Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].Cl.[OH2:4].[NH:5]1[CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]1.[O:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>>[CH2:13]([O:12][C:16]([CH:15]=[C:8]1[CH2:9][CH2:10][NH:5][CH2:6][CH2:7]1)=[O:4])[CH3:14]
Reactant: O
Reactant: C1CCOC1
Reactant: O=C1CCNCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)C=C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (2.6 g) in 30 ml of tetrahydrofuran, cooled to 0° C. and kept under nitrogen atmosphere, 13 ml of triethylphosphonoacetate, dissolved in 10 ml of tetrahydrofuran are added dropwise. The temperature is then brought to room temperature and the stirring is continued for 30 minutes. The mixture is again cooled to 0° C. and it is added dropwise with a solution obtained by adding portionwise to a solution of 4-piperidone monohydrate hydrochloride (10 g) in THF 2.6 g of sodium hydride, filtered to eliminate the sodium chloride which formed. At the end of the addition, the temperature is brought to room temperature and the stirring is continued for 20 hours. The solvent is then evaporated under reduced pressure and the residue is redissolved in ethyl acetate and washed with 1 N hydrochloric acid. The aqueous phase is extracted with ethyl acetate and chloroform, then it is basified to pH=9-10 by adding 20% sodium hydroxide and it is extractedb with chloroform. The aqueous phase is then salted and extracted again with chloroform three times. The pooled extracts are dried over sodium sulfate and evaporated to give 7.1 g of the product as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:15][N:14]3[C:10]([S:11][CH2:12][CH2:13]3)=[N:9]2)[CH:5]=[CH:6][CH:7]=1.C[Al](C)C.C([O:22][C:23]([C:25]1[N:29]([CH3:30])[N:28]=[C:27]([CH3:31])[CH:26]=1)=O)C.Cl.N>ClCCl>[CH3:30][N:29]1[C:25]([C:23]([NH:1][C:2]2[CH:3]=[C:4]([CH:8]3[CH2:15][N:14]4[C:10]([S:11][CH2:12][CH2:13]4)=[N:9]3)[CH:5]=[CH:6][CH:7]=2)=[O:22])=[CH:26][C:27]([CH3:31])=[N:28]1
Reactant: CCOC(=O)c1cc(C)nn1C
Reactant: Nc1cccc(C2CN3CCSC3=N2)c1
Agent: C[Al](C)C
Agent: Cl
Agent: N
Solvent: ClCCl
Product: Cc1cc(C(=O)Nc2cccc(C3CN4CCSC4=N3)c2)n(C)n1
Yield: 34.1 %

Procedure:
To 6-(m-aminophenyl)-2,3,5,6-tetrahydroimidazo[2,1-b]thiazole (2.4 g, 11 mmol) in dry dichloromethane (30 ml) under nitrogen was added trimethylaluminium (4.8 ml; 25% in hexane). After 20 mins at room temperature 1,3-dimethylpyrazole-5-carboxylic acid ethyl ester (1.8 g, 11 mmol) in dry dichloromethane (1 ml) was added and the mixture heated under reflux for 24 hours. Hydrochloric acid (20 ml; 2 N aqueous) was added slowly, the resulting mixture basified with aqueous ammonia solution (5 N; 100 ml) and extracted with chloroform (3×200 ml) which after drying (MgSO4) and concentrating in vacuo afforded an oil. Separation of the oil on alumina eluting with chloroform gave the amide (1.28 g; 34%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[NH2:37][CH2:38][CH2:39][CH2:40][OH:41]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([NH:37][CH2:38][CH2:39][CH2:40][OH:41])=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCCCO
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCCCO)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-amino-1-propanol.
Reaction SMILES: Br.BrCC([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1)=O.Cl.[C:13]([NH2:16])(=[NH:15])[CH3:14].[CH3:17][C:18](C)([O-])C.[K+]>CO>[CH3:14][C:13]1[NH:15][CH:17]=[C:18]([C:9]2[CH:8]=[N:7][CH:6]=[CH:11][CH:10]=2)[N:16]=1
Reactant: O=C(CBr)c1ccccn1
Reactant: CC(C)(C)[O-]
Reactant: CC(=N)N
Agent: Br
Agent: Cl
Agent: [K+]
Solvent: CO
Product: Cc1nc(-c2cccnc2)c[nH]1
Yield: 13.9 %

Procedure:
Bromoacetylpyridine hydrobromide (1.0 g) and acetamidine hydrochloride (0.505 g) were suspended in methanol. Potassium tert-butoxide (1.0 g) was added in one portion—the mixture turned slightly yellow. The resulting suspension was heated to reflux for 6 hours and was then cooled and filtered. Solvent was removed in vacuo and the residue was dissolved in CHCl3 and adsorbed onto silica gel that was charged onto a silica gel column. The column was eluted with CH2Cl2/MeOH/NH4OH 90:10:1 and the fractions containing the desired product were combined and evaporated to give an oil (79 mg).
Reaction SMILES: Cl.[CH2:2]([NH2:4])[CH3:3].CCN(C(C)C)C(C)C.[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([OH:45])=O)[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:14][C:15]([C:19]1[N:23]([CH2:24][CH:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:22]2[CH:31]=[CH:32][C:33]([S:35]([N:38]3[CH:42]=[C:41]([C:43]([NH:4][CH2:2][CH3:3])=[O:45])[CH:40]=[N:39]3)(=[O:37])=[O:36])=[CH:34][C:21]=2[N:20]=1)([CH3:18])[CH2:16][CH3:17]
Reactant: CCN
Reactant: CCC(C)(C)c1nc2cc(S(=O)(=O)n3cc(C(=O)O)cn3)ccc2n1CC1CCOCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCNC(=O)c1cnn(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)CC)n3CC2CCOCC2)c1
Yield: 60.4 %

Procedure:
Following the same procedure in Example 24, Step A, using ethylamine hydrochloride (29 mg, 0.36 mmol), DIPEA (104 uL, 77 mg, 0.59 mmol), 1-{[2-(1,1-dimethylpropyl)-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}-1H-pyrazole-4-carboxylic acid (0.18 mmol) and HATU (109 mg, 0.29 mmol) in DMF (3 mL). The crude product was purified by MPLC using Hex/EtOAc (1:4) on silica gel to give 53 mg (61%) of a white solid as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 0.77 (t, J=7.42 Hz, 3 H), 1.15 (t, J=7.32 Hz, 3 H), 1.39-1.57 (m, 4 H), 1.58 (s, 6 H), 1.94 (q, J=7.68 Hz, 2 H), 2.19-2.37 (m, 1 H), 3.24-3.40 (m, 4 H), 3.83-3.94 (m, 2 H), 4.41 (d, J=7.23 Hz, 2 H), 7.92 (d, J=8.8 Hz, 1 H), 7.99 (dd, J=8.8, 1.4 Hz, 1 H), 8.04 (s, 1 H), 8.34 (d, J=1.17 Hz, 1 H), 8.74 (s, 1 H); MS (ESI) (M+H)+=488.0; Anal. Calcd for C24H33N5O4S+0.9 TFA+0.3H2O (595.65): C, 52.02; H, 5.84; N, 11.76. Found: C, 52.01; H, 5.66; N, 11.91.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12.[CH3:26][N:27]([CH:29]=O)[CH3:28].P(Cl)(Cl)Cl>C(=O)(O)[O-].[Na+].C(OCC)(=O)C>[ClH:10].[CH3:26][N:27]([CH:29]=[N:2][C@@H:3]1[C:24](=[O:25])[N:5]2[C:6]([C:11]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([N+:21]([O-:23])=[O:22])=[CH:19][CH:20]=3)=[O:12])=[C:7]([Cl:10])[CH2:8][S:9][C@H:4]12)[CH3:28]
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Reactant: CN(C)C=O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClP(Cl)Cl
Product: CN(C)C=N[C@@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(Cl)CS[C@H]12
Temperature: 25 °C
Reaction time: 48 h
Yield: 67 %

Procedure:
To a solution of 12.8 g. (31.5 mmole) of p-nitrobenzyl 7-amino-3-chloro-3-cephem-4-carboxylate hydrochloride in 115 ml. of dry DMF were added with stirring 10.4 g (6.5 ml., 72 mmole) of phosphorus trichloride. The reaction mixture was stirred at room temperature for about 2 days and was then dispersed in a mixture of 5% aqueous sodium bicarbonate and ethyl acetate. The organic layer was separated and treated with 1 N hydrochloric acid. The title compound precipitated from solution and was filtered and dried under vacuum. There were obtained 11.3 g. (67% yield) of the salt.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[SH:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[Na+].[Na+].CCO>O>[NH2:9][C:8]1[C:7]2[C:2](=[N:3][CH:4]=[CH:5][CH:6]=2)[S:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: N#Cc1cccnc1Cl
Reactant: CCOC(=O)CS
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1sc2ncccc2c1N
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 2-chloro-3-cyanopyridine (330 g, 2.3 mol), ethyl 2-mercaptoacetate (361.2 g, 3.0 mol), sodium carbonate (265 g, 2.5 mol) and EtOH (1.2L) was heated to reflux for 4.5 hours. The reaction mixture was cooled to ambient temperature and added to water (15L). The resultant precipitate was stirred for 30 minutes and then filtered. The filter cake was washed with two portions of water (2×2.5L) and dried to constant weight under vacuum at 45° C. to yield the title compound as a brown solid (493.1 g, 93.2%). δH (CDCl3) 8.68 (1H, dd, J 4.7, 1.2 Hz), 7.93 (1H, dd, J 8.5, 1.2 Hz), 7.29 (1H, dd, J 8.5, 4.7 Hz), 5.90 (2H, b), 4.38 (2H, q, J 7.0 Hz), 1.40 (3H, t, J 7.0 Hz). LCMS RT 2.9 minutes, 223 (M+H)+.
Reaction SMILES: [CH:1]([C:3]1[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=1)=[O:2].[CH3:13][C:14](=[N:18]O)[C:15](=O)[CH3:16].[ClH:20].C(OCC)(=O)C>C(OCC)C>[Cl:20][CH2:13][C:14]1[N:18]=[C:1]([C:3]2[O:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:5][CH:4]=2)[O:2][C:15]=1[CH3:16]
Reactant: CC(=O)C(C)=NO
Reactant: CCOC(=O)c1ccc(C=O)o1
Reactant: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ccc(-c2nc(CCl)c(C)o2)o1
Temperature: 25 °C
Reaction time: 72 h
Yield: 30 %

Procedure:
A mixture of ethyl 5-formyl-2-furancarboxylate (5.33 g), 2,3-butanedione-2-oxime (3.21 g) and 4N hydrogenchloride-ethyl acetate solution (100 mL) was stirred at room temperature for 3 days. After concentration of the reaction mixture, diethyl ether was added to the residue and the precipitated crystals were collected by filtration. A mixture of the obtained crystal, tetrahydrofuran (100 mL) and thionyl chloride (5.66 g) was heated under reflux for 3 hrs. The reaction mixture was concentrated and ethyl acetate was added to the residue. The ethyl acetate layer was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 5-(4-chloromethyl-5-methyl-1,3-oxazol-2-yl)-2-furancarboxylate as colorless crystals (2.60 g, yield 30%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 117-118° C.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[NH:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N+:17]([O-:19])=[O:18])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].CI.[C:24]([O-])(O)=O.[Na+]>C1COCC1>[CH3:24][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[C:8]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[N+:17]([O-:19])=[O:18]
Reactant: O=C([O-])O
Reactant: Cc1cccc2nc(-c3ccccc3[N+](=O)[O-])[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: Cc1cccc2c1nc(-c1ccccc1[N+](=O)[O-])n2C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution 4-methyl-2-(2-nitrophenyl)-benzimidazole (5.06 g, 20 mmol) in THF (50 mL) was added to a stirring suspension of NaH (1.2 g, 60% dispersion in mineral oil, 30 mmol) in THF (50 mL) at 0° C. under N2. The mixture was stirred at 0° C. for 30 min. and was then allowed to warm to r.t. for 1 h to form a orange solution. MeI (8.52 g, 60 mmol) was transfered into the above mixture dropwisely by a cannular at r.t under N2. This mixture was stirred for 24 h under N2 to result in a pale yellow solution. Saturated NaHCO3 (100 mL) was added. The water layer was extracted with CHCl3, the combined extracts was washed with brine, dried over Na2SO4. After removing of solvent, the residue was purified by column chromatography on silica gel using a mixture of hexane/ethyl acetate (1:1) as the eluent to give N-methyl-4-methyl-2-(2-nitrophenyl)-benzimidazole (3.0 g, 58%) as a yellow needle crystal. Rf=0.21 (hexane/ethyl acetate 1:1); 1H NMR (300 MHz, CDCl3) δ 2.68 (s, 3H), 3.60 (s, 3H), 7.12 (m, 1H), 7.26 (m, 2H), 7.65-7.80 (m, 3H), 8.23 (d, J=7.9 Hz, 1H). HRMS: Calcd for C15H13N3O2 267.1007, found 267.1007.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.Cl[CH:20]([CH3:24])[C:21]([OH:23])=[O:22].[OH-].[Na+]>>[F:1][C:2]([F:17])([F:18])[C:3]1[CH:16]=[CH:15][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([O:14][CH:20]([CH3:24])[C:21]([OH:23])=[O:22])=[CH:12][CH:13]=2)=[CH:5][CH:4]=1
Reactant: CC(Cl)C(=O)O
Reactant: Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reaction time: 0.5 h
Yield: 83.9 %

Procedure:
5.1 g of 4-(4-trifluoromethylphenoxy)phenol and 2.1 g of α-chloropropionic acid were heated at 80° C. with stirring, and 6.2 g of a 30% aqueous solution of sodium hydroxide was added. The reaction was carried out for 0.5 hour at 90° to 95° C. After allowing the reaction mixture to cool, the resulting solid precipitate was withdrawn, and washed with a small amount of methanol. The precipitate was dried overnight at reduced pressure to afford 5.3 g (yield: 81.5%) of the final product having a melting point of 138° to 140° C.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][C:21]=1[Br:22])[NH2:18].CCN(C(C)C)C(C)C.[CH:32]1([C:35]([N:37]2[CH2:41][CH2:40][C@@H:39]([CH2:42][C:43]([NH:45][NH2:46])=[O:44])[CH2:38]2)=[O:36])[CH2:34][CH2:33]1>ClCCl>[Br:22][C:21]1[CH:20]=[CH:19][C:17]([NH:18][C:2]([NH:46][NH:45][C:43](=[O:44])[CH2:42][C@@H:39]2[CH2:40][CH2:41][N:37]([C:35]([CH:32]3[CH2:34][CH2:33]3)=[O:36])[CH2:38]2)=[O:4])=[CH:16][C:15]=1[O:14][CH3:13]
Reactant: COc1cc(N)ccc1Br
Reactant: NNC(=O)C[C@@H]1CCN(C(=O)C2CC2)C1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC(=O)NNC(=O)C[C@@H]2CCN(C(=O)C3CC3)C2)ccc1Br
Temperature: -78 °C

Procedure:
To a round bottom flask was added triphosgene (0.514 g, 1.732 mmol) and dichloromethane (30 mL) under nitrogen, and the solution was cooled to −78° C. In a separate vial, 3-methoxy 4-bromoaniline (1 g, 4.95 mmol) was dissolved in dichloromethane (20 mL) and Hunig's base (1.753 mL, 9.90 mmol) was added. This solution was slowly added to the cooled solution and then the reaction was allowed to warm to room temperature. Analysis by LCMS indicated desired intermediate formation. The reaction was cooled again to −78° C. and 2-[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]acetohydrazide (0.575 g, 2.72 mmol) in dichloromethane (5 mL) was added slowly. The reaction was allowed to warm to room temperature and analysis by LCMS indicated desired product formation. The reaction was poured into a reparatory funnel and partitioned with saturated aq sodium bicarbonate. The aqueous layer was extracted with dichloromethane (3×) and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to an oil. The residue was purified by silica gel chromatography (0-40% isopropanol/ethyl acetate). The desired product fractions were combined and concentrated in vacuo to afford the title product as a tan solid (500 mg, 42%). MS(ES)+ m/e 439.0, 441.1 M+H]+.
Reaction SMILES: [C:1]([CH:3]([O:11][N:12]=[C:13]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[CH2:4][CH2:5][C:6]([O:8]CC)=[O:7])#[N:2].[OH-].[Na+]>O1CCOCC1>[C:1]([CH:3]([O:11][N:12]=[C:13]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=1)[CH2:4][CH2:5][C:6]([OH:8])=[O:7])#[N:2]
Reactant: CCOC(=O)CCC(C#N)ON=C(c1ccc(OC)cc1)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=NOC(C#N)CCC(=O)O)c2ccc(OC)cc2)cc1
Reaction time: 5 h
Yield: 97.8 %

Procedure:
3.96 g of the 4,4'-dimethoxybenzophenone O-(1-cyano-3-ethoxycarbonylpropyl)oxime was dissolved in 20 ml of dioxane and 3 mil of a 5 N aqueous solution of caustic soda was added thereto. Then the mixture was allowed to react at 20 C. for five hours. After the completion of the reaction, the reaction mixture was acidified and extracted with ethyl acetate. Thus 3.6 g of the title compound was obtained in the form of a colorless oily product.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11](=[O:19])[NH:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1.[CH3:20][C:21]([O:23][CH2:24][C@H:25]1[O:30][C@H:29](Br)[C@H:28]([O:32][C:33]([CH3:35])=[O:34])[C@@H:27]([O:36][C:37]([CH3:39])=[O:38])[C@@H:26]1[O:40][C:41]([CH3:43])=[O:42])=[O:22].C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]2[C:11]([O:19][C@@H:29]3[O:30][C@H:25]([CH2:24][O:23][C:21](=[O:22])[CH3:20])[C@@H:26]([O:40][C:41](=[O:42])[CH3:43])[C@H:27]([O:36][C:37](=[O:38])[CH3:39])[C@H:28]3[O:32][C:33](=[O:34])[CH3:35])=[N:12][NH:13][C:14]=2[C:15]([F:18])([F:17])[F:16])=[CH:5][CH:4]=1
Reactant: CSc1ccc(Cc2c(C(F)(F)F)[nH][nH]c2=O)cc1
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CSc1ccc(Cc2c(O[C@@H]3O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)n[nH]c2C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.6 %

Procedure:
To a solution of 1,2-dihydro-4-[(4-methylthiophenyl)-methyl]-5-trifluoromethyl-3H-pyrazol-3-one (2.0 g) in acetonitrile (100 mL) were added acetobromo-α-D-glucose (3.1 g) and potassium carbonate (1.1 g), and the mixture was stirred at room temperature overnight. Water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=1/1) to give 4-[(4-methylthiophenyl)methyl]-3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-5-trifluoromethyl-1H-pyrazole (2.0 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1.C(OCC)C.C([Li])CCC.[F:23][C:24]1[CH:29]=[C:28]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:25]=1[C:39]([F:43])=[C:40](F)[F:41]>C1(C)C=CC=CC=1>[F:43]/[C:39](/[C:25]1[CH:26]=[CH:27][C:28]([CH:30]2[CH2:35][CH2:34][CH:33]([CH2:36][CH2:37][CH3:38])[CH2:32][CH2:31]2)=[CH:29][C:24]=1[F:23])=[C:40](/[F:41])\[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[C:4]([F:12])[CH:3]=1
Reactant: Fc1cc(Br)ccc1C(F)(F)F
Reactant: CCCC1CCC(c2ccc(C(F)=C(F)F)c(F)c2)CC1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCCC1CCC(c2ccc(/C(F)=C(\F)c3ccc(C(F)(F)F)c(F)c3)c(F)c2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 4-bromo-2-fluoro-1-(trifluoromethyl)benzene (2.28 g) and diethyl ether (70 ml) were added, and cooling was carried out to −70° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (7.10 ml) was added dropwise in a temperature range of −70° C. to −65° C., and stirring was carried out for another 1 hour. Subsequently, a diethyl ether (10 ml) solution of compound (T-9) (2.68 g) was added dropwise in a temperature range of −70° C. to −65° C., and stirring was carried out for 4 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (100 ml), and mixing was carried out. Toluene (100 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with a 1 N hydrochloric acid solution, a saturated aqueous solution of sodium hydrogencarbonate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by fractionation by means of column chromatography (silica gel; heptane), and further purified by recrystallization from a heptane/Solmix A-11 mixed solvent, and thus (E)-1-(1,2-difluoro-2-[3-fluoro-4-(trifluoromethyl)phenyl]vinyl)-2-fluoro-4-(4-propylcyclohexyl)benzene (1-1-25) (2.24 g) was obtained. The yield based on compound (T-9) was 57%.
Reaction SMILES: CO[C:3]([C@@H:5]1[C@H:10]([NH2:11])[CH2:9][CH2:8][N:7]([C:12](OC(C)(C)C)=O)[CH2:6]1)=[O:4].[S:19]1[CH2:23][CH2:22][NH:21][CH2:20]1.BrC[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[NH2:11][C@@H:10]1[CH2:9][CH2:8][N:7]([CH2:12][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:6][C@@H:5]1[C:3]([N:21]1[CH2:22][CH2:23][S:19][CH2:20]1)=[O:4]
Reactant: COC(=O)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@H]1N
Reactant: C1CSCN1
Reactant: BrCCc1ccccc1
Product: N[C@@H]1CCN(CCc2ccccc2)C[C@@H]1C(=O)N1CCSC1

Procedure:
This material was obtained as described in example 34 from the opposite enantiomer (3S, 4R)-4-amino-piperidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester, thiazolidine and 2-(bromoethyl)-benzene. Yellow oil. MS (ESI): 320.4 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:10](N)=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:20]>>[Br:20][C:10]1[C:4]2[C:5](=[N:6][CH:7]=[C:2]([F:1])[CH:3]=2)[NH:8][N:9]=1
Reactant: BrC(Br)Br
Reactant: Nc1n[nH]c2ncc(F)cc12
Agent: CC(C)(C)ON=O
Product: Fc1cnc2[nH]nc(Br)c2c1
Temperature: 61 °C

Procedure:
To the miture of 5-fluoro-1H-pyrazolo[3,4-b]pyridin-3-amine, 3, (0.88 g, 5.79 mmol) in bromoform (8.8 mL) was added tert-butyl nitrite (1.38 mL, 11.57 mmol). This mixture was heated to 61° C. for 1 h and then heated to 90° C. for an additional hour. The mixture was cooled to room temperature and bromoform was removed under reduced pressure. The resulting crude residue was purified by silica gel chromatography (5-50% ethyl acetate/hexanes) to afford 970 mg of the desired product as a white solid: 1H NMR (300 MHz, DMSO) δ 14.22 (s, 1H), 8.67 (dd, J=2.7, 1.9 Hz, 1H), 8.07 (dd, J=8.2, 2.7 Hz, 1H); LC/MS Gradient 10-90%, 0.1% formic 5 min, C18/ACN, Retention Time=2.42 min, (M+H) 216.11.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]2[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=2)=[N:7][CH:8]=1.[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][C:32]=1[CH3:38])([CH3:29])[CH3:28])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH2:23]([O:25][C:26](=[O:39])[C:27]([O:30][C:31]1[CH:36]=[CH:35][C:34]([O:37][CH2:2][C:3]2[C:4]([CH2:19][CH2:20][O:21][CH3:22])=[N:5][C:6]([C:9]3[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=3)=[N:7][CH:8]=2)=[CH:33][C:32]=1[CH3:38])([CH3:28])[CH3:29])[CH3:24]
Reactant: COCCc1nc(-c2ccc(C(F)(F)F)nc2)ncc1CCl
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2cnc(-c3ccc(C(F)(F)F)nc3)nc2CCOC)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 55.8 %

Procedure:
To a solution of 133 mg (0.40 mmol) 5-chloromethyl-4-(2-methoxy-ethyl)-2-(6-trifluoromethyl-pyridin-3-yl)-pyrimidine (example 101F]) and 95 mg (0.40 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) in 12 ml of acetonitrile was added 143 mg (0.44 mmol) cesium carbonate. The reaction mixture was stirred for 16 h at RT. The mixture was filtered, taken up in dichloromethane dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography over silica gel with heptane/AcOEt 9:1, to give 119 mg of the title compound as light yellow viscous oil.