Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([OH:10])=O)[N:6]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O.[NH2:28][C@@H:29]1[C:63](=[O:64])[N:31]2[C:32]([C:47]([O:49][CH:50]([C:57]3[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=3)[C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)=[O:48])=[C:33](/[CH:36]=[C:37]3/[O:38][C:39]([C:41]4[C:46]/3=[CH:45][CH:44]=[CH:43][CH:42]=4)=[O:40])[CH2:34][S:35][C@H:30]12>CN(C=O)C.ClCCl.N1C=CC=CC=1>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:11]/[O:12][CH3:13])/[C:8]([NH:28][C@@H:29]2[C:63](=[O:64])[N:31]3[C:32]([C:47]([O:49][CH:50]([C:57]4[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=4)[C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=4)=[O:48])=[C:33](/[CH:36]=[C:37]4/[O:38][C:39]([C:41]5[C:46]/4=[CH:45][CH:44]=[CH:43][CH:42]=5)=[O:40])[CH2:34][S:35][C@H:30]23)=[O:10])[N:6]=1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C3/OC(=O)c4ccccc43)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(N)n1
Agent: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CO/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C3/OC(=O)c4ccccc43)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C

Procedure:
2-(2-Aminothiazol-4-yl)-2-Z-methoxyiminoacetic acid (0.018 g) in dry DMF (2 mls) under argon was cooled to -50° C. and treated successively with diisopropylethylamine (0.091 mls) and methanesulphonyl chloride (0.04 mls) for 1 h. A solution of diphenylmethyl 7β-amino-3-(E-phthalidylidenemethyl)ceph-3-em-4-carboxylate (0.222 g) in dichloromethane (3 mls) and pyridine (0.035 mls) was added to the activated intermediate at -50° C. and the solution then allowed to warm slowly to room temperature. The solution was diluted with dichloromethane and washed with water and brine, and then dried. After removal of solvent, the crude product was purified by flash chromatography on silica gel, eluting with ethyl acetate. The title compound was obtained as a yellow amorphous solid, (0.051 g), 17%), νmax (CH2Cl2) 1780(s), 1720(w), 1680(w), 1600(w), 1520(w br) and 1365cm-1 ; δH (CDCl3) 3.59 (2H,ABq,J18.6Hz), 4.09 (3H,s), 5.28(1H,d,J4.9Hz), 5.48 (2H,br.s, exch.), 6.20 (1H,dd,J4.9,8.9Hz; collapses to d on D2O shake, J4.9Hz), 6.42 (1H,s), 6.83 (1H,s), 6.88(1H,s), 7.22 (10 H,m), 7.4-7.6 (3H,m), 7.86 (1H,m) and 7.98 (1H,d,J8.9Hz, exch.); [mass spectrum: +ve ion (3-NOBA, Na+) MNa+, 716].
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:19][CH3:20])[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])[CH:10]=O)(=[O:6])=[O:5].[CH3:21][O:22][C:23]1[CH:24]=[C:25]([CH:35]([SH:38])[CH2:36][SH:37])[CH:26]=[C:27]([O:33][CH3:34])[C:28]=1[O:29][CH2:30]OC.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:10]2[S:38][C@H:35]([C:25]3[CH:24]=[C:23]([O:22][CH3:21])[C:28]([O:29][CH3:30])=[C:27]([O:33][CH3:34])[CH:26]=3)[CH2:36][S:37]2)[CH:12]=[C:13]([O:19][CH3:20])[C:14]=1[O:15][CH2:16][CH2:17][CH3:18])(=[O:6])=[O:5]
Reactant: CCCOc1c(OC)cc(C=O)cc1S(=O)(=O)CCO
Reactant: COCOc1c(OC)cc(C(S)CS)cc1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCOc1c(OC)cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc1S(=O)(=O)CCO

Procedure:
1-(3-(2-hydroxyethylsulfonyl)-5-methoxy-4-propoxybenzaldehyde (54) (FIG. 24) (0.88 g,2.91 mmole), 1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (39) (FIG. 19) (0.947 g, 3.64 mmole) and 0.365 g of pyridinium para-toluene sulfonate was added to 120 ml dry benzene and refluxed with Dean-Stark removal of the benzene- water azeotrope for 24 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer was washed with 10% NaHCO3 and H2O. The organic layer was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 1:1 hex/ethyl acetate as eluent. The product mixture (white foam) contains a 1.0/1.0 cis/trans ratio (1.254 g, 79%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2.[S:15](Cl)([Cl:18])(=[O:17])=[O:16]>C(Cl)(Cl)Cl>[Cl:18][S:15]([N:1]1[CH2:6][CH2:5][O:4][C:3]2[N:7]=[CH:8][C:9]([C:11]([O:13][CH3:14])=[O:12])=[CH:10][C:2]1=2)(=[O:17])=[O:16]
Reactant: COC(=O)c1cnc2c(c1)NCCO2
Reactant: O=S(=O)(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cnc2c(c1)N(S(=O)(=O)Cl)CCO2
Temperature: -78 °C
Yield: 88.5 %

Procedure:
A 100 mL round-bottomed flask was charged with methyl 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (4 g, 20.60 mmol) and CHCl3 (200 mL) was added to form a clear solution which was stirred and cooled to −78° C. To the resulting white suspension was added TEA (8.61 mL, 61.8 mmol). A solution of sulfuryl chloride (3.35 mL, 41.2 mmol) in CHCl3 (10 mL) was added dropwise and the reaction mixture was maintained at −78° C. for 1 h. The solution was warmed to 0° C. at which time the mixture turned clear yellow. The reaction was stirred at 0° C. for 2 h. The reaction was quenched with H2O (200 mL) and extracted with DCM (2×200 mL). The combined organics were washed with 1 N HCl (200 mL) then dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting solid was purified by flash column chromatography using a gradient elution with 0-25% acetonitrile in DCM to provide methyl 1-(chlorosulfonyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine-7-carboxylate (5.34 g, 18.24 mmol, 89% yield) as a white solid. 1H-NMR (CDCl3) δ 8.82. (br s, 1H), 8.63 (d, 1H), 4.72 (dd, 2H), 4.10 (dd, 2H), 3.92 (s, 3H).
Reaction SMILES: C1(OC2C=C(NC(C3C=CN=CC=3)=O)C=CC=2OC)CCCC1.C1(OC2C=C(C=CC=2OC)NC(=O)C2C=CC=C([N+:41]([O-:43])=[O:42])C=2)CCCC1.[CH:50]1([O:55][C:56]2[CH:57]=[C:58]([NH:64][C:65]([C:67]3[C:68](C(N)=O)=[CH:69][CH:70]=[CH:71][CH:72]=3)=[O:66])[CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[CH2:54][CH2:53][CH2:52][CH2:51]1.C(NC1C=CC(OC)=C(OC2CCCC2)C=1)(=O)C1C=CC=CC=1.C1(OC2C=C(NC(C3C(Cl)=CN=CC=3Cl)=O)C=CC=2OC)CCCC1>>[CH:50]1([O:55][C:56]2[CH:57]=[C:58]([CH:59]=[CH:60][C:61]=2[O:62][CH3:63])[NH:64][C:65](=[O:66])[C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][C:68]=2[N+:41]([O-:43])=[O:42])[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: COc1ccc(NC(=O)c2ccccc2C(N)=O)cc1OC1CCCC1
Reactant: COc1ccc(NC(=O)c2cccc([N+](=O)[O-])c2)cc1OC1CCCC1
Agent: COc1ccc(NC(=O)c2c(Cl)cncc2Cl)cc1OC1CCCC1
Agent: COc1ccc(NC(=O)c2ccccc2)cc1OC1CCCC1
Agent: COc1ccc(NC(=O)c2ccncc2)cc1OC1CCCC1
Product: COc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])cc1OC1CCCC1

Procedure:
N-(3-Cyclopentyloxy-4-methyloxyphenyl)-4-pyridinecarboxamide; 3-Cyclopentyloxy-4-methyloxy-N-(3-Nitrobenzoyl)aniline; N-(3-Cyclopentyloxy-4-methyloxyphenyl)-1,2-benzenedicarboxamide; N-Benzoyl-3-cyclopentyloxy-4-methyloxyaniline; Methyl 2-[N-3-(Cyclopentyloxy-4-methyloxyphenyl)carbamoyl]benzoate; N-(3-Cyclopentyloxy-4-methyloxyphenyl)-3,5-dichloro-4-pyridinecarboxamide; and the salts, solvates and hydrates thereof.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][OH:15])[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(OCC)(=O)C>ClCCl.CCCCCC>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[C@H:13]([CH2:14][O:15][CH:18]3[CH2:19][CH2:20][CH2:21][CH2:22][O:17]3)[O:12][C:11](=[O:16])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](CO)O1
Reactant: C1=COCCC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: ClCCl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1N[C@@H](c2ccc(F)c(F)c2)[C@H](COC2CCCCO2)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To a solution of (4S,5R) 4-(3,4-difluorophenyl)-5-hydroxymethyl-oxazolidin-2-one (695 mg, 3.0 mmol) in dry dichloromethane (30 mL) was added 2,3-dihydropyran (0.3 mL, 3.6 mmol) and camphorsulfonic acid (70 mg, 0.3 mmol). The reaction mixture was stirred at ambient temperature for 3 h. The reaction mixture was diluted with dichloromethane (100 mL) and washed with saturated sodium bicarbonate solution (2×100 ml), brine (1×100 ml), dried over magnesium sulfate and filtered. The volatiles were removed under reduced pressure and the resulting solid was purified by pressurized silica gel chromatography (1:1 then 2:1 ethyl acetate:hexane) to afford (4S,5R)-4-(3,4-difluorophenyl)-5-(tetrahydropyran-2-yloxymethyl)-oxazolidin-2-one as a colorless oil (750 mg, 2.4 mmol, 80%).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:7]1[CH:12]=[C:11]([Cl:13])[N:10]=[N:9][C:8]=1[Cl:14].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[Cl:14][C:8]1[N:9]=[N:10][C:11]([Cl:13])=[CH:12][C:7]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Clc1cc(Br)c(Cl)nn1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1cc(N2CCCC2)c(Cl)nn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 91.7 %

Procedure:
Pyrrolidine (3.36 ml, 40 mmol) was added to a stirred solution/suspension of 4-bromo-3,6-dichloropyridazine (8.3 g, 36 mmol) and potassium carbonate (13.8 g, 0.1 mol) in dry DMF (100 ml) at room temperature under nitrogen. The mixture was stirred at room temperature for 16 hours, then at 60° C. for 3 hours. The reaction was poured into water (250 ml). The aqueous was extracted with ethyl acetate (×3). The combined extracts were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography on silica gel, eluting with 0.5% methanol/dichloromethane to afford the title pyridazine (7.2 g, 92%) as a colourless oil. 1H NMR (250 MHz, CDCl3) 2.00-2.05 (4H, m) 3.61-3.69 (4H, m), 6.46 (1H, s). MS (ES+) 218 [MH]+, 220 [MH]+.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=O)[NH2:2].CN(C=O)C.ClC1N=C(Cl)N=C(Cl)N=1>C(OCC)(=O)C>[C:1]([C@@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:13])[CH3:15])#[N:2]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(N)=O
Agent: Clc1nc(Cl)nc(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C#N
Reaction time: 2 h
Yield: 93.4 %

Procedure:
A mixture of tert-butyl [(1S,2R)-2-carbamoylcyclopentyl]carbamate (500 mg) and DMF (5.0 ml) was ice-cooled, and 2,4,6-trichloro-1,3,5-triazine (404 mg) was added thereto, followed by stirring under ice-cooling for 1 hour, and further at room temperature for 2 hours. To the reaction mixture were added ethyl acetate and a saturated sodium bicarbonate solution, and then liquid-separation was carried out. The aqueous layer was extracted with ethyl acetate, and the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to obtain tert-butyl [(1S,2R)-2-cyanocyclopentyl]carbamate (430 mg) as a white solid.
Reaction SMILES: [O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([OH:25])=[O:24].[OH-].[Na+:27].CCOCC>CN(C)C=O>[O:1]=[C:2]1[N:7]2[CH:8]=[N:9][C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:22])[C:18]([CH3:20])([CH3:21])[CH3:19])=[CH:14][C:15]=3[C:6]2=[N:5][CH:4]=[C:3]1[C:23]([O-:25])=[O:24].[Na+:27]
Reactant: CC(C)(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)O)cnc3c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)(C)C(=O)Nc1ccc2ncn3c(=O)c(C(=O)[O-])cnc3c2c1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
4-Oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylic acid (3.06 g) was suspended in N,N-dimethylformamide (60 ml). To this suspension was added dropwise sodium hydroxide solution (sodium hydroxide 0.36 g in water 1 ml and ethanol 7 ml) at ambient temperature to give a clear solution. After 30 minutes, ether was added and the precipitated crystals were collected by filtration and washed with ether. The crude crystals were dissolved in water (150 ml) under heating. The solution was filtered to remove insoluble materials, diluted with acetone (800 ml), and allowed to stand at ambient temperature. The crystals were filtered, washed with acetone, and dried to give sodium 4-oxo-10-(pivalamido)-4H-pyrimido[1,2-C]quinazoline-3-carboxylate (1.73 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].C(O)C.O.Cl>O>[C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1ccc(NCCCc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc(NCCCc2ccccc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-[(3-phenylpropyl)amino]benzoate (prepared as described in Example 26), 10 g. of KOH and 200 ml. of ethanol-water (9:1) is refluxed for 4 hours. The mixture is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give off-white crystals. Recrystallization from ethanol gives off-white crystals, m.p. 162°-163° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5](O)=[O:6].S(Cl)([Cl:20])=O>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:9]=[C:8]([O:16][CH3:17])[C:4]=1[C:5]([Cl:20])=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(OC)c1C(=O)O
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc(C(F)(F)F)cc(OC)c1C(=O)Cl
Temperature: 85 °C
Yield: 98.9 %

Procedure:
To a suspension of 14.47 g (57.84 mmol) 2,6-dimethoxy-4-trifluoromethyl-benzoic acid (intermediate AJ) in 160 ml toluene containing four drops DMF under nitrogen at room temperature, was added 42 ml (578.4 mmol) thionyl chloride. The mixture was heated in an 85° C. oil bath for 3 hours. The solvent was removed in vacuo to provide 15.37 g (yield: 98.9%) of the title compound as an off-white solid.
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1)([O-])=O.C1CCCCC1>C1C=CC=CC=1.[Pd]>[NH2:1][C:4]1[CH:17]=[CH:16][C:7]2[C:8](=[O:15])[O:9][C:10]([O:12][CH2:13][CH3:14])=[N:11][C:6]=2[CH:5]=1
Reactant: CCOc1nc2cc([N+](=O)[O-])ccc2c(=O)o1
Agent: [Pd]
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: CCOc1nc2cc(N)ccc2c(=O)o1
Yield: 47 %

Procedure:
7-Nitro-2-ethoxy-4H-3,1-benzoxazin-4-one (1 gm, 4.2 m mol.), 10% Pd-C (1 gm), and cyclohexane (2.5 ml) were refluxed in dry benzene (50 ml) under anhydrous conditions for 3 hours. The hot reaction mixture was filtered immediately through celite and the catalyst on celite was washed with hot benzene (25 ml). The combined filtrate was evaporated to dryness under reduced pressure. The residue was stirred in anhydrous ether (30 ml) to give 410 mg (47%) of the title compound, 7-amino-2-ethoxy-4H-3,1-benzoxazin-4-one, as a pale yellow powder, after filtration. The product can be further purified by chromatography on silica gel column, if necessary (silica gel 60; EtOAc:pet. ether=1:2); m. p. 185°-187° C.; IR (KBr): νmax 3425, 3330 cm-1 (NH2), 1740 cm-1 (C=O), 1640 cm-1 (C=N); H'NMR (CDCl3): δ1.43 ppm (t, J=7.1 Hz, 3H, OCH2CH3), 4.30 ppm (b, 2H, NH2), 4.75 ppm (q, J=7.1 Hz, 2H, OCH2CH3), 6.5-7.98 ppm (m, 3H, aromatic protons).
Reaction SMILES: [CH3:1][C:2]1[C:9](C(=O)C)=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1.[N:13]([O-])=O.[Na+].[OH-].[Na+]>Cl.[Zn]>[CH3:1][C:2]1[C:9]([NH2:13])=[C:5]2[S:6][CH:7]=[CH:8][N:4]2[N:3]=1
Reactant: O=N[O-]
Reactant: CC(=O)c1c(C)nn2ccsc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1nn2ccsc2c1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 69.8 %

Procedure:
A mixture of 1-(6-methylpyrazolo[5,1-b][1,3]thiazol-7-yl)ethanone (1.02 g, 5.66 mmol) and a 5N aqueous solution of hydrochloric acid (23.8 mL) was cooled to 0° C., and an aqueous (1.5 mL) solution of sodium nitrite (781 mg, 11.3 mmol) was added. This reaction mixture was stirred at 0° C. for two hours, then, warmed to room temperature, and further stirred at room temperature over one day and night. A 5N aqueous solution of sodium hydroxide was added to the mixture so that the solution became basic, and a produced blue solid was filtered and washed with a small amount of water. The obtained blue solid was dissolved in a 2N aqueous solution of hydrochloric acid (22 mL), zinc powder (370 mg, 5.66 mmol) was added thereto, and the mixture was stirred at room temperature for 15 minutes. To the mixture, zinc powder (370 mg, 5.66 mmol) was added again, and the mixture was stirred at room temperature for one hour. The insoluble matters were filtered off and then a 5N aqueous solution of sodium hydroxide was added to the filtrate at 0° C. for neutralization. A substance of interest was extracted with ethyl acetate, and the organic layer washed with brine, and dried over magnesium sulfate. The mixture was filtered to yield a filtrate, and the solvent was distilled off under reduced pressure, and the obtained solid was dried to obtain 605.8 mg (3.95 mmol) of the title compound.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([O:11][CH3:12])[N:5]=[CH:4][CH:3]=1.Cl.[CH:14]1([NH:20][NH2:21])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O.C(N(CC)CC)C>[CH:14]1([NH:20][NH:21][C:8](=[O:10])[C:7]2[C:2]([I:1])=[CH:3][CH:4]=[N:5][C:6]=2[O:11][CH3:12])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NNC1CCCCC1
Reactant: COc1nccc(I)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: COc1nccc(I)c1C(=O)NNC1CCCCC1
Yield: 68.6 %

Procedure:
A solution of 4-iodo-2-methoxynicotinic acid (558 mg), cyclohexyl hydrazine hydrochloride (362 mg), EDCI hydrochloride (575 mg), HOBt (405 mg) and triethylamine (304 mg) in DMF (10 mL) was stirred overnight at room temperature. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (515 mg).
Reaction SMILES: [CH3:1]OC1C=CC(C2C=CC(CC(O)=O)=CC=2)=CC=1.S(=O)(=O)(O)O.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1.C([N-]C(C)C)(C)C.[Li+].CI>O1CCCC1.O.C(O)C>[CH3:1][CH:38]([C:35]1[CH:36]=[CH:37][C:32]([C:29]2[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=2)=[CH:33][CH:34]=1)[C:39]([O:41][CH2:42][CH3:43])=[O:40]
Reactant: CCOC(=O)Cc1ccc(-c2ccc(OC)cc2)cc1
Reactant: COc1ccc(-c2ccc(CC(=O)O)cc2)cc1
Agent: CC(C)[N-]C(C)C
Agent: O=S(=O)(O)O
Agent: [Li+]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C(C)c1ccc(-c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.6 %

Procedure:
The known starting material, 4'-methoxy-4-biphenylacetic acid (J. Chem. Soc. 1959, 557) is first converted to its ethyl ester by Fisher esterification with ethanol and concentrated sulfuric acid. To a solution of 4'-methoxy-4-biphenylacetic acid, ethyl ester (30.0 g, 0.110 mol) in tetrahydrofuran (400 mL) at -78° C. is added slowly, 2.01 M lithium diisopropylamide (63 mL). The mixture is stirred for 30 minutes and then methyl iodide (30 mL) is added rapidly. The reaction mixture is warmed to 0° C. for 30 minutes, then at room temperature for 3 hours. The mixture is poured into water (2 L) and is extracted with ethyl acetate (3×1 L). The combined ethyl acetate extract is washed with 1N HCl (1 L), water (1 L) and brine (1 L), dried over MgSO4 and is concentrated under reduced pressure to give 48 g of crude yellow oil. Purification of the product by column chromatography (12% ethyl acetate in hexane) gives 22.0 g (69.6 %) of crystalline material, m.p. 52°-54° C.
Reaction SMILES: SC[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=[O:7].C(OC(C)(C)C)(=O)C=C.C1CCN2C(=NCCC2)CC1>C(#N)C>[C:6]([OH:8])(=[O:7])[C:5]1[CH:9]=[CH:10][CH:11]=[CH:3][CH:4]=1
Reactant: O=C(O)c1cccc(CS)c1
Agent: C=CC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: O=C(O)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
Into a 500-mL round-bottom flask, was placed a solution of 3-(mercaptomethyl)benzoic acid (12 g, 71.43 mmol, 1.00 equiv) in acetonitrile (200 mL), and tert-butyl acrylate (60 mL), DBU (21.7 g, 142.76 mmol, 2.00 equiv). The resulting solution was stirred overnight at 80° C. in an oil bath. The resulting mixture was concentrated under vacuum. The resulting solution was diluted with 200 mL of water and adjusted to pH 2˜3 with 10% hydrochloric acid. The resulting solution was extracted with 3×200 mL of ethyl acetate and the organic layers combined. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with petroleum ether/ethyl acetate (50:1). This resulted in 10.5 g (47%) of 34(3-tert-butoxy-3-oxopropylthio)methyl)benzoic acid as red oil. 1H-NMR (300 MHz, CDCl3, ppm): δ 8.08 (s, 1H), 8.04 (d, J=7.8 Hz, 1H), 7.62 (d, J=7.8 Hz, 1H), 7.46 (t, 1H), 3.81 (s, 2H), 2.68 (t, 2H), 2.50 (t, 2H), 1.48 (s, 9H). MS (ES, m/z): 295 [M−H]−.
Reaction SMILES: [CH:1]1([CH2:4][CH:5]([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:17])([F:16])[F:15])=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1.CI.[CH3:20]C([O-])(C)C.[K+]>O1CCOCC1>[CH:1]1([CH2:4][C:5]([CH3:20])([C:8]2[CH:9]=[N:10][C:11]([C:14]([F:16])([F:17])[F:15])=[N:12][CH:13]=2)[C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: N#CC(CC1CC1)c1cnc(C(F)(F)F)nc1
Agent: [K+]
Solvent: CI
Solvent: C1COCCO1
Product: CC(C#N)(CC1CC1)c1cnc(C(F)(F)F)nc1
Reaction time: 1 h
Yield: 36.4 %

Procedure:
To a solution of 3-cyclopropyl-2-(2-(trifluoromethyl)pyrimidin-5-yl)propanenitrile (310 mg, 1.29 mmol) and MeI (0.27 g, 1.9 mmol) in dioxane (10 ml) was added t-BuOK (1.39 mL, 1.39 mmol, 1M in THF) dropwise at room temperature under N2. The mixture was stirred for 1 h, then quenched by sat.aq. NH4Cl (10 mL), and extracted with EtOAc(3×10 ml). The organic layer was concentrated under reduced pressure to give crude product, which was purified by column chromatography on silica gel (EtOAc/Petroleum ether=1:4) to give compound the title compound (120 mg, yield: 36%). 1H NMR(CDCl3 varian 400): δ9.02 (s, 2H), 1.92 (d, J=6.8 Hz, 2H), 1.87 (s, 3H), 0.80-0.67 (m, 1H), 0.65-0.56 (m, 1H), 0.55-0.45 (m, 1H), 0.30-0.20 (m, 1H), 0.05-0.04 (m, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([OH:16])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:24])[F:23])[O:11][N:10]=1.S(Cl)(Cl)=O.[CH3:36]O>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH3:36])=[O:15])=[C:12]([C:17]2[CH:18]=[N:19][N:20]([C:26]3[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=3)[C:21]=2[C:22]([F:25])([F:23])[F:24])[O:11][N:10]=1
Reactant: O=C(O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Reactant: CO
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COC(=O)c1c(-c2c(F)cccc2Cl)noc1-c1cnn(-c2cccnc2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 9 %

Procedure:
To a mixture of 3-(2-chloro-6-fluorophenyl)-5-(1-(pyridin-3-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)isoxazole-4-carboxylic acid (30 mg, 0.1 mmol) in methanol (1.5 mL) was added thionylchloride (5 μL, 0.1 mmol). The mixture was stirred at room temperature for 60 h and for 5 h at reflux. The mixture was diluted with dichloromethane and washed with water (3×), dried over sodium sulfate, filtered and concentrated under reduced pressure. The product (example IB-67) was purified by pTLC (1:1 EE/PE) to give 3 mg of a white solid (yield 9%).