Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:23][CH2:22][C:21]([CH3:25])([CH3:24])[CH2:20][CH2:19]1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:35][C:36]1[N:37]=[C:38]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[S:39][C:40]=1[CH2:41]O.CCOC(/N=N/C(OCC)=O)=O.[OH-].[Na+]>C1COCC1.CO>[C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:34])=[N:14][C:15]([CH3:33])=[C:16]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:41][C:40]3[S:39][C:38]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)=[N:37][C:36]=3[CH3:35])=[CH:28][CH:27]=2)[C:17]=1[N:18]1[CH2:19][CH2:20][C:21]([CH3:24])([CH3:25])[CH2:22][CH2:23]1)[C:7]([OH:9])=[O:8])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1nc(-c2ccccc2)sc1CO
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)nc(C)c(-c2ccc(O)cc2)c1N1CCC(C)(C)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1nc(-c2ccccc2)sc1COc1ccc(-c2c(C)nc(C)c([C@H](OC(C)(C)C)C(=O)O)c2N2CCC(C)(C)CC2)cc1
Reaction time: 18 h
Yield: 34 %

Procedure:
To a stirred solution of (S)-ethyl 2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-5-(4-hydroxyphenyl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.053 mmol), (4-methyl-2-phenylthiazol-5-yl)methanol (32.9 mg, 0.160 mmol) and Ph3-resin (69.7 mg, 0.267 mmol) in THF (2 mL) was added DEAD (0.025 mL, 0.160 mmol) at rt. After 18 h, mixture was filtered to remove polymer, concentrated and treated with 1N NaOH (1.067 mL, 1.067 mmol) in MeOH (1 mL) at 75° C. for 16 h. Mixture was then cooled and purified by prep-HPLC to afford (S)-2-(tert-butoxy)-2-(4-(4,4-dimethylpiperidin-1-yl)-2,6-dimethyl-5-(4-((4-methyl-2-phenylthiazol-5-yl)methoxy)phenyl)pyridin-3-yl)acetic acid (11.6 mg, 0.018 mmol, 34.6% yield). 1H NMR (500 MHz, DMSO-d6) δ 7.89 (d, J=7.3 Hz, 2H), 7.52-7.41 (m, 4H), 7.25 (d, J=8.1 Hz, 1H), 7.14 (t, J=7.9 Hz, 2H), 7.10-7.04 (m, 1H), 5.82 (br. s., 1H), 5.41 (q, J=12.8 Hz, 2H), 3.26 (d, J=11.7 Hz, 1H), 2.77 (br. s., 1H), 2.47 (s, 3H), 2.43 (s, 3H), 2.15 (d, J=10.3 Hz, 1H), 2.07 (s, 3H), 1.88 (br. s., 1H), 1.46 (br. s., 1H), 1.24 (br. s., 1H), 1.15 (br. s., 1H), 1.12 (s, 9H), 0.92 (d, J=10.3 Hz, 1H), 0.77 (br. s., 3H), 0.51 (br. s., 3H). LCMS (M+H)=628.6.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>ClCCl.C(N(CC)CC)C>[S:21]([O:1][CH2:2][CH2:3][CH2:4][C@@H:5]1[O:10][C:9]2[CH:11]=[C:12]3[C:17](=[CH:18][C:8]=2[NH:7][C:6]1=[O:19])[CH2:16][CH2:15][CH2:14][CH2:13]3)([CH3:20])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1Nc2cc3c(cc2O[C@H]1CCCO)CCCC3
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCC[C@@H]1Oc2cc3c(cc2NC1=O)CCCC3
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 79.7 %

Procedure:
To a stirred , ice-cooled suspension of (S)-6,7,8,9-tetrahydro-2-(3-hydroxypropyl)-2H-naphtho[2,3-b][1,4] oxazin-3(4H)-one (1.15 g) in a mixture of dichloromethane (40 ml) and triethylamine (0.45 g), was added dropwise methanesulfonyl chloride (1.01 g). The whole was stirred at 0° C. for 1.5 hour, washed with water and dried over magnesium sulfate. The solvent was distilled off and the residue was purified by column chromatography on silica gel (60 g) with ethyl acetate-hexane (3:2, v/v). The resulting crystals were recrystallized from methanol to yield (S)-6,7,8,9-tetrahydro-2-(3-mesyloxypropyl)-2H-naphto[2,3-b][1,4]oxazin-3(4H)-one as colorless needles (1.19 g, 79.7%), m.p. 153°-154° C. [α]D26 +4.8° (c=0.8, CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:11])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH3:12][O:13][CH2:14]OC.CN(C)C=O.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([O:11][CH2:12][O:13][CH3:14])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]
Reactant: COCOC
Reactant: O=[N+]([O-])c1ccc(O)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COCOc1ccc([N+](=O)[O-])c(F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 31.1 %

Procedure:
A solution of 3-fluoro-4-nitrophenol (10.0 g, 0.064 mol), dimethoxymethane (19.3 g, 0.255 mol) and N,N-dimethylformamide (6.0 g, 0.083 mol) in toluene is heated to 65° C., treated dropwise with phosphorus oxychloride (15.7 g, 0.102 mol), stirred at 90° C. for two hours, cooled to room temperature and poured into ice water which contains five mL of 50% sodium hydroxide solution. After the ice has melted, the mixture is extracted with ether. The organic extract is washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a yellow liquid (4.0 g) which is identified by 1HNMR spectral analysis.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([CH:36]2[CH2:39][N:38](C(OC(C)(C)C)=O)[CH2:37]2)=[O:35])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@@H:9]([NH:33][C:34]([CH:36]2[CH2:39][NH:38][CH2:37]2)=[O:35])[C:10]([N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[N:24]([CH2:29][CH:30]3[CH2:32][CH2:31]3)[S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)N[C@H](Cc2ccc(Cl)cc2)C(=O)N2CCC(c3ccccc3N(CC3CC3)S(C)(=O)=O)CC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N(CC1CC1)c1ccccc1C1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC(=O)C2CNC2)CC1

Procedure:
The title compound was prepared according to the procedure described in Example 3 (Step b) using tert-butyl 3-(N-[(1R)-1-[(4-chlorophenyl)methyl]-2-(4-{2-[(cyclopropylmethyl)-(methylsulfonyl)amino]phenyl}piperidyl)-2-oxoethyl]carbamoyl)azetidine-carboxylate (Step a) (565 mg, 0.84 mmol) and 50% TFA in CH2Cl2 (6 mL). Purification by reverse phase preparative HPLC [YMC-Pack ODS-AM 250×20 mm 5 μm column, 40% to 75% CH3CN (0.1% TFA) in H2O(0.1% TFA) over 10 min] provided the title compound (TFA salt) as an amorphous white solid (420 mg). MS (ESI, pos. ion) m/z: 573 (M+1). Calcd for C29H37ClN4O4S: 572.22. Anal. Calcd for C29H37ClN4O4S 1.7C2HF3O2: C, 50.74; H, 5.09; N, 7.30, S, 4.18. Found: C. 50.47; H, 5.03; N, 7.36; S, 4.28.
Reaction SMILES: BrBr.[C:3]([NH:7][NH:8][C:9]1([C:18]#[N:19])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)([CH3:6])([CH3:5])[CH3:4]>>[C:3]([N:7]=[N:8][C:9]1([C:18]#[N:19])[CH2:14][CH:13]([CH3:15])[CH2:12][C:11]([CH3:17])([CH3:16])[CH2:10]1)([CH3:5])([CH3:4])[CH3:6]
Reactant: CC1CC(C)(C)CC(C#N)(NNC(C)(C)C)C1
Agent: BrBr
Product: CC1CC(C)(C)CC(C#N)(N=NC(C)(C)C)C1

Procedure:
1-tert.-butylazo-1-cyano-3,3,5-trimethylcyclohexane was prepared by bromine oxidation of the above 1-tert.-butylhydrazo-1-cyano-3,3,5-trimethylcyclohexane in the same way that 4-tert.-butylhydrazo-4-cyano-2,6-dimethylheptane was oxidized in Example VII C. The yield of liquid product was 8.2 g. (63%) and the infrared spectrum was consistent with the structure of the proposed compound.
Reaction SMILES: [CH3:1][C@:2]12[CH2:19][C:18](=[O:20])[C@H:17]3[C@@H:7]([CH2:8][CH2:9][C@@H:10]4[C@:15]3([CH3:16])[CH2:14][CH:13]=[CH:12][CH2:11]4)[C@@H:6]1[CH2:5][CH2:4][C@@H:3]2[C:21]([OH:23])=[O:22].ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)(Cl)Cl>[O:32]1[C@H:12]2[CH2:11][C@H:10]3[C@:15]([CH3:16])([CH2:14][C@@H:13]12)[C@@H:17]1[C@H:7]([C@H:6]2[C@@:2]([CH2:19][C:18]1=[O:20])([CH3:1])[C@@H:3]([C:21]([OH:23])=[O:22])[CH2:4][CH2:5]2)[CH2:8][CH2:9]3
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@]12CC=CC[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Solvent: ClC(Cl)Cl
Product: C[C@]12C[C@H]3O[C@H]3C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12

Procedure:
A solution of 5α-androst-2-en-11one 17β-carboxylic acid (1.397 g.) and m-chloroperbenzoic acid (850 mg.) in chloroform (20 ml.) was stirred at room temperature for 3.25 hr. and then diluted with chloroform (75 ml.) prior to washing with 10% aqueous sodium bicarbonate and water. The chloroform solution was dried, filtered and evaporated to give a foam (1.04g.) which, after preparative t.l.c. afforded the pure title compound as a foam; [α]D + 69°, (c 0.3).
Reaction SMILES: [Sn](Cl)(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[C:12]([O:14][CH3:15])[CH:11]=[C:10]([O:16][CH3:17])[CH:9]=1.[Cl:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](Cl)=[O:24].Cl>C1C=CC=CC=1>[CH3:17][O:16][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[C:23]([CH2:22][CH2:21][CH2:20][CH2:19][Cl:18])=[O:24]
Reactant: O=C(Cl)CCCCCl
Reactant: COc1cc(OC)cc(OC)c1
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: COc1cc(OC)c(C(=O)CCCCCl)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 91 g (0.384 mol) of tin tetrachloride in 112.5 ml of benzene is added over 1 h 30 min to a solution, maintained at about +5° C., of 50.4 g (0.3200 mol) of 1,3,5-trimethoxybenzene and 50.2 g (0.324 mol) of 5-chlorovaleryl chloride in 225 ml of benzene. The mixture is stirred overnight at room temperature and the reaction medium is poured into 325 ml of ice-cold water and 75 ml of 12N hydrochloric acid. The organic phase is separated out after settling has taken place, washed with water and dried over dry sodium sulphate.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[CH3:8].Br[CH2:10][C:11]([O:13][CH3:14])=[O:12].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:8][C:2]1[CH:1]=[C:6]([CH:5]=[CH:4][CH:3]=1)[O:7][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CBr
Reactant: Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(C)c1
Reaction time: 8 h

Procedure:
A mixture of m-cresol (10.8 g), methyl bromoacetate (15.3 g) and potassium carbonate (69 g) in dimethylformamide (200 ml) was stirred overnight and partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. Purified by chromatography eluting with toluene. Yield 12.7 g.
Reaction SMILES: [Cl:1][C:2]1[C:11]([NH2:12])=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[N+:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[S:24](Cl)(=[O:26])=[O:25])([O-:17])=[O:16]>N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([NH:12][S:24]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[N+:15]([O-:17])=[O:16])(=[O:25])=[O:26])=[C:10]2[C:5]([C:6]([O:13][CH3:14])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccnc2c(N)c(Cl)ccc12
Solvent: c1ccncc1
Product: COc1ccnc2c(NS(=O)(=O)c3ccccc3[N+](=O)[O-])c(Cl)ccc12
Yield: 56.6 %

Procedure:
In a similar fashion using route 18 general procedure 26, 8-amino-7-chloro-4-methoxyquinoline 70 (550 mg, 2.6 mmol), 2-nitrobenzenesulphonylchloride (642 mg, 2.9 mmol) in pyridine (10 ml) gave the title compound (580 mg, 55%) which was used in the next step without further purification.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][OH:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:15](N(CC)CC)[CH3:16].CS(Cl)(=O)=O.C(=O)(O)[O-].[Na+]>C1COCC1>[C:4]([Si:1]([O:8][CH2:9][C:10]([CH3:14])([CH3:13])[CH2:11][O:12][CH2:15][CH3:16])([CH3:3])[CH3:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CCN(CC)CC
Reactant: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCC(C)(C)CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropan-1-ol (Registry No. 117932-70-4) (2.18 g, 10 mmol) in THF (30 ml) were added triethylamine (1.67 ml, 12 mmol) and methanesulfonyl chloride (0.85 ml, 11 mmol) under ice cooling. The reaction liquid was stirred at room temperature for 30 minutes, and to the reaction liquid was added an aqueous solution of sodium bicarbonate.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([O:31]C)=[O:30])[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]4[CH:45]=[CH:44][C:43]([N+:46]([O-:48])=[O:47])=[CH:42][CH:41]=4)[CH:34]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12].O[Li].O.Cl>O1CCCC1.O.C(OCC)(=O)C>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]([C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][C:40]4[CH:41]=[CH:42][C:43]([N+:46]([O-:48])=[O:47])=[CH:44][CH:45]=4)[CH:34]=3)=[CH:25][CH:24]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: COC(=O)c1nc(N2CCc3cccc(C(=O)Nc4nc5ccccc5s4)c3C2)ccc1-c1cccc(Oc2ccc([N+](=O)[O-])cc2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1nc2ccccc2s1)c1cccc2c1CN(c1ccc(-c3cccc(Oc4ccc([N+](=O)[O-])cc4)c3)c(C(=O)O)n1)CC2
Reaction time: 8 h

Procedure:
To an ambient solution of EXAMPLE 104B (75 mg) in tetrahydrofuran (1.5 mL) and water (0.5 mL) was added LiOH H2O (13 mg). The reaction was stirred overnight, diluted with 2 mL water and 2 mL ethyl acetate, and acidified to pH ˜3 with 10% aqueous HCl solution. The layers were separated, and the aqueous layer was extracted with additional ethyl acetate (2×8 mL). The combined organic layers were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to provide the title compound. 1H NMR (300 MHz, dimethylsulfoxide-d6) δ ppm 12.85 (s, 1H), 8.26 (m, 2H), 8.03 (d, 1H), 7.79 (d, 1H), 7.71 (d, 1H), 7.62 (d, 1H), 7.43 (m, 5H), 7.26 (d, 1H), 7.14 (m, 4H), 7.00 (d, 1H), 4.99 (s, 2H), 3.91 (t, 2H), 3.01 (t, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[NH:11][C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([O:31][CH3:32])=[O:30].C(OCC)(=O)C>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([N:8]2[CH2:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=3[N:11]([CH2:25][C:26]3[CH:35]=[CH:34][CH:33]=[C:28]([C:29]([O:31][CH3:32])=[O:30])[CH:27]=3)[C:10](=[O:19])[CH2:9]2)=[O:7])=[CH:4][CH:3]=1
Reactant: O=C1CN(C(=O)c2ccc(Cl)cc2)Cc2ccccc2N1
Reactant: COC(=O)c1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cccc(CN2C(=O)CN(C(=O)c3ccc(Cl)cc3)Cc3ccccc32)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
150 mg (0.50 mmol) of 4-(4-chlorobenzoyl)-1,3,4,5-tetrahydrobenzo[e][1,4]diazepin-2-on was dissolved in 10 ml of DMF. 24 mg (0.60 mmol) of sodium hydride was added to the obtained solution, and they were stirred at room temperature for 30 minutes. 160 mg (0.70 mmol) of methyl 3-(bromomethyl)benzoate was added to the reaction mixture, and they were stirred at room temperature overnight. After the treatment with ethyl acetate as the extracting solvent by an ordinary method, the obtained crude product was purified by the silica gel column chromatography.
Reaction SMILES: [ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH:7]=[CH:8][CH:9]1[NH:15][C:14](=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]1>CCO.[Pd]>[ClH:1].[S:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][CH2:8][CH:9]1[NH:15][C:14](=[NH:16])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: N=C1CCCCC(C=Cc2cccs2)N1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: N=C1CCCCC(CCc2cccs2)N1

Procedure:
The title material of Example 175 in EtOH is hydrogenated over 10% Pd on carbon catalyst in a standard Parr apparatus by the method of Example 35 to generate the title product.
Reaction SMILES: [OH:1][C:2]1[N:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[CH:4]=O.C([O-])=O.[Na+].Cl.[NH2:19]O>C(O)=O>[OH:1][C:2]1[N:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][C:3]=1[C:4]#[N:19]
Reactant: NO
Reactant: O=Cc1cc(C(F)(F)F)cnc1O
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: N#Cc1cc(C(F)(F)F)cnc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2-hydroxy-5-(trifluoromethyl)nicotinaldehyde (3.80 g, 17.9 mmol) (approx. 90% purity), sodium formate (1.46 g, 20.8 mmol), hydroxylamine hydrochloride (1.47 g, 20.8 mmol) in formic acid (36.6 mL) was stirred at room temperature for 2 h (cloudy brown solution) and then heated to reflux overnight (first clear brown solution, then cloudy again). After being cooled to room temperature, the reaction mixture was quenched with water and extracted with EtOAc three times. The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to yield 3.03 grams (90%) of the desired crude product (approx. 75% purity) as a brown solid. MS calculated for C7H3F3N2O: (M+H)+189; found 189.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([O:12]CC)=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][OH:35])[CH:29]=2)[CH:19]=1)=[O:17].O[Li].O>>[F:1][C:2]1[CH:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([OH:12])=[O:11])=[CH:4][C:3]=1[NH:15][C:16]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[C:20]([C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([CH2:34][OH:35])[CH:29]=2)[CH:19]=1)=[O:17]
Reactant: CCOC(=O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cccc(CO)c3)cc3ccccc23)c1
Agent: [Li]O
Solvent: O
Product: O=C(O)/C=C/c1ccc(F)c(NC(=O)c2cc(-c3cccc(CO)c3)cc3ccccc23)c1
Yield: 27.86 %

Procedure:
Compound 17f (27.86%) was synthesized from 16f (0.89 mmol) and LiOH.H2O (8.94 mmol) using the procedure according to Method E described above.
Reaction SMILES: C(Cl)Cl.[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].O=[CH:17][C@@H:18]([C@H:20]([C@@H:22]([C@@H:24]([CH2:26]O)O)O)O)[OH:19].C(O[BH:33][O:34][CH2:35][CH2:36][CH2:37][CH3:38])CCC>O>[O:4]=[CH:5][C@@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14][OH:15])[OH:13])[OH:11])[OH:9])[OH:7].[C:35]1([O:34][BH:33][O:19][C:18]2[CH:17]=[CH:26][CH:24]=[CH:22][CH:20]=2)[CH:36]=[CH:37][CH:38]=[CH:6][CH:5]=1
Reactant: CCCCOBOCCCC
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: ClCCl
Solvent: O
Product: B(Oc1ccccc1)Oc1ccccc1
Reaction time: 0 h

Procedure:
A solution of 100 mg/dL of glucose bis phenylboronate and dry methylene chloride was prepared and applied to CLINISTIX® glucose test strip pad. No color development was observed. The pads were then wetted with water and in 2 or 3 minutes color development was observed. Glucose bis butylboronate was similarly applied to CLINISTIX® strips. Again no color was observed upon application. After wetting with water strong color development was observed in 10 to 15 seconds.
Reaction SMILES: [NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([SH:7])=[N:5][N:6]=1.C([O-])([O-])=O.[K+].[K+].Cl[CH2:28][C:29]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=1[Cl:42])=[O:30]>CN(C=O)C>[NH2:1][C:2]1[N:3]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([CH:18]3[CH2:20][CH2:19]3)=[CH:10][CH:9]=2)[C:4]([S:7][CH2:28][C:29]([NH:31][C:32]2[CH:37]=[CH:36][C:35]([S:38](=[O:41])(=[O:40])[NH2:39])=[CH:34][C:33]=2[Cl:42])=[O:30])=[N:5][N:6]=1
Reactant: Nc1nnc(S)n1-c1ccc(C2CC2)c2ccccc12
Reactant: NS(=O)(=O)c1ccc(NC(=O)CCl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nc1nnc(SCC(=O)Nc2ccc(S(N)(=O)=O)cc2Cl)n1-c1ccc(C2CC2)c2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.3 %

Procedure:
In a solution of 5-amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazole-3-thiol (708 mg, 2.5 mmol), K2CO3 (380 mg, 2.5 mmol) in DMF (20 mL) was added 2-chloro-N-(2-chloro-4-sulfamoylphenyl)acetamide (710 mg, 2.5 mmol). The reaction mixture was stirred at room temperature overnight. Upon completion of the reaction, the solvent was evaporated. The residue was purified by silica gel chromatography to yield 2-[5-Amino-4-(4-cyclopropylnaphthalen-1-yl)-4H-[1,2,4]triazol-3-ylsulfanyl]-N-(2-chloro-4-sulfamoylphenyl)acetamide (1.26 g, 95%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1(O)[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2].C(N(S(F)(F)[F:27])CC)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][C:6]1([F:27])[CH2:11][CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7]1)[CH3:2]
Reactant: CCOC(=O)CC1(O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)CC1(F)CCN(C(=O)OC(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-hydroxypiperidine-1-carboxylate (12 g) in DCM (60 ml) at −78° C. under nitrogen was added by syringe diethylaminosulfur trifluoride (DAST) (8.3 ml). The mixture was stirred at −78° C. for 3 hours, then slowly warming up to rt, the mixture was then poured to aqueous sodium bicarbonate (200 ml), extracted with ethyl acetate (200 ml+100 ml), organic layer dried over sodium sulphate, solvent removed under vacuum. The oily residue was taken into ethanol (150 ml) and water (150 ml). Magnesium sulphate (5.4 g) was then added, followed by potassium permanganate (7.2 g). The mixture was stirred at rt for 1 hour, then extracted with ethyl acetate (600 ml). Organic layer was washed with brine (150 ml), dried over sodium sulphate, solvent removed under vacuum, residue was columned on silica gel using heptane:EtOAc (7:1) as eluant to give tert-butyl 4-(2-ethoxy-2-oxoethyl)-4-fluoropiperidine-1-carboxylate (3.8 g) as a colourless oil. 1H NMR (CDCl3) δ: 4.16 (q, 2H), 3.95 (br, 2H), 3.10 (t, br, 2H), 2.64 (d, 2H), 1.93 (t, br, 2H), 1.6-1.85 (m, 2H), 1.46 (s, 9H), 1.27 (t, 3H).
Reaction SMILES: C(N1C2C(=CC(S(N)(=O)=O)=CC=2)CC1)C.[C:16]([N:19]1[C:27]2[C:22](=[CH:23][C:24]([Br:32])=[C:25]([S:28]([NH2:31])(=[O:30])=[O:29])[CH:26]=2)[CH2:21][CH2:20]1)(=O)[CH3:17]>>[Br:32][C:24]1[CH:23]=[C:22]2[C:27](=[CH:26][C:25]=1[S:28]([NH2:31])(=[O:30])=[O:29])[N:19]([CH2:16][CH3:17])[CH2:20][CH2:21]2
Reactant: CC(=O)N1CCc2cc(Br)c(S(N)(=O)=O)cc21
Agent: CCN1CCc2cc(S(N)(=O)=O)ccc21
Product: CCN1CCc2cc(Br)c(S(N)(=O)=O)cc21
Yield: 51.1 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 53, 1-acetyl-5-bromoindoline-6-sulfonamide (Intermediate 60A, 110 mg, 0.34 mmol) was converted to the title compound (53 mg, 50%). 1H NMR (DMSO-d6) δ 7.34 (s, 1H), 7.32 (s, 2H), 7.00 (s, 1H), 3.41 (t, J=8.5 Hz, 2H), 3.14 (q, J=7.1 Hz, 2H), 2.95 (t, J=8.5 Hz, 2H), 1.10 (t, J=7.2 Hz, 3H); MS(ESI+) m/z 307.1 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=O.FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.O[NH:48]/[C:49](=[N:57]\[H])/[C:50]1[CH:55]=[CH:54][C:53]([CH3:56])=[CH:52][CH:51]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[CH3:56][C:53]1[CH:54]=[CH:55][C:50]([C:49]2[N:57]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:2]3=[O:1])[O:22][N:48]=2)=[CH:51][CH:52]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C)cc1
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: Cc1ccc(-c2noc(CN3CCC(c4ccccc4)(c4ccccc4)C3=O)n2)cc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)—N-hydroxy-4-methylbenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.93-7.87 (m, 2H), 7.43-7.22 (m, 10H), 7.08 (s, 1H), 6.90-6.81 (m, 1H), 4.88 (s, 2H), 3.56 (t, J=6.5, 2H), 2.88 (t, J=6.5, 2H), 2.42 (s, 3H)); MS (DCI) m/z 410.1 (M+H)+.