Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8](=[O:31])[CH:9]([C:17]1[CH:30]=[CH:29][C:20]2[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:23][C:19]=2[CH:18]=1)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:6])([CH3:5])[CH3:4].CN(C=O)C.[B-](F)(F)(F)[F:38].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>C1COCC1>[C:3]([O:7][C:8](=[O:31])[C:9]([C:17]1[CH:30]=[CH:29][C:20]2[CH:21]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[S:23][C:19]=2[CH:18]=1)([F:38])[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:5])[CH3:6]
Reactant: F[B-](F)(F)F
Reactant: CCOC(=O)c1cc2ccc(C(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccc(C(F)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc2s1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a suspension of sodium hydride (0.96 g, 24.0 mmol) in THF (75 mL) cooled to 0° C. was added a solution of di-tert-butyl[2-(ethoxycarbonyl)-1-benzothien-6-yl]malonate (described above) (9.66 g, 23.0 mmol) in THF (150 mL) under nitrogen. The resulting orange solution was stirred at 4° C. for 15 minutes. DMF (225 mL) was added followed by Selectfluor (8.15 g, 23.0 mmol). The reaction was warmed to ambient temperature and stirred for 4 hours under nitrogen. The reaction was quenched with ammonium chloride solution and partitioned between ethyl acetate and water. The organics were washed with water and brine, dried over magnesium sulfate, filtered and evaporated in vacuo. Purification by flash column chromatography (2-20% ethyl acetate/hexanes) gave a mixture of starting material and product. This was resubjected to above reaction conditions and purified in a similar manner to give a pale yellow solid. 1H NMR (DMSO-d6) δ 8.21 (s, 1H), 8.17 (s, 1H), 8.07 (d, J=8.8 Hz, 1H), 7.52 (d, J=9.1 Hz, 1H), 4.33 (q, J=7.3 Hz, 2H), 1.44 (s, 18H), 1.31 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]=[CH2:10].[CH:11](C1C=CC=CC=1C)(C)C.ClCC1C(Cl)=C(C(C)C)C=CC=1>>[Cl:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([CH3:11])=[CH2:10]
Reactant: Cc1ccccc1C(C)C
Reactant: C=Cc1ccccc1CCl
Agent: CC(C)c1cccc(CCl)c1Cl
Product: C=C(C)c1ccccc1CCl

Procedure:
Finally the art teaches in U.S. Pat. No. 2,780,604 that chloromethyl vinyl benzene can be prepared via a two step liquid phase reaction whereby isopropyl toluene is chlorinated via ultraviolent light and the subsequently distilled chloromethyl chloroisopropyl benzene is dehydrohalogenated with heat to give chloromethylisopropenylbenzene.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:8](C(O)=O)[C:7](O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C1C=CC2N([OH:23])N=NC=2C=1.CC(C)N=C=NC(C)C>>[N+:1]([C:4]1[CH:12]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:23])([O-:3])=[O:2]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1O
Reactant: On1nnc2ccccc21
Agent: CC(C)N=C=NC(C)C
Product: O=[N+]([O-])c1ccccc1O

Procedure:
This material was prepared from 5-nitrosalicylic acid (1c) (1 g, 5.46 mmol), HOBt (1 g, 7.4 mmol), DIC (1,3-diisopropylcarbodiimide, 1 mL, 6.4 mmol), and an amino polystyrene resin (1 g, 1.2 mmol) using a procedure similar to polystyrene resin (PS-2a).
Reaction SMILES: C(OC(N1CCC[C@H]1C([N:18]1[C:26]2[C:21](=[CH:22][C:23]([O:27][CH3:28])=[CH:24][CH:25]=2)[CH:20]=[CH:19]1)=O)=O)C1C=CC=CC=1.[CH2:29]([N:31]([CH2:34][CH3:35])[CH2:32][CH3:33])C.[C:36](OCC)(=O)C>>[CH3:28][O:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[NH:18][CH:19]=[C:20]2[CH2:33][C@@H:32]1[CH2:36][CH2:35][CH2:34][N:31]1[CH3:29]
Reactant: CCN(CC)CC
Reactant: CCOC(C)=O
Reactant: COc1ccc2c(ccn2C(=O)[C@@H]2CCCN2C(=O)OCc2ccccc2)c1
Product: COc1ccc2[nH]cc(C[C@@H]3CCCN3C)c2c1
Yield: 22 %

Procedure:
(S)-(N-Benzyloxycarbonylpyrrolidin-2-ylcarbonyl)-5-methoxy-1H-indole was used. The chromatographic eluent was 8% triethylamine in ethyl acetate to afford the title compound (yields ranged from 22 to 57%) as an oil: IR (CHCl3) 3475, 1625, 1585, 1480, 1455 cm-1 ; 1H NMR (CDCl3) δ8.13 (br s, 1H), 7.23 (d, J=8.8 Hz, 1H), 7.04 (d, J=2.4 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.84 (dd, J=2.4 and 8.8 Hz, 1H), 3.86 (s, 3H), 3.17-3.10 (m, 2H), 2.58 (dd, J=9.9 and 13.9 Hz, 1H), 2.50-2.40 (m, 1H), 2.47 (s, 3H), 2.26-2.17 (m, 1H), 1.89-1.72 (m, 2H), 1.70-1.52 (m, 2H); 13C NMR (CDCl3) δ153.8, 131.4, 128.2, 122.7, 113.9, 111.8, 111.7, 101.1, 66.6, 57.5, 56.0, 40.8, 31.5, 30.0, 21.9; LRMS, m/z (relative intensity) 244 (M+, 7), 160 (20), 145 (16), 117 (21), 84 (100); HRMS: calculated for C15H20N2O: 244.1573; found: 244.1575; [α]25D =-96° (CHCl3, c=1.0).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8](Cl)(=[O:10])=[O:9].[CH2:12]([NH2:14])[CH3:13].Cl.CCOC(C)=O>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:14][CH2:12][CH3:13])(=[O:10])=[O:9]
Reactant: CCN
Reactant: O=S(=O)(Cl)c1ccccc1Br
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCNS(=O)(=O)c1ccccc1Br
Reaction time: 24 h
Yield: 56 %

Procedure:
To a 20 mL vial were added a stirbar, 2-bromobenzene-1-sulfonyl chloride (0.995 g, 3.89 mmol), and THF (5 mL). The vial was then charged with EtNH2 in THF (5 mL, 2.0 M). The mixture was stirred for 24 hours before adding it to a separatory funnel containing 1 N HCl and EtOAc. The layers were mixed thoroughly and then separated. The organic layer was then washed with water followed by sat. NaHCO3, dried over MgSO4, filtered and concentrated to dryness to give the crude product. Subjecting the oil to FCC yielded the title compound (580 mg, 56%). 1H NMR (600 MHz, CDCl3) δ 8.17-8.10 (dd, J=7.8, 1.7, 1H), 7.75-7.69 (dd, J=7.8, 1.2, 1H), 7.48-7.43 (m, 1H), 7.43-7.37 (m, 1H), 5.16-4.91 (t, J=6.7, 1H), 3.06-2.87 (m, 2H), 1.19-1.00 (t, J=7.3, 3H).
Reaction SMILES: CC12CCCCN1C=CCNC2.[CH3:13][C:14](=[CH:16][CH2:17][CH2:18][N+:19]([O-:21])=[O:20])[CH3:15].[C:22]([O:27][CH3:28])(=[O:26])/[CH:23]=[CH:24]/[CH3:25]>CO>[CH3:25][CH:24]([CH:18]([N+:19]([O-:21])=[O:20])[CH2:17][CH:16]=[C:14]([CH3:15])[CH3:13])[CH2:23][C:22]([O:27][CH3:28])=[O:26]
Reactant: C/C=C/C(=O)OC
Reactant: CC(C)=CCC[N+](=O)[O-]
Agent: CC12CCCCN1C=CCNC2
Solvent: CO
Product: COC(=O)CC(C)C(CC=C(C)C)[N+](=O)[O-]
Reaction time: 144 h
Yield: 19.5 %

Procedure:
Methyl 3,7-Diazabicyclo[5,4,0]undec-5-ene (4 ml) is added to a solution of 2-methyl-5-nitro-2-pentene (25.0 g, 0.193 m) in methanol (200 ml). The resulting mixture is heated to 60° and methyl crotonate (30.85 g, 0.308 m) is added under nitrogen. The mixture is then stirred for 6 days at 60° after which it is cooled to room temperature and most of the methanol is removed in vacuo. The residue is treated with ether (500 ml) and washed with 2 N HCl (250 ml) and water (250 ml). The organic layer is dried (Na2SO4) and evaporated in vacuo to give 42.5 g of crude product. The crude product is purified by column chromatography on silica gel (500 g, ethyl acetate/hexane 2:98) to give methyl 3,7-dimethyl-4-nitro-6-octenoate (8.65 g, 42%).
Reaction SMILES: [Br-:1].[CH3:2][N+:3]1([CH3:22])[C:12]2[C:7](=[C:8]([N:14]=NC3C=CC=CC=3)[CH:9]=[CH:10][C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1.CO.[H][H]>[Pd].O>[Br-:1].[CH3:2][N+:3]1([CH3:22])[C:12]2[C:7](=[C:8]([NH2:14])[CH:9]=[CH:10][C:11]=2[OH:13])[CH2:6][CH2:5][CH2:4]1
Reactant: C[N+]1(C)CCCc2c(N=Nc3ccccc3)ccc(O)c21
Reactant: [H][H]
Agent: [Pd]
Agent: [Br-]
Solvent: O
Solvent: CO
Product: C[N+]1(C)CCCc2c(N)ccc(O)c21

Procedure:
Into a stainless steel autoclave, one introduces 36.2 g of N,N-dimethyl-1,2,3,4-tetrahydro-5-phenylazo-8-hydroxyquinolinium bromide (i.e. 0.1 mole), 200 ml of methanol and 3 g of 5% palladium on charcoal. The reduction is carried out at a pressure of 3-5 kg/cm2 of hydrogen and a temperature of 50°-60°C. After cooling, one adds a sufficient quantity of water to dissolve the entire mass, then one filters off the catalyst. One evaporates the filtrate to the dry state. The residue is extracted by means of ether so as to remove the aniline. One washes, with acetone, the clear brown compound that is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([Cl:10])[CH:3]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:4]([Cl:10])[CH:3]=1
Reactant: C1CCNCC1
Reactant: O=Cc1ccc(Br)cc1Cl
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Clc1cc(Br)ccc1CN1CCCCC1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To a pre-stirred solution of 4-bromo-2-chlorobenzaldehyde (1.01 g, 4.6 mmol) and piperidine (500 μL, 5.0 mmol) in DCM (20 mL) at 0° C. was added sodium triacetoxyborohydride (1.46 g, 6.9 mmol) in portions. The reaction mixture was allowed to warm to ambient temperature and then partitioned between water (50 mL) and dichloromethane (50 mL). The organic phase was separated, washed with saturated aqueous sodium carbonate (50 mL), dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant residue was loaded onto a 20 g SCX-2 cartridge which was washed with methanol then 2N ammonia in methanol. Concentration of the combined basic fractions in vacuo afforded the title compound as a colourless oil (1.15 g, 87%). NMR (CDCl3, 400 MHz): 7.50-7.48 (m, 1H); 7.40-7.33 (m, 2H); 3.50 (s, 2H); 2.46-2.38 (m, 4H); 1.62-1.53 (m, 4H); 1.49-1.40 (m, 2H). LCMS (Method B): RT=2.03 min, M+H+=288.
Reaction SMILES: [OH:1][CH:2]([C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=2)[N:16]=1)N1C=C(C(OC)=O)C=N1.[OH-:27].[Na+].Cl.[CH2:30]([OH:32])[CH3:31]>>[OH:1][CH:2]([C:12]1[S:13][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=2)[N:16]=1)[C:17]1[CH:18]=[CH:19][C:31]([C:30]([OH:27])=[O:32])=[CH:14][CH:15]=1
Reactant: CCO
Reactant: [OH-]
Reactant: COC(=O)c1cnn(C(O)c2nc(-c3cccc(C(F)(F)F)c3)cs2)c1
Agent: Cl
Agent: [Na+]
Product: O=C(O)c1ccc(C(O)c2nc(-c3cccc(C(F)(F)F)c3)cs2)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of the compound (0.65 g) obtained in Example 198b, 2N aqueous sodium hydroxide solution (10 mL) and ethanol (10 mL) was stirred at room temperature for 4 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was adjusted to pH 2-3 and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative liquid chromatography to give the title compound (0.21 g) as a colorless solid.
Reaction SMILES: [C:1]([C:3]1[C:11]2[S:10][C:9]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])=[N:8][C:7]=2[CH:6]=[CH:5][C:4]=1[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([NH:25]C(=O)C(F)(F)F)[CH:20]=1)#[N:2].O.[OH-].[Li+].Cl>O1CCCC1.CO.O>[NH2:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[O:18][C:4]1[CH:5]=[CH:6][C:7]2[N:8]=[C:9]([NH:12][C:13]([CH:15]3[CH2:17][CH2:16]3)=[O:14])[S:10][C:11]=2[C:3]=1[C:1]#[N:2]
Reactant: N#Cc1c(Oc2cccc(NC(=O)C(F)(F)F)c2)ccc2nc(NC(=O)C3CC3)sc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: N#Cc1c(Oc2cccc(N)c2)ccc2nc(NC(=O)C3CC3)sc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
N-(7-Cyano-6-{3-[(trifluoroacetyl)amino]phenoxy}-1,3-benzothiazol-2-yl)cyclopropanecarboxamide (1.06 g, 2.37 mmol) was dissolved in a mixed solvent of tetrahydrofuran (25 mL)/methanol (25 mL)/water (25 mL), lithium hydroxide monohydrate (1.05 g, 25.7 mmol) was added, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was neutralized with 1N hydrochloric acid, and concentrated under reduced pressure. The obtained residue was repeatedly washed with water to give the title compound (0.79 g, 95%) as a white powder.
Reaction SMILES: [C:1]([C:9]1[C:18]([CH3:19])=[N+:17]([O-:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:22]Br>CO>[C:1]([C:9]1[C:18]([CH2:19][Br:22])=[N+:17]([O-:20])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N+:10]=1[O-:21])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1c(C(=O)c2ccccc2)[n+]([O-])c2ccccc2[n+]1[O-]
Reactant: BrBr
Solvent: CO
Product: O=C(c1ccccc1)c1c(CBr)[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C
Yield: 85 %

Procedure:
To a stirred suspension of 28 g. (0.10 mol.) of 2-benzoyl-3-methylquinoxaline 1,4-dioxide in 1,000 ml. of methanol was added 5.6 ml. (0.11 mol.) of bromine. The reaction mixture was refluxed for 2 hours and then an additional 5.6 ml. (0.11 mol.) of bromine was added. The mixture was refluxed for an additional 2 hours and then it was cooled to 25° C. The solid which had precipitated was collected by filtration, washed with methanol, and dried to afford 30.4 g.(85% yield) of 2-benzoyl-3-bromomethylquinoxaline 1,4 -dioxide, m.p. 183°-185° C.
Reaction SMILES: C[S:2](Cl)(=[O:4])=[O:3].[N:6]1([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[O:20])=[CH:14][CH:13]=2)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1.N[C:31]1C=C2C(=[CH:38][CH:39]=1)CN(C(NC1C=CC(C(=O)NCCC)=CC=1)=O)C2>>[CH:39]([S:2]([N:9]1[CH2:10][CH2:11][N:6]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:22]3)=[O:20])=[CH:14][CH:13]=2)[CH2:7][CH2:8]1)(=[O:4])=[O:3])([CH3:38])[CH3:31]
Reactant: O=C(Nc1ccc(N2CCNCC2)cc1)N1Cc2ccccc2C1
Reactant: CS(=O)(=O)Cl
Reactant: CCCNC(=O)c1ccc(NC(=O)N2Cc3ccc(N)cc3C2)cc1
Product: CC(C)S(=O)(=O)N1CCN(c2ccc(NC(=O)N3Cc4ccccc4C3)cc2)CC1

Procedure:
The title compound was prepared as described in Example 283, substituting isopropylsulfonyl chloride for methanesulfonyl chloride and N-(4-(piperazin-1-yl)phenyl)isoindoline-2-carboxamide for 5-amino-N-(4-(propylcarbamoyl)phenyl)isoindoline-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.16 (s, 1H), 7.39-7.45 (m, 2H), 7.27-7.38 (m, 4H), 6.88-6.92 (m, 2H), 4.74 (s, 4H), 3.07-3.12 (m, 4H), 1.25 (d, J=6.8 Hz, 6H); MS (ESI(+)) m/e 429 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2].[H-].[Na+].Br[CH2:19][C:20]1[CH:24]=[C:23]([C:25]2[S:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[O:22][N:21]=1.O>CN(C=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:19][C:20]2[CH:24]=[C:23]([C:25]3[S:26][C:27]([Cl:30])=[CH:28][CH:29]=3)[O:22][N:21]=2)[N:8]=[C:9]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2cccs2)n[nH]1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2cccs2)nn1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
To a solution of 2.0 g 5-Thiophen-2-yl-2H-pyrazole-3-carboxylic acid ethyl ester in 5 ml DMF, 360 mg NaH (60% in mineral oil) and subsequently 2.8 g 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole [prepared by adopting a procedure described by Ewing, William R.; Becker, Michael R.; Choi-Sledeski, Yong Mi; Pauls, Heinz W.; He, Wei; Condon, Stephen M.; Davis, Roderick S.; Hanney, Barbara A.; Spada, Alfred P.; Burns, Christopher J.; Jiang, John Z.; Li, Aiwen; Myers, Michael R.; Lau, Wan F.; Poli, Gregory B; PCT Int. Appl. (2001) 460 pp. WO 0107436 A2] were added and the mixture was stirred at 80° C. for 1 h. After the addition of 5 ml water the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate and then concentrated under reduced pressure. The residue was directly subjected to the subsequent saponification reaction without further purification. Yield: 4 g.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:19])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[O:14][C:15]([CH3:18])=[N:16][N:17]=2)=[CH:9][CH:8]=1.CO.C1COCC1>O>[CH3:18][C:15]1[O:14][C:13]([C:10]2[CH:11]=[CH:12][C:7]([C:6]([OH:19])=[O:5])=[CH:8][CH:9]=2)=[N:17][N:16]=1
Reactant: COC(=O)c1ccc(-c2nnc(C)o2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nnc(-c2ccc(C(=O)O)cc2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.7 %

Procedure:
Oxalyl chloride (1.05 g, 8.3 mmol) was added to a stirred solution of terephthalic acid monomethyl ester (1 g, 5.55 mmol) in DCM (12 mL) and stirring was continued at ambient temperature for 4 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was dissolved in DCM (4 mL) and to the resulting solution was added, acetic acid hydrazide (490 mg, 6.66 mmol), Et3N (670 mg, 6.66 mmol) and stirring was continued at temperature overnight. The reaction mixture was diluted with water and extracted with ethylacetate, dried over sodium sulfate and concentrated under reduced pressure to afford 1 g (76.39% Yield) of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester. A stirred solution of 4-(N′-acetyl-hydrazinocarbonyl)-benzoic acid methyl ester (500 mg, 5.55 mmol) in POCl3 (12 mL) was heated at 100° C. for 3 hr. The reaction mixture was concentrated under reduced pressure to afford the residue. The residue was diluted with cold water, extracted with ethyl acetate, washed the organic layer with sodium bicarbonate solution, saturated brine solution and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to 350 mg (75.92% Yield) of afford 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester. LiOH.H2O (330 mg, 8 mmol) was added to a solution of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid methyl ester (350 mg, 1.6 mmol) in the mixture of methanol (4 mL), THF (10 mL) and H2O (4 mL). The resulting reaction mixture was stirred at ambient temperature for 2 hrs. The reaction mixture was concentrated The residue was diluted with water, acidified with aqueous citric acid solution, extracted with ethyl acetate and dried over sodium sulfate. The organic layer was concentrated under reduced pressure to afford 280 mg (87.46% Yield) of 4-(5-methyl-[1,3,4]oxadiazol-2-yl)-benzoic acid.
Reaction SMILES: [CH2:1]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([O:26]CC)=[O:25])=[O:18])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].O[Li].O.C(O)(=O)C>C1COCC1.O>[CH2:1]([C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])=[O:18])[CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCc1ccnc(C(=O)NCCCCC(=O)OCC)c1
Agent: [Li]O
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCCCCc1ccnc(C(=O)NCCCCC(=O)O)c1
Yield: 95.5 %

Procedure:
A solution of 0.20 g (0.52 mmol) of 5-[[(4-decyl-2-pyridinyl)carbonyl]amino]pentanoic acid, ethyl ester prepared in Example 7, 0.05 g (1 mmol, 2 eq) of LiOH·H2O in 4 ml of THF and 1 ml of H2O was stirred at room temperature for 21 hours, then 1.5 eq of glacial acetic acid was added. The resulting solution was poured into H2O and extracted with Et2O. The organic layers were combined, poured into H2O and extracted with Et2O. The organic layers were combined, dried (Na2SO4) and concentrated in vacuo. Hexanes were added to the residue and the flask was cooled. The resulting white solid was collected, yielding 180 mg (97%) of title compound: m.p. 54°-56° C.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=CC=CC=2)[C:5](NS(C2SC=CC=2)(=O)=O)=[CH:4][C:3]=1SC1N(C)N=NN=1.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](/[N:38]=[C:39]2\[CH:40]=[C:41]([S:50][C:51]3[N:55]([CH3:56])[N:54]=[N:53][N:52]=3)[C:42](=[O:49])[C:43]3[C:48]\2=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:37])=[O:36])=[CH:31][CH:30]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([S:35]([NH:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[C:42]([OH:49])=[C:41]([S:50][C:51]3[N:55]([CH3:56])[N:54]=[N:53][N:52]=3)[CH:40]=2)(=[O:37])=[O:36])=[CH:33][CH:34]=1.[CH3:56][N:55]1[C:51]([S:50][C:41]2[C:42](=[O:49])[C:43]3[C:48](=[CH:47][CH:46]=[CH:45][CH:44]=3)/[C:39](=[N:38]/[S:35]([C:32]3[CH:33]=[CH:34][C:29]([C:2]4[CH:11]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:30][CH:31]=3)(=[O:37])=[O:36])/[CH:40]=2)=[N:52][N:53]=[N:54]1
Reactant: Cn1nnnc1Sc1cc(NS(=O)(=O)c2cccs2)c2ccccc2c1O
Reactant: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(Cl)cc2)c2ccccc2C1=O
Product: Cn1nnnc1SC1=C/C(=N\S(=O)(=O)c2ccc(-c3ccccc3)cc2)c2ccccc2C1=O
Product: Cn1nnnc1Sc1cc(NS(=O)(=O)c2ccc(Cl)cc2)c2ccccc2c1O
Yield: 99.3 %

Procedure:
4-chloro-N-(4-hydroxy-3-(1-methyl-1H-tetrazol-5-ylthio)naphthalen-1-yl)benzenesulfonamide (14y) was prepared according to the procedure for 14d except using 13y, which afforded the title compound 40.0 mg (99.3%) as an off-white solid.
Reaction SMILES: O[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[F:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][C:19]=1[F:20])[CH:15]=O.C[O-:22].[Na+].CO>C(OC)(OC)OC>[F:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:2][C:3]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[OH:22])=[O:4])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: O=C(CO)c1ccccc1
Reactant: O=Cc1ccc(F)c(F)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: COC(OC)OC
Solvent: CO
Product: O=C(C=Cc1ccc(F)c(F)c1)c1ccccc1O
Reaction time: 0.5 h

Procedure:
A mixture of 2-hydroxyacetophenone on Wang resin (2.0 g, 1.76 mmol) was swelled in trimethyl orthoformate (20 mL) for 10 min. 3,4-Difluorobenzaldehyde (6.0 mmol) was added and 25% NaOMe in MeOH (0.86 g, 4.0 mmol) was added to the mixture dropwise over 30 min. The mixture was then stirred for an additional 0.5 h. The resin was filtered and washed with alternating MeOH and CH2Cl2 (×5) and dried under high vacuum overnight to give 2.17 g of 3-(3,4-difluorophenyl)-1-(2-hydroxyphenyl)-2-propen-1-one on Wang resin.
Reaction SMILES: [CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H](C#N)[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[OH-:20].[K+].Cl.C(O)CO[CH2:26][CH2:27][OH:28]>>[CH2:1]([C@H:6]1[CH2:11][CH2:10][C@H:9]([C@H:12]2[CH2:17][CH2:16][C@H:26]([C:27]([OH:28])=[O:20])[CH2:14][CH2:13]2)[CH2:8][CH2:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5]
Reactant: OCCOCCO
Reactant: [OH-]
Reactant: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C#N)CC2)CC1
Agent: Cl
Agent: [K+]
Product: C=CCCC[C@H]1CC[C@H]([C@H]2CC[C@H](C(=O)O)CC2)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
A solution of 1.71 g of trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarbonitrile (prepared according to Example 2) in 30 ml of diethylene glycol was treated with 3.11 g of potassium hydroxide and stirred at 130° C. for 3 hours. The mixture was then poured on to ice-water, acidified with 25 percent hydrochloric acid and extracted three times with diethyl ether. The organic phases were combined, washed three times with water, dried over magnesium sulfate and evaporated. Recrystallization of the brown, crystalline residue (1.74 g) from 30 ml of hexane gave 996 mg of trans-4-[trans-4-(4-pentenyl)cyclohexyl]cyclohexanecarboxylic acid as yellowish crystals.