Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[N:5]=1)=[N+:2]=[N-:3].[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>CC(O)(C)C.O.C([O-])(O)=O.[Na+]>[Cl:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N:1]2[CH:16]=[C:15]([Si:12]([CH3:14])([CH3:13])[CH3:11])[N:3]=[N:2]2)[N:5]=1
Reactant: [N-]=[N+]=Nc1cccc(Cl)n1
Reactant: C#C[Si](C)(C)C
Agent: O=C([O-])O
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: C[Si](C)(C)c1cn(-c2cccc(Cl)n2)nn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Azido-6-chloropyridine (500 mg, 3.24 mmol) and trimethylsilylacetylene (545 μL, 3.88 mmol) were combined in t-BuOH (5.0 mL) and water (3.0 mL) CuSO4.5H2O (40 mg, 0.16 mmol) in water (1.0 mL) was added, followed by sodium ascorbate (128 mg, 0.65 mmol) in water (1.0 mL). The reaction was stirred at room temperature overnight, diluted with saturated NaHCO3, and extracted with EtOAc (2×). The combined organic layers were washed with brine, dried (MgSO4), and evaporated to a crude residue that was purified by flash chromatography (0-40% EtOAc/hexanes) to afford the title compound as a colorless solid.
Reaction SMILES: CC([Si](C(C)C)(C(C)C)[N:5]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6]1)C.Cl[C:20]1[CH:25]=[CH:24][N:23]=[C:22]([S:26][CH3:27])[N:21]=1>>[CH3:27][S:26][C:22]1[N:23]=[C:24]([C:7]2[CH:8]=[CH:9][NH:5][CH:6]=2)[CH:25]=[CH:20][N:21]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc(B(O)O)c1
Reactant: CSc1nccc(Cl)n1
Product: CSc1nccc(-c2cc[nH]c2)n1
Yield: 95 %

Procedure:
The title compound was prepared analogous to Step A of Method B, starting from [1-[tris(1-methylethyl)silyl]-1H-pyrrol-3-yl]-boronic acid and 4-chloro-2-methylsulfanyl-pyrimidine. Under the reaction conditions, the triisopropylsilyl protecting group was cleaved. Yield: 95%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14])[N:3]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1>CN(C)C=O>[OH:12][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2]([S:28][C:25]2[CH:26]=[CH:27][C:22]([O:21][CH3:20])=[CH:23][CH:24]=2)=[N:3][C:4]=1[C:13]([NH:15][CH2:16][C:17]([OH:19])=[O:18])=[O:14]
Reactant: O=C(O)CNC(=O)c1nc(Cl)c2ccccc2c1O
Reactant: COc1ccc(S)cc1
Solvent: CN(C)C=O
Product: COc1ccc(Sc2nc(C(=O)NCC(=O)O)c(O)c3ccccc23)cc1
Temperature: 125 °C

Procedure:
To a solution of 100 mg of [(1-Chloro-4-hydroxy-isoquinoline-3-carbonyl)-amino]-acetic acid, (U.S. Pat. No. 6,093,730, disclosed as N-((1-Chloro-4-hydroxyisoquinoline-3-yl)carbonyl)glycine), in 1 ml N,N-dimethylformamide was added 1 ml of 4-methoxybenzenethiol. The solution was heated at 120 to 130° C. in a sealed tube for 72 h. The solution was then concentrated under vacuum. The resultant residue (76 mg) was purified by chromatography on silica gel using a gradient of 0 to 15% methanol in dichloromethane with 0.5% acetic acid to elute the product. 6 mg of product was obtained; MS (+) m/z 385.05 (M+1)
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=[N+]=[N-]>CO.[Pd]>[O:8]1[CH:9]=[CH:10][CH:11]=[C:7]1[CH2:6][CH2:5][CH2:4][NH2:1]
Reactant: [N-]=[N+]=NCCCc1ccco1
Agent: [Pd]
Solvent: CO
Product: NCCCc1ccco1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
At 0° C., butyllithium (70 mL, 1.6 M in hexane) was added to a solution of furan (10 g, 0.15 mol) in THF (150 mL). The mixture was stirred at 0° C. for 1h, then treated with a solution of 1,3-dibromopropane (30 g, 0.15 mol) in THF (50 mL). The mixture was allowed to warm to 25° C. over 2 h, then quenched with a saturated NH4Cl solution (50 mL). The aqueous phase was extracted with diethyl ether (3×50 mL) and the combined organic extracts was dried over Na2SO4. The solvent was evaporated to give crude 2-(3-bromopropyl)furan (30 g), which was purified by silica gel chromatography (10% methylene chloride in hexanes). A mixture of 2-(3-bromopropyl)furan (7.6 g, 40 mmol) and sodium azide (10 g, 150 mmol) in DMF (200 mL) was stirred for 15 h at 90 C. Water (250 mL) was then added and the mixture was extracted by diethyl ether (3×100 mL). The combined organic extracts was washed with water (3×50 mL) and dried over sodium sulfate. The solvent was removed to give pure 2-(3-azidopropyl)-furan as an oil (5 g). A mixture of 2-(3-azidopropyl)furan (0.5 g) and Pd/C (0.05 g, 10%) in methanol (15 mL) was stirred at 25° C. for 8 h under a hydrogen atmosphere. The catalyst was filtered off and solvent was evaporated to give 3-Furan-2-yl-propylamine in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](F)=[N:6][CH:7]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1COCC1.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1F
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(Cl)cnc1N1CCOCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 5-chloro-2-fluoro-3-nitropyridine (5 g, 28 mmol) in THF (40 mL) was added morpholine (4 mL, 42 mmol). The reaction was stirred at 0° C. for ten min, at rt for 1 h, and refluxed for four h. The reaction was then cooled to rt, taken up in EtOAc, and washed with satd aq. sodium bicarbonate and brine. The organic layer was dried (magnesium sulfate) and concentrated, affording 4-(5-chloro-3-nitropyridin-2-yl)morpholine as a yellow oil. Mass Spectrum (ESI) m/e=244.0 (M+1).
Reaction SMILES: CC1C=CC(S(NCl)(=O)=O)=CC=1.[Br:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=1.[I-:21].[Na+].Cl>C(OCC)(=O)C.O.CN(C)C=O>[Br:13][C:14]1[C:19]([OH:20])=[CH:18][CH:17]=[C:16]([I:21])[N:15]=1
Reactant: Oc1cccnc1Br
Reactant: [I-]
Agent: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Oc1ccc(I)nc1Br
Reaction time: 0.17 h
Yield: 88.2 %

Procedure:
17.6 g of Chloramine T was added to a mixture of 10.9 g of 2-bromo-3-hydroxypyridine, 9.35 g of sodium iodide and 110 ml of N,N-dimethylformamide under stirring in an ice bath, followed by stirring at the same temperature for 30 minutes and then at room temperature for 10 minutes. Water, ethyl acetate and 11 ml of an aqueous 6N hydrochloric acid solution were added thereto, and the organic phase was washed with brine and the solvent was removed. The residue was subjected to silica gel column chromatography and eluted with 30% ethyl acetate/hexane, to give 16.5 g of the target compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[S:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:2]1
Reactant: OB(O)c1ccsc1
Reactant: O=Cc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cccc(-c2ccsc2)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
3.11 g of 3-thiopheneboronic acid (0.024 mol) are added to a solution of 3-bromobenzaldehyde (3 g, 0.016 mol) in 1,2-dimethoxyethane (80 ml), followed by addition of aqueous 2N sodium carbonate solution (5.15 g, 0.048 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.56 g, 4.9 10−4 mol). The reaction mixture is heated at 80° C. for 16 hours and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 90/10 cyclohexane/ethyl acetate). 2.61 g of a pale yellow solid are recovered.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:46]=[N:47][CH:48]=[CH:49][CH:50]=3)[C:19]2=[O:51])=[N:9]1
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(C(=O)OC(C)(C)C)c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(N(C(=O)CN2C(=O)C(Cc3n[nH]c4ccccc34)C(=O)N(c3cccnc3)c3ccccc32)C(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
To 561 mg (0.95 mmol) of 2-[3-(1-tert-butoxycarbonyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-pyridin-3-yl-2,3,4,5-tetrahydrobenzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide, prepared as in Intermediate 75, is added 10 mL of a 4N solution of HCl in dioxane. The reaction is stirred overnight at RT. The reaction is concentrated, then purified by silica gel flash column chromatography (gradient 2:1-4:1 ethyl acetate:hexanes) to afford an oil which is triturated from hexane to afford 284 mg of the title compound as a white powder: 1H NMR (CDCl3, 400 MHz) δ8.49 (d, br, 2H), 7.79 (d, 2H, J=8.0), 7.29-7.07 (m, 8H) 6.95-6.85 (m, 4H ) 4.94 (m, 1H), 4.38 (d, br, 1H, J=15.6) 4.25-4.14 (m, 2H) 3.82 (s, 3H) 3.77 (m, 1H) 3.60 (dd, 1H, J=6.0, 16.1) 1.02 (t, 6H, J=7.7); low resolution MS (FAB)m/e 589 (MH+); Anal. (C34H32N6O4) Calcd. C, 69.4; H, 5.5; N, 14.3 Found C, 68.4; H, 5.6; N, 14.1. To a stirred solution of 1.0 g (1.69 mmol) of the title compound in 10 mL of DCM is added 1.86 mL (2.54 mmol, 1.5 equiv.) of a 1.36M solution of 2-Oxo-4-thiazolidinecarboxylic acid chloride in DCM (prepared by stirring 1.0 g (6.8 mmol) of (-)-2-Oxo-4-thiazolidine carboxylic acid, 0.593 mL (6.8 mmol), and 0.1 mL DMF in 50.0 mL DCM until gas evolution stopped). The solution is stirred at RT for 4 h and then concentrated in vacuo. Purification by silica gel gravity column chromatography using DCM/THF 8/2 as eluent afforded 415 mg of the less polar eluting diastereomer as 2-{2,4-Dioxo-3-[1-(2-oxo-thiazolidine-4-carbonyl)-1H-indazol-3-yl methyl]-5-pyridin-3-yl-2,3,4,5-tetrahydro benzo[b][1,4]diazepin-1-yl}-N-isopropyl-N-(4-methoxyphenyl) acetamide. 1H NMR (CDCl3, 300 MHz) δ8.53 (d, 1H, J=4), 8.45 (s, 1H), 8.33 (d, 1H, J=28), 7.82 (d, 1H, J=26), 7.72 (d, 1H, J=9), 7.62-7.57 (m, 2H), 7.45-6.94 (m, 9H), 6.72 (s, 1H), 5.62 (bt, 1H), 5.05-4.90 (m, 1H), 4.51-4.42 (m, 2H), 3.97-3.87 (m, 2H), 3.83 (s, 3H), 3.75 (dd, 1H, J=5, 18), 3.64-3.57 (m, 2H), 3.48 (dd, 1H, J=4, 22), 1.10 (d, 3H, J=7), 0.97 (d, 3H, J=7).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH:13]=[O:14])[CH:7]=[CH:6]2.[BH4-].[Na+].Cl>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([CH2:13][OH:14])[CH:7]=[CH:6]2
Reactant: COc1ccc2cc(C=O)ccc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2cc(CO)ccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of commercially available 6-methoxy-2-naphthaldehyde (200 mg; 1.07 mmol) in MeOH (5 ml) was treated portionwise at rt with NaBH4 (50 mg; 1.31 mmol), and the resulting mixture was further stirred at rt, under nitrogen, for 1 h. 2 M aq. HCl was added, and the organic solvent was removed under reduced pressure. AcOEt and water were added, and the separated organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure affording (6-methoxynaphthalen-2-yl)methanol as a colorless solid. LC-MS (conditions E): tR=0.55 min.; no ionisation.
Reaction SMILES: Cl[CH2:2][C:3]1[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=1[CH3:11].[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17](B(O)O)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([O:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=2[F:31])=[C:17]([CH2:2][C:3]2[N:8]=[C:7]([C:9]#[N:10])[CH:6]=[CH:5][C:4]=2[CH3:11])[CH:18]=1
Reactant: Cc1ccc(C#N)nc1CCl
Reactant: OB(O)c1cc(Cl)ccc1OCc1ccc(Cl)cc1F
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: CCO
Solvent: Cc1ccccc1
Product: Cc1ccc(C#N)nc1Cc1cc(Cl)ccc1OCc1ccc(Cl)cc1F
Yield: 40.5 %

Procedure:
To a solution of 6-(chloromethyl)-5-methyl-2-pyridinecarbonitrile (132.5 mg) in dry toluene (4 ml) and ethanol (4 ml) was added (5-chloro-2-{[(4-chloro-2-fluorophenyl)methyl]oxy}phenyl)boronic acid (250 mg), potassium carbonate (330 mg) and tetrakis(triphenylphosphine)palladium(0) (92 mg) and the mixture stirred under reflux for 2 hours. Solvent was removed in vacuo and water (20 ml) and ether (20 ml) added. Insoluble solid was filtered over Celite and washed with ether. The aqueous layer was further extracted with ether (15 ml) and the combined extracts washed with brine (10 ml), dried (MgSO4) and concentrated in vacuo. The residue was purified by mass-directed autopreparation to afford the title compound (129 mg, 40%) as a pale buff solid.
Reaction SMILES: [Br:1]N1C(=O)NC(=O)N(Br)C1=O.CN(C=O)C.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]=[O:31])=[C:26]([O:32][CH3:33])[CH:25]=2)=[CH:20][CH:19]=1>O>[Br:1][C:29]1[CH:28]=[C:27]([CH:30]=[O:31])[C:26]([O:32][CH3:33])=[CH:25][C:24]=1[C:21]1[CH:20]=[CH:19][C:18]([F:17])=[CH:23][CH:22]=1
Reactant: COc1cc(-c2ccc(F)cc2)ccc1C=O
Reactant: O=c1[nH]c(=O)n(Br)c(=O)n1Br
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(-c2ccc(F)cc2)c(Br)cc1C=O
Reaction time: 0.67 h
Yield: 180.3 %

Procedure:
Dibromoisocyanuric acid (10.6 g) was added at 15° C. to 30° C. to a DMF (90 mL) solution of 4′-fluoro-3-methoxybiphenyl-4-carbaldehyde (16.0 g), and the mixture was stirred for 40 minutes. Then, water (30 mL) was added thereto, and the mixture was further stirred for 1 hour. The deposited solid was collected by filtration and washed with a mixed solution of DMF (15 mL) and water (15 mL) and water (30 mL) in this order to obtain the title compound (20.6 g).
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C:12]3=[O:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>>[O:4]1[C:5]2([CH2:6][CH2:7][N:8]([C@H:11]3[CH2:16][C@H:15]4[C@H:17]5[C@H:27]([CH2:28][CH2:29][C@:13]4([CH3:14])[C@H:12]3[OH:31])[C@:25]3([CH3:26])[C@H:20]([CH2:21][C@@H:22]4[O:30][C@@H:23]4[CH2:24]3)[CH2:19][CH2:18]5)[CH2:9][CH2:10]2)[O:1][CH2:2][CH2:3]1
Reactant: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Agent: [BH4-]
Agent: [Na+]
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](O)[C@@H](N3CCC4(CC3)OCCO4)C[C@@H]12
Yield: 91.1 %

Procedure:
16β-(1,4-Dioxa-8-azaspiro[4.5]dec-8-yl)-2α,3α-epoxy-5α-androstan-17-one is reduced by using sodium borohydride as described in Example 2 to give the title compound in a yield of 91.1%, m.p.: 186°-188° C.
Reaction SMILES: C(OC(=O)[C:5]([C:7]1(Br)[CH2:11][CH2:10][O:9][CH:8]1[O:12][CH2:13]C)=[O:6])C.S([O-])([O-])=O.[Na+].[Na+].[Cl-].[NH4+].Cl>ClCCl>[O:12]1[CH:8]2[O:9][CH2:10][CH2:11][CH:7]2[CH:5]([OH:6])[CH2:13]1
Reactant: CCOC(=O)C(=O)C1(Br)CCOC1OCC
Agent: Cl
Agent: O=S([O-])[O-]
Agent: [Cl-]
Solvent: ClCCl
Product: OC1COC2OCCC12
Temperature: 37.5 °C
Reaction time: 6.5 h

Procedure:
To the solution of Ethyl-2-(3-bromo-2-ethoxy tetra hydrofuran-3-yl)-2-oxoacetate in dichloromethane (V, 500 mL) as prepared in above example, sodium sulphite solution (225 g was dissolved in 1700 mL of water) was added at 25-35° C. Reaction mass was stirred for 5-8 hours at the same temperature and separated the organic and aqueous layers. Organic layer was washed with water (340 mL). Distilled out the solvent completely get ethyl-2-(2-ethoxy tetra hydrofuran-3-yl)-2-oxoacetate. Sodium borohydride (35.5 g) was dissolved in ethanol (400 mL) under nitrogen atmosphere, ethyl-2-(2-ethoxytetra hydrofuran-3-yl)-2-oxoacetate was dissolved in ethanol (100 mL) and slowly added to above solution at 15-30° C. Reaction mass was heated to 30-45° C., maintained for 5-8 hours, the reaction mass temperature was raised to 55° C. and stirred for 8 hours. The reaction mass was cooled to 20-30° C., ammonium chloride solution (115 g in 200 mL water) was slowly added and stirred for 1-2 hours. The reaction mass was filtered and filtrate was distilled out under vacuum to get residue. Dichloromethane (600 mL) was added to residue and cooled to −10° C. Hydrochloric acid (85 mL) was added slowly drop wise in 2 hours by maintaining temp −5 to 0° C., reaction mass was stirred for 60 minutes at −5 to 0° C. and distilled the solvent completely. The obtained residue was stripped out with isopropyl alcohol (2×200 mL, 1×100 mL), ethyl acetate (500 mL) was added to the resultant residue, stirred for 30-60 minutes and cooled to 10-15° C. The solution was filtered and filtrate was concentrated to get title compound IV (yield 56 g).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21](=[O:31])(=[O:30])[NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1)(C)(C)C.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]>C(Cl)Cl>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([S:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([NH:22][C:23]3[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=3)(=[O:30])=[O:31])=[CH:17][C:16]=2[NH:32][C:33]2[C:34]3[CH:42]=[CH:41][C:40]([CH:43]([CH3:45])[CH3:44])=[N:39][C:35]=3[N:36]=[CH:37][N:38]=2)=[CH:10][CH:9]=1.[F:47][C:48]([F:53])([F:52])[C:49]([OH:51])=[O:50]
Reactant: CC(C)c1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(S(=O)(=O)Nc4ccc(Br)cc4)ccc3Sc3ccc(N)cc3)ncnc2n1

Procedure:
The product from Example 149E (44 mg, 0.061 mmol) was treated with trifluoroacetic acid (2 mL) in methylene chloride (2 mL) at room temperature for 30 minutes. The solvents were removed by rotary evaporation under vacuum and the residual oil dried under hi-vacuum. Purification by silica gel chromatography using 5% methanol/methylene chloride as eluent provided the title compound as a trifluoroacetic acid salt (25 mg, 48%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.35 (d, J=6.62 Hz, 6H), 3.13-3.38 (m, 1H), 6.63 (d, J=8.46 Hz, 2H), 6.87 (d, J=7.72 Hz, 1H), 7.01-7.09 (d, J=8.82 Hz, 2H), 7.12 (d, J=8.46 Hz, 2H), 7.44 (d, J=8.82 Hz, 2H), 7.61 (dd, J=7.72, 1.47 Hz, 1H), 7.71 (s, 1H), 7.81 (dd, J=6.62, 1.47 Hz, 1H), 8.66-8.80 (m, 1H), 8.90 (d, J=6.99 Hz, 1H), 10.55 (s, 1H); MS (ESI+) m/z 621/623 (M+H)+.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]([CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11])=[CH:6][C:5]=1[O:16][CH3:17])(O)=[O:2].Cl.CN.Cl.[CH2:22]([N:24]=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[CH3:17][O:16][C:5]1[CH:6]=[C:7]([CH:14]=[CH:15][C:4]=1[C:1](=[O:2])[NH:24][CH3:22])[CH:8]=[CH:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C=Cc1ccc(C(=O)O)c(OC)c1
Reactant: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CNC(=O)c1ccc(C=CC(=O)OC)cc1OC
Reaction time: 18 h
Yield: 75.6 %

Procedure:
To a solution of methyl 4-carboxy-3-methoxycinnamate (400 mg) in N,N-dimethylformamide were added methylamine hydrochloride (126 mg), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (390 mg) and 1-hydroxybenzotriazole (320 mg) at ambient temperature, and the mixture was stirred for 18 hours at the same temperature. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water, saturated sodium bicarbonate solution and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel (chloroform methanol=40:1, v/v) to give methyl 3-methoxy-4-(methylcarbamoyl)cinnamate (319 mg).
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH:11]([NH:12][S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH2:10][CH2:9][N:8]([C:35](=[O:37])[CH3:36])[CH2:7]1)=[O:5])C.Cl>O1CCOCC1>[C:35]([N:8]1[CH2:9][CH2:10][CH:11]([NH:12][S:13]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[N:27]=[C:26]([CH3:34])[CH:25]=3)=[CH:20][CH:21]=2)(=[O:15])=[O:14])[CH:6]([C:4]([OH:5])=[O:3])[CH2:7]1)(=[O:37])[CH3:36]
Reactant: CCOC(=O)C1CN(C(C)=O)CCC1NS(=O)(=O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1CCC(NS(=O)(=O)c2ccc(OCc3cc(C)nc4ccccc34)cc2)C(C(=O)O)C1
Temperature: 60 °C
Yield: 70.5 %

Procedure:
To a solution of 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid ethyl ester (0.6 g, 1.14 mmol) in 1,4-dioxane (10 mL) was added concentrated HCl (10 mL). The reaction was heated at 60° C. for 19 h. The solvent was removed in vacuo and the residue was diluted with CH2Cl2. The organics were dried over MgSO4, filtered and concentrated. The residue was purified by reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column eluting an acetonitrile:water gradient, to afford 1-acetyl-4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid as an amorphous white solid (0.4 g, 70.1%). MS: 498 (M+H)+.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.[C:22]1([C:28]2[O:29][CH2:30][C:31](=[O:34])[NH:32][N:33]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)(O)[O-].[Na+]>CN(C=O)C>[CH:17]1([CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][N:32]3[C:31](=[O:34])[CH2:30][O:29][C:28]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:33]3)=[CH:4][CH:5]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: CC(C)(C)OC(=O)C(c1ccc(CBr)cc1)C1CCCC1
Reactant: O=C1COC(c2ccccc2)=NN1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)C(c1ccc(CN2N=C(c3ccccc3)OCC2=O)cc1)C1CCCC1

Procedure:
8.16 g (23.1 mmol) of tert-butyl [4-(bromomethyl)phenyl](cyclopentyl)acetate, 3.7 g (21 mmol) of 2-phenyl-4H-1,3,4-oxadiazin-5(6H)-one and 7.53 g (23.1 mmol) of cesium carbonate in 147 ml of DMF were stirred at room temperature for 12 h. The reaction solution was then stirred with saturated aqueous sodium bicarbonate solution and extracted twice with ethyl acetate. The combined organic phases were dried over magnesium sulfate and evaporated to dryness under reduced pressure. The crude product obtained was purified chromatographically on silica gel (mobile phase cyclohexane/ethyl acetate 5:1). This gave 6.51 g (14.5 mmol, 69% of theory) of the title compound.