Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[C:11]=2[F:18])(O)[CH2:5][CH2:4]1)[CH3:2].S(=O)(=O)(O)O.C1(C)C=CC=CC=1>O>[CH2:1]([N:3]1[CH2:4][CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16][CH3:17])[C:11]=2[F:18])[CH2:7][CH2:8]1)[CH3:2]
Reactant: CCN1CCC(O)(c2cccc(SC)c2F)CC1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1
Product: CCN1CC=C(c2cccc(SC)c2F)CC1
Temperature: 70 °C
Yield: 57.6 %

Procedure:
A mixture of 1-ethyl-4-[2-fluoro-3-(methylthio)phenyl]piperidin-4-ol (42 g, 156 mmol), sulphuric acid (cone, 8.5 ml) and toluene (200 ml) was heated in a Dean-Stark trap for 20 h. The mixture was cooled to 70° C., water (200 ml) was added and the phases were separated. The aqueous phase was basified with aqueous sodium hydroxide (5 M) and extracted with ethyl acetate (2×50 ml). The combined organic phases was dried (MgSO4) and evaporated to dryness to give the title compound (22.6 g). MS m/z (rel. intensity, 70 eV) 251 (M+, bp), 236 (85), 147 (65), 146 (45), 110 (44).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O-:20])=[O:19])[CH2:14][CH:13]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:8][CH:7]=1.[C:33](Cl)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:33]([O:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:9]([CH3:12])([CH3:10])[CH3:8])=[O:19])[CH2:14][CH:13]2[O:21][CH2:22][C:23]2[CH:32]=[CH:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[CH:24]=2)=[CH:8][CH:7]=1)(=[O:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C([O-])N1CCC(c2ccc(OCCCO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C(Cl)c1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 22(k), by acylating (3RS,4RS)-4-[4-(3-hydroxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate with benzoyl chloride there was obtained tert-butyl (3RS,4RS)-4-[4-(3-benzoyloxy-propoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; Rf : 0.84 (SiO2, hexane:ethyl acetate=1:1). (d) A mixture of 1.0 g (3.41 mmol) of tert-butyl (3RS,4RS)-3-hydroxy-4-(4-hydroxy-phenyl)-piperidine-1-carboxylate, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide in 30 ml of dimethylformamide was stirred at room temperature for 2 hours and at 80° C. for 15 hours. Subsequently, 471 mg (34.1 mmol, 10 eq.) of potassium carbonate and 607 ml (5.11 mmol, 1.5 eq.) of benzyl bromide were again added and the mixture was stirred at 80° C. for a further 6 hours. The reaction mixture, cooled to room temperature, was poured into 300 ml of an ice/water mixture and extracted three times with 250 ml of ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The yellow oil (1.82 g) was separated on silica gel using an eluent gradient of 4:1 to 3:2 of a mixture of hexane and ethyl acetate as the eluent. There were obtained 620 mg (72% of theory) of tert-butyl (3RS,4RS)-4-(4-benzyloxy-phenyl)-3-hydroxy-piperidine-1-carboxylate which, after recrystallization from a mixture of methylene chloride and hexane, gave 361 mg (28% of theory) as a white, crystalline product; MS: 383 (M)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH2:10][CH2:9]1.[OH-].[Na+].P(Cl)(Cl)([Cl:27])=O>>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:21])[C:14]=3[N:13]=[C:12]([Cl:27])[C:11]=2[CH2:10][CH2:9]1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccccc1N1CCc2c1c1cccc(C)c1[nH]c2=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1ccccc1N1CCc2c(Cl)nc3c(C)cccc3c21

Procedure:
1-(2-Methylphenyl)-4-oxo-6-methyl-2,3,4,5-tetrahydropyrrolo[3,2-c]quinoline(16 g) was dissolved in phosphoryl chloride (100 ml) and heated at reflux for 5 hours. After cooling, the solution was poured onto ice, made alkaline with aqueous sodium hydroxide solution, and extracted with dichloromethane, which was dried and evaporated. Crystallisation from ethyl acetate gave 1-(2-methylphenyl)-4-chloro-6-methyl-2,3-dihydropyrrolo-[3,2-c]quinoline, which was used without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([OH:9])=[O:8].[CH:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[CH2:16].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[C:7]([O:9][CH2:16][CH2:15][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:8]
Reactant: O=C(O)C(c1cccs1)c1cccs1
Reactant: C=Cc1ccccn1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: c1ccccc1
Product: O=C(OCCc1ccccn1)C(c1cccs1)c1cccs1

Procedure:
The crude product of newly synthesized dithiophenyl acetic acid (10 g, 59 mmol theoretically), freshly distilled 2-vinylpyridine (6.25 g, 59 mmol), and 1 mol % toluene sulfonic acid were dissolved in benzene and placed in a round bottom flask equipped with a vigreaux column and magnetic stirbar. The reaction was then heated to reflux and allowed to react for 16 hours. The viscous liquid that remained after the solvent was removed was then purified by column chromatography (silica 2/1 v/v hexane/ethyl acetate). Yield=3.9 g. 1H NMR (CDCl3) δ=3.042 (t, 2 H), δ=3.573 (t, 2 H), δ=4.233 (s, 2H ) δ=6.968-7.476 (m, 8H), δ=8.467, (d, 1H). 13C NMR (CDCl3) δ=35.627 (CH2), δ=36.180 (CH2), δ=58.323 (CH2), δ=121.932 (CH), δ=123.383 (CH2), δ=127.501 (CH), δ=128.818 (CH), δ=129.346 (CH), δ=137.272 (C), δ=149.668 (CH), δ=159.305 (C), δ=235.369 (C═S).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][NH:7][CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2].[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([N+:23]([O-:25])=[O:24])=[CH:18][N:17]=1.C(=O)(O)[O-].[K+]>O.C(OCC)C>[CH2:1]([O:3][C:4](=[O:14])[CH2:5][CH2:6][N:7]([C:18]1[C:19]([N+:23]([O-:25])=[O:24])=[CH:20][N:21]=[C:16]([Cl:15])[N:17]=1)[CH:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[CH3:13])[CH3:2]
Reactant: CCOC(=O)CCNC1CCCC1C
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)CCN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCCC1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.5 %

Procedure:
A solution of 2.2 g (0.011 mole) of (rac)-3-(2-methyl-cyclopentylamino)-propanoic acid ethyl ester in 30 mL of water was added dropwise to a solution of 1.94 g (0.01 mole) of 2,4-dichloro-5-nitro-pyrimidine in 30 mL of ethyl ether. At 0 degrees, 2.0 g (0.010 mole) of potassium bicarbonate was added. The mixture was stirred at ambient temperature for 3 hours. The layers were then separated, and the aqueous layer extracted twice with 30 mL of ether. The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with hexanes-ethyl acetate (100:0-92:8) gave 3.3 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(2-methyl-cyclopentyl)-amino]-propanoic acid ethyl ester (IV-57).
Reaction SMILES: [Na].[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[NH:13][CH:14]=[N:15]3)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5].[C:21]1([CH3:47])[CH:26]=[CH:25][C:24]([C:27]([O:29][C@@H:30]2[C@@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:44]=[CH:43][C:42]([CH3:45])=[CH:41][CH:40]=3)=[O:38])[O:33][C@H:32](Cl)[CH2:31]2)=[O:28])=[CH:23][CH:22]=1>CC#N.C(Cl)Cl>[CH2:2]([C:6]1[N:7]([C:11]2[N:19]=[C:18]([Cl:20])[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[C@@H:32]2[O:33][C@H:34]([CH2:35][O:36][C:37]([C:39]3[CH:40]=[CH:41][C:42]([CH3:45])=[CH:43][CH:44]=3)=[O:38])[C@@H:30]([O:29][C:27]([C:24]3[CH:23]=[CH:22][C:21]([CH3:47])=[CH:26][CH:25]=3)=[O:28])[CH2:31]2)[CH:8]=[CH:9][N:10]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1nccn1-c1nc(Cl)nc2nc[nH]c12
Reactant: Cc1ccc(C(=O)OC[C@H]2O[C@H](Cl)C[C@@H]2OC(=O)c2ccc(C)cc2)cc1
Agent: [Na]
Solvent: CC#N
Solvent: ClCCl
Product: CCCCc1nccn1-c1nc(Cl)nc2c1ncn2[C@H]1C[C@H](OC(=O)c2ccc(C)cc2)[C@@H](COC(=O)c2ccc(C)cc2)O1

Procedure:
The sodium salt of 6-(2-butylimidazol-1-yl)-2-chloropurine (0.139 g, 0.5 mmol) in dried CH3CN (10 mL) was treated with 2-deoxy-3,5-di-O-(p-toluoyl)-α-D-erythro-pentofuranosyl chloride (0.334 g, 0.86 mmol) in CH2Cl2 (10 mL) by general method 2. Sampling of the reaction mixture showed traces of α-nucleoside by 1H NMR (500 MHz) (1:24). Volatiles were evaporated in vacuo, and the residue was chromatographed (25 g silica gel, EtOAc/hexanes, 3:7→EtOAc) to give the β-anomer (274 mg, 86%) with traces of the α-anomer. Recrystallization (EtOAc/hexanes) gave 6-(2-butylimidazol-1-yl)-2-chloro-9-[2-deoxy-3,5-di-O-(p-toluoyl)-β-D-erythro-pentofuranosyl]purine: UV (MeOH) max 223, 241, 287 nm (∈ 29 900, 33 400, 13 200), min 230, 265 nm (∈ 28 100, 7500); 1H NMR (500 MHz, CDCl3) δ 8.51 (s, 1H), 8.26 (s, 1H), 7.98 (d, J=8.0 Hz, 2H), 7.84 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 7.09 (s, 1H), 6.60 (t, J=6.9 Hz, 1H), 5.80 (br s, 1H), 4.78-4.81 (m, 1H), 4.66-4.70 (m, 2H), 3.31 (t, J=7.8 Hz, 2H), 2.97-3.00 (m, 2H), 2.46 (s, 3H), 2.37 (s, 3H), 1.80 (quint, J=7.4 Hz, 2H), 1.50 (sext, J=7.4 Hz, 2H), 0.97 (t, J=7.5 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 166.05, 165.98, 154.13, 153.17, 151.43, 147.92, 144.71, 144.39, 142.18, 129.87, 129.53, 129.35, 129.31, 128.91, 126.38, 126.20, 122.70, 120.33, 85.20, 83.57, 74.94, 63.87, 38.61, 30.70, 30.07, 22.64, 21.79, 21.66, 13.91; HRMS 771/z 629.2270 (MH+[C33H34ClN6O5=629.2279]).
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][S:16]([C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[C:20]=2[O:27][CH:28]([CH3:30])[CH3:29])(=[O:18])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[Cl:26][C:21]1[C:20]([O:27][CH:28]([CH3:30])[CH3:29])=[C:19]([S:16]([NH:15][C:6]2([C:4]([OH:5])=[O:3])[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)(=[O:17])=[O:18])[CH:24]=[C:23]([Cl:25])[CH:22]=1
Reactant: CCOC(=O)C1(NS(=O)(=O)c2cc(Cl)cc(Cl)c2OC(C)C)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)Oc1c(Cl)cc(Cl)cc1S(=O)(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.5 %

Procedure:
The mixture of 2-(3,5-dichloro-2-isopropoxy-benzenesulfonylamino)-indan-2-carboxylic acid ethyl ester (31) (248 mg, 0.52 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (10 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (32) as white solid (230 mg, 100%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7](F)[C:6]=1[Cl:14].[C:16](=O)([O-])[O-:17].[K+].[K+]>CO>[CH3:1][O:2][C:3](=[O:15])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]#[N:12])=[C:7]([O:17][CH3:16])[C:6]=1[Cl:14]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)Cc1ccc(C#N)c(F)c1Cl
Agent: [K+]
Solvent: CO
Product: COC(=O)Cc1ccc(C#N)c(OC)c1Cl
Temperature: 130 °C

Procedure:
A solution of methyl(2-chloro-4-cyano-3-fluorophenyl)acetate (1.40 g, 6.15 mmol) in methanol (30 mL) was divided into two 20 mL microwave (MW) vials. Potassium carbonate (2×850 mg) was added to each MW vial. Each was heated in a microwave at 130° C. for 60 minutes at which time HPLC/MS indicated no starting material was left and the product was all hydrolyzed to the acid. Most of the methanol was removed in vacuo and the residue was diluted with water, acidified with 2M HCl and the mixture was extracted twice with ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude product was taken up in 1:1 methanol:dichloromethane (50 mL) and 2M trimethylsilyldiazomethane in ether was added until the yellow color persisted to re-esterify the acid. The excess diazomethane was quenched with acetic acid and the mixture was concentrated. The residue was purified by flash chromatography (40% DCM/hexanes to 100% DCM) to give the title product. 1H-NMR (400 MHz, CDCl3) δ ppm 3.73 (s, 3H), 3.83 (s, 2H), 4.07 (s, 3H), 7.139 (d, J=8.1 Hz, 1H), 7.468 (d, J=8.0, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH:15](=O)[CH2:16][CH2:17][CH3:18]>>[CH2:15]([NH:14][C:10]1[CH:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[CH:12][CH:11]=1)[CH2:16][CH2:17][CH3:18]
Reactant: Nc1cccc(-c2cccc(Cl)c2)c1
Reactant: CCCC=O
Product: CCCCNc1cccc(-c2cccc(Cl)c2)c1

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 137, 3′-chlorobiphenyl-3-amine (Oakwood, 15 mg, 0.074 mmol) and butyraldehyde (7 μL, 0.074 mmol) were converted to a crude oil which was used without purification in the preparation of Example 143. 1H NMR (CDCl3) δ 8.17 (d, J=0.9 Hz, 1H), 7.86-7.42 (m, 3H), 7.41-7.07 (m, 3H), 6.78-6.57 (m, 1H), 3.00-2.87 (m, 2H), 1.63-1.46 (m, 2H), 1.47-1.34 (m, 2H), 1.02 (t, J=7.4 Hz, 3H); MS(ESI+) m/z 260.2 (M+H)+.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and ethanesulfonyl chloride (Aldrich), to give [4-amino-2-(1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 438.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23]([CH:24]=O)=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1.[C:37]([CH2:39]P(=O)(OCC)OCC)#[N:38].CN(C)C=O.[H-].[Na+]>O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:36])=[C:9]([CH2:11][O:12][C:13]2[CH:33]=[CH:32][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:39]/[C:37]#[N:38])=[CH:22][N:21]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[N:20]=3)=[CH:15][C:14]=2[O:34][CH3:35])[N:10]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2C=O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: CCOP(=O)(CC#N)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C#N)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 7.6 %

Procedure:
To a mixture of 3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazole-4-carbaldehyde (0.50 g), diethyl cyanomethylphosphonate (0.19 g) and N,N-dimethylformamide (10 mL) was added sodium hydride (60% in oil, 0.050 g) under ice-cooling. The mixture was stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenenitrile as colorless crystals (0.040 g, yield 8%) from a fraction eluted with ethyl acetate-hexane (1:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 177-178° C.
Reaction SMILES: [N+]([CH2:4][CH:5](O)[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]CC)([O-])=O.[C:15]([O-:18])(=[O:17])[CH3:16].[Ca+2].[C:20]([O-:23])(=[O:22])[CH3:21]>C(O)(=O)C>[C:15]([O:18][CH:21]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11])[C:20]([OH:23])=[O:22])(=[O:17])[CH3:16]
Reactant: CC(=O)[O-]
Reactant: CCCCCCCCC(O)C[N+](=O)[O-]
Agent: [Ca+2]
Solvent: CC(=O)O
Product: CCCCCCCCC(OC(C)=O)C(=O)O
Temperature: 118 °C
Yield: 92.9 %

Procedure:
To 10.0 grams (0.05 mole) of 1-nitro-2-decanol and 7.9 grams (0.05 mole) of calcium acetate maintained at 10° C. was added 100 millilliters of acetic acid. Heating for 6 hours at 118° C. and extracting as in Example 1 above, provided 10.7 grams (approximately 90% yield) of 2-acetoxydecanoic acid.
Reaction SMILES: [CH2:1]([N:3]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([O:15]CC)=[O:14])=[CH:9]2)[CH3:2].[OH-].[Na+].O1CCCC1>CO>[CH2:1]([N:3]([S:18]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)(=[O:20])=[O:19])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9]2)[CH3:2]
Reactant: CCOC(=O)c1cc2cccc(N(CC)S(=O)(=O)c3cccs3)c2[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCN(c1cccc2cc(C(=O)O)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 50 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A mixture of ethyl 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carboxylate (0.54 g), 2N aqueous sodium hydroxide solution (2.2 mL), tetrahydrofuran (4 mL) and methanol (4 mL) was stirred at 50° C. for 1 hr. The reaction mixture was concentrated, and water was added to the residue. The mixture was acidified with 10% aqueous citric acid solution, and the resulting crystals were filtrated, washed with water, and dried to give the title compound (0.43 g, yield 86%) as colorless crystals. melting point>222° C. (decomposition).
Reaction SMILES: S(Cl)(Cl)=O.[NH:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1.[CH3:14][S:15][CH2:16][CH2:17][C:18](O)=[O:19]>ClCCl>[N:5]1([C:18](=[O:19])[CH2:17][CH2:16][S:15][CH3:14])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[N:7]=[N:6]1
Reactant: CSCCC(=O)O
Reactant: c1ccc2[nH]nnc2c1
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: CSCCC(=O)n1nnc2ccccc21
Reaction time: 0.5 h
Yield: 55.6 %

Procedure:
Sulfurous dichloride (4.95 g, 41.6 mmol) was added to a stirred solution of 1H-benzo[d][1,2,3]triazole (19.83 g, 166 mmol) in anhydrous dichloromethane (300 mL) at room temperature under argon. The mixture was stirred for 30 min and 3-(methylthio)propanoic acid (5.0 g, 41.6 mmol) was added in one portion and stirring was continued for 2 h. The resulting suspension was filtered off and the filtrated was washed with 2 M NaOH (3×50 mL), dried over MgSO4, and purified by column chromatography to give the title compound as clear oil (5.12 g). LCMS m/z=222.1 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 2.21 (s, 3H), 3.05 (t, J=7.07 Hz, 2H), 3.74 (t, J=7.07 Hz, 2H), 7.42-7.54 (m, 1H), 7.56-7.69 (m, 1H), 8.08 (d, J=8.34 Hz, 1H), 8.24 (d, J=8.08 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([OH:17])=O)[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].[NH2:18][C:19]1[CH:20]=[CH:21][C:22]([N:27]2[CH2:32][CH2:31][CH:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[CH2:29][CH2:28]2)=[C:23]([CH:26]=1)[C:24]#[N:25]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([CH3:14])=[C:12]([C:15]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([N:27]4[CH2:32][CH2:31][CH:30]([N:33]5[CH2:34][CH2:35][O:36][CH2:37][CH2:38]5)[CH2:29][CH2:28]4)=[C:23]([C:24]#[N:25])[CH:26]=3)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cc1c(C(=O)O)cnn1-c1ccc(F)c(Cl)c1
Reactant: N#Cc1cc(N)ccc1N1CCC(N2CCOCC2)CC1
Product: Cc1c(C(=O)Nc2ccc(N3CCC(N4CCOCC4)CC3)c(C#N)c2)cnn1-c1ccc(F)c(Cl)c1
Yield: 42.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 64 using 1-(3-chloro-4-fluorophenyl)-5-methylpyrazole-4-carboxylic acid (1.5 g) and 5-amino-2-(4-morpholinopiperidin-1-yl) benzonitrile (1.9 g), the title compound (1.3 g) was obtained, melting point: 266° C.
Reaction SMILES: [CH:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([Cl:11])=[N:9][OH:10])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>C1C=CC=CC=1.C(N(CC)CC)C>[CH3:14][S:15]([O:10][N:9]=[C:8]([Cl:11])[C:7]1[CH:12]=[CH:13][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=1)(=[O:17])=[O:16]
Reactant: CC(C)c1ccc(C(Cl)=NO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(C)c1ccc(C(Cl)=NOS(C)(=O)=O)cc1
Reaction time: 0.5 h
Yield: 86.7 %

Procedure:
Into a solution of 6.7 g of 4-isopropylbenzohydroximoyl chloride in 175 ml of benzene was added in one portion 5.2 g of triethylamine. To this solution was added dropwise during 15 minutes (mildly exothermic reaction) 4.0 g of methanesulfonyl chloride. The mixture was stirred for 30 minutes and filtered. The filtrate was concentrated and the residue recrystallized twice from ethanol to give 8.1 g of N-(methanesulfonyloxy)-4-isopropylbenzimidoyl chloride, m.p. 79.5°-82°. The ir spectrum was consistent with the assigned structure.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]#[N:24])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[O:33][CH3:34]>>[CH3:34][O:33][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[C:18]([C:23]#[N:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: COc1ccccc1Br
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1
Product: COc1ccccc1C(=O)c1cn(-c2cccc(-c3ccccc3C#N)c2)cn1

Procedure:
This compound is prepared by method C using compound 12d and 2-bromoanisole.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([OH:11])=O)[O:4][N:3]=1.[NH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]2[CH:29]=[C:28]([Cl:30])[CH:27]=[C:26]([Cl:31])[CH:25]=2)=[O:21])[CH:16]([CH3:32])[CH2:15]1.CCN(C(C)C)C(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[OH:1][C:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([NH:12][CH2:13][CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][C:24]3[CH:25]=[C:26]([Cl:31])[CH:27]=[C:28]([Cl:30])[CH:29]=3)=[O:21])[CH:16]([CH3:32])[CH2:15]2)=[O:11])[O:4][N:3]=1
Reactant: O=C(O)CCc1cc(O)no1
Reactant: CC1CC(CN)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1CC(CNC(=O)CCc2cc(O)no2)CCN1C(=O)OCc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture comprising of 3-(3-hydroxyisoxazol-5-yl)propanoic acid (40.2 mg, 0.256 mmol), 3,5-dichlorobenzyl 4-(aminomethyl)-2-methylpiperidine-1-carboxylate (step 4) (84.7 mg, 0.128 mmol), Huenig's base (89 μl, 0.511 mmol) and T3P® (50% solution in DMF)(149 μl, 0.256 mmol) in DMF (426 μl) was left stirring at room temperature 18 hours. The resulting mixture was concentrated under pressure and diluted with water. The aqueous solution was extracted with EtOAc and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. Further purification was carried out using preparative LC-MS. The resulting product fractions were concentrated under reduced pressure to give an aqueous solution and then extracted with EtOAc. The organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure to afford the title compound.