Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5](=O)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.P(Cl)(Cl)(Cl)(Cl)Cl.[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[CH:25]=[C:24]([CH:35]([CH3:37])[CH3:36])[C:23]=1[NH2:38])([CH3:21])[CH3:20]>C1(C)C=CC=C(C)C=1>[CH:19]([C:22]1[C:30]2[C:29]3[CH:31]=[CH:32][CH:33]=[CH:34][C:28]=3[O:27][C:26]=2[CH:25]=[C:24]([CH:35]([CH3:37])[CH3:36])[C:23]=1[N:38]1[CH2:2][CH2:3][N:4]=[C:5]1[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:21])[CH3:20]
Reactant: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N
Reactant: O=C(NCCCl)c1ccccc1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: Cc1cccc(C)c1
Product: CC(C)c1cc2oc3ccccc3c2c(C(C)C)c1N1CCN=C1c1ccccc1
Temperature: 25 °C
Yield: 54.1 %

Procedure:
N-(2-chloroethyl)benzamide (4.09 g, 22.27 mmol) and 90 mL m-xylene were added to a 250 ml, round-bottom flask. Next, phosphorus pentachloride (6.96 g, 33.4 mmol) was added carefully. The reaction mixture was heated to reflux under nitrogen for 2 h. The reaction mixture was cooled down to room temperature and 1,3-diisopropyldibenzo[b,d]furan-2-amine (6.55 g, 24.50 mmol) in 30 mL m-xylene was added. The reaction mixture was refluxed overnight under nitrogen. The reaction mixture was cooled in an ice bath. White solid was collected by filtration. The solid was washed with hexanes, dissolved in ethyl acetate, and washed twice with 10% sodium hydroxide solution. The organic layer was dried over magnesium sulfate, filtered, evaporated to a white solid which was dried under vacuum. 4.78 g (54% yield) of product was obtained.
Reaction SMILES: Br[C:2]1[C:11]([CH2:12][O:13][C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])=[C:10]2[C:5]([NH:6][C:7]([CH3:25])([CH3:24])[C:8](=[O:23])[N:9]2[CH3:22])=[CH:4][CH:3]=1.[CH3:26][O:27][C:28]1[CH:33]=[C:32]([O:34][C:35]([F:38])([F:37])[F:36])[CH:31]=[CH:30][C:29]=1B(O)O.C(=O)([O-])[O-].C(OCC)(=O)C>CN(C)C=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.O>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([CH:19]=1)[O:13][CH2:12][C:11]1[C:2]([C:29]2[CH:30]=[CH:31][C:32]([O:34][C:35]([F:37])([F:38])[F:36])=[CH:33][C:28]=2[O:27][CH3:26])=[CH:3][CH:4]=[C:5]2[C:10]=1[N:9]([CH3:22])[C:8](=[O:23])[C:7]([CH3:25])([CH3:24])[NH:6]2
Reactant: COc1cc(OC(F)(F)F)ccc1B(O)O
Reactant: Cc1ccc(F)cc1OCc1c(Br)ccc2c1N(C)C(=O)C(C)(C)N2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(OC(F)(F)F)ccc1-c1ccc2c(c1COc1cc(F)ccc1C)N(C)C(=O)C(C)(C)N2
Temperature: 80 °C
Reaction time: 2 h
Yield: 83.3 %

Procedure:
A mixture of 7-bromo-8-(5-fluoro-2-methylphenoxymethyl)-1,3,3-trimethyl-3,4-dihydro-1H-quinoxalin-2-one (Reference Compound No. 8-1, 49.7 mg, mmol), 2-methoxy-4-trifluoromethoxyphenylboronic acid (58.1 mg, 0.246 mmol), cessium carbonate (119 mg, 0.36 mmol) and bis(triphenylphosphin)palladium (II) dichloride (12.0 mg, 0.0171 mmol) was suspended in anhydrous N,N-dimethylformamide (0.5 ml) and stirred at 80° C. for 2 hours under argon atomosphere. After cooling down, ethyl acetate (100 mL) and water (100 mL) was added and partitioned. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (52.7 mg) as a colorless amorphous product. (Yield 58%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([N+:21]([O-])=O)[CH:5]=1.CC(C)=O>CO.[Ni]>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([S:10](=[O:13])(=[O:12])[NH2:11])[C:7]([O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:6]([NH2:21])[CH:5]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Oc2ccccc2)c(S(N)(=O)=O)c1
Agent: [Ni]
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)c1cc(N)c(Oc2ccccc2)c(S(N)(=O)=O)c1

Procedure:
35 g (~0.1 mol) of 3-nitro-4-phenoxy-5-sulphamylbenzoic acid methyl ester are suspended in 150 ml of methanol and are hydrogenated with Raney nickel (5-10%) in an autoclave at 40° -50° and 100 atmospheres gauge. The precipitated amino compound is dissolved by the addition of acetone on a steambath and the Raney nickel is removed by filtration.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[S:7][C:6]([NH:8][C:9](=O)OC(C)(C)C)=[CH:5][CH:4]=1.[H-].[Na+].CI.FC(F)(F)C(O)=O>CN(C=O)C.C(Cl)Cl>[CH3:9][NH:8][C:6]1[S:7][C:3]([C:2]([F:17])([F:1])[F:16])=[CH:4][CH:5]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(F)(F)F)s1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CNc1ccc(C(F)(F)F)s1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 5-(trifluoromethyl)thiophen-2-ylcarbamate (0.40 g, 1.5 mmol) in DMF (9 mL) at 0° C. was added NaH (72 mg, 1.8 mmol, 60% dispersion in mineral oil) in one portion. After 40 minutes MeI (0.20 mL, 1.8 mmol) was added via syringe. After stirring for 30 minutes at 0° C., TLC of a quenched aliquot showed the reaction was complete. The reaction was quenched by pouring into a biphasic mixture of 1N HCl and EtOAc. The layers were separated, and the organic layer was washed 3× with H2O, 1× with brine, dried over MgSO4, filtered, and concentrated under reduced pressure to afford a yellow oil. The crude oil was added to CH2Cl2 (2 mL) and trifluoroacetic acid (2 mL). After this mixture had been stirred at ambient temperature for 80 minutes, TLC showed the reaction was complete. The solvents were removed under reduced pressure and the residue was taken up in CH2Cl2 and was washed with NaHCO3 aq sat. This aqueous wash was back extracted 1× with CH2Cl2, then the combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. N-Methyl-5-(trifluoromethyl)thiophen-2-amine was used directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([C:8]([OH:10])=O)=[CH:4][CH:3]=1.S(Cl)(Cl)=O.[CH2:15]([NH2:20])[CH2:16][CH2:17][CH2:18][CH3:19]>O1CCOCC1>[CH2:15]([NH:20][C:8]([C:5]1[N:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:10])[CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: O=C(O)c1ccc(Cl)nn1
Reactant: CCCCCN
Solvent: O=S(Cl)Cl
Solvent: C1COCCO1
Product: CCCCCNC(=O)c1ccc(Cl)nn1
Temperature: 25 °C
Yield: 57.4 %

Procedure:
To a flask containing 6-chloropyridazine-3-carboxylic acid (375 mg, 2.37 mmol) in dioxane (5 mL) was added thionyl chloride (420 mg, 0.26 mL, 3.56 mmol). The brown mixture was refluxed for 6 hours under nitrogen with stirring. After cooling to ambient temperature, the solvent was removed by rotary evaporator. The gummy black material was diluted with dioxane (5 mL) and the resulting solution was cooled in an ice-water bath. To the cooled solution was added amyl amine (410 mg, 0.55 mL, 4.74 mmol). The resulting black reaction solution was stirred at ambient temperature for 16 hours under nitrogen. The solvent was removed in vacuo and the residue was dissolved in dichloromethane (25 mL). The solution was washed with water (2×10 mL) and the organic layer was dried over MgSO4, filtered-off the solid and concentrated to afford a gummy material which was purified by column chromatography eluted with dichloromethane to yield 310 mg (57%) of the product as a colourless solid. m.p. 98-101° C. 1H NMR (300 MHz, CDCl3) δ 8.28, 8.05, 7.68, 3.51, 1.69-1.63, 0.90. MS (ES+) m/z 228 (M+1).
Reaction SMILES: FC(F)(F)C([O-])=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([C:17]2[CH:21]=[N:20][S:19][N:18]=2)=[C:13]([CH:16]=1)[CH2:14][NH3+:15].[C:22]([O:26][C:27]([NH:29][C@H:30]([CH:41]1[CH2:46][CH2:45][CH2:44][CH2:43][CH2:42]1)[C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35](O)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C=O)C>[C:22]([O:26][C:27]([NH:29][C@H:30]([CH:41]1[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]1)[C:31]([N:33]1[CH2:40][CH2:39][CH2:38][C@H:34]1[C:35]([NH:15][CH2:14][C:13]1[CH:16]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=1[C:17]1[CH:21]=[N:20][S:19][N:18]=1)=[O:36])=[O:32])=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)O)C1CCCCC1
Reactant: [NH3+]Cc1cc(Cl)ccc1-c1cnsn1
Agent: O=C([O-])C(F)(F)F
Agent: On1nnc2cccnc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N[C@@H](C(=O)N1CCC[C@H]1C(=O)NCc1cc(Cl)ccc1-c1cnsn1)C1CCCCC1

Procedure:
To a stirred solution of 5-chloro-2-(1,2,5-thiadiazol-3-yl)benzylammonium trifluoroacetate (40.9 mg, 0.13 mmol), 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-cyclohexylethanoyl}-L-proline (prepared by standard peptide coupling protocols, 45.0 mg, 0.13 mmol), HOAt (22.5 mg, 0.17 mmol) and N-methylmorpholine (0.03 mL, 0.25 mmol) in DMF (0.5 mL) was added EDC (31.7 mg, 0.17 mmol). After 16 h the solution was partitioned between EtOAc and water. The organic phase was washed with brine, dried (Na2SO4) and reduced in vacuo. 1-{(2R)-2-[(tert-Butoxycarbonyl)amino]-2-cyclohexylethanoyl}-N-[5-chloro-2-(1,2,5-thiadiazol-3-yl)benzyl]-L-prolinamide was obtained as an oil. MS m/z=562.6.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].C([O:47][C:48](=[O:51])[CH2:49]Br)(C)(C)C.COC(C)(C)C>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.C(OCOCC)C>[CH2:1]([O:8][C@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][CH:10]1[O:11][CH2:49][C:48]([OH:51])=[O:47])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: CCOCOCC
Product: O=C(O)COC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 0 °C

Procedure:
A mixture that consists of 54.1 g (100 mmol) of 2,3,4,6-tetra-O-benzyl-mannopyranose, 1.70 g (5 mmol) of tetrabutylammonium hydrogen sulfate and 33.7 g (600 mmol) of fine-powder potassium hydroxide in 350 ml of diethoxymethane is cooled to 0° C. At 0° C., 29.3 g (150 mmol) of bromoacetic acid tert-butyl ester is added in drops over 10 minutes while being stirred vigorously. It is stirred for one hour at 0° C. 250 ml of MTB (methyl-tert-butyl ether) is added, solid is filtered out, and the filtrate is evaporated to the dry state in a vacuum. The residue is taken up in 500 ml of ethanol. 40 ml of 50% aqueous sodium hydroxide solution is added, and it is refluxed for 0.5 hour. It is cooled to 0° C., set at pH 8 with 10% aqueous hydrochloric acid, and then the solvent is distilled off (vacuum). The residue is taken up in 300 ml of water and 500 ml of ethyl acetate, and the pH of the aqueous phase is set at 2 while being stirred (10% aqueous hydrochloric acid). The organic phase is separated, and the aqueous phase is extracted once more with 200 ml of ethyl acetate. The combined organic phases are dried on magnesium sulfate, the solvent is distilled off in a vacuum, and the residue is chromatographed on silica gel (mobile solvent: dichloromethane/nhexane/ethanol/acetic acid=20:5:3:0.5). The product-containing fractions are concentrated by evaporation, dissolved in 400 ml of ethyl acetate and shaken out three times with 200 ml of water. Then, the organic phase is separated and evaporated to the dry state in a vacuum.
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][CH:9]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:7]1)(=O)=O.[F:20][C:21]([F:30])([F:29])[C:22]1[CH:27]=[CH:26][C:25]([SH:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.O>[F:30][C:21]([F:20])([F:29])[C:22]1[CH:23]=[CH:24][C:25]([S:28][CH:6]2[CH2:7][CH2:8][CH:9]([NH:12][C:13](=[O:14])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[CH2:10][CH2:11]2)=[CH:26][CH:27]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Reactant: FC(F)(F)c1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1CCC(Sc2ccc(C(F)(F)F)cc2)CC1
Temperature: 130 °C
Yield: 43 %

Procedure:
4-[(tert-Butoxycarbonyl)amino]cyclohexyl methanesulfonate (0.7 g, 2.39 mmol), 4-(trifluoromethyl)thiophenol (1.28 g, 7.16 mmol) and K2CO3 (1.32 g, 9.54 mmol) was dissolved in THF (21 ml) and the reaction mixture was heated in a microwave reactor at 130° C. for 30 mins. The reaction mixture was diluted with water (300 ml) and extracted with EtOAc (2×150 ml). The combined organic phases were dried over Na2SO4, filtrated and evaporated. The residue was purified by silica gel column chromatography using a 85:15 mixture of heptane:EtOAc to give the title compound (0.386 g, 43%) as a 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 7.55-7.50 (m, 4H), 7.45-7.40 (m, 4H), 4.70-4.23 (m, 2H), 3.69-3.36 (m, 3H), 3.16-3.05 (m, 1H), 2.13-2.04 (m, 4H), 1.95-1.64 (m, 9H), 1.54-1.40 (m, 1H), 1.45 (ds, 18H), 1.30-1.15 (m, 2H); 13C-NMR (CDCl3, 125 MHz): δ 155.4, 141.1, 140.7, 130.5, 129.9, 128.6, 128.5, 128.2, 126.0, 125.9, 125.9, 125.9, 125.4, 123.2, 79.5, 49.1, 47.9, 44.8, 43.8, 33.4, 32.0, 29.2, 29.1, 28.6.
Reaction SMILES: CO.S([O:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([OH:18])[CH3:17])[C:11]([O:19][CH3:20])=[CH:10][C:9]=1[CH3:21])(=O)(=O)C.[OH-].[Na+].C(O)(=O)C>O>[CH3:21][C:9]1[CH:10]=[C:11]([O:19][CH3:20])[C:12]([NH:14][CH2:15][CH:16]([OH:18])[CH3:17])=[CH:13][C:8]=1[OH:7]
Reactant: COc1cc(C)c(OS(C)(=O)=O)cc1NCC(C)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: COc1cc(C)c(O)cc1NCC(C)O
Yield: 83.2 %

Procedure:
Into 100 ml of methanol was added 2.0 g (13.1 mmol) of 2-methyl-4-methoxy-5-(2-hydroxypropyl)aminophenyl mesylate. After conducting nitrogen substitution at room temperature, 40 ml of 7.5N aqueous solution of sodium hydroxide was added to the mixture and the resulting mixture was heated under reflux for 7 hours with blowing nitrogen gas thereinto. After allowing to cool, the mixture was neutralized with acetic acid and poured into 400 ml of water. The resulting solution was extracted with 400 ml of ethyl acetate. The organic layer was washed with a saturated aqueous solution of common salt and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain an oily matter. The oily matter was crystallized from the solvent mixture of hexane/ethyl acetate (1:1 by volume) to give 2.30 g (10.9 mmol) of 2-methyl-4-methoxy-5-(2-hydroxypropyl)aminophenol. The yield was 49%.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:20][S:21]([N:24]1[CH2:29][CH2:28][CH:27]([O:30][C:31]2[CH:32]=[CH:33][C:34]([S:37](Cl)(=[O:39])=[O:38])=[N:35][CH:36]=2)[CH2:26][CH2:25]1)(=[O:23])=[O:22]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]([CH2:8][CH:9]([CH3:11])[CH3:10])[S:37]([C:34]2[CH:33]=[CH:32][C:31]([O:30][CH:27]3[CH2:28][CH2:29][N:24]([S:21]([CH3:20])(=[O:22])=[O:23])[CH2:25][CH2:26]3)=[CH:36][N:35]=2)(=[O:38])=[O:39])=[CH:12][CH:13]=1
Reactant: CS(=O)(=O)N1CCC(Oc2ccc(S(=O)(=O)Cl)nc2)CC1
Reactant: CC(C)CNCc1ccc(F)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CN(Cc1ccc(F)cc1)S(=O)(=O)c1ccc(OC2CCN(S(C)(=O)=O)CC2)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 37 %

Procedure:
A solution of (4-fluorobenzyl)-isobutylamine (53 mg, 0.295 mmol) and pyridine (34 μL, 0.423 mmol) in DCM (3 mL) was treated with 5-(1-methanesulfonyl-piperidin-4-yloxy)-pyridine-2-sulfonyl chloride (75 mg, 0.211 mmol) and stirred at room temperature for 18 hours. The mixture was diluted with DCM, washed with 1 M aqueous citric acid, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. Purification by silica gel column chromatography (0-100% EtOAc in cyclohexane) and re-purification by silica gel column chromatography (0-10% EtOAc in DCM) to give the title compound (39 mg, 37%). 1H NMR (400 MHz, DMSO) δ 8.45 (d, J=2.8 Hz, 1H), 7.89 (d, J=8.7 Hz, 1H), 7.66 (dd, J=8.8, 2.9 Hz, 1H), 7.38-7.32 (m, 2H), 7.17-7.09 (m, 2H), 4.84-4.76 (m, 1H), 4.39 (s, 2H), 3.43-3.34 (m, 2H), 3.18-3.10 (m, 2H), 3.00 (d, J=7.5 Hz, 2H), 2.92 (s, 3H), 2.11-2.01 (m, 2H), 1.84-1.73 (m, 2H), 1.63-1.52 (m, 1H), 0.68 (d, J=6.6 Hz, 6H). LCMS (m/z, Method B) ES+ 499.9 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([NH2:9])[CH:3]=1.[C:10](OCC)(=[O:16])[C:11](OCC)=[O:12]>>[OH:12][C:11]1[C:10]([OH:16])=[N:9][C:4]2[C:5](=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)[N:8]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: Nc1ccc(F)cc1N
Product: Oc1nc2ccc(F)cc2nc1O
Temperature: 25 °C

Procedure:
A mixture consisting of 26.3 g. (0.19 mole) of 4-fluoro-1,2-phenylenediamine [Journal of the American Chemical Society, Vol. 75, P.1294 (1953)] and 150 ml. of diethyl oxalate was refluxed under a nitrogen atmosphere for a period of 18 hours. Upon completion of this step, the reaction mixture was cooled to room temperature (~20° C.), filtered and the recovered product subsequently washed with four-100 ml. portions of ethanol and air-dried to constant weight to ultimately afford 19.3 g. (80%) of pure 2,3-dihydroxy-6-fluoroquinoxaline, m.p. >300° C. (literature m.p. 387°-390° C., according to U.S. Pat. No. 3,992,378). Mass Spectrum: m/e, 180 (P+).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[NH:10][C:9]=2[CH:15]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[Cl:22][CH2:23][CH2:24][CH2:25]I>CCCCCCC.CCOC(C)=O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][CH2:12][C:11](=[O:14])[N:10]([CH2:25][CH2:24][CH2:23][Cl:22])[C:9]=2[CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccc2c(c1)NC(=O)CO2
Reactant: ClCCCI
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CC(C)(C)c1ccc2c(c1)N(CCCCl)C(=O)CO2
Yield: 49.3 %

Procedure:
6-tert-Butyl-4H-benzo[1,4]oxazin-3-one (81MF2248a) (2.07 g, 10.0 mmol), Cs2CO3 (4.88 g, 15.0 mmol) and 3-chloro-1-iodopropane (2.25 g, 11.0 mmol) were mixed according to GP6. CC (SiO2; Heptane/EtOAc 10:1-5) to give the title compound (81MF2248b) (1.39 g, 49%). 1H NMR (CDCl3) d 7.12 (d, J=2.0 Hz, 1H), 7.03 (dd, J=8.4 Hz, J=2.0 Hz, 1H), 6.92 (d, J=8.4 Hz, 1H), 4.54 (s, 2H), 4.14 (t, J=7.2 Hz, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.21-2.14 (m, 2H), 1.32 (s, 9H); 13C NMR (CDCl3) d 164.8, 146.4, 143.1, 127.9, 120.9, 116.7, 112.2, 67.8, 42.6, 38.9, 34.8, 31.6, 30.2.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2]CCCC.[C:9]1([C:15]#[C:16][C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30](=[O:33])(=[O:32])[NH2:31])=[O:22])=[CH:19][CH:18]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[C:9]1([C:15]#[C:16][C:17]2[CH:35]=[CH:34][C:20]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[S:30]([NH:31][C:1](=[O:7])[CH3:2])(=[O:33])=[O:32])=[O:22])=[CH:19][CH:18]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Reactant: CCCCCC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1ccc(C#Cc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
In a stream of nitrogen and at 0° C., 0.20 ml (1.46 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 500 mg (1.30 mmol) of 4-phenylethynyl-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 10 and 320 mg (2.60 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 460 mg (yield: 74.6%) of the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]([O:45][CH3:46])=[O:44])=[O:36])[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][O:27]C2CCCCO2)[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][CH2:14][C@@H:15]([C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43]([O:45][CH3:46])=[O:44])=[O:36])[NH:16][C:17](=[O:34])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH2:25][CH2:26][OH:27])[CH:19]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cccc(OCCOC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COC(=O)[C@@H]1CCC[C@@H]1NC(=O)[C@H](CCCNC(=O)OCc1ccccc1)NC(=O)c1cccc(OCCO)c1
Temperature: 25 °C
Yield: 70.2 %

Procedure:
To a mixture of methyl (1R,2S)-2-[(N5-[(benzyloxy)carbonyl]-N2-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethoxy]benzoyl}-L-ornithyl)amino]cyclopentanecarboxylate (0.64 g), methanol (10 ml), and methylene chloride (6.0 ml) was added p-toluenesulfonic acid monohydrate (0.22 g) under ice-cooling, followed by stirring at room temperature over one night. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added to the residue, followed by washing with water. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain methyl (1R,2S)-2-({N5-[(benzyloxy)carbonyl]-N2-[3-(2-hydroxyethoxy)benzoyl]-L-ornithyl}amino)cyclopentanecarboxylate (0.39 g).
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28]([NH2:30])=O)[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:40])=CC=1>>[C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([N:11]2[CH2:16][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][CH:18]=3)[CH2:14][CH:13]([C:28](=[S:40])[NH2:30])[CH2:12]2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#CC1CCN(C(=O)N2CC(C(N)=O)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1
Product: N#CC1CCN(C(=O)N2CC(C(N)=S)CC(c3ccc(OC(F)(F)F)cc3)C2)CC1

Procedure:
1.50 g (3.53 mmol) of the compound from Example 116A and 786 mg (1.94 mmol) of Lawesson reagent were reacted according to the General Method 10A. Yield: 1.34 mg (39% of theory, 45% pure)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].C[O:8][C:9]([C:11]1([C:20]([CH3:22])=[CH2:21])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=O.Cl>CCOCC>[C:20]([C:11]1([CH2:9][OH:8])[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)([CH3:22])=[CH2:21]
Reactant: C=C(C)C1(C(=O)OC)Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [H-]
Solvent: CCOCC
Product: C=C(C)C1(CO)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.3 %

Procedure:
To 50 ml of dried ether containing 0.86 g (0.018 mole) of lithium aluminum hydride, with ice-cooling, was added dropwise over a period of 10 minutes a solution of 4.15 g (0.018 mole) of 2-methoxycarbonyl-2-isopropenylindane in 10 ml of dried ether. The mixture was then stirred at room temperature for 2 hours to continue the reaction. The reaction mixture was poured into a mixture of 5% aqueous hydrochloric acid solution and ice. And then the ether layer was separated and the aqueous layer was extracted twice with 25 ml of ether. The ether layers were combined, washed with saturated aqueous sodium hydrogencarbonate solution, then with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated in vacuo to obtain 3.23 g of 2-isopropenyl-2-indanemethanol.