Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=O)=[CH:7][C:6]=1[CH3:14])[CH:2]([CH3:4])[CH3:3].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.O[N:38]=[C:39]([C:41]1[C:42]([CH3:59])=[N:43][C:44]([CH2:47][O:48][Si](C(C)C)(C(C)C)C(C)C)=[CH:45][CH:46]=1)[NH2:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]2[O:11][N:40]=[C:39]([C:41]3[CH:46]=[CH:45][C:44]([CH2:47][OH:48])=[N:43][C:42]=3[CH3:59])[N:38]=2)=[CH:7][C:6]=1[CH3:14])[CH:2]([CH3:3])[CH3:4]
Reactant: Cc1nc(CO[Si](C(C)C)(C(C)C)C(C)C)ccc1C(N)=NO
Reactant: Cc1cc(C(=O)O)ccc1CC(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(-c2nc(-c3ccc(CO)nc3C)no2)ccc1CC(C)C

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 12 (12a) using 4-isobutyl-3-methylbenzoic acid (96 mg, 0.50 mmol) that was obtained in Example 27 (27d), 1-hydroxybenzotriazole (72 mg, 0.53 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.10 g, 0.53 mmol), N′-hydroxy-2-methyl-6-{[(triisopropylsilyl)oxy]methyl}pyridine-3-carboximidamide (0.16 g, 0.48 mmol) that was obtained in Example 24 (24d) and a 1.0 M solution of tetrabutylammonium fluoride in tetrahydrofuran (0.96 ml, 0.96 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (1:2) as the eluent to afford the title compound (0.15 g) in a yield of 91% as a white crystalline solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[CH:4][C:3]=1[O:10][C:11]([F:14])([F:13])[F:12].S(Br)(Br)=O.[CH2:19]([C@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:32](=[O:47])[CH2:33][C@@H:34]([C:40]1[CH:45]=[CH:44][C:43](O)=[CH:42][CH:41]=1)[C:35]1[CH:39]=[CH:38][O:37][N:36]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:43]2[CH:42]=[CH:41][C:40]([C@@H:34]([C:35]3[CH:39]=[CH:38][O:37][N:36]=3)[CH2:33][C:32]([N:27]3[C@@H:26]([CH2:19][C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:30][O:29][C:28]3=[O:31])=[O:47])=[CH:45][CH:44]=2)=[CH:4][C:3]=1[O:10][C:11]([F:13])([F:12])[F:14]
Reactant: OCc1ccc(Br)c(OC(F)(F)F)c1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: O=S(Br)Br
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(C[C@@H](c1ccc(OCc2ccc(Br)c(OC(F)(F)F)c2)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A mixture of 28.3 (1.30 g, 4.80 mmol), thionyl bromide (1.01 g, 4.84 mmol), and DMF (0.1 mL) in DCM (8.0 mL) was stirred at room temperature for 50 minutes. The solvent was then removed. To the residue was added 7.5 (1.10 g, 2.80 mmol) and Cs2CO3 (1.10 g, 3.36 mmol) in DMF (8.0 mL). The mixture was stirred at room temperature for 4 hours. EtOAc (150 mL) was added, and the mixture was washed with brine (25×3 mL) and dried with MgSO4. The solvent was removed, and the crude product was purified by CombiFlash, eluting with EtOAc and hexane, to give the title compound 28.4. 1H NMR (CDCl3) δ 2.77 (dd, J=4.2, 9.5 Hz, 1 H), 3.21 (dd, J=4.2, 9.5 Hz, 1 H), 3.52 (dd, J=8.6, 17.6 Hz, 1 H), 4.04 (dd, J=8.6, 17.6 Hz, 1 H), 4.63 (m, 1 H), 4.76 (m, 1 H), 5.01 (s, 2 H), 6.14 (d, J=1.5 Hz, 1 H), 6.92 (d, J=6.9,Hz, 2 H), 7.20-7.35 (m, 9 H), 7.64 (d, J=8.3,Hz, 1H), 8.31 (d, J=1.5 Hz, 1 H). MS ESI (pos.) m/e: 647 (M+H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:7].[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][C:6](=[O:7])[C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH2:27][CH2:26]2)[CH:20]=1)=[O:17]
Reactant: O=C(CCCCCl)c1ccccc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 using 5-chloro-1-phenyl-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 407.1 (M+H)+.
Reaction SMILES: [Na+].[C:2]([CH:7]([N:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH:33]=[CH:32]1)[C:8]([NH:10][CH:11]1[C:18](=[O:19])[N:17]2[CH:12]1[S:13][CH2:14][C:15]([CH2:23][S:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)=[C:16]2[C:20]([O-:22])=[O:21])=[O:9])([O:4][CH2:5][CH3:6])=[O:3].Cl[CH2:41][O:42][C:43](=[O:56])[C@H:44]([CH:53]([CH3:55])[CH3:54])[NH:45][C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47]>CN(C)C=O.C(OCC)(=O)C>[C:49]([O:48][C:46]([NH:45][CH:44]([CH:53]([CH3:55])[CH3:54])[C:43]([O:42][CH2:41][O:21][C:20]([C:16]1[N:17]2[CH:12]([S:13][CH2:14][C:15]=1[CH2:23][S:24][C:25]1[S:26][C:27]([CH3:30])=[N:28][N:29]=1)[CH:11]([NH:10][C:8](=[O:9])[CH:7]([C:2]([O:4][CH2:5][CH3:6])=[O:3])[N:31]1[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[CH:33]=[CH:32]1)[C:18]2=[O:19])=[O:22])=[O:56])=[O:47])([CH3:52])([CH3:51])[CH3:50]
Reactant: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(CSc3nnc(C)s3)CSC12)n1ccc2ccccc21
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C(=O)NC1C(=O)N2C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)=C(CSc3nnc(C)s3)CSC12)n1ccc2ccccc21
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 7-[[2-carbethoxy-2-(1H-indol-1-yl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared by the general procedure described in W. German Offen. No. 2,236,620 are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water, aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 7-[[2-carbethoxy-2-(1H-indol-1-yl)acetyl]amino]-3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: [OH-].[Na+].C([O:7][C:8](=[O:22])[CH2:9][N:10]([S:12]([C:15]1[CH:16]=[N:17][C:18](Cl)=[CH:19][CH:20]=1)(=[O:14])=[O:13])[CH3:11])(C)(C)C.[C:23]([OH:27])#[C:24][CH2:25][CH3:26]>O>[CH2:23]([O:27][C:18]1[N:17]=[CH:16][C:15]([S:12]([N:10]([CH2:9][C:8]([OH:7])=[O:22])[CH3:11])(=[O:13])=[O:14])=[CH:20][CH:19]=1)[C:24]#[C:25][CH3:26]
Reactant: CCC#CO
Reactant: CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CC(=O)O)cn1
Yield: 45 %

Procedure:
To a solution of 0.77 mL (19.3 mmol) of 2-butynl-ol and 0.18 g (4.37 mmol) of sodium hydroxide were heated at 100° C. for one hour. [(6-chloro-pyridine-3-sulfonyl)-methyl-amino]-acetic acid tert-butyl ester (1.0 g, 3.12 mmol) was added to this solution. Additional butynol was added to facilitate stirring, and the reaction was stirred at 100° C. overnight. The reaction was cooled, diluted with water, and washed with ethyl acetate. The aqueous layer was acidified with 2N HCl, and extracted with ethyl acetate (2×). The combined organics were washed with brine, dried over MgSO4, concentrated to solids which were slurried in 1:1:1 dichloromethane:hexane:ethyl acetate to afford 0.41 g (45%) of [(6-but-2-ynyloxy-pyridine-3-sulfonyl)-methyl-amino]-acetic acid as an off-white solid. Electrospray Mass Spec 299.0 (M+H)+
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[N:12][N:13]([CH2:21][C:22]([O:24]CC)=O)[C:14]=2[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][NH2:33])[CH3:28]>>[CH2:27]([N:29]([CH2:34][CH3:35])[CH2:30][CH2:31][CH2:32][NH:33][C:22](=[O:24])[CH2:21][N:13]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:10]([C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH:11]=[N:12]1)[CH3:28]
Reactant: CCOC(=O)Cn1ncc(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1
Reactant: CCN(CC)CCCN
Product: CCN(CC)CCCNC(=O)Cn1ncc(-c2ccc([N+](=O)[O-])cc2)c1-c1ccccc1

Procedure:
A solution of 3.51 g (0.01 mol) of ethyl 4-(4-nitrophenyl)-5-phenyl-1H-pyrazole-1-acetate of example 8 in 10 mL of 3(diethylamino)propanamine was reacted as in example 44. The product was recrystallized from methyl t-butyl ether to yield 5.4 g, mp 100°-101° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:10]([C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][N:30]=[C:31](F)[CH:32]=3)[N:27]=[CH:26][C:25]=2[C:35]#[N:36])=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([C:17]1[CH:18]=[CH:19][C:20]([NH:23][C:24]2[C:33]3[C:28](=[CH:29][N:30]=[C:31]([NH:1][CH2:2][CH2:3][N:4]4[CH2:9][CH2:8][O:7][CH2:6][CH2:5]4)[CH:32]=3)[N:27]=[CH:26][C:25]=2[C:35]#[N:36])=[CH:21][CH:22]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCCN1CCOCC1
Reactant: N#Cc1cnc2cnc(F)cc2c1Nc1ccc(Cc2ccccc2)cc1
Product: N#Cc1cnc2cnc(NCCN3CCOCC3)cc2c1Nc1ccc(Cc2ccccc2)cc1
Yield: 144 %

Procedure:
Following the procedure described above in Example 1,4-(4-benzylphenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.675 g, 1.90 mmol) was reacted with 4-(2-aminoethyl)morpholine (5.0 mL, 5.0 g, 38 mmol). This process was repeated with three additional aliquots of 4-(4-benzylphenylamino)-6-fluoro-1,7-naphthyridine-3-carbonitrile (0.62 g, 0.62 g, 0.30 g). The contents of all four tubes were worked up together, and the crude product purified by flash chromatography over silica gel (5-6% MeOH in CH2Cl2) to give pure product as bright yellow crystals (1.17 g, 40% yield): 1H NMR (400 MHz, DMSO-D6) δ 2.43 (br s, 4 H) 2.56 (t, J=6.7 Hz, 2 H) 3.31-3.39 (m, 2 H) 3.50-3.66 (m, 4 H) 3.99 (s, 2 H) 6.58 (t, J=4.9 Hz, 1 H) 7.04 (s, 1 H) 7.13-7.35 (m, 9 H) 8.22 (s, 1 H) 8.82 (s, 1 H) 9.56 (s, 1 H); HRMS (ESI+) calcd for C28H29N6O (MH+) 465.2398, found 465.2396.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>C(Cl)Cl>[CH2:1]([C@H:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][S:16]([C:19]2[CH:24]=[CH:23][C:22]([O:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[CH:29][CH:28]=3)=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:10][C@H:9]1[OH:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CCl)cc1
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(S(=O)(=O)CCN2CC[C@H](Cc3ccccc3)[C@H](O)C2)cc1)c1ccc(CN2CCOCC2)cc1
Yield: 31.6 %

Procedure:
To a solution of 200 mg (0.38 mmol) 4-chloromethyl-benzoic acid-(3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester in 10 ml CH2Cl2 were added 53 □l (0.38 mmol) Et3N and 33 μl (0.38 mmol) morpholine. After 16 hours the reaction mixture was purified by chromatography over silica gel to give 70 mg (0.12 mmol, 32%) 4-morpholin-4-ylmethyl-benzoic acid (3S,4S)-4-[2-(4-benzyl-3-hydroxy-piperidin-1-yl)-ethanesulfonyl]-phenyl ester as a colorless solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH3:8])=[CH:5][C:6]=1[CH3:7].[C:9](Cl)(=[O:11])[CH3:10].[Cl-].[Al+3].[Cl-].[Cl-]>>[C:9]([C:5]1[C:6]([CH3:7])=[C:2]([Cl:1])[S:3][C:4]=1[CH3:8])(=[O:11])[CH3:10]
Reactant: CC(=O)Cl
Reactant: Cc1cc(C)c(Cl)s1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)c1c(C)sc(Cl)c1C
Temperature: 0 °C
Reaction time: 24 h
Yield: 72.9 %

Procedure:
To a stirred solution of 2-chloro-3,5-dimethylthiophene (0.9 g, 6.18 mmol) in petroleum ether (5 mL) was added acetyl chloride (0.9 mL, 12.4 mmol) and aluminum chloride (0.99 g, 7.42 mmol) at room temperature under nitrogen, and the mixture stirred for 1 day. The reaction mixture was poured into ice water (50 mL) and the whole was extracted with diethyl ether (70 mL×2). The combined organic layers were washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with hexane-ethyl acetate (20:1) to provide the title product (0.85 g, 73% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16]([OH:18])=O)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:20][NH:21][O:22][CH3:23].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH3:23][O:22][N:21]([CH3:20])[C:16]([CH:12]1[CH2:11][CH:10]2[CH:14]([CH2:15][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]2)[CH2:13]1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)O)CC2C1
Reactant: CNOC
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CON(C)C(=O)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.3 %

Procedure:
To a mixture of 3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxylic acid (0.930 g, 3.65 mmol), N,O-dimethylhydroxylamine hydrochloride (0.71 g, 7.3 mmol) and diisopropylethylamine (DIPEA) (3.24 mL, 18.3 mmol) in N,N-dimethylformamide (DMF) (50 mL) was added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HBTU) (2.07 g, 5.48 mmol), and the mixture was stirred at ambient temperature overnight. The reaction was poured into saturated aqueous sodium bicarbonate (100 mL) and extracted with ethyl acetate (100 mL). The organic layer was washed with water (200 mL), dried over anhydrous sodium sulfate, concentrated by rotary evaporation and purified by silica gel flash column chromatography, to obtain 0.94 g (86% yield) of the N-methoxy-N-methyl-3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]octane-7-carboxamide, as an oil (1H NMR (CDCl3, 300 MHz): δ 3.69 (s, 3H), 3.6-3.42 (m, 2H), 3.36-3.05 (m, 3H), 3.18 (s, 3H), 2.82-2.57 (m, 2H), 2.08-2.02 (m, 2H), 1.82-1.65 (m, 2H), 1.46 (d, 9H); MS (m/z: 299 (M+1), 243 (M+1-56)).
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[C:9]([S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:17](I)[CH3:18].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([O:11][C:10]1[C:2]([Cl:1])=[C:3]([CH:7]=[CH:8][C:9]=1[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])[C:4]([OH:6])=[O:5])[CH3:18]
Reactant: CCI
Reactant: CCS(=O)(=O)c1ccc(C(=O)O)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(S(=O)(=O)CC)ccc(C(=O)O)c1Cl
Temperature: 90 °C

Procedure:
A mixture of the 2-chloro-4-ethylsulfonyl-3-hydroxybenzoic acid prepared in Example 4 (0.075 mole), ethyl iodide (0.5 mole), and potassium carbonate (0.1 mole) in dimethylformamide (150 ml) was heated at 90° C. for 7 hours. After cooling, the reaction mixture was partitioned between ethyl acetate and 5% potassium carbonate. The ethyl acetate layer was then washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford the crude ethyl ester of the desired benzoic acid. Hydrolysis of the ester to the acid was accomplished by stirring the ester (0.075 mole) with a base such as sodium hydroxide (0.1 mole) in ethanol (100 ml) at room temperature for 16 hours. The reaction mixture was acidified with 2N HCl, and then partitioned between methylene chloride and water. The methylene chloride layer was dried over magnesium sulfate and concentrated in vacuo to afford the acid as an oil.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:3](O)=[O:4].S(Cl)([Cl:14])=O>C(Cl)(Cl)Cl>[CH3:1][C:2]([C:7]1[CH:11]=[CH:10][S:9][CH:8]=1)([CH3:6])[C:3]([Cl:14])=[O:4]
Reactant: CC(C)(C(=O)O)c1ccsc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: CC(C)(C(=O)Cl)c1ccsc1
Reaction time: 0.5 h

Procedure:
The 2-methyl-2-(3-thienyl)propionic acid (34.0 g); obtained in Example 8, was dissolved in chloroform (60 ml) and to this solution was added thionyl chloride (31.0 g), followed by a 30 minute-refluxing under heating. After the reaction, the solvent and remaining thionyl chloride was removed under reduced pressure. The remaining crude product was distilled under reduced pressure to obtain 2-methyl-2-(3-thienyl) propionic acid chloride with bp 86°-88° C./2.Otorr.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7](=[O:27])[C:8]([F:26])([F:25])[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([CH3:5])[CH3:4].[H-].[Na+].[CH3:30]I.Cl>CN(C)C=O.O.C(OCC)(=O)C>[CH3:30][O:1][CH2:2][C:3]([NH:6][C:7](=[O:27])[C:8]([F:25])([F:26])[C:9]([C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][C:18]=1[F:24])([OH:16])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1)([CH3:5])[CH3:4]
Reactant: CC(C)(CO)NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reactant: CI
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COCC(C)(C)NC(=O)C(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 29 %

Procedure:
In 2 ml of N,N-dimethylformamide was dissolved 0.1 g of N-(1-hydroxy-2-methylpropan-2-yl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4-(1H-1,2,4-triazol-1-yl)butanamide. To the resulting solution was added 0.012 g of 60% sodium hydride at 0°-5° C. The solution was subjected to reaction at 20°-25° C. for 30 minutes. To the reaction mixture was added 0.04 g of methyl iodide at 0°-5° C. The resulting mixture was subjected to reaction at 20°-25° C. for 12 hours. The reaction mixture was introduced into a mixed solvent consisting of 10 ml of ethyl acetate and 5 ml of water. The resulting solution was adjusted to pH 2.0 with 6N hydrochloric acid. The organic layer was separated, washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure. The residue thus obtained was purified by a column chromatography (eluant: chloroform/methanol=100/1) to obtain 30 mg of N-(1-methoxy-2-methylpropan-2-yl)-3-(2,4-difluorophenyl)-2,2-difluoro-3-hydroxy-4- (1H-1,2,4-triazol-1-yl)butanamide.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([O:38]CC)=[O:37])=[CH:5]2)[CH2:3][CH2:2]1.[OH-].[Na+].O1CCOCC1.Cl>C(O)C>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:34])=[C:11]([C:15]4[CH:16]=[C:17]5[C:21](=[CH:22][CH:23]=4)[CH2:20][N:19]([S:24]([C:27]4[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=4)(=[O:26])=[O:25])[CH2:18]5)[C:12]=3[CH3:14])[C:7](=[O:35])[C:6]([C:36]([OH:38])=[O:37])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(C)c(-c3ccc4c(c3)CN(S(=O)(=O)c3ccc(C)cc3)C4)c(F)cc2c1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(S(=O)(=O)N2Cc3ccc(-c4c(F)cc5c(=O)c(C(=O)O)cn(C6CC6)c5c4C)cc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In 3 ml of ethanol was suspended 0.30 g of ethyl 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylate, and 3 ml of 1N aqueous sodium hydroxide solution and 3 ml of dioxane were added to the suspension, after which the resulting mixture was stirred at room temperature for two hours. To the reaction mixture was added 3 ml of 1N hydrochloric acid, and the crystals thus formed were collected by filtration, to obtain 0.27 g of colorless, crystalline 1-cyclopropyl-6-fluoro-8-methyl-7-[2-(p-toluenesulfonyl)isoindolin-5-yl]-1,4-dihydro-4-oxoquinoline-3-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N+:12]([O-])=O)[CH:8]=2)[N:3]=1.NC1C=C2C(=CC=1)N=CC=N2>CO>[CH3:1][C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH2:12])[CH:8]=2)[N:3]=1
Reactant: Cc1cnc2cc([N+](=O)[O-])ccc2n1
Agent: Nc1ccc2nccnc2c1
Solvent: CO
Product: Cc1cnc2cc(N)ccc2n1
Yield: 88 %

Procedure:
A thick-walled Parr hydrogenation flask was charged with 2-methyl-6-nitroquinoxaline (10.0 g, 52.9) and CH3OH (200 ml). The flask was flushed with a stream of nitrogen and 10% by weight palladium on charcoal (500 mg) was added. The flask was pressurized with hydrogen to 50 psi and maintained at this pressure for three (3) hours. The reaction mixture was filtered and washed through silicon dioxide and concentrated in vacuo to yield a tan solid. The crude material was chromatographed (SiO2 ; 95/5 CHCl3 /CH3OH saturated with NH3 (g)) and recrystallized from benzene to yield 7.4 g (a yield of 88%) of a tan solid. Using various analytical procedures, this tan solid was determined to be 2-methyl-,6-aminoquinoxaline.
Reaction SMILES: [N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=3)[C:19](O)=O)=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)[Cl:26].C[Si](Cl)(C)C.S(Cl)(Cl)=O>C(N(CC)CC)C>[N:1]1([S:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[NH:16][C:17](=[O:24])[C:18](=[CH:22][CH:23]=3)[CH2:19][Cl:26])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(-c2ccc(S(=O)(=O)N3CCCC3)cc2)[nH]c1=O
Reactant: ClCCl
Agent: C[Si](C)(C)Cl
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: O=c1[nH]c(-c2ccc(S(=O)(=O)N3CCCC3)cc2)ccc1CCl

Procedure:
From 4.4 g. of 6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinic acid in 150 ml. of methylene chloride, 1.6 ml. of triethylamine, 1.45 ml. of trimethylsilyl chloride and 1.7 ml. of thionyl chloride, following the procedure of a) above, there is obtained 6-[4-(1-pyrrolidinylsulfonyl)phenyl]-1,2-dihydro-2-oxonicotinyl chloride.
Reaction SMILES: [I:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[OH:9])=[CH:4][CH:3]=1.[H-].[Na+].[Cl-].[NH4+].[CH3:24]N(C)C=O>IC>[I:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[O:9][CH3:24])=[CH:4][CH:3]=1
Reactant: COc1cccc(C(O)COc2ccc(I)cc2)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CI
Product: COc1cccc(C(COc2ccc(I)cc2)OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(4-iodophenoxy)-1-(3-methoxyphenyl)ethanol (215 mg) in dimethylformamide (2 ml), 0.072 ml of iodomethane and 46 mg of sodium hydride were added under ice-cooling, and the reaction solution was stirred at room temperature for 30 minutes. To the reaction solution was added an aqueous saturated ammonium chloride solution, and the mixture was extracted with ethyl acetate. The combined organic layers were washed with a saturated saline solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (98:2-50/50)) to afford the title compound as a colorless oil.