Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[NH2:2][CH2:3][CH2:4][SH:5].[Na].BrC[CH2:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1>C(O)C>[ClH:1].[NH2:2][CH2:3][CH2:4][S:5][CH2:9][C:10]1[CH:14]=[CH:13][S:12][N:11]=1
Reactant: BrCCc1ccsn1
Reactant: NCCS
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: NCCSCc1ccsn1
Reaction time: 2 h
Yield: 99.7 %

Procedure:
A solution was prepared by the gradual addition of cysteamine hydrochloride (2.03 g.) to sodium (0.83 g.) dissolved in ethanol (50 ml.) with stirring at 0° under a nitrogen atmosphere. After starting for 2 hours at 0°, 3-bromoethylisothiazole (3.2 g.) was added dropwise over 15 minutes at 0°, the reaction mixture subsequently being set aside overnight at room temperature. Following acidification to pH 3.5 with hydrochloric acid, concentration and re-evaporation with ethanol, the residue was dissolved in ethanol, filtered and concentrated to yield 3-[(2-aminoethyl)thiomethyl]isothiazole hydrochloride (3.5 g.). This was converted directly to the free base by treatment with aqueous potassium carbonate and extraction with ether. The extracts were dried over magnesium sulphate, filtered and concentrated to yield the amine base as an oil (1.56 g.). The amine was dissolved in ethanol (10 ml.), methyl isothiocyanate (0.66 g.) added, and the solution heated under reflux for 30 minutes. Concentration, followed by purification of the crude product by chromatography on a column of silica gel with ethyl acetate as eluant followed by chromatography on a column of alumina with benzene/ethyl acetate as eluant gave N-methyl-N'-[2-(3-isothiazolylmethylthio)ethyl]thiourea. (Found: C, 38.9; H, 5.4; N, 16.5; S, 38.3. C8H13N3S3 requires: C, 38.8; H, 5.3; N, 17.0; S, 38.9).
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.[C:17]([C:21]1[CH:22]=[C:23]([C:44]2[C:45]([O:51][CH3:52])=[N:46][CH:47]=[C:48]([F:50])[CH:49]=2)[CH:24]=[C:25](/[CH:29]=[CH:30]/[Sn](CCCC)(CCCC)CCCC)[C:26]=1[O:27][CH3:28])([CH3:20])([CH3:19])[CH3:18].I[C:54]1[CH:59]=[CH:58][C:57]([NH2:60])=[CH:56][N:55]=1.[Cl-].[Li+]>CN(C=O)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[C:17]([C:21]1[C:26]([O:27][CH3:28])=[C:25](/[CH:29]=[CH:30]/[C:54]2[N:55]=[CH:56][C:57]([NH2:60])=[CH:58][CH:59]=2)[CH:24]=[C:23]([C:44]2[C:45]([O:51][CH3:52])=[N:46][CH:47]=[C:48]([F:50])[CH:49]=2)[CH:22]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Nc1ccc(I)nc1
Reactant: CCCC[Sn](/C=C/c1cc(-c2cc(F)cnc2OC)cc(C(C)(C)C)c1OC)(CCCC)CCCC
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ncc(F)cc1-c1cc(/C=C/c2ccc(N)cn2)c(OC)c(C(C)(C)C)c1
Temperature: 110 °C
Yield: 87.1 %

Procedure:
step 1—A solution of Pd2(dba)3 (27.8 mg, 0.030 mmol) and tris-(2-furyl)phosphine (28.0 mg, 0.121 mmol) in anhydrous DMF (3 mL) was stirred at RT for 15 min under argon. To the resulting solution was added via cannula a solution of 364 (672 mg, 1.11 mmol) and 2-iodo-5-aminopyridine (294 mg, 1.33 mmol) in anhydrous DMF (6 mL) at RT. Lithium chloride (97.1 mg, 2.23 mmol) was then added under argon. The reaction mixture was heated at 110° C. for 18 h. After cooling to RT, the reaction mixture was poured into H2O (90 mL) and thrice extracted with EtOAc (60 mL). The combined extracts were washed with H2O (130 mL) and brine (130 mL), dried (Na2SO4), filtered and concentrated. The crude product was purified by SiO2 chromatography eluting with an EtOAc/hexane gradient (37 to 100% EtOAc) to afford 0.394 g (85%) of 6-{(E)-2-[3-tert-butyl-5-(5-fluoro-2-methoxy-pyridin-3-yl)-2-methoxy-phenyl]-vinyl}-pyridin-3-ylamine (370).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[C:12]1([S:18](Cl)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:12]1([S:18]([N:1]2[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]2)(=[O:20])=[O:19])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CCOC(=O)C1CCCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A mixture of ethyl piperidine-3-carboxylate (1.00 g, 6.36 mmol), benzenesulfonyl chloride (0.812 mL, 6.36 mmol), and triethylamine (2.66 mL, 19.1 mmol) in methylene chloride (10.0 mL) was stirred at r.t. for 2 hours. The mixture was quenched with water, then extracted with ethyl acetate. The extract was washed with 1N HCl solution, water, sat'd sodium bicarbonate solution, water, and brine, successively. Then, the extract was dried over sodium sulfate (anhydrous). After filtration, the filtrate was concentrated to yield 1.79 g (94%) of ethyl 1-(phenylsulfonyl)piperidine-3-carboxylate.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:15](=[O:23])[N:16]([CH3:22])[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(O)=O>C(O)(=O)C.[Pd]>[CH3:20][N:18]1[CH:19]=[C:14]([N:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[C:15](=[O:23])[N:16]([CH3:22])[C:17]1=[O:21]
Reactant: Cn1cc(N2CCN(Cc3ccccc3)CC2)c(=O)n(C)c1=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: O=CO
Product: Cn1cc(N2CCNCC2)c(=O)n(C)c1=O
Temperature: 100 °C
Yield: 56.7 %

Procedure:
2.6 g (8.26 mmol) of compound 13a are placed in the presence of 1.3 g of palladium and of 130 mL of formic acid in 300 mL of acetic acid at room temperature for 4 h. The mixture is heated to 100° C.° for 2 h 30 min. After neutralization with a 10% soda solution, the reaction medium is extracted with CHCl3. The organic phase is washed with water and then with a saturated NaCl solution. After drying on MgSO4, the organic phase is concentrated. The obtained residue is purified by flash chromatography (CH2Cl2-MeOH—NH4OH, gradient 90-10-0 to 90-9-1 over 30 min). 1.05 g of intermediate 13b is obtained as a beige solid (yield: 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[NH:20][CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Br[C:30]1[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=1[C:32]([O:34][CH3:35])=[O:33].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:30]4[CH:39]=[CH:38][CH:37]=[CH:36][C:31]=4[C:32]([O:34][CH3:35])=[O:33])[CH2:19][CH2:18][O:17][C:16]=3[CH:21]=2)(=[O:11])=[O:10])=[CH:27][CH:28]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3)cc1
Reactant: COC(=O)c1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccccc1N1CCOc2cc(S(=O)(=O)N(Cc3ccc(OC)cc3)c3nccs3)ccc21
Reaction time: 1 h
Yield: 75.8 %

Procedure:
A mixture of N-(4-methoxybenzyl)-N-(thiazol-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine-7-sulfonamide (Intermediate M; 500 mg, 1.196 mmol), methyl 2-bromobenzoate (687 mg, 2.99 mmol, Spectrochem), Pd2(dba3)2 (109 mg, 0.119 mmol), Xantphos (138 mg, 0.239 mmol) and sodium-tert-butoxide (229 mg, 2.392 mmol) in toluene (10 mL) was degassed for 10 minutes. The reaction mixture was subjected to microwave for 1 h at 100° C. After completion, reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain the crude material which was purified by combi flash column chromatography (column size: 12 g; elution: 0-20% ethyl acetate in hexane) to get methyl 2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)benzoate (500 mg, 75.7%) as a yellow solid. MS (ESI, positive ion) m/z; 552.1 (M+1)
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([C:9]2[S:17][C:16]3[C:11](=[N:12][CH:13]=[CH:14][C:15]=3[Cl:18])[CH:10]=2)=[O:8])[CH2:3]1.[CH:19]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][CH2:20]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:18][C:15]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:10]=[C:9]([C:7]([N:4]3[CH2:5][CH2:6][CH:2]([NH:1][C:23]([CH:19]4[CH2:22][CH2:21][CH2:20]4)=[O:24])[CH2:3]3)=[O:8])[S:17][C:16]=12
Reactant: O=C(Cl)C1CCC1
Reactant: NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(NC1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1)C1CCC1
Yield: 70.7 %

Procedure:
To a solution of (3-amino-pyrrolidin-1-yl)-(7-chloro-thieno[3,2-b]pyridin-2yl)-methanone (0.40 g, 1.4 mmol) and DMAP (0.693 g, 5.68 mmol) in CH2Cl2 (20 mL) was added cyclobutane carboxylic acid chloride (0.20 g, 1.7 mmol). After 3 h the reaction was quenched with distilled water (10 mL). The aqueous layer was extracted with CH2Cl2 (2×10 mL). The combined organic extracts were dried (Na2SO4), and concentrated onto silica gel (5 mL). Purification by flash chromatography on silica gel (CH2Cl2/MeOH 97:3) afforded the title compound as a white solid (0.36 g, 69%). MS: 364/366 (MH+); HPLC Rf: 4.24 min; HPLC purity: 94%.
Reaction SMILES: OC1C=C(OC(CCCC2C=CC=CC=2)C)C=C2C=1C(C(OC1C=CC([N+]([O-])=O)=CC=1)=O)CC(C)(C)C2.CN.Cl.C[NH-].C[NH:44][C:45]([CH:47]1[C:56]2[C:51](=[CH:52][C:53]([O:58][CH:59]([CH2:61][CH2:62][CH2:63][C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[CH3:60])=[CH:54][C:55]=2[OH:57])[CH2:50][C:49]([CH3:71])([CH3:70])[CH2:48]1)=[O:46]>O1CCCC1>[OH:57][C:55]1[CH:54]=[C:53]([O:58][CH:59]([CH2:61][CH2:62][CH2:63][C:64]2[CH:65]=[CH:66][CH:67]=[CH:68][CH:69]=2)[CH3:60])[CH:52]=[C:51]2[C:56]=1[CH:47]([C:45]([NH2:44])=[O:46])[CH2:48][C:49]([CH3:71])([CH3:70])[CH2:50]2
Reactant: CNC(=O)C1CC(C)(C)Cc2cc(OC(C)CCCc3ccccc3)cc(O)c21
Agent: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)CC(C)(C)CC2C(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CN
Agent: C[NH-]
Solvent: C1CCOC1
Product: CC(CCCc1ccccc1)Oc1cc(O)c2c(c1)CC(C)(C)CC2C(N)=O

Procedure:
Reaction of 0.55 g. (1.1 mmole) p-nitrophenyl 8-hydroxy-3,3-dimethyl-6-(5-phenyl-2-pentyloxy)tetralin-1-carboxylate in 10 ml. tetrahydrofuran with an excess of methylamine (gas) at room temperature, pouring the resulting mixture into 10% hydrochloric acid, extracting with ethyl acetate and work-up in the usual manner affords 0.50 g, of the N-methyl amide: N-methyl 8-hydroxy-3,3-dimethyl-6-(5-phenyl-2-pentyloxy)tetralin-1-carboxamide as a foam.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:21]=[CH:20][C:19]2[CH2:18][CH2:17][CH2:16][CH:15](C)[C:14]=2[C:13]=1[C:23]([O:25]C)=[O:24])(=[O:10])=[O:9].[F:27][C:28]([F:46])([F:45])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][NH2:44])[CH2:37][CH2:36]2)[N:30]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN1CCCC1=O>[F:46][C:28]([F:27])([F:45])[C:29]1[CH:34]=[CH:33][N:32]=[C:31]([N:35]2[CH2:40][CH2:39][N:38]([CH2:41][CH2:42][CH2:43][NH:44][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[S:8]([NH:11][C:12]3[CH:21]=[CH:20][C:19]4[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=4[C:13]=3[C:23]([OH:25])=[O:24])(=[O:9])=[O:10])[CH2:37][CH2:36]2)[N:30]=1
Reactant: NCCCN1CCN(c2nccc(C(F)(F)F)n2)CC1
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccccc2F)ccc2c1C(C)CCC2
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(O)c1c(NS(=O)(=O)c2ccccc2NCCCN2CCN(c3nccc(C(F)(F)F)n3)CC2)ccc2c1CCCC2
Temperature: 160 °C
Reaction time: 16 h
Yield: 37 %

Procedure:
A mixture of Example 275F (100 mg, 0.275 mmol) in 1.0 mL of N-methylpyrrolidinone was treated with 151 mg of 3-[4-(4-trifluoromethylpyrimidin-2-yl)-piperazin-1-yl]-propylamine and 58 mg of potassium phosphate, warmed to 160° C., stirred for 16 hours, concentrated, and purified by C18 reverse-phase HPLC using acetonitrile/water/0.1% TFA to provide the desired product (63 mg, 36%). MS (ESI) m/e 619 (M+H)+; 1H NMR (400 MHz, CD3OD) δ 8.66 (d, J=4.80 Hz, 1H), 7.52 (dd, J=7.96, 1.51 Hz, 1H), 7.34 (m, 1H), 7.24 (d, J=8.37 Hz, 1H), 7.03 (d, J=4.94 Hz, 1H), 6.97 (d, J=8.37 Hz, 1H), 6.80 (d, J=7.68 Hz, 1H), 6.57-6.61 (m, 1H), 3.75-4.25 (m, 4H), 3.25-3.40 (m, 8H), 2.65-2.76 (m, 4H), 2.03-2.10 (m, 2H), 1.65-1.69 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][N:10]=1)[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.FC(F)(F)C(O)=O.[CH:49]1([C@H:55]([NH:60][C:61]([C:63]2[O:64][C:65]([C:68]3[CH:73]=[CH:72][CH:71]=[C:70]([CH2:74][NH2:75])[CH:69]=3)=[CH:66][CH:67]=2)=[O:62])[C:56](=[O:59])[NH:57][CH3:58])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>CN(C=O)C.C(OCC)(=O)C>[CH:49]1([C@H:55]([NH:60][C:61]([C:63]2[O:64][C:65]([C:68]3[CH:69]=[C:70]([CH:71]=[CH:72][CH:73]=3)[CH2:74][NH:75][C:5](=[O:7])[C:4]3[CH:8]=[CH:9][N:10]=[C:2]([F:1])[CH:3]=3)=[CH:66][CH:67]=2)=[O:62])[C:56](=[O:59])[NH:57][CH3:58])[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1
Reactant: O=C(O)c1ccnc(F)c1
Reactant: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CN)c2)o1)C1CCCCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)[C@@H](NC(=O)c1ccc(-c2cccc(CNC(=O)c3ccnc(F)c3)c2)o1)C1CCCCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-fluoro-isonicotinic acid (22 mg, 0.16 mmol) in DMF (1 mL) is added HATU (61 mg, 0.16 mmol) and Et3N (0.044 mL, 0.3 mmol). After stirring at room temperature for 30 minutes, a solution of 5-(3-aminomethyl-phenyl)-furan-2-carboxylic acid ((S)-cyclohexyl-methylcarbamoyl-methyl)-amide trifluoroacetate salt (50 mg, 0.12 mmol) in DMF (1 mL) is added. The reaction is stirred for 2 hours, diluted with ethyl acetate and the organic layer washed with water and brine. The organic layer is evaporated in vacuo, and the resulting oil is purified by reverse phase HPLC to give the title compound as a solid, 21 mg, 41%, LC/MS ESI m/z (M+H)+493.5.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:14]S(C2C=CC=CC=2)(=O)=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10].Br.Br[CH2:26][C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]>>[CH3:12][O:11][C:9](=[O:10])[CH2:8][C:7]1[C:6]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:13]=2)[NH:14][C:26]=1[C:27]([C:29]1[CH:34]=[C:33]([CH2:35][CH2:36][CH3:37])[CH:32]=[CH:31][N:30]=1)=[O:28]
Reactant: CCCc1ccnc(C(=O)CBr)c1
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1NS(=O)(=O)c1ccccc1
Agent: Br
Product: CCCc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)OC)c1

Procedure:
The title compound was prepared according to the procedure described in Example 57 from methyl trans-5-chloro-2-(penylsulfonylamino)cinnamate (Example 36, step 3) and 2-bromoacetyl-4-propylpyridine hydrobromide (Preparation is described in Example 65).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[Cl-].O.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](O)(=[O:22])=[O:21])=[CH:16][CH:15]=1>CO>[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20]([O:6][C@H:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)[CH2:4][CH2:3][NH:2][CH3:1])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CNCC[C@H](O)c1cccs1
Agent: [Cl-]
Solvent: CO
Solvent: O
Product: CNCC[C@H](OS(=O)(=O)c1ccc(C)cc1)c1cccs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.1 %

Procedure:
A mixture of (S)-3-methylamino-1-thiophen-2-yl-propan-1-ol (5.0 g, 29.2 mmol), methylene to chloride (50 mL), p-toluenesulfonic acid hydrate (5.55 g, 29.2 mmol) and methanol (20 mL) is stirred 1 h at 25° C., then concentrated to dryness. The residue (10.8 g) which solidifies after a few hours is finally recrystallised from butanol (30 mL) affording a white powder (6.0 g, 60%);
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[NH:6][N:5]=[C:4]([CH2:7][C:8]([OH:11])([CH3:10])[CH3:9])[CH:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13]>C(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH3:17][C:2]1([CH3:1])[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:4]([CH2:7][C:8]([OH:11])([CH3:10])[CH3:9])[N:5]=[N:6]1
Reactant: CCOC(=O)C1C(CC(C)(C)O)=NNC1(C)C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CCOC(=O)C1=C(CC(C)(C)O)N=NC1(C)C
Reaction time: 0.25 h
Yield: 93.3 %

Procedure:
A suspension of 1.5 g of manganese dioxide in 50 ml of methylene chloride was stirred under an inert gas for 15 minutes and 200 mg of the product of Step C were added. The mixture was stirred for one hour and was filtered. The filtrate was evaporated to dryness to obtain 185 mg of ethyl 3,3-dimethyl-5-(2-hydroxy-2-methyl-propyl)-[3H]-pyrazole-4-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([CH:9]=1)C=O.ClC1C=CC=C(C(OO)=[O:22])C=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:11][O:12][CH3:13])=[C:6]([OH:22])[CH:9]=1
Reactant: COCOc1ccc(Br)cc1C=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: COCOc1ccc(Br)cc1O
Temperature: 25 °C
Reaction time: 72 h
Yield: 79.2 %

Procedure:
To 660 ml of dichloromethane solution containing 27.9 g (0.11 mol) of 5-bromo-2-methoxymethoxybenzaldehyde obtained in Reference example 5-(a) was added 42.9 g (0.132 mol) of m-chloroperbenzoic acid (purity: 53%), and the mixture was stirred at room temperature for 3 days. After completion of the reaction, the precipitated solid was removed from the reaction suspension by filtration, 97 ml of 2M aqueous sodium thiosulfate solution was added to the filtrate, and the mixture was stirred at room temperature for 2 hours. The organic layer after separation was concentrated under reduced pressure and the obtained solid was dissolved in diethyl ether. The solution was washed successively with 1M aqueous sodium thiosulfate solution, a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was applied to silica gel column chromatography (Eluent; hexane:ethyl acetate=4:1 (V/V)), and the fractions containing the desired compound were concentrated under reduced pressure to obtain 20.3 g of the title compound as a colorless oil. (Yield: 79%)
Reaction SMILES: [OH-].[Na+].[F:3][C:4]([F:31])([F:30])[C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[C:8]([O:28][CH3:29])[CH:9]=[CH:10][C:11]=2[C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([O:26]C)=[O:25])=[CH:23][C:17]=3[N:16]=2)[N:6]=1>C(O)C>[CH3:29][O:28][C:8]1[CH:9]=[CH:10][C:11]([C:15]2[NH:19][C:18]3[CH:20]=[CH:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:17]=3[N:16]=2)=[C:12]2[C:7]=1[N:6]=[C:5]([C:4]([F:30])([F:31])[F:3])[CH:14]=[CH:13]2
Reactant: COC(=O)c1ccc2[nH]c(-c3ccc(OC)c4nc(C(F)(F)F)ccc34)nc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(-c2nc3cc(C(=O)O)ccc3[nH]2)c2ccc(C(F)(F)F)nc12
Temperature: 25 °C
Yield: 91.2 %

Procedure:
Sodium hydroxide (1M, 40 ml) was added to a stirred suspension of 2-(2-trifluoromethyl-8-methoxyquinolin-5-yl)-1H-benzimidazole-5-carboxylic acid, methyl ester (1 g) in ethanol (40 ml) at room temperature. The reaction was heated to 80° C. for 4h and cooled to room temperature. The ethanol was removed in vacuo and the remaining aqueous phase acidified to pH 5 with glacial acetic acid. The resulting solid was collected by filtration and dried in vacuo to give the titled compound as a brown solid (0.88 g).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[NH:3][C:4]([N:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)[OH:7])=[O:5].[OH-].[Na+].Cl[C:20](OCC)=[O:21]>O1CCOCC1>[F:14][C:11]1[CH:12]=[CH:13][C:8]([N:6]2[C:4](=[O:5])[N:3]([C:2]([F:15])([F:1])[F:16])[C:20](=[O:21])[O:7]2)=[CH:9][CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: O=C(NC(F)(F)F)N(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=c1on(-c2ccc(F)cc2)c(=O)n1C(F)(F)F

Procedure:
1-Trifluoromethyl-3-(4'-fluorophenyl)-3-hydroxyurea (11.9 grams; 0.05 mol) is dissolved in dioxane (80 ml) and mixed with 2N aqueous sodium hydroxide (30 ml). Ethyl chloroformate (5.7 ml; 0.06 mol) is then added dropwise to the mixture at 10° to 15°C, with stirring, resulting in the formation of a precipitate. The precipitate is recovered by filtration, washed with water and dried to yield 2-(4'-fluorophenyl)-4-trifluoromethyl-1,2,4-oxadiazolidine-3,5-dione.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[N:5][CH:4]=[N:3]1.[F:11][C:12]1[CH:40]=[CH:39][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][C:13]=1[CH3:41]>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:39]=[CH:40][C:12]([F:11])=[C:13]([CH3:41])[CH:14]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[N:5][CH:4]=[N:3]1
Reactant: O=C(O)Cn1cncn1
Reactant: Cc1cc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](Cc4ccc(F)cc4)CN3)cc2)ccc1F
Agent: Cl
Product: Cc1cc(Oc2ccc(NC(=O)[C@@H]3C[C@@H](Cc4ccc(F)cc4)CN3C(=O)Cn3cncn3)cc2)ccc1F
Yield: 84 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,4-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide, gave Compound 73, (2S,4R)-1-(2-(1H-1,2,4-triazol-1-yl)acetyl)-N-(4-(4-fluoro-3-methylphenoxy)phenyl)-4-(4-fluorobenzyl)pyrrolidine-2-carboxamide (149 mg, 84%). 1H-NMR (400 MHz, CDCl3): σ 8.90 (s, 1H), 8.24 (s, 1H), 7.99 (s, 1H), 7.40 (d, 2H), 7.17-7.14 (m, 2H), 7.00 (t, 2H), 6.95-6.88 (m, 3H), 6.79-6.72 (m, 2H), 5.03 (d, 1H), 4.95 (d, 1H), 4.80 (d, 1H), 3.64 (t, 1H), 3.23 (t, 1H), 3.05-2.85 (2H), 2.69-2.61 (m, 2H), 2.22 (s, 3H), 1.72-1.67 (m, 1H). MS (EI) for C29H27F2N5O3. found 530.2 (MH−).
Reaction SMILES: S[C:2]1[NH:6][N:5]=[C:4]([CH2:7][CH2:8][C:9]([O:11]CC)=[O:10])[N:3]=1.N([O-])=O.[Na+].[N+]([O-])(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[NH:6]1[CH:2]=[N:3][C:4]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[N:5]1
Reactant: CCOC(=O)CCc1n[nH]c(S)n1
Agent: O=C([O-])[O-]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: O=[N+]([O-])O
Product: O=C(O)CCc1nc[nH]n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
ethyl 3-(5-mercapto-1H-1,2,4-triazol-3-yl)propanoate obtained in Reference Example 21 (650 mg, 3.23 mmol) was added slowly to a mixed solution of sodium nitrite (8.91 mg, 0.129 mmol), nitric acid (3 mL) and water (6 mL) while keeping 45° C. or less. The solution was stirred at room temperature for 15 hr, and neutralized with saturated aqueous sodium carbonate solution. The mixture was concentrated under reduced pressure, and the residue was crystallized from THF, and washed with THF. Ethanol was added thereto, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound as a pale-yellow powder (454 mg, 99%).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].[CH2:11](Br)[CH:12]=[CH2:13].Cl>C1COCC1>[CH2:13]([C:3]([OH:4])([C:5]([F:8])([F:7])[F:6])[C:2]([F:10])([F:9])[F:1])[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Product: C=CCC(O)(C(F)(F)F)C(F)(F)F
Reaction time: 4 h

Procedure:
One mol of hexafluoroacetone was added dropwise at 0° C. to 1.1 mol of allylbromide in THF solution. The reaction was carried out at room temperature for 4 hours. After treating with HCl, the reaction mixture was extracted with H2O and ether, and the organic layer was evaporated under reduced pressure to provide an intermediate product, allylhexafluoroisopropanol. Cyclopentadiene (1 mol) and 1 mol of the intermediate product then were placed into a reactor and reacted at about 80° C. for about 24 hours.