Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]2[O:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:11]([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])#[N:12]>>[CH2:9]1[O:8][C:5]2[CH:6]=[CH:7][C:2]([CH:13]([C:11]#[N:12])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:3][C:4]=2[O:10]1
Reactant: CCOC(=O)CC#N
Reactant: Clc1ccc2c(c1)OCO2
Product: CCOC(=O)C(C#N)c1ccc2c(c1)OCO2
Yield: 81.9 %

Procedure:
Method B of the above general procedure was followed using 4-chloro-1,2-(methylenedioxy)benzene (157 mg, 1.00 mmol) and ethyl cyanoacetate (124 mg, 1.10 mmol). The reaction mixture was purified by column chromatography on silica gel (1:3 dichloromethane/hexanes) to give the desired product (191 mg, 82%) as a colorless oil: 1H NMR (CDCl3) δ 6.93-6.90 (m, 2H), 6.83-6.80 (m, 1H), 6.00 (s, 2H), 4.62 (s, 1H), 4.30-4.19 (m, 2H), 1.29 (t, 7.2 Hz, 3H). 13C{1H} NMR (CDCl3) δ 165.07, 148.46, 148.44, 123.33, 121.76, 115.75, 108.79, 108.25, 101.68, 63.34, 43.31, 13.92. Anal. Calcd. for C12H11NO4: C, 61.80; H, 4.75; N, 6.01. Found: C, 62.08: H, 4.62: N, 6.13.
Reaction SMILES: [CH2:1]([C:3]1([C:16]([O-:18])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1)C.[CH:19]([N-]C(C)C)(C)[CH3:20].[Li+].CI.[Cl-].[NH4+]>C1COCC1>[CH3:1][C:3]1([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4]1
Reactant: CC(C)[N-]C(C)C
Reactant: CCC1(C(=O)[O-])CCCN(C(=O)OC(C)(C)C)C1
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOC(=O)C1(C)CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
A THF (5 mL) solution of 1-tert-butyl 3-ethylpiperidine-1,3-dicarboxylate (1 g, 3.89 mmol) was added dropwise to a THF (15 mL) solution of lithium diisopropylamide (5.83 mmol) in a nitrogen atmosphere at −78 degrees over 5 minutes. The mixture was raised to room temperature, and stirred for 50 minutes. The temperature of the reaction mixture was lowered to −78 degrees again, and methyl iodide (1.21 mL, 19.43 mmol) was added dropwise at −78 degrees over 5 minutes. The reaction mixture was then raised to room temperature, and stirred for 5 hours. After being added to a saturated ammonium chloride aqueous solution, the reaction mixture was stirred for a while, and extracted with diethyl ether. The organic layer was collected, washed once with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was then purified using silica gel column chromatography to obtain the target (698 mg, 66%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[CH:12]=[N:13][CH:14]=[N:15][CH:16]=2)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21]Br>>[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[F:26])[CH2:21][N:10]([C:11]1[CH:16]=[N:15][CH:14]=[N:13][CH:12]=1)[C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=1
Reactant: Fc1ccc(CBr)cc1F
Reactant: O=[N+]([O-])c1ccc(Nc2cncnc2)nc1
Product: O=[N+]([O-])c1ccc(N(Cc2ccc(F)c(F)c2)c2cncnc2)nc1

Procedure:
Starting compounds: 5-[N-(5-nitro-2-pyridyl)amino]pyrimidine and 3,4-difluorobenzyl bromide
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][CH2:13][CH2:14][OH:15].Br[CH2:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH3:28])[C:19]=1[O:20][CH2:21][C:22]#[N:23]>>[CH3:17][C:18]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][O:15][CH2:14][CH2:13][O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)[C:19]=1[O:20][CH2:21][C:22]#[N:23]
Reactant: OCCOCc1ccc2ccccc2n1
Reactant: Cc1cccc(CBr)c1OCC#N
Product: Cc1cccc(COCCOCc2ccc3ccccc3n2)c1OCC#N

Procedure:
MS (ESI) 363 (M+H)+. Prepared from 2-(quinolin-2-ylmethoxy)-ethanol (EXAMPLE 34d) and (2-bromomethyl-6-methyl-phenoxy)-acetonitrile.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@@:24]([CH2:27][OH:28])([CH3:26])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Si:42](Cl)([CH3:45])([CH3:44])[CH3:43].O>ClCCl>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:39])[C:16]([N:18]2[CH2:30][CH2:29][C@:21]3([NH:25][C@:24]([CH3:26])([CH2:27][O:28][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH2:23][CH2:22]3)[CH2:20][C@@H:19]2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[CH3:38])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: C[Si](C)(C)Cl
Reactant: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO)N2
Solvent: ClCCl
Solvent: O
Product: Cc1cc(F)ccc1[C@H]1C[C@@]2(CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC[C@@](C)(CO[Si](C)(C)C)N2
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 97.8 %

Procedure:
To a solution of (2S,5S,7R)—N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-7-(4-fluoro-2-methylphenyl)-2-(hydroxymethyl)-N,2-dimethyl-1,8-diazaspiro[4.5]decane-8-carboxamide (Example 19, 80 mg, 0.136 mmol) in dichloromethane (DCM) (2 ml), TEA (0.021 ml, 0.149 mmol) was added and the reaction mixture was stirred at 0° C. for 5 min. TMS-Cl (0.026 ml, 0.204 mmol) was added dropwise and mixture was stirred at the same temperature overnight. Water (2 ml) was added and two phases were separated. The organic layer was dried and evaporated in vacuo affording the title compound (88 mg) that was used in the next step without further purifications.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:9]=1[C:10]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([O:17]CCCCCC)=[O:16])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[OH-].[Na+]>O>[CH2:1]([O:7][C:8]1[CH:30]=[C:29]([CH3:31])[CH:28]=[CH:27][C:9]=1[C:10]([C:12]1[CH:13]=[C:14]([CH:24]=[CH:25][CH:26]=1)[C:15]([OH:17])=[O:16])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOC(=O)c1cccc(C(=O)c2ccc(C)cc2OCCCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCCCCOc1cc(C)ccc1C(=O)c1cccc(C(=O)O)c1

Procedure:
mixture of 3-(2-hydroxy-4-methylbenzoyl)benzoic acid (2.97 g), 2N sodium hydroxide (12.8 ml), and ethanol (25 ml) is heated under reflux for 15 minutes. Then, 1-bromohexane (4.21 g) is added to the cooled solution and the resulting mixture refluxed for 48 hours. The cooled mixture is diluted with water (100 ml) and extracted with ether (3×75 ml). The ether extracts are dried over magnesium sulfate and concentrated in vacuo to yield hexyl 3-(2-n-hexyloxy-4-methylbenzoyl)benzoate (4.56 g) as a dark brown oil. This ester is mixed with 2N sodium hydroxide (6.4 ml) and refluxed for 4 hours. The cooled reaction mixture is diluted with water (50 ml), washed with ether (25 ml) and acidified to pH 2.0 with concentrated hydrochloric acid. The product is extracted with ether (3×35 ml) and the combined extracts dried over magnesium sulfate, filtered, and concentrated in vacuo. The product is then dissolved in 2N sodium hydroxide (2.95 ml) and water is added to brink the total volume to 10 ml. This sodium salt is chromatographed on a Water's Prep 500A/LC System using the reverse phase prep pack-500/C18 column (water:acetone; 80:20). The fraction containing the major component is acidified to pH 2.0 with concentrated hydrochloric acid and extracted with ether (3×100 ml). The combined ether extracts are dried over magnesium sulfate, filtered, and concentrated in vacuo. The residue is recrystallized from heptane to yield 3-(2-n-hexyloxy-4-methylbenzoyl)benzoic acid (1.50 g), m.p. 118° C.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][C:3]([OH:5])=[O:4].[CH3:8][CH:9]([CH2:11][CH:12](O)[CH3:13])[CH3:10].S(=O)(=O)(O)O.O>C1(C)C=CC=CC=1>[C:1]([O:7][CH:12]([CH3:13])[CH2:11][CH:9]([CH3:10])[CH3:8])(=[O:6])[CH2:2][C:3]([O:5][CH:12]([CH3:13])[CH2:11][CH:9]([CH3:10])[CH3:8])=[O:4]
Reactant: CC(C)CC(C)O
Reactant: O=C(O)CC(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CC(C)OC(=O)CC(=O)OC(C)CC(C)C
Yield: 83.9 %

Procedure:
Malonic acid (72.8 g, 0.7 mol) and 2-methyl-4-pentanol(286 g, 2.8 mol) in 200 ml of toluene are refluxed for 2 hours in the presence of 1.8 ml of concentrated sulfuric acid in a reactor equipped with Dean-Stark apparatus. The water formed is removed azeotropically. The organic phase is washed three times with water and dried over sodium sulfate. This solution is filtered and the solvent is evaporated off. The product obtained distils at 147° C. under 20 hPa. 160 g (79% yield) of bis(1,3-dimethylbutyl) malonate are obtained in the form of a colorless oil, which is used in the next step without further purification.
Reaction SMILES: Cl([O-])(=O)(=O)=O.[N+:6]([C:9]1[O:13][C:12]([C:14]2[C:18]([CH:19]=[N+](C)C)=[CH:17][N:16]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:15]=2)=[CH:11][CH:10]=1)([O-:8])=[O:7].C([O-])(=O)C.[Na+].[C:34]([O:38][CH2:39][CH3:40])(=[O:37])[NH:35][NH2:36].CN(C)C=O>O>[CH2:39]([O:38][C:34]([NH:35][N:36]=[CH:19][C:18]1[C:14]([C:12]2[O:13][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=2)=[N:15][N:16]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1)=[O:37])[CH3:40]
Reactant: C[N+](C)=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reactant: CCOC(=O)NN
Agent: CC(=O)[O-]
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NN=Cc1cn(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])o1
Reaction time: 0.5 h
Yield: 95 %

Procedure:
Add 2.0 g of [3-(5-nitro-2-furyl)-1-phenylpyrazol-4-ylmethylene]dimethylammonium perchlorate, 0.4 g. of anhydrous sodium acetate and 0.63 g of ethyl carbazate to 10.5 ml of dimethylformamide. Stir the resulting admixture for 30 minutes before adding 30 ml of water dropwise thereto to obtain a 95% yield of 3-(5-nitro-2-furyl)-1-phenylpyrazole-4-carboxaldehyde-ethoxycarbonylhydrazone [m.p. 200° to 201° C].
Reaction SMILES: [Cl:1][C:2]1[CH:10]=CC(C(O)=O)=[C:4](C)[CH:3]=1.B.[CH2:13]1[CH2:17][O:16][CH2:15][CH2:14]1.CO>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:13]([CH2:17][OH:16])[CH:14]=[CH:15][C:3]=1[CH3:4]
Reactant: C1CCOC1
Reactant: Cc1cc(Cl)ccc1C(=O)O
Agent: B
Solvent: CO
Product: Cc1ccc(CO)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To a solution of 4-chloro-2-methylbenzoic acid (800 mg, 4.69 mmol) in THF (8 mL) that was cooled at 0° C., BH3.THF (14 mL, 1M in THF) was added into the solution drop wise. The mixture was then stirred at r.t. overnight. Add methanol to the system at 0° C. slowly until no gas released. Remove the solvent and the residue was extracted with ethylacetate, concentrated the organic phase to give 894 mg of the title compound (85%). 1H NMR (400 MHz, CDCl3): δ 2.36 (3H, s), 4.63 (2H, s), 7.13-7.22 (2H, m), 7.35 (1H, s).
Reaction SMILES: [NH3:1].C([O:4][C:5](=O)[CH2:6][S:7]([NH:10][C:11]1[CH:16]=[C:15]([CH:17]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])[C:14]([Cl:36])=[CH:13][N:12]=1)(=[O:9])=[O:8])C>CO>[Cl:36][C:14]1[C:15]([CH:17]([S:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)(=[O:28])=[O:27])[C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[F:25])=[CH:16][C:11]([NH:10][S:7]([CH2:6][C:5]([NH2:1])=[O:4])(=[O:8])=[O:9])=[N:12][CH:13]=1
Reactant: N
Reactant: CCOC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Solvent: CO
Product: NC(=O)CS(=O)(=O)Nc1cc(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(Cl)cc2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a methanol solution (5 ml) of 7N ammonia was added the ethyl[[[5-chloro-[(4-chlorophenylsulfonyl)(2,5-difluorophenyl)methyl]pyridin-2-yl]amino]sulfonyl]acetate (78 mg, 0.135 mmol) obtained in Example 283. The resulting mixture was stirred at room temperature for 3 days, followed by concentration under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:25) eluate was concentrated under reduced pressure to give the title compound (66 mg, 0.120 mmol, 89%) as a white solid.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C@H:15]2[CH2:17][C@@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:21]C1C=CC(/C=C/[N+]([O-])=O)=CC=1>>[Br:21][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Reactant: O=[N+]([O-])[C@H]1C[C@@H]1c1ccc(OCc2ccccc2)cc1
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 27 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate A, using the commercially available 1-bromo-4-[(trans)-2-nitrovinyl]benzene as starting material. 27% yield
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:5]=[CH:6][CH:7]=1.[C:32]1([C@@H]2C[C@H]2C(O)=O)C=CC=CC=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:11]([CH2:10][C@@H:9]2[CH2:32][C@H:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[CH:2][CH:3]=2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH2:26][CH2:27]1
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(C[C@@H]2C[C@H]2c2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexy)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using trans-2-phenylcyclopropanecarboxylic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([F:14])([F:13])[CH3:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([CH:21]=[CH:22][C:23]=1[C:24]([F:27])([F:26])[F:25])[NH2:20]>C(O)C>[F:13][C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([NH:20][C:19]3[CH:21]=[CH:22][C:23]([C:24]([F:25])([F:26])[F:27])=[C:17]([F:16])[CH:18]=3)[N:7]2[N:8]=1)([F:14])[CH3:12]
Reactant: Cc1cc(Cl)n2nc(C(C)(F)F)nc2n1
Reactant: Nc1ccc(C(F)(F)F)c(F)c1
Solvent: CCO
Product: Cc1cc(Nc2ccc(C(F)(F)F)c(F)c2)n2nc(C(C)(F)F)nc2n1
Temperature: 50 °C

Procedure:
A suspension of Intermediate 3 (0.1 g, 0.43 mmol) and 3-fluoro-4-(trifluoromethyl)aniline (ALFAAESAR, 0.077 g, 0.43 mmol) in ethanol (5 mL) was heated at 50° C. for 1 h. The reaction mixture was concentrated under vacuum, redissolved in DCM (20 mL) and washed with aq. Na2CO3 (2×15 mL). The organic layer was dried over anhydrous Na2SO4 filtered and concentrated under vacuum to afford a white solid.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[CH:4]=1)[CH3:2].[C:12](Cl)(=[O:14])[CH3:13].Cl>ClC(Cl)C>[CH2:1]([C:3]1[S:7][C:6]2[CH:8]=[CH:9][CH:10]=[CH:11][C:5]=2[C:4]=1[C:12](=[O:14])[CH3:13])[CH3:2]
Reactant: CCc1cc2ccccc2s1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CC(Cl)Cl
Product: CCc1sc2ccccc2c1C(C)=O
Reaction time: 14 h
Yield: 765 %

Procedure:
Into a one-litre flask fitted with a mechanical stirrer and a dropping-funnel, 32.45 g (0.2 mol) of 2-ethyl-benzo[b]thiophene and 14.3 ml of acetyl chloride were introduced with 400 ml of dichloroethane. After the solution was cooled to between 5 and 10° C by means of an ice-bath, 23.2 ml (0.2 mol) of stannic chloride were introduced through the dropping-funnel. The mixture was then allowed to return to room temperature and was stirred for about 14 hours. The complex so formed was then hydrolysed with diluted hydrochloric acid. The organic and aqueous phases were separated by decantation and the aqueous phase was extracted with ether. The ethereal fraction was then added to the organic phase and the mixture was washed with water and evaporated to dryness to give, after distillation between 124°-134° C (0.01 mm/Hg), 31.3 g of 2-ethyl-3-acetyl-benzo[b]thiophene. Yield 765%.
Reaction SMILES: [BH4-].[Na+].[C:3]1([CH:9]([O:16][C:17]([C:19]2[N:24]3[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:23]3[S:22][CH2:21][C:20]=2[OH:39])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>CN(C)C=O.C(O)=O>[C:3]1([CH:9]([O:16][C:17]([C@@H:19]2[N:24]3[C:25](=[O:38])[C@@H:26]([NH:27][C:28](=[O:37])[CH2:29][O:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C@H:23]3[S:22][CH2:21][CH:20]2[OH:39])=[O:18])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(COc1ccccc1)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(O)CS[C@H]12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O=CO
Solvent: CN(C)C=O
Product: O=C(COc1ccccc1)N[C@@H]1C(=O)N2[C@@H]1SCC(O)[C@@H]2C(=O)OC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.8 %

Procedure:
28.4 mg of sodium borohydride are added to a solution of 516 mg of 3-hydroxy-7β-phenoxyacetylamino-3-cephem-4-carboxylic acid diphenylmethyl ester in 4 ml of dimethylformamide and 1 ml of formic acid at room temperature. After stirring the reaction mixture for one hour at room temperature, it is poured onto a mixture of ice and 2 N hydrochloric acid and extracted with ethyl acetate. The combined organic phases are washed successively with water, three times with saturated sodium bicarbonate solution and saturated, aqueous sodium chloride solution, dried over sodium sulphate and concentrated in vacuo. The residue is substantially freed from dimethylformamide under a high vacuum. The resulting white foam (580 mg) is subjected to chromatography on preparative silica gel thick-layer plates with toluene/ethyl acetate 1:1 and yields 403 mg of the title compound.
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:9]([O:16][CH2:17][CH2:18][C:19]1([CH3:22])[CH2:21][O:20]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[F:23][C:24]([F:48])([F:47])[O:25][C:26]1[CH:46]=[CH:45][C:29]([CH2:30][CH2:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38]3[CH:43]=[CH:42][C:41]([OH:44])=[CH:40][CH:39]=3)[CH2:34][CH2:33]2)=[CH:28][CH:27]=1.O>C(O)C>[CH2:9]([O:16][CH2:17][CH2:18][C:19]([CH3:22])([OH:20])[CH2:21][O:44][C:41]1[CH:40]=[CH:39][C:38]([N:35]2[CH2:34][CH2:33][CH:32]([CH2:31][CH2:30][C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]([F:47])([F:23])[F:48])=[CH:46][CH:45]=3)[CH2:37][CH2:36]2)=[CH:43][CH:42]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC1(CCOCc2ccccc2)CO1
Reactant: Oc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(O)(CCOCc1ccccc1)COc1ccc(N2CCC(CCc3ccc(OC(F)(F)F)cc3)CC2)cc1
Yield: 83.8 %

Procedure:
A tripotassium phosphate (0.44 g, 2.1 mmol) was added to a solution of 2-[2-(Benzyloxy)ethyl]-2-methyloxirane (1.00 g, 5.2 mmol) and 4-{4-[4-(trifluoromethoxy)phenethyl]piperidin-1-yl}phenol (2.28 g, 6.2 mmol) in ethanol (10 ml), and then the mixture was heated at reflux overnight. Water was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a saturated sodium chloride aqueous solution, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=100:0→50:50) to afford the title compound as a brown powder (2.43 g, 86%).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10](O)=O.[CH3:14][NH:15][C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][C:17]=1[NH2:23]>O1CCCC1>[C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH2:9][C:10]1[N:15]([CH3:14])[C:16]2[C:21]([NH2:22])=[CH:20][CH:19]=[CH:18][C:17]=2[N:23]=1
Reactant: Cc1cc(C)c(CC(=O)O)c(C)c1
Reactant: CNc1c(N)cccc1N
Solvent: C1CCOC1
Product: Cc1cc(C)c(Cc2nc3cccc(N)c3n2C)c(C)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24 %

Procedure:
To a solution of mesityleneacetic acid (904 mg, 5.08 mmol) in tetrahydrofuran (20 mL) was added N,N′-carbonyldiimidazole (823 mg, 5.08 mmol) at room temperature. After the mixture was stirred for 1 hr at 50° C., N2-methylbenzene-1,2,3-triamine (700 mg, 5.08 mmol) in tetrahydrofuran (8 mL) was added to the mixture and the mixture was refluxed for further 18 hr. After the mixture was cooled, the solvent was evaporated in vacuo, and the residue was purified by silica gel column chromatography eluting with a 60-80% ethyl acetate/n-hexane gradient mixture to give the title compound (340 mg, 1.22 mmol, 24%) as a colorless solid. The resulting solid was recrystallized from n-hexane/tetrahydrofuran to give the title compound (254 mg, 0.85 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:34])([F:33])[F:32])[CH:24]=2)=[CH:4][CH:3]=1.[F:37][C:38]([F:43])([F:42])[CH2:39][CH:40]=O>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][N:11]([C:13]([CH:15]3[CH2:20][CH2:19][N:18]([CH2:40][CH2:39][C:38]([F:43])([F:42])[F:37])[CH2:17][CH2:16]3)=[O:14])[CH2:10][CH:9]2[N:21]([CH3:36])[C:22](=[O:35])[C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[C:25]([C:31]([F:33])([F:32])[F:34])[CH:24]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCNCC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F
Reactant: O=CCC(F)(F)F
Product: COc1ccc(C(=O)N(C)C2CN(C(=O)C3CCN(CCC(F)(F)F)CC3)CC2c2ccc(Cl)cc2)cc1C(F)(F)F

Procedure:
In analogy to the procedure described for the synthesis of example 104, the title compound N-{(3RS,4SR)-4-(4-chloro-phenyl)-1-[1-(3,3,3-trifluoro-propyl)-piperidine-4-carbonyl]-pyrrolidin-3-yl}-4-methoxy-N-methyl-3-trifluoromethyl-benzamide was prepared from N-[(3RS,4SR)-4-(4-chloro-phenyl)-1-(piperidine-4-carbonyl)-pyrrolidin-3-yl]-4-methoxy-N-methyl-3-trifluoromethyl-benzamide using 3,3,3-trifluoropropanal instead of acetone and was obtained as a light brown oil. MS m/e: 620.3 [M]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1.C(N(CC)CC)C.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>ClCCl>[CH3:26][S:27]([O:1][CH:2]1[CH2:5][N:4]([C:6]([C:8]2[O:9][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[N:11][N:12]=2)=[O:7])[CH2:3]1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1nnc(-c2ccccc2)o1)N1CC(O)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OC1CN(C(=O)c2nnc(-c3ccccc3)o2)C1
Reaction time: 8 h
Yield: 97.8 %

Procedure:
A suspension of 1B (2.00 g, 8.16 mmol) in dichloromethane (200 mL) was cooled in an ice-bath. Triethylamine (1.58 mL, 11.42 mmol) was added followed by methane-sulfonyl chloride (0.85 mL, 11.01 mmol). After the addition, the cooling bath was removed. The mixture was stirred overnight and then transferred to a separatory funnel. The mixture was washed with water and then with aqueous NaHCO3. The organic solution was dried (phase separator) and evaporated. There was obtained 2.58 g (98%) of 1C as a solid. 1H NMR (500 MHz, CDCl3): δ 3.13 (s, 3H), 4.43 (dd, 1H), 4.64 (dd, 1H), 4.87 (dd, 1H), 5.12 (dd, 1H), 5.40 (m, 1H), 7.54 (t, 2H), 7.59 (t, 1H), 8.15 (d, 2H), MS (APCI+) m/z 324 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][CH:30]=1)[C:24]([NH:26][NH2:27])=[S:25]>C(O)C.C(Cl)Cl>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][C:11]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:27][N:26]=[C:24]([C:23]2[CH:28]=[CH:29][CH:30]=[C:21]([F:20])[CH:22]=2)[S:25]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NCCCC(=O)c1ccccc1
Reactant: NNC(=S)c1cccc(F)c1
Solvent: CCO
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCC1(c2ccccc2)NN=C(c2cccc(F)c2)S1
Reaction time: 72 h
Yield: 89.8 %

Procedure:
To a solution of (4-oxo-4-phenylbutyl)-carbamic acid tert-butyl ester (2.2 g, 8.5 mmol) in ethanol/DCM (30 mL/10 mL) was added 3-fluorothiobenzoic acid hydrazide (Takasugi, J. J.; Buckwalter, B. L. European patent EP 1004241, 2004) (1.2 g, 7.1 mmol) at room temperature. After stirring for 3 days, the reaction mixture was concentrated and purified by flash column chromatography (20:1 Hexanes/EtOAc) to provide the product (2.65 g, 90%).