Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:13]2[S:14][C:15]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:16]([CH3:18])[N:17]=2)[CH:5]=[CH:6][C:7]=1[S:8][CH2:9][CH:10]([CH3:12])[CH3:11].[N-:24]=[N+:25]=[N-:26].[Na+].[CH:28](OCC)(OCC)OCC.O>C(O)(=O)C>[CH3:18][C:16]1[N:17]=[C:13]([C:4]2[CH:5]=[CH:6][C:7]([S:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[C:2]([N:1]3[CH:28]=[N:26][N:25]=[N:24]3)[CH:3]=2)[S:14][C:15]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)c1sc(-c2ccc(SCC(C)C)c(N)c2)nc1C
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)c1sc(-c2ccc(SCC(C)C)c(-n3cnnn3)c2)nc1C
Temperature: 70 °C

Procedure:
A reaction mixture solution prepared by suspending 155.2 mg of ethyl 2-[4-fluoro-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate and 244.4 mg of cesium carbonate in 1.5 mL of N,N-dimethylformamide and adding 49.6 mg of 2-methylpropylthiol was heated under stirring at 80° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, 3 mL of water was added and extraction was performed using ethyl acetate. The organic layer was concentrated under reduced pressure to obtain a crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate. (2) The crude product of ethyl 2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate obtained above was reduced using palladium carbon under a hydrogen atmosphere to obtain ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate. (3) A reaction mixture solution prepared by suspending ethyl 2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate obtained above in 2.0 mL of acetic acid and adding 65 mg of sodium azide and 148 mg of triethyl ortho formate was heated at 70° C. for 5 hours under a nitrogen atmosphere. The reaction mixture solution was cooled to room temperature, water was added and extraction was performed using ethyl acetate. The organic layer was washed with saline and then dried and concentrated under reduce pressure, followed by purifying by a conventional method to obtain 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate. (4) A reaction mixture solution prepared by adding 123 mg of ethyl 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate to 2 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding 0.5 mL of 2 M sodium hydroxide aqueous solution was stirred at room temperature for 3 hours. After the addition of 0.5 mL of 2 M hydrochloric acid to the reaction mixture solution under stirring, 3 mL of water was added and extraction was performed using ethyl acetate. The organic phase was concentrated, followed by purifying by a conventional method to obtain 67.9 mg of 4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylic acid.
Reaction SMILES: C(O)(=O)C.[N+:5]([C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[C:11]([NH:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=[O:22])=[O:12])([O-])=O>[Pd].CO.O>[NH2:5][C:8]1[CH:9]=[C:10]([CH:33]=[CH:34][CH:35]=1)[C:11]([NH:13][C:14]1[CH:32]=[CH:31][CH:30]=[CH:29][C:15]=1[O:16][C:17]1[CH:18]=[C:19]([C:26]([OH:28])=[O:27])[C:20](=[CH:24][CH:25]=1)[C:21]([OH:23])=[O:22])=[O:12]
Reactant: O=C(Nc1ccccc1Oc1ccc(C(=O)O)c(C(=O)O)c1)c1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O
Solvent: CO
Product: Nc1cccc(C(=O)Nc2ccccc2Oc2ccc(C(=O)O)c(C(=O)O)c2)c1
Reaction time: 20 h

Procedure:
100% acetic acid (250 μl) and palladium on activated charcoal (10% Pd, 40 mg) was added to a solution of 4-[2-(3-nitrobenzoylamino)phenoxy]phthalic acid (130 mg, 0.308 mmol) in methanol/water (10:1) (11 ml). The mixture was hydrogenated in a Parr apparatus at 276 kPa (40 psi) for 20 hours. The mixture was filtered and evaporated to dryness in vacuo to give 4-[2-(3-aminobenzoylamino)phenoxy]phthalic acid as an oil (yield: 114 mg (95%)). LC-MS: m/e 393 (MH+), 375 (MH+-H2O).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[CH2:15][C:16](N)=[O:17])=[CH:10][CH:9]=1.[CH3:20][Mg]I.[Mg].CI.S(=O)(=O)(O)O>C(Cl)Cl.CCOCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:19])[CH2:15][C:16](=[O:17])[CH3:20])=[CH:10][CH:9]=1
Reactant: C[Mg]I
Reactant: CC(CC(N)=O)c1ccc(-c2ccccc2F)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CI
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)CC(C)c1ccc(-c2ccccc2F)cc1
Temperature: 0 °C

Procedure:
A solution of 25.7 gm (0.1 mol) of 3-(2'-fluoro-4-biphenylyl)-butyramide in 750 ml of dry methylene chloride was added dropwise over a period of one hour to a methyl magnesium iodide solution which was prepared from 12.2 gm (0.5 mol) of magnesium and 71 gm (0.5 mol) of methyl iodide in a total of 400 ml of anhydrous ether, and the resulting mixture was refluxed for 6 hours to make the reaction go to completion. After cooling, the reaction mixture was stirred into a mixture consisting of 2 kg of ice and 100 ml of concentrated sulfuric acid. The ethereal phase was separated, washed twice with water, once with an aqueous saturated sodium bicarbonate solution, and again with water, dried over anhydrous magnesium sulfate and evaporated in vacuo. The solid residue was recrystallized twice from gasoline (b.p. range 60° to 80°C), yielding 22.0 gm (86% of theory) of the colorless crystalline compound, m.p. 60°-61°C, of the formula ##SPC22##
Reaction SMILES: [Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]#N)=[CH:10][C:9]=2[CH:16]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1.[OH-:27].[K+].C[OH:30]>>[Br:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][O:7][C:8]2[CH:15]=[CH:14][C:11]([C:12]([OH:30])=[O:27])=[CH:10][C:9]=2[CH:16]([N:20]2[CH:24]=[CH:23][N:22]=[CH:21]2)[CH2:17][CH2:18][CH3:19])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCCC(c1cc(C#N)ccc1OCc1ccc(Br)cc1)n1ccnc1
Reactant: CO
Agent: [K+]
Product: CCCC(c1cc(C(=O)O)ccc1OCc1ccc(Br)cc1)n1ccnc1

Procedure:
1.5 g of 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)butyl]-benzonitrile (of example 3) is reacted with 3 g of potassium hydroxide in an aqueous methanol solution for 24 hours under reflux. After working up, 1.1 g of 4-(4-bromobenzyloxy)-3-[1-(1-imidazolyl)-butyl]-benzoic acid with a melting point of 187°-189° C. is obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[C:3](Cl)=[O:4].[NH2:7][C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][CH:21]=1)[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:12].Cl>CN(C)C=O.C(N(CC)CC)C>[C:11]([C:10]1[CH:9]=[C:8]([NH:7][C:3](=[O:4])[N:2]([CH3:6])[CH3:1])[CH:21]=[CH:20][CH:19]=1)(=[O:12])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: Nc1cccc(C(=O)c2ccccc2)c1
Reactant: CN(C)C(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN(C)C(=O)Nc1cccc(C(=O)c2ccccc2)c1
Temperature: 60 °C

Procedure:
Dimethylcarbamoyl chloride (7.5 grams, 0.07 mole) was added to a solution of 3-aminobenzophenone (10 grams, 0.05 mole) in dimethylformamide (150 ml.), triethylamine (10 ml.) at 10° C. with stirring and ice cooling. The reaction temperature was next raised to 60° C. for 20 hours, then cooled and poured onto ice water (500 grams) containing dilute hydrochloric acid. A tarry solid was obtained by decanting off the aqueous organic solution. Purification was effected by dissolving the tarry solid in methylene chloride and passing through a silica gel dry column - eluent methylene chloride. On elution with dichloromethane, the product, 3(-m-benzoylphenyl)-1,1-dimethyl urea, is obtained. Melting point was 104° C.-105° C. Crystallization from benzene-hexane (9:1) mixture gave solid 109° C.-110° C., which on benzene-hexane crystallizations afforded a melting point of from 121° C. to 122° C. identified as the desired urea by comparison with the sample prepared from phosgene and dimethylamine.
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[CH2:4]([C@@H:6]1[O:8][CH2:7]1)[Cl:5].[C]=O.C1C[O:14][CH2:13]C1>CN(C)C1C=CN=CC=1>[CH2:1]([O:3][C:13](=[O:14])[CH2:7][C@@H:6]([OH:8])[CH2:4][Cl:5])[CH3:2]
Reactant: ClC[C@H]1CO1
Reactant: C1CCOC1
Reactant: CCO
Agent: CN(C)c1ccncc1
Agent: [C]=O
Product: CCOC(=O)C[C@@H](O)CCl
Temperature: 25 °C
Yield: 83 %

Procedure:
In a 50 mL-volumetric autoclave were added deaerated ethanol (10 mL) and THF (10 mL), and thereto were added 4-dimethylaminopyridine (61 mg, 0.5 mmol) and (R)-epichlorohydrin (1.9 g, 20 mmol, >99% ee). Then to the mixture was added crystalline dicobaltoctacarbonyl complex (171 mg, 0.5 mmol). After covering the autoclave with a cap, carbon monoxide (2 MPa) was introduced therein and the mixture was reacted at 40° C. for 16 hours. After cooling to room temperature, the solvent was removed in vacuo. The residue was subjected to Kugelrohr distillation to give (R)-4-chloro-3-hydroxybutanoic acid ethyl ester (2.8 g, 83%, >99% ee) as a colorless oil.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6](Cl)=[O:7].[N+](=[CH2:11])=[N-].[ClH:12]>CCOCC.ClCCl>[Cl:12][CH2:11][C:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)=[O:7]
Reactant: C=[N+]=[N-]
Reactant: Cl
Reactant: O=C(Cl)C1CCCO1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(CCl)C1CCCO1
Reaction time: 0.25 h
Yield: 41 %

Procedure:
Oxalyl chloride (5.2 ml, 60 mmol) and DMF (1 drop) were added to (RS)-2-tetrahydrofuroic acid (W. E. Kaufmann and R. Adams, J.Amer.Chem.Soc., 1923, 45, 3029) (4.64 g, 40 mmol) in dichloromethane (25 ml). The mixture was stirred 1 h, evaporated in vacuo, dichloromethane added and reevaporated to give 2-tetrahydrofuroyl chloride, νmax (CH2Cl2) 1795 cm-1. 2-Tetrahydrofuroyl chloride in ether (25 ml) and dichloromethane (10 ml) was added dropwise to an ice bath cooled solution of diazomethane (ca 80 mmol) in ether (150 ml). The reaction mixture was stirred 0.25 h then a stream of hydrogen chloride gas passed into the solution for ca 2 minutes then stirred a further 0.25 h, washed with saturated brine, dried, concentrated and flash chromatographed on silica gel eluting with 5, 7.5 and 10% ethyl acetate in hexane to provide the title compound (2.46 g, 41%); (Found: M+, 148.0279. C6H9ClO2 requires M, 148.0291); νmax (CH2Cl2) 1739, 1395, 1071 and 936 cm-1 ; δH (CDCl3, 250 MHz) 1.8-2.4 (4H, m) and 3.9-4.6 (5H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:7]=[C:6]([CH3:8])[O:5][N:4]=1.[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][O+](C)C>C(Cl)Cl>[F:9][B-:10]([F:13])([F:12])[F:11].[CH3:14][N+:4]1[O:5][C:6]([CH3:8])=[CH:7][C:3]=1[O:2][CH3:1]
Reactant: COc1cc(C)on1
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COc1cc(C)o[n+]1C

Procedure:
The starting material may be prepared by reaction of 3-methoxy-5-methylisoxazole with trimethyloxonium tetrafluoroborate in CH2Cl2 for 3.5 hours at reflux to give 2,5-dimethyl-3-methoxyisoxazolium tetrafluoroborate.
Reaction SMILES: N#N.[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10](/[C:13](/[CH3:21])=C/C2C=CC=CC=2)[O:11][CH:12]=1)=[O:7])[CH3:4].[OH2:22]>CC(C)=O>[CH2:3]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:13](=[O:22])[CH3:21])[O:11][CH:12]=1)=[O:7])[CH3:4]
Reactant: O
Reactant: CCOC(=O)c1coc(/C(C)=C/c2ccccc2)n1
Agent: N#N
Solvent: CC(C)=O
Product: CCOC(=O)c1coc(C(C)=O)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of NaIO4 (23 g, 108 mmol) in water (150 mL) was slowly added to a vigorously stirred suspension of silica gel (110 g) in acetone (500 mL). The mixture was then concentrated under reduced pressure and the lumpy solid slurried in CH2Cl2 and the solvent was evaporated under reduced pressure. CH2Cl2 (500 mL) was added and the reaction mixture was treated at rt with (E)-2-(1-phenylprop-1-en-2-yl)oxazole-4-carboxylic acid ethyl ester (8.3 g, 32 mmol) and RuCl3 hydrate (1.1 g, 2 mmol). The reaction mixture was stirred at rt in the dark for 60 min, filtered and concentrated under reduced pressure. Purification of the residue by FC (1:0 to 1:5 petroleum ether-Et2O) gave the title compound as a pale yellow solid. TLC:rf (1:1 EA-Hept)=0.52. LC-MS-conditions 01: tR=0.70 min; [M+H]+=183.99.
Reaction SMILES: [C:1]1([NH2:8])[C:2]([NH2:7])=[CH:3][CH:4]=[CH:5][CH:6]=1.[CH:9]1([CH:12]=O)[CH2:11][CH2:10]1.[BH3-]C#N.[Na+].C(O)(=O)C>CO>[CH:9]1([CH2:12][NH:7][C:2]2[C:1]([NH2:8])=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:11][CH2:10]1
Reactant: O=CC1CC1
Reactant: Nc1ccccc1N
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: Nc1ccccc1NCC1CC1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a solution of benzene-1,2-diamine (1.62 g, 15.0 mmol) and cyclopropanecarbaldehyde (1.05 g, 15.0 mmol) in MeOH (15 mL) at 0° C. was added NaCNBH3 (2.07 g, 33.0 mmol) and acetic acid (0.2 mL). The ice bath was removed and the resulting mixture was stirred at room temperature over night. The resulting mixture was diluted with EtOAc, washed with H2O, dried over Na2SO4, filtered, and concentrated in vacuo. The resultant residue was purified by flash column chromatography (SiO2), eluting with a hexanes-EtOAc gradient to yield N-cyclopropylmethyl-benzene-1,2-diamine (836 mg, 34%). MS 163 (M+1)+.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3C2CCCCO2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:28]([Cl:31])=[N:29][CH:30]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Cl:31][C:28]1[C:27]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[CH:26][C:25]([NH:24][C:2]2[C:7]([C:8]3[N:16]=[C:15]([CH3:17])[N:14]=[C:13]4[C:9]=3[N:10]=[CH:11][NH:12]4)=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:30][N:29]=1
Reactant: Cc1nc(-c2cccnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: CS(=O)(=O)Nc1cc(N)cnc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cccnc2Nc2cnc(Cl)c(NS(C)(=O)=O)c2)c2nc[nH]c2n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 15 %

Procedure:
To a stirred solution of 6-(2-fluoropyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (Example 4, 0.0895 g, 0.286 mmol) and N-(5-amino-2-chloropyridin-3-yl)methanesulfonamide (Example 330, Step 2, 0.0772 g, 0.348 mmol) in THF (1 mL) in 5 mL microwave vial, LiHMDS (1.14 mL, 1.14 mmol) was added dropwise at 0° C. The dark red mixture was stirred at 0° C. for 30 min. The reaction was quenched by adding saturated aqueous sodium chloride (0.2 mL). The reaction mixture was partitioned between buffer (pH 5.0, citric acid/NaOH) (30 mL) and EtOAc (30 mL). The aqueous phase was extracted with EtOAc (30 mL). The combined organic phases were washed with water (40 mL) and saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated in vacuo. The residue was taken into THF (5 mL) and 5N HCl (1 mL) was added. The yellow mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated and the crude product was purified by preparative HPLC using a Phenomenex, Gemni 5 micron C18 100×30 mm column (1% to 90% CH3CN w/0.1% TFA/H2O w/0.1% TFA in 10 min). The pure fractions were collected and lyophilized to afford N-(2-chloro-5-(3-(2-methyl-9H-purin-6-yl)pyridin-2-ylamino)pyridin-3-yl)methanesulfonamide (TFA salt, 0.0185 g, 11% yield) as an orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 13.12 (br. s., 1H) 9.79 (d, J=7.63 Hz, 1H) 9.67 (s, 1H) 8.74 (d, J=2.54 Hz, 1H) 8.63 (s, 1H) 8.50 (d, J=2.54Hz, 1H) 8.41 (dd, J=4.69, 1.96 Hz, 1H) 7.14 (dd, J=7.92, 4.79 Hz, 1H) 3.13-3.18 (m, 3H) 2.86-2.90 (m, 3H). Note: one proton was missing from the NMR spectrum. m/z (ESI, positive ion): 430.9 (M+H)+ as parent ion.
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:11]=[C:10]([CH:12]([OH:14])[CH3:13])[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[N:8]=2)[CH:4]=1.[Cl:25][C:26]([Cl:30])([Cl:29])[C:27]#[N:28].N12CCCN=C1CCCCC2>ClCCl>[Cl:25][C:26]([Cl:30])([Cl:29])[C:27](=[NH:28])[O:14][CH:12]([C:10]1[C:9]2[C:5](=[CH:6][N:7]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:20])([CH3:22])[CH3:21])[N:8]=2)[CH:4]=[C:3]([C:2]([F:1])([F:23])[F:24])[CH:11]=1)[CH3:13]
Reactant: N#CC(Cl)(Cl)Cl
Reactant: CC(O)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CC(OC(=N)C(Cl)(Cl)Cl)c1cc(C(F)(F)F)cc2cn(COCC[Si](C)(C)C)nc12
Reaction time: 4 h

Procedure:
To a solution of (±)-1-(5-(trifluoromethyl)-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)ethanol (2.5 g, 6.94 mmol) and trichloroacetonitrile (6.95 mL, 69.4 mmol) in dichloromethane (50 mL) at room temperature was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.1 mL, 0.66 mmol). After stirring for 4 h, the reaction was concentrated and purified by column chromatography (12% EtOAc/Hex+0.1% Et3N) to give 3.1 g, (89%) as a white powder. 1H-NMR (CDCl3, 500 MHz) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.57 (s, 1H), 6.67 (q, J=6.6 Hz, 1H), 5.73 (s, 2H), 3.65 (t, J=8.4 Hz, 2H), 1.80 (d, J=6.6 Hz, 3H), 0.93 (m, 2H), −0.05 (s, 9H). Mass spec.: 526.90 (MH)+.
Reaction SMILES: O1CCN([C:7]2[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]=2)CC1.[S:13](Cl)(=[O:16])(=[O:15])[NH2:14].C(N(CC)CC)C.[O:25]1CCCC1>>[O:25]=[C:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[S:13]([NH2:14])(=[O:16])=[O:15]
Reactant: C1=C(N2CCOCC2)CCCC1
Reactant: C1CCOC1
Reactant: NS(=O)(=O)Cl
Solvent: CCN(CC)CC
Product: NS(=O)(=O)C1CCCCC1=O
Reaction time: 2 h

Procedure:
A solution of 16.7 g (0.1 mol) of morpholinocyclohexene in 200 ml of tetrahydrofuran was treated simultaneously, over a period of 2 hours, at -50° C., with solutions of 12.7 g (0.11 mol) of sulfamoyl chloride and 11.1 g (0.11 mol) of triethylamine each in 100 ml of tetrahydrofuran, the mixture was brought from -50° to 20° C. over a period of 2 hours and filtered, the filtrate was evaporated to dryness in vacuo and the residue was chromatographed on 400 g of silica gel with methylene chloride. After recrystallization from isopropanol, the main fraction yielded 9.7 g (54.8% of theory, based on enamine) of 2-oxocyclohexanesulfonamide of melting point 118°-119° C.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:14]=[C:15]([F:50])[CH:16]=[C:17]2[C:22]=1[N:21]=[C:20]([C:23]1[N:27]3[CH:28]=[C:29]([C@@H:32]([N:37]4[CH2:41][CH2:40][C@H:39]([NH:42]C(=O)OC(C)(C)C)[CH2:38]4)[C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:31][C:26]3=[N:25][N:24]=1)[CH:19]=[CH:18]2)(C(C)(C)C)(C)C.[Cl:51]CCl>FC(F)(F)C(O)=O>[ClH:51].[ClH:51].[NH2:42][C@H:39]1[CH2:40][CH2:41][N:37]([C@H:32]([C:29]2[CH:30]=[CH:31][C:26]3[N:27]([C:23]([C:20]4[CH:19]=[CH:18][C:17]5[C:22](=[C:13]([O:12][CH2:11][CH2:10][CH2:9][OH:8])[CH:14]=[C:15]([F:50])[CH:16]=5)[N:21]=4)=[N:24][N:25]=3)[CH:28]=2)[C:33]([F:35])([F:34])[F:36])[CH2:38]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)cc(OCCCO[Si](C)(C)C(C)(C)C)c5n4)n3c2)C(F)(F)F)C1
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@H]1CCN([C@H](c2ccc3nnc(-c4ccc5cc(F)cc(OCCCO)c5n4)n3c2)C(F)(F)F)C1
Yield: 84 %

Procedure:
A solution of tert-butyl (S)-1-((R)-1-(3-(8-(3-(tert-butyldimethyl silyloxy)propoxy)-6-fluoroquinolin-2-yl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)-2,2,2-trifluoroethyl)pyrrolidin-3-ylcarbamate (0.18 g, 0.24 mmol) in dichloromethane (1 mL) and trifluoroacetic acid (2 mL) was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography on a C18 column (0-80% acetonitrile/water). The material isolated after purification was dissolved in methanol (0.5 mL) and added dropwise to hydrochloric acid (2M in diethyl ether; 5 mL). The resulting salt was collected by vacuum filtration to provide the title compound (0.12 g, 84%). FIA-MS APCI (+) m/z 505 (M+H).
Reaction SMILES: O[CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21].C(N(S(F)(F)[F:28])CC)C.O>C(Cl)Cl>[F:28][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:5]=2[N:4]([CH3:20])[C:3]1=[O:21]
Reactant: CCN(CC)S(F)(F)F
Reactant: CN1C(=O)C(O)N=C(c2ccccc2)c2cc(Cl)ccc21
Solvent: O
Solvent: ClCCl
Product: CN1C(=O)C(F)N=C(c2ccccc2)c2cc(Cl)ccc21
Temperature: 0 °C
Yield: 70 %

Procedure:
A solution of 12.1 g (0.04 mol) of 3-hydroxy-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one in 25 ml of anhydrous methylene chloride was added dropwise over a period of 15 min. to a stirred solution of 12.6 ml (0.1 mol) of diethylaminosulfur trifluoride in 300 ml of anhydrous methylene chloride cooled to -70° . The reaction mixture was allowed to warm slowly over a period of 45 min. to 5° and then poured into 500 ml of ice and water. The lower organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and evaporated to drynes under reduced pressure to give 10.9 g (90% yield) of crude product as a light yellow solid residue. Recrystallization from heptane gave 8.48 g (70% yield) of 3-fluoro-1,3-dihydro-1-methyl-7-chloro-5-phenyl-2H-1,4-benzodiazepin-2-one as colorless crystals: mp 138°-140°; 19F nmr (CCl3D) δ -161.7 ppm (d, J=57 Hz); 1H nmr (CCl3D) δ 3.43 ppm (s, 3H), 5.54 ppm (d, J=57 Hz, 1H), 7.5 ppm (m, 8H).
Reaction SMILES: [CH3:1][NH2:2].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1>O1CCCC1.C(Cl)Cl>[CH3:1][NH:2][S:17]([C:14]1[CH:15]=[CH:16][C:11]([O:10][C:7]2[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=2)=[CH:12][CH:13]=1)(=[O:19])=[O:18]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CNS(=O)(=O)c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
To 20 ml of a 2 molar solution of methylamine in tetrahydrofuran chilled in an ice bath was added a solution of 5.16 g of 4-(4-chlorophenyloxy)benzene-sulfonyl chloride in 50 ml of tetrahydrofuran and 20 ml of CH2Cl2. The mixture was refluxed for 2 hours and the solvent removed under vacuum and the residue partitioned between CH2Cl2·H2O (1:1). The CH2Cl2 layer was separated and washed with 2 N citric acid, brine and dried (Na2SO4). The solution was filtered through a thin pad of hydrous magnesium silicate and the filter pad washed with CH2Cl2. The filtrate was concentrated to give 4.5 g of N-methyl-4-(4-chlorophenoxy)benzene-sulfonamide as a yellow solid, m.p. 80-83° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:17]1[O:18][C:19]2[C:20](=[C:22]([C:34]#[N:35])[C:23]([CH3:33])=[C:24]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:25]=2[F:26])[N:21]=1>ClCCl>[F:26][C:25]1[C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:23]([CH3:33])[C:22]([C:34]#[N:35])=[C:20]2[C:19]=1[O:18][C:17]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[N:21]2
Reactant: C1COCCN1
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCOCC3)nc2c1C#N
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
With cooling with ice, morpholine (36 μl, 0.413 mmol) and diisopropylethylamine (140 μl, 0.825 mmol) were added to a dichloromethane (3 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenylbenzoxazole-4-carbonitrile (I-130) (99 mg, 0.344 mmol), followed by stirring at room temperature for 2 hours. The reaction liquid was concentrated under reduced pressure, then the resulting residue was purified by silica gel column chromatography (eluent, n-hexane:ethyl acetate=2:1, v/v) to obtain the entitled compound (115 mg, 99%) as a white solid.