Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]#[C:2][NH2:3].[H-].[Na+].[N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N:12]=[C:13]=[S:14])[CH:7]=1>C1COCC1>[C:2]([NH:3][C:13]([NH:12][C:8]1[CH:7]=[N:6][CH:11]=[CH:10][CH:9]=1)=[S:14])#[N:1]
Reactant: S=C=Nc1cccnc1
Reactant: N#CN
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#CNC(=S)Nc1cccnc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.5 %

Procedure:
A solution of cyanamide (352 mg, 8.40 mmol) in THF (20 mL) at 0° C. was treated with sodium hydride (211 mg of 95% reagent, 8.80 mmol). The slurry was stirred for 30 minutes at 0° C. and treated with a solution of 3-pyridyl isothiocyanate (1.12 g, 8.20 mmol) in THF (8 mL). The cooling bath was removed, and the reaction mixture was stirred for 30 minutes. The reaction was quenched with water (15 mL), poured into ethyl acetate (40 mL), and partitioned. The organic phase was washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated. The residue was dissolved in diethyl ether, treated with HCl (2M solution in diethyl ether), and the resulting precipitate was collected providing 1.06 g of the desired product as an off-white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:28][C:29]([O:31]CC1C=CC=CC=1)=[O:30])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:21][CH2:20][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2]>O1CCCC1.[Pd]>[C:1]([O:5][C:6](=[O:39])[CH:7]([CH2:28][C:29]([OH:31])=[O:30])[CH2:8][C:9]1([C:14](=[O:27])[NH:15][C@H:16]2[CH2:17][CH2:18][C@@H:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:20][CH2:21]2)[CH2:13][CH2:12][CH2:11][CH2:10]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CC(=O)OCc3ccccc3)C(=O)OC(C)(C)C)CCCC2)CC1
Agent: [Pd]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H]1CC[C@@H](NC(=O)C2(CC(CC(=O)O)C(=O)OC(C)(C)C)CCCC2)CC1

Procedure:
2-(Benzyloxycarbonylmethyl)-3-{1-[(cis-4-ethoxycarbonylcyclohexyl)carbamoyl]cyclopentyl}propanoic acid t-butyl ester (3.50 g, 6.45 mmole) was dissolved in tetrahydrofuran (100 ml) and stirred with 5% palladium on carbon catalyst (200 mg) at room temperature under hydrogen at 50 p.s.i. (3.5 bar). After 36 hours the catalyst was removed by filtration and the solvent evaporated to give the product as a colourless oil (2.8 g, 96%). Found: C,63.28; H,8.70; N,3.20. C24H39NO7 requires C,63.55; H,8.67; N,3.09%.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:8](=[O:29])[CH:9]=[CH:10][C:11]=1[CH2:12][N:13]([CH2:24][C:25]([O:27][CH3:28])=[O:26])S(C1C=CC(C)=CC=1)(=O)=O)=O)C.C[O-].[Na+].Cl>CO>[CH3:28][O:27][C:25]([C:24]1[C:4]([OH:3])=[C:6]2[C:11]([CH:10]=[CH:9][C:8](=[O:29])[N:7]2[CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:12][N:13]=1)=[O:26]
Reactant: CCOC(=O)c1c(CN(CC(=O)OC)S(=O)(=O)c2ccc(C)cc2)ccc(=O)n1Cc1ccccc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ncc2ccc(=O)n(Cc3ccccc3)c2c1O
Reaction time: 8 h
Yield: 90.7 %

Procedure:
1-Benzyl-3-{[methoxycarbonylmethyl-(toluene-4-sulfonyl)-amino]-methyl}-6-oxo-1,6-dihydro-pyridine-2-carboxylic acid ethyl ester (0.14 g, 0.27 mmol) was dissolved in MeOH (10 mL) and cooled in an ice bath. NaOMe solution (0.2 mL, 0.82 mmol, 25 wt % in MeOH) was added, and the mixture was stirred overnight. The mixture was placed in an ice bath, and 1 M HCl was added until pH was about 3. The resulting mixture was extracted with CH2Cl2. The organic layer was dried over MgSO4 and concentrated. The residue was chromatographed (10-90% EtOAc/hexanes+2% AcOH) to give 76 mg of the title compound. MS: (−) m/z 311.30 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[CH2:7]([N:4]1[CH2:5][CH2:6][C@H:2]([OH:1])[CH2:3]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: O[C@H]1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: O[C@H]1CCN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A solution of (3S)-3-hydroxypyrrolidine (2.0 g, 25 mmol) 50 mL CH2Cl2, under a nitrogen atmosphere, was cooled to 0° C. and benzaldehyde (2.92 g, 27.5 mmol was added, followed by 1 g of powdered 4A molecular sieves. Sodium triacetoxyborohydride (7.4 gm, 35 mmol)was added in several portions over 30 min, and the reaction was allowed to stir at room temperature for 18 h. The reaction was again cooled to 0° C. and quenched by addition of 10 mL methanol, followed by 5 mL of 1N HCl. The molecular sieve solids were removed by filtration through a glass fiber paper, and the filtrate was extracted with 20 mL diethyl ether. The organic phase was discarded, and the aqueous phase was first basified by addition of conc. ammonium hydroxide, and then extracted with EtOAc (3×20 mL). The combined extracts were washed with 20 mL brine, dried (MgSO4), filtered, and concentrated in vacuo to furnish 3.2 g (73%) of clear yellow oil, which required no further purification. 1H-NMR (400 MHz, CDCl3) δ7.2-7.4 (m, 5H), 4.33 (, 11H), 3.63, (s, 2H), 2.83-3.89 (m, 1H), 2.67 (d, J=9.9 Hz, 1H), 2.53-2.55 (m, 1H), 2.23-2.34 (m, 1H), 2.14-2.20 (m, 2H), 1.70-1.77 (n, 11H).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([CH2:11][C:12]([NH:14][NH2:15])=O)[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:17]1[N:18]=[N:19][C:20]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:21][CH:22]=1>>[N:25]1[CH:26]=[CH:27][CH:28]=[C:23]([C:20]2[CH:21]=[CH:22][C:17]3[N:14]([C:12]([CH2:11][C:9]4[CH:8]=[CH:7][C:5]5[N:6]=[C:2]([NH2:1])[S:3][C:4]=5[CH:10]=4)=[N:19][N:18]=3)[N:15]=2)[CH:24]=1
Reactant: Clc1ccc(-c2cccnc2)nn1
Reactant: NNC(=O)Cc1ccc2nc(N)sc2c1
Product: Nc1nc2ccc(Cc3nnc4ccc(-c5cccnc5)nn34)cc2s1

Procedure:
The title compound was prepared as described in Example 1 from (2-amino-benzothiazol-6-yl)-acetic acid hydrazide (0.65 mmol) and 3-chloro-6-pyridin-3-yl-pyridazine (0.34 mmol) to afford a yellow solid. 1H NMR (DMSO-d6) δ 9.30 (1H, d, J=1.6 Hz), 8.78 (1H, dd, J=4.8 Hz, 1.7 Hz), 8.50 (1H, m), 8.49 (1H, d, J=9.5 Hz), 8.01 (1H, d, J=9.6 Hz), 7.69 (1H, s), 7.64 (1H, ddd, J=8.1 Hz, 4.8 Hz, 1.0 Hz), 7.42 (2H, s), 7.26 (2H, s), 4.61 (2H, s). ESI-MS (m/z): Calcd for C18H13N7S: 359.1; found 360.3 (M+H).
Reaction SMILES: [Si:1]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][C:11](OC)=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C.Cl>C(Cl)Cl>[Si:1]([O:8][CH:9]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]/[CH:22]=[CH:23]\[CH2:24]/[CH:25]=[CH:26]\[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH2:10][CH:11]=[O:12])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CCCCC/C=C\C/C=C\CCCCCCCC(CC(=O)OC)O[Si](C)(C)C(C)(C)C
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCC/C=C\C/C=C\CCCCCCCC(CC=O)O[Si](C)(C)C(C)(C)C
Reaction time: 1 h
Yield: 79.6 %

Procedure:
A solution of (11Z,14Z)-methyl 3-((tert-butyldimethylsilyl)oxy)icosa-11,14-dienoate (4) (5.0 g, 11.0 mmol) in CH2Cl2 (75 mL) was cooled (−78° C.) and treated, dropwise, with DIBAL (11.0 mL, 11.0 mmol; as a 1M solution in hexanes). The mixture was then warmed (−20° C.-−30° C.) and stirred (60 min). The mixture was poured into cold HCl (5% aq.), extracted with CH2Cl2, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was subjected to chromatography (1%→10% EtOAc-hexanes) to yield (11Z,14Z)-3-((tert-butyldimethylsilyl)oxy)icosa-11,14-dienal (5) (3.7 g, 79%) as a pale yellow oil. Rf 0.64 (10% EtOAc-hexanes), FW 422.79, C26H50O2Si.
Reaction SMILES: C(=O)([O-])[O-:2].[Na+].[Na+].[CH3:7][C:8]1([CH3:15])[O:14][CH2:13][CH:12]=[CH:11][CH2:10][O:9]1.C(#N)C1C=CC=CC=1.OO>CO>[CH3:7][C:8]1([CH3:15])[O:14][CH2:13][CH:12]2[CH:11]([O:2]2)[CH2:10][O:9]1
Reactant: CC1(C)OCC=CCO1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: N#Cc1ccccc1
Solvent: CO
Product: CC1(C)OCC2OC2CO1
Yield: 70 %

Procedure:
To a suspension of sodium carbonate (37 g, 0.35 mole) in a mixture of the dioxepin (II) (158.7 g, 1.26 mole), benzonitrile (127.9 g, 1.26 mole) and methanol (150 ml), was added 30% aqueous hydrogen peroxide (42.2 g, 1.24 mole) during 30 min at such a rate that the temperature stayed below 80°. The mixture was kept at 80° with an oil bath for 2 hr, by which time 99% of the hydrogen peroxide added had reacted. The mixture was decanted and, then, subjected to fractional distillation first at 60 mm, then at 20 mm and finally at 6 mm. The fraction boiling at 75°-85° at 6 mm was refractionated at 6 mm to obtain the product (III) as a colorless liquid. (125.5 g) (70% yield). b.p. 82°-87°/6 mm.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C@@H:4]1[CH2:6][C@@H:5]1[CH:7]1[CH2:12][CH2:11][N:10]([C:13]#[N:14])[CH2:9][CH2:8]1.[OH:15][NH:16][C:17](=N)[CH2:18][O:19][CH3:20].CC1C=CC(S(O)(=O)=O)=CC=1>C1COCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:20][O:19][CH2:18][C:17]1[N:14]=[C:13]([N:10]2[CH2:9][CH2:8][CH:7]([C@H:5]3[CH2:6][C@H:4]3[CH2:3][CH2:2][OH:1])[CH2:12][CH2:11]2)[O:15][N:16]=1
Reactant: COCC(=N)NO
Reactant: N#CN1CCC([C@H]2C[C@H]2CCO)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COCc1noc(N2CCC([C@H]3C[C@H]3CCO)CC2)n1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
In a 500 ml RBF was added a solution of 4-[(1R,2S)-2-(2-hydroxyethyl)cyclopropyl]piperidine-1-carbonitrile (from Step B, Intermediate 7; 7.5 g, 40 mmol) in 1:1 THF:EtOAc (150 ml). To this solution was added N-hydroxy-2-methoxyethanimidamide (5 g, 45 mmol) as a solid and the resulting mixture was stirred to yield a clear solution. An addition funnel was added to the flask and the whole set up was set under nitrogen atmosphere. The solution was placed in an oil bath heated to 70° C. A 0.5M solution of zinc chloride (100 ml, 50 mmol) in THF was placed in the addition funnel and added over a 5 minute period to the reaction mixture. Upon complete addition, the resulting mixture was stirred at 70° C. for 2 hours. After 30 minutes the clear solution became cloudy. After 1 hour at 70° C., a thick white precipitate formed. TLC indicates consumption of the all starting material. The mixture was cooled to RT and the white solid was filtered off and washed with 1:1 THF:EtOAc (200 mL) and dried. The white solid in the fritted funnel was dissolved in 50 mL of DMF and drawn through by vacuum into a 250 ml RBF. To this solution was then added Tosic Acid (4 g, 20 mmol) and the resulting mixture stirred at 80° C. overnight. The mixture was allow to cool to room temperature and then was diluted with 150 mL of ethyl acetate. The mixture was placed in a separatory funnel and washed with sat'd sodium bicarbonate solution (150 mL). The aqueous was extracted once with ethyl acetate (100 mL) and the organics were combined. The organics were washed with 1M Na2CO3 (50 mL), followed by water (2×100 mL), and then brine (100 mL). The organics were dried over sodium sulfate, filtered, and the filtrate concentrated to dryness under reduced pressure. The residue was taken up in 50 mL DCM and loaded onto a Flash 75 system (silica gel column). Biotage Flash 75 purification was done eluting with 40-80% ethyl acetate/hexane for 4 column volumes followed by 80% ethyl acetate for 4 column volumes (total solvent 16 L). The fractions containing the product were collected and concentrated under reduced pressure to afford the pure product. LC/MS (m/z): 282 (M+H)+.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].F[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][N:5]([CH3:6])[C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][C:12]([NH:18][C:19]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=34)[CH:22]=[CH:21][N:20]=2)=[C:11]([O:34][CH3:35])[CH:10]=1
Reactant: CNCCN(C)C
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N(C)CCN(C)C)c([N+](=O)[O-])cc1Nc1nccc(-c2cnn3ccccc23)n1
Temperature: 85 °C
Yield: 85 %

Procedure:
N1,N1,N2-trimethylethane-1,2-diamine (138 mg, 1.35 mmol) was added to a suspension of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 155, 428 mg, 1.13 mmol) and DIPEA (0.234 mL, 1.35 mmol) in DMA (3.3 mL), and the mixture was heated at 85° C. for 1.5 h. Part-purification was achieved by ion exchange chromatography, using an SCX column and eluting with 7M methanolic ammonia. Clean fractions were combined and concentrated in vacuo. Further purification by FCC, eluting with 0-10% CH3OH in CH2Cl2 gave the title compound (444 mg, 85%) as an orange oil; 1H NMR: 2.18 (6H, s), 2.50-2.53 (2H, m), 2.87 (3H, s), 3.26-3.30 (2H, m), 3.95 (3H, s), 6.86 (1H, s), 7.09 (1H, td), 7.30 (1H, d), 7.35-7.40 (1H, m), 8.27 (1H, s), 8.37 (1H, d), 8.47-8.51 (2H, m), 8.79 (1H, s), 8.79-8.82 (1H, m); m/z: ES+ MH+ 463.33.
Reaction SMILES: Br[CH:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13][CH2:12]2)=[CH:7][CH:6]=1)=O.[NH2:29][C:30]1[N:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[C:23]1([C:2]2[N:31]3[N:32]=[C:33]([O:36][CH3:37])[CH:34]=[CH:35][C:30]3=[N:29][C:3]=2[C:5]2[CH:6]=[CH:7][C:8]([C:11]3([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:19])([CH3:21])[CH3:20])[CH2:12][CH2:13][CH2:14]3)=[CH:9][CH:10]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(C(=O)C(Br)c3ccccc3)cc2)CCC1
Reactant: COc1ccc(N)nn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)n2n1
Yield: 78 %

Procedure:
A mixture of crude tert-butyl (1-{4-[bromo(phenyl)acetyl]phenyl}cyclobutyl)carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-1-A (0.67 g, 1.50 mmol), 3-amino-6-methoxypyridazine (CAS Registry No. 7252-84-8, 0.23 g, 1.80 mmol, 1.2 eq), N,N-diisopropylethylamine (0.74 mL, 1.50 mmol, 1.0 eq) and powdered activated 3 Å molecular sieves (10 g) in isopropanol (78 mL) was heated at the reflux temperature for 8 h. On cooling, the mixture was filtered through a pad of Celite. The Celite was washed with DCM, and the combined organics were washed with water, dried with sodium sulfate and concentrated under reduced pressure to give tert-butyl (1-{4-[3-phenyl-6-methoxyimidazo[1,2-b]pyridazin-2-yl]phenyl}cyclobutyl)carbamate (0.55 g, 78% yield).
Reaction SMILES: N.C([S:5][CH2:6][CH:7]([CH3:19])[C:8]([N:10]([CH:15]1[CH2:18][CH2:17][CH2:16]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:9])(=O)C>>[SH:5][CH2:6][CH:7]([CH3:19])[C:8]([N:10]([CH:15]1[CH2:18][CH2:17][CH2:16]1)[CH2:11][C:12]([OH:14])=[O:13])=[O:9]
Reactant: CC(=O)SCC(C)C(=O)N(CC(=O)O)C1CCC1
Agent: N
Product: CC(CS)C(=O)N(CC(=O)O)C1CCC1
Temperature: 25 °C
Yield: 91.5 %

Procedure:
Ammonia gas was bubbled through a stirred methanolic solution of N-(3-acetylthio-2-methylpropanoyl)-N-cyclobutylglycine (14.1 g, 0.052 mol) for 1 hour. This reaction mixture was left stirring 1 more hour at room temperature. Concentration on a rotary evaporator removed the remaining ammonia and most of the solvent. The residue was rediluted with methanol (500 ml) and the resultant solution was stirred with Bio-Rad AG-50W-X2 cation exchange resin (200 ml) for 1 hour. Filtration followed by concentration of the filtrate yielded 11 g (91%) of a thick yellow oil. This material was purified by HPLC with ethyl acetate, toluene, hexane, acetic acid (25:15:25:1) as the eluent to afford 8.8 g of the compound as a very viscous colorless oil.
Reaction SMILES: [OH:1][CH:2]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:29]=3[C:30]([F:33])([F:32])[F:31])[O:22][N:21]=2)=[CH:16][CH:15]=1)[C:3]([NH:5][CH2:6][C:7]([O:9]C(C)(C)C)=[O:8])=[O:4].[Li+].[OH-].Cl>C1COCC1.CO>[OH:1][CH:2]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:24]=[C:23]([C:25]3[CH:26]=[N:27][N:28]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)[C:29]=3[C:30]([F:31])([F:32])[F:33])[O:22][N:21]=2)=[CH:16][CH:15]=1)[C:3]([NH:5][CH2:6][C:7]([OH:9])=[O:8])=[O:4]
Reactant: CC(C)(C)OC(=O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CNC(=O)C(O)c1ccc(-c2noc(-c3cnn(-c4ccccc4)c3C(F)(F)F)n2)cc1
Reaction time: 0.33 h
Yield: 52.7 %

Procedure:
(R/S)-tert-Butyl 2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetate (Example 56, 30 mg, 0.055 mmol) was dissolved in THF (3 mL) and MeOH (1.50 mL). Next, LiOH (2.64 mg, 0.110 mmol) was added. After 20 min, additional LiOH (2.64 mg, 0.110 mmol) was added. After another 20 min, 1N HCl was used to adjust the pH to 4-5. The reaction mixture was concentrated. EtOAc was added and the resulting mixture was filtered. The filtrate was concentrated to provide (R/S)-2-(2-hydroxy-2-(4-(5-(1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)phenyl)acetamido)acetic acid (15 mg, 0.029 mmol, 52.2% yield): LCMS=488.2 [M+H]+; 1H NMR (400 MHz, methanol-d4) δ ppm 8.47 (1 H, s), 8.13 (2 H, d, J=8.35 Hz), 7.53-7.75 (7 H, m), 5.17 (1 H, s), 3.99 (2 H, s); HPLC peak RT=7.1 min (Method A).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:21]([O:23]C)=[O:22])=[CH:18][CH:19]=4)[C:14]([NH:25][CH3:26])=[N:13]3)[CH:10]=1)[N:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:6]=[CH:5]2.[OH-].[Li+].O.CO>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([CH2:11][N:12]3[C:20]4[C:15](=[CH:16][C:17]([C:21]([OH:23])=[O:22])=[CH:18][CH:19]=4)[C:14]([NH:25][CH3:26])=[N:13]3)[CH:10]=1)[N:7]([CH2:27][CH:28]([CH3:30])[CH3:29])[N:6]=[CH:5]2
Reactant: CNc1nn(Cc2cc(Cl)cc3cnn(CC(C)C)c23)c2ccc(C(=O)OC)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CNc1nn(Cc2cc(Cl)cc3cnn(CC(C)C)c23)c2ccc(C(=O)O)cc12
Temperature: 100 °C

Procedure:
A mixture of compound 69 (0.021 g, 0.05 mmol), lithium hydroxide (0.09 g, 0.2 mmol) in a mixture of tetrahydrofuran (1 mL), water (0.5 mL) and methanol (0.5 mL) was heated at 100° C. under microwave conditions for 10 minutes. Then, the reaction was quenched by adding water and diluted with ethyl acetate. The organic layer was separated, washed with Brine, dried (MgSO4), filtered and the solvent was evaporated.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Br)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Fc1cc(Br)c(F)cc1Cl
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 1-bromo-4-chloro-2,5-difluorobenzene (200 mg, 0.879 mmol) in THF (10 mL) cooled to −10° C. was added isopropylmagnesium bromide (1M in THF, 1.055 mL, 1.055 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0° C. and stirred for another 1 h. The resultant mixture was again cooled to −10° C. and treated dropwise with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 1.055 mmol). The reaction mixture was allowed to warm up to room temperature and treated with a saturated solution of ammonium chloride (3 mL). The layers were separated and aqueous layer was extracted with dichloromethane (2×2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography on a silica (7:3-Ethyl acetate:hexane) to afford 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 0.546 mmol, 62% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.49 (m, 1H), 7.09-7.13 (m, 1H), 1.35 (s, 12H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O.[CH3:13][C:14]1[NH:15][CH:16]=[CH:17][N:18]=1>>[CH3:13][C:14]1[N:18]2[CH2:2][CH2:3][CH:4]=[C:5]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:17]2=[CH:16][N:15]=1
Reactant: Cc1ncc[nH]1
Reactant: O=C(CCCCl)c1ccccc1
Product: Cc1ncc2n1CCC=C2c1ccccc1

Procedure:
Combine 270 g (1.48 mol) of 4-chlorobutyrophenone with 600 g (7.3 mol) of 2-methylimidazole and heat to 175° C. for 24 hr. Crystallization from ether provides the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13](O)=[O:14])[CH3:2].C1(C)C=CC=CC=1.S(Cl)([Cl:26])=O>CN(C)C=O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:16])[C:13]([Cl:26])=[O:14])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCc1cc(C)cc(CC)c1C(=O)C(=O)Cl
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a 50 ml volume four-necked flask, 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetic acid (8-a) (0.94 g), toluene (anhydrous) (3.0 ml) and dimethylformamide (anhydrous) (0.2 m) were added under a nitrogen atmosphere and the internal temperature was raised to about 50° C. Thionyl chloride (0.45 ml) was added thereto and the resulting mixture was stirred at 50° C. for 2 hours. The mixture was concentrated under reduced pressure, and azeotropically distilled with toluene to give 0.96 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl chloride (6-a).
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]([CH2:7][N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)=[CH:5][CH:4]=1)#[N:2].[Li]CCCC.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH2:29]Br)=[CH:23][CH:22]=1>>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:7]([N:8]2[CH:12]=[N:11][CH:10]=[N:9]2)[CH2:29][CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:13][CH:14]=1)#[N:2]
Reactant: N#Cc1ccc(Cn2cncn2)cc1
Reactant: Fc1ccc(CCCBr)cc1
Agent: [Li]CCCC
Product: N#Cc1ccc(C(CCCc2ccc(F)cc2)n2cncn2)cc1

Procedure:
The compound is prepared by the method described in Example 1 starting from 1-(4-cyanobenzyl)-1,2,4-triazole (6.0 g, 0.0272 mol), n-BuLi (0.0272 mol) and 3-(4-fluorophenyl)propylbromide (7.6 g, 0.035 mol). The product is purified first by suspending the residue with 2 M aqueous hydrogen chloride and petrol ether. Petrol ether phase is separated and the aqueous layer and the separated oil are extracted with diethyl ether. Diethyl ether phase is evaporated and the residue is purified by flash chromatography.
Reaction SMILES: ClC1C(C)=NOC=1[NH:7][S:8]([C:11]1[CH:15]=[CH:14][S:13][C:12]=1C(NC1C=C(OC)C(OC)=CC=1C(OC)=O)=O)(=[O:10])=[O:9].Cl>[OH-].[Na+]>[S:13]1[CH:14]=[CH:15][C:11]([S:8]([NH2:7])(=[O:10])=[O:9])=[CH:12]1
Reactant: COC(=O)c1cc(OC)c(OC)cc1NC(=O)c1sccc1S(=O)(=O)Nc1onc(C)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NS(=O)(=O)c1ccsc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
NaOH (1.5 N, 250 ml) was added to N-(4-chloro-3-methyl-5-isoxazolyl)-2-[(4,5-dimethoxy-2-methoxycarbonylphenyl)aminocarbonyl]thiophene-3-sulfonamide (EXAMPLE 149); 410 mg). The resulting suspension was stirred at room temperature overnight to give a clear solution. The mixture was acidified using concentrated HCl with cooling. The resulting precipitate was filtered, washed with water (3×50 ml) and dried on a lyophilyzer to give N-(4-chloro-3-methyl-5-isoxazolyl)2-{[2-carboxyl-4,5-(methylenedioxy)phenyl]aminocarbonyl})thiophene-3-sulfonamide as a yellow powder (87% yield, m.p. 192-195° C.).