][OH:17])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)CCC1C(C)CCN1C(=O)OC(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CC1CCN(C(=O)OC(C)(C)C)C1C=CCO
Temperature: -78 °C
Reaction time: 2 h
Yield: 50.6 %

Procedure:
A solution containing crude 61 (16.7 g, 0.059 mol) in DCM (150 mL) was cooled to −78° C. BF3.Et2O (8.9 mL, 0.07 mol) was added followed by the dropwise addition of DIBAL (2 M/DCM, 200 mL, 0.4 mol). After 2 h, TLC analysis indicated complete consumption of the 61 [TLC analysis: 1:1 hexane/EtOAc, Rf(62)=0.3]. EtOAc (40 mL) was added and the reaction mixture was warmed to −15° C. The reaction mixture was carefully quenched with 1M HCl until pH=2. The product was extracted with DCM. The organic extracts were washed with 1M HCl, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude 62 was purified by silica gel chromatography (2:1 hexanes/EtOAc) to afford 7.2 g (51%) of 62. 1H NMR (CDCl3, 300 MHz) δ5.8-5.5 (m, 2H), 4.18 (m, 2H), 4.0-3.25 (m, 3H), 2.2-1.85 (m, 2H), 1.55-1.3 (m. 1H), 1.43 (s, 9H), 1.15 (d, J=6 Hz, 3H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]=O)[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].Cl.[NH2:18][OH:19].N1C=CC=CC=1>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]=[C:13](/[CH:15]=[N:18]/[OH:19])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C=O)c1
Reactant: NO
Agent: Cl
Solvent: C1COCCO1
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)c1cc(Br)cc(/C=N/O)c1
Temperature: 68 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 3-bromo-5-formylbenzoate (119 g, 417 mmol) in dioxane (2.4 L) were added hydroxylamine hydrochloride (44.0 g, 633 mmol) and pyridine (103 mL, 1.27 mol). The reaction mixture was heated to 68° C. After 16 h, the mixture was concentrated. Saturated aqueous amonium chloride was added the mixture was extracted with dichloromethane (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated (125.0 g). MS 243 (M-tert-butyl).
Reaction SMILES: [O:1]=[S:2]1(=[O:20])[NH:7][CH2:6][CH2:5][CH:4](C)[N:3]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([O:15]C)=[O:14])=[CH:11][C:10]=1[CH3:19].[OH-].[Li+].[CH2:23](O)C>>[O:1]=[S:2]1(=[O:20])[N:7]([CH3:23])[CH2:6][CH2:5][CH2:4][N:3]1[C:9]1[CH:18]=[CH:17][C:12]([C:13]([OH:15])=[O:14])=[CH:11][C:10]=1[CH3:19]
Reactant: COC(=O)c1ccc(N2C(C)CCNS2(=O)=O)c(C)c1
Reactant: CCO
Agent: [Li+]
Agent: [OH-]
Product: Cc1cc(C(=O)O)ccc1N1CCCN(C)S1(=O)=O

Procedure:
Prepared analogously to Example 39d from methyl 4-(1,1-dioxo-3-methyl-[1,2,6]thiadiazinan-2-yl)-3-methyl-benzoate and lithium hydroxide in ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:16])[C@H:10]([OH:25])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:45]([C:48]1[CH:56]=[CH:55][C:51]([C:52](O)=[O:53])=[CH:50][CH:49]=1)([O-:47])=[O:46].CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1.CCOCC>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])[C@H:10]([O:25][C:52](=[O:53])[C:51]2[CH:50]=[CH:49][C:48]([N+:45]([O-:47])=[O:46])=[CH:56][CH:55]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](NC(=O)OCc2ccccc2)[C@H](O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)OCc2ccccc2)[C@H](OC(=O)c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 4 h

Procedure:
To a stirred mixture of (±)-trans-4-benzyloxycarbonylamino-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (1 mmol, 0.35 g), triphenylphosphine (1.5 mmol, 0.393 g) and p-nitrobenzoic acid (1.5 mmol, 0.25 g) in anhydrous THF (6 mL) at −60° C. was added DIAD drop-wise over 5 min period. After completion of addition, the reaction mixture was stirred for 4 h during which period the reaction mixture was slowly let attain room temperature. The reaction mixture was diluted with ether (100 mL) and washed with saturated sodium bicarbonate solution (2×50 mL). The organic layer was dried, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography by eluting with 30% ethyl acetate in hexanes to get (±)-cis-4-benzyloxycarbonylamino-3-(4-nitro-benzoyloxy)-piperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:11].NC(N)=[S:14]>C(O)C>[F:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][SH:14])[C:7]#[N:8]
Reactant: N#Cc1ccc(CBr)c(F)c1
Reactant: NC(N)=S
Solvent: CCO
Product: N#Cc1ccc(CS)c(F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(bromomethyl)-3-fluorobenzonitrile (0.8 g, 3.7 mmol) and thiourea (0.57 g, 7.4 mmol) in ethyl alcohol (EtOH; 20 mL) was heated to reflux for 1 h. The progress of the reaction was monitored by TLC; the reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was washed with EtOAc (50 mL), treated with 1.6 N NaOH and stirred for 20 h at RT. The reaction mixture was adjusted to pH˜4 with concentrated HCl and diluted with Et2O (50 mL). The organic layer was washed with H2O (25 mL) and brine (25 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford the crude I-2 (300 mg). The crude material was used without further purification. 1H NMR (500 MHz, CDCl3): δ 7.45 (dd, J=9.5 Hz, 1.5 Hz, 1H), 7.40-7.37 (m, 2H), 3.76 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([O:43][CH3:44])=[CH:38][C:37]=1[O:45][CH3:46])=[O:34].CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:32][C:33](=[O:34])[NH:35][C:36]3[CH:41]=[C:40]([Cl:42])[C:39]([O:43][CH3:44])=[CH:38][C:37]=3[O:45][CH3:46])[C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)c(OC)cc3OC)c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottomed flask charged with [4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate H) (2.0 g, 6.17 mmol), K2CO3 (2.5 eq, 2.14 g, 15.52 mmol), and 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (Intermediate C) (1.02 eq, 1.99 g, 6.49 mmol) is treated with dry DMF (20 ml). The reaction is stirred at RT for 72 hours. The reaction mixture is diluted with distilled water and stirred for 15 minutes. The precipitate formed was filtered, washed with water and dried under vacuum to give the title compound; [M+H]+ 552
Reaction SMILES: F[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[CH:15]=[CH:16][C:17]4[C:23](=[O:24])[NH:22][C:21]5[CH:25]=[C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][C:20]=5[NH:19][C:18]=4[CH:34]=3)=[CH:10][C:9]=2[O:35][CH3:36])=[CH:4][CH:3]=1.C(O)(=[O:39])C>O.C(OCC)(=O)C>[CH3:36][O:35][C:9]1[CH:10]=[C:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:23](=[O:24])[NH:22][C:21]4[CH:25]=[C:26]([CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH:27]=[CH:28][C:20]=4[NH:19][C:18]=3[CH:34]=2)[CH:12]=[CH:13][C:8]=1[C:5]1[CH:4]=[CH:3][C:2](=[O:39])[NH:7][CH:6]=1
Reactant: CC(=O)O
Reactant: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(-c3ccc(-c4ccc(F)nc4)c(OC)c3)cc1N2
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)Cc1ccc2c(c1)NC(=O)c1ccc(-c3ccc(-c4ccc(=O)[nH]c4)c(OC)c3)cc1N2
Temperature: 25 °C
Yield: 13 %

Procedure:
A mixture of Example 656A (20 mg, 0.04 mmol) in acetic acid (1 mL) and water (200 μL) was heated at 100° C. overnight, cooled to room temperature, diluted with ethyl acetate, washed with water and brine, dried (MgSO4), filtered and concentrated. The concentrate was purified by preparative HPLC (2.5 mg, 13% yield). MS (ESI) m/e 482 (M+H)+; 1H NMR (400 MHz, DMSO-d.6 □ 11.67 (br s, 1H), 9.83 (s, 1H), 7.95 (s, 1H), 7.77 (d, J=8.1 Hz, 1H), 7.69 (dd, J=9.7, 2.5 Hz, 1H), 7.56 (m, 1H), 7.24-7.43 (m, 5H), 6.96 (d, J=8.1 Hz, 1H), 6.82-6.87 (m, 2H), 6.39 (d, J=9.2 Hz, 1H), 3.90 (s, 3H), 3.60 (s, 3H), 3.54 (s, 2H).