Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](F)[N:3]=1.[NH2:9][CH2:10][C:11]1([C:17]#[N:18])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[Br:1][C:2]1[N:3]=[C:4]([NH:18][CH2:17][C:11]2([C:10]#[N:9])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: Fc1cccc(Br)n1
Reactant: N#CC1(CN)CCOCC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: N#CC1(CNc2cccc(Br)n2)CCOCC1
Temperature: 110 °C
Yield: 132.2 %

Procedure:
To 2-bromo-6-fluoropyridine (400 mg, 2.273 mmol) in DMSO (4 ml) at ambient temperature was sequentially added 4-(aminomethyl)tetrahydro-2H-pyran-4-carbonitrile (Intermediate R, 382 mg, 2.73 mmol) and triethylamine (0.792 ml, 5.68 mmol). The resulting light brown mixture was heated at 110° C. in a sealed glass bomb for 18 hours. The reaction mixture then was cooled to ambient temperature, reaction mixture diluted with EtOAc, washed with saturated NaHCO3 solution and brine, dried over sodium sulfate and concentrated in vacuo to yield 890 mg of a light brown liquid. The crude material was purified by silica gel chromatography using a 12 g column, eluting with 5%-20% ethyl acetate in hexane to afford 410 mg (60.9%) of the desired product “S”. LCMS (m/z): 297.9 [M+H]+; Retention time=0.823 min. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 1.67-1.96 (m, 4H), 3.59-3.78 (m, 4H), 3.98 (m, 2H), 4.82 (t, J=6.65 Hz, 1H), 6.39 (d, J=8.22, 1H), 6.72-6.84 (m, 1H), 7.16-7.33 (m, 1H).
Reaction SMILES: C[C:2]([O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1)([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][CH:7]=1)[C:3]([OH:5])=[O:4].[OH-].[K+].Cl>C(O)C.O>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:25]=[CH:24][C:23]([O:22][CH:2]([C:6]2[CH:11]=[CH:10][C:9]([O:12][CH2:13][O:14][C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=3)=[CH:8][CH:7]=2)[C:3]([OH:5])=[O:4])=[CH:28][CH:27]=1
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)(C(=O)O)c1ccc(OCOc2ccc(Cl)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C(Oc1ccc(C(F)(F)F)cc1)c1ccc(OCOc2ccc(Cl)cc2)cc1
Yield: 81.3 %

Procedure:
To a solution of 8.5 g of methyl(α,α,α-trifluoro-p-tolyloxy){p-[(p-chlorophenoxy)methoxy]phenyl}acetic acid in 50 ml of ethanol is added a solution of 6 g of potassium hydroxide in 50 ml of water. The mixture is refluxed for 4 hours and while hot, is acidified with 10 ml of concentrated HCl. The mixture is chilled immediately and extracted with dichloromethane. The extract is washed with a solution of sodium chloride, dried (MgSO4) and the solvent is removed under reduced pressure. The residue is triturated with hexane containing small amounts of ether and dichloromethane and chilled to give 6.7 g of product as white crystals. The product is recrystallized by dissolving in 50 ml of benzene, filtering the solution and diluting the filtrate with 75 ml of hexane. Chilling and filtering gives 6.1 g of white crystals, mp 88°-89° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]#[N:12].[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1B(O)O>CCCCCCC.CCOC(C)=O>[C:14]1([CH3:13])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[NH:8][CH2:9][CH2:10][C:11]#[N:12]
Reactant: N#CCCNc1cnccc1I
Reactant: Cc1ccccc1B(O)O
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: Cc1ccccc1-c1ccncc1NCCC#N

Procedure:
The title compound was prepared in analogy to example 72, from 3-(4-iodo-pyridin-3-ylamino)-propionitrile and 2-methylphenylboronic acid (CAS RN 16419-60-6) and using a gradient of heptane:EtOAc (100:0 to 0:100) for the chromatographic purification. Light brown solid (81%). MS (ESI): m/z=238.13 [M+H]+.
Reaction SMILES: [NH:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1.[CH2:10]([O:17][C:18](Cl)=[O:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[C:18]([N:1]1[CH2:9][CH2:8][CH2:7][CH:3]([C:4]([OH:6])=[O:5])[CH2:2]1)([O:17][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:19]
Reactant: O=C(O)C1CCCNC1
Reactant: O=C(Cl)OCc1ccccc1
Product: O=C(O)C1CCCN(C(=O)OCc2ccccc2)C1

Procedure:
By substantially following the procedures of Example 15, A, 25.0 g (194 mmol) of nipecotic acid was protected with benzylchloroformate under basic conditions to afford 18.0 g (68 mmol; 35%) of analytically pure N-Cbz-nipecotic acid as a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1([C:11]2[N:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]3=[N:13][N:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7]1.N1C=CC=CC=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>ClCCl>[C:27]([N:18]1[CH2:19][CH2:20][C:14]2=[N:13][N:12]=[C:11]([C:6]3([C:2]4[S:1][CH:5]=[CH:4][CH:3]=4)[CH2:7][CH2:8][CH2:9][CH2:10]3)[N:15]2[CH2:16][CH2:17]1)(=[O:29])[CH3:28]
Reactant: CC(=O)OC(C)=O
Reactant: c1csc(C2(c3nnc4n3CCNCC4)CCCC2)c1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)N1CCc2nnc(C3(c4cccs4)CCCC3)n2CC1
Reaction time: 15 h

Procedure:
3-[1-(2-Thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (190 mg) was dissolved in dichloromethane (15 ml) and then pyridine (106 μl) and acetic anhydride (62 μl) were added at room temperature, followed by stirring at the same temperature for 15 hours. The residue obtained by removing the solvent by evaporation was diluted with ethyl acetate and washed with 0.3M hydrochloric acid, water, and brine, successively. The solution was dried over anhydrous magnesium sulfate and filtered and then the solvent was removed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=99:1 to 95:5) to obtain 110 mg of 7-acetyl-3-[1-(2-thienyl)cyclopentyl]-6,7,8,9-tetrahydro-5H-[1,2,4]triazolo[4,3-d][1,4]diazepine (white solid).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH:10]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C@H:11]([C:16](ON1C(=O)CCC1=O)=[O:17])[C@H:12]([CH2:14][CH3:15])[CH3:13].OS([O-])(=O)=O.[K+].O>C(OC(C)C)(=O)C.[Na+].[Cl-]>[NH:10]([C:26]([O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[O:27])[C@H:11]([C:16]([NH:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5])=[O:17])[C@H:12]([CH2:14][CH3:15])[CH3:13]
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: O=S(=O)([O-])O
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)OC(C)C
Product: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Yield: 80 %

Procedure:
1.01 equivalents of H-Leu-OH (Mw=131.2) was first silylated with 2.10 equivalents TMA (Mw=145.12) at about 50° C. until a clear solution was obtained. The solution was cooled to room temperature and diluted with isopropyl acetate. 1.00 equivalent of the Boc-Ile-OSu solid (Mw=328.26; 100.0%) was then added to silylated H-Leu-OH solution. The reaction mixture was further stirred at room temperature for at least 8 hours. After the completion of the reaction was confirmed by HPLC, the solution was quenched by adding DMAPA and water, washed with KHSO4 (1.00 equivalent) in 500 ml 5% (weight) aqueous NaCl solution; 500 ml 5% (weight) aqueous NaCl solution, and water. After evaporation of the isopropyl acetate in vacuo, the excess of water was eliminated by azeotropic distillation with isopropyl acetate. The peptide precipitated during the concentration. The concentrated suspension was then diluted in cyclohexane. The precipitate was stirred at room temperature for at least 10 min, filtered and finally dried in vacuum at 45° C. The dried precipitate yielded (based on NMR content) 80% of Boc-Ile-Leu-OH as white solid.
Reaction SMILES: Br[CH2:2][C:3]1[C:4]([F:13])=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7].C(=O)(O)[O-:15].[Na+]>CS(C)=O>[F:13][C:4]1[C:3]([CH:2]=[O:15])=[CH:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C([O-])O
Reactant: COC(=O)c1cccc(CBr)c1F
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C=O)c1F
Yield: 64.4 %

Procedure:
A mixture of methyl 3-(bromomethyl)-2-fluorobenzoate (11.5 g, 46.4 mmol) from Step B above and solid sodium bicarbonate (33.0 g, 398.7 mmol) in DMSO (150 mL) was refluxed until the reaction was complete by TLC (2-3 h). The mixture was cooled in an ice bath immediately and then partitioned between brine and ethyl acetate. The combined organics were concentrated and purified by column chromatography (silica gel, 9:1 hexanes/ethyl acetate) to afford methyl 2-fluoro-3-formylbenzoate as a white solid (5.44 g, 64%): 1H NMR (300 MHz, CDCl3) δ 10.43 (s, 1H), 8.21 (t, J=7.8 Hz, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.35 (t, J=7.8 Hz, 1H), 3.93 (s, 3H).
Reaction SMILES: [NH2-].[Na+].Cl[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([CH3:11])[N:5]=1.[NH2:12][C:13]1[S:14][C:15]([C:18]([NH:20][C:21]2[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=2[Cl:28])=[O:19])=[CH:16][N:17]=1.Cl>O.C1COCC1>[Cl:10][C:8]1[N:7]=[C:6]([CH3:11])[N:5]=[C:4]([NH:12][C:13]2[S:14][C:15]([C:18]([NH:20][C:21]3[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])=[O:19])=[CH:16][N:17]=2)[CH:9]=1
Reactant: Cc1cccc(Cl)c1NC(=O)c1cnc(N)s1
Reactant: Cc1nc(Cl)cc(Cl)n1
Agent: Cl
Agent: [NH2-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(Cl)cc(Nc2ncc(C(=O)Nc3c(C)cccc3Cl)s2)n1
Temperature: 7.5 °C
Reaction time: 0.21 h

Procedure:
Into a RBF 6.6 g of Sodium Amide was added at 30-35° C. under N2 atmosphere and stirring was done for 10-15 minutes. Then the reaction mass was cooled to 5-10° C. and 120.0 mL THF and 7.92 g 4,6-Dichloro-2-methyl pyrimidine were added to the reaction mass. Addition of 10.0 g 2-amino-N-(2-chloro-6-methyl phenyl)-5-thiazole carboxamide was then performed into the reaction mass. The reaction mass was stirred for ˜40 mins at 30-35° C. to get clear solution which was transferred to an addition dropper. At temperature of 5-10° C., the reaction mass was slowly added over 30 minutes, into another RBF having 40.0 mL THF. At the same temperature, the reaction mass was stirred for 1.0-1.5 hrs. Then the reaction mass temperature was increased to 30-35° C., where stirring was performed for 3 to 4 hrs. On completion of the reaction as verified by TLC, the reaction mass was cooled slowly to a temperature of 0-5° C. Then the reaction mass pH was adjusted to 3-4 by addition of 22.4 mL HCl and 240 mL water over 10-15 mins. The reaction mass was then stirred for 2.0-2.5 hrs at 0-5° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[C:12]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:6]([S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH:5]2[CH3:27].B(Br)(Br)[Br:29].ClCCl>C(=O)(O)[O-].[Na+]>[Br:29][C:10]1[CH:9]=[CH:8][C:7]2[N:6]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:5]([CH3:27])[C:4]3[C:13](=[CH:14][CH:15]=[C:2]([F:1])[CH:3]=3)[C:12]=2[CH:11]=1
Reactant: COc1ccc(S(=O)(=O)N2c3ccccc3-c3ccc(F)cc3C2C)cc1
Reactant: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(O)cc1
Temperature: 25 °C

Procedure:
8-Fluoro-5-(4-methoxyphenylsulfonyl)-6-methyl-5,6-dihydrophenanthridine (0.64 g, 1.7 mmol) was treated with 1 M boron tribromide in dichloromethane (6.6 mL, 6.6 mmol) and stirred at room temperature for twelve hours. A solution of saturated, aqueous, sodium bicarbonate (50 mL) was added slowly to the reaction, followed by extraction of the mixture with dichloromethane (6×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude material. The crude material was filtered through a short column of silica gel, eluted with a mixture of ethyl acetate-hexane (1:4), and the filtrate concentrated in vacuo to a solid. After trituration with dichloromethane and filtration, the title compound was obtained as a homogeneous solid (0.23 g, 37%), m.p. 237-239° C.;
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([SH:19])[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1.[CH3:24][O:25][C:26]1[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=1)[CH2:29]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:16]([C:17]#[N:18])=[C:15]([S:19][CH2:29][C:28]3[CH:31]=[CH:32][CH:33]=[C:26]([O:25][CH3:24])[CH:27]=3)[N:14]=[C:13]([O:20][CH3:21])[C:12]=2[C:22]#[N:23])=[CH:7][CH:6]=1
Reactant: COc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: COc1cccc(CBr)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(CSc2nc(OC)c(C#N)c(-c3ccc(OCCO)cc3)c2C#N)c1

Procedure:
75 mg (0.229 mmol) of 4-[4-(2-hydroxyethoxy)phenyl]-2-methoxy-6-sulphanylpyridine-3,5-dicarbonitrile together with 36 μl (0.253 mmol) of 3-methoxybenzyl bromide and 52 mg (0.380 mmol) of potassium carbonate are stirred in 1 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5, with 0.1% formic acid added). This gives 16 mg (56% of theory) of the target compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[C:21](=[O:20])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][NH:10]1
Reactant: COc1ccccc1NN
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2ccccc2OC)c1=O
Yield: 77.5 %

Procedure:
In the same manner as in Reference Example 63 and using (2-methoxyphenyl)hydrazine•hydrochloride (5.3 g, 30 mmol), water (100 mL), potassium carbonate (9.1 g, 66 mmol) and diethyl ethoxymethylenemalonate (7.8 g, 36 mmol) as starting materials, the title compound (6.1 g, 78%) was obtained as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][N:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16](O)=[O:17])=[N:14][CH:15]=1.[NH2:33][CH2:34][CH2:35][OH:36].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][N:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([NH:33][CH2:34][CH2:35][OH:36])=[O:17])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C(F)(F)F)cn1
Reactant: NCCO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: Cc1cc(C(=O)NCCO)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 72 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl)[[5-(trifluoromethyl)pyridin-2-yl]sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (118 mg, 0.25 mmol) in methylene chloride (3 ml), 2-aminoethanol (0.017 ml, 0.28 mmol), 1-hydroxybenzotriazole (37 mg, 0.28 mmol), 4-methylmorpholine (0.030 ml, 0.28 mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53 mg, 0.28 mmol) were added at room temperature. After stirring for 5 hours at room temperature, the reaction mixture was washed with water and then with saturated brine. The organic layer was dried over anhydrous sodium sulfate and filtered, then the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to flash silica gel chromatography. The fraction obtained from an elution with hexane:ethyl acetate=1:1 was concentrated under reduced pressure, and the resulting residue was washed with hexane, and was dried under reduced pressure to obtain the title compound (91 mg, 0.18 mmol, 71%) as a colorless foamy substance.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][CH:10]([C:12]([Cl:15])([Cl:14])[Cl:13])[O:9][CH:8]([C:16]([Cl:19])([Cl:18])Cl)[C:7]=2[CH:20]=1)#[N:2].[Cl-].[NH4+].[N-:23]=[N+:24]=[N-:25].[Na+]>CN(C)C=O>[Cl:18][C:16]([Cl:19])=[C:8]1[C:7]2[CH:20]=[C:3]([C:1]3[NH:25][N:24]=[N:23][N:2]=3)[CH:4]=[CH:5][C:6]=2[O:11][CH:10]([C:12]([Cl:13])([Cl:14])[Cl:15])[O:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc2c(c1)C(C(Cl)(Cl)Cl)OC(C(Cl)(Cl)Cl)O2
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: ClC(Cl)=C1OC(C(Cl)(Cl)Cl)Oc2ccc(-c3nnn[nH]3)cc21
Reaction time: 16 h

Procedure:
A mixture of 6-cyano-2,4-bis(trichloromethyl)benzo[1,3]dioxin (1.98 g.), ammonium chloride (0.33 g.) and sodium azide in anhydrous dimethylformamide was warmed on the steam bath for 16 hours. The reaction mixture was cooled, poured onto ice and kept for 16 hours. The amorphous white product was filtered off, triturated with acetic acid, and crystallised from chloroform to give 4-dichloromethylene-6-(tetrazol-5-yl)-2-trichloromethylbenzo[1,3]dioxin, m.p. 222° C.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:18])[CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCC>C(OCC)C>[CH2:1]([O:8][CH:9]([CH3:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCC1=CCCC1=O)OCc1ccccc1
Solvent: CCOCC
Solvent: CCCCC
Product: CC(CCC1CCCC1=O)OCc1ccccc1
Yield: 94 %

Procedure:
General procedure B using (S)-p-tol-BfNAP and 3-benzyloxybutyl-cyclopent-2-enone (0.146 g, 0.6 mmol) gave, after 30 h at 0° C. and flash chromatography (1:2 pentane:diethyl ether), the title compound as a clear oil (0.139 g, 94% yield). 1H NMR (300 MHz, CDCl3): δ7.37-7.23 (m, 5 H), 4.50 (s, 2 H), 3.47 (t, J=6.3 Hz, 2 H), 2.43-2.04 (m, 5 H), 1.78 (ddd, J=18.0, 9.6, 1.2 Hz, 1 H), 1.70-1.56 (m, 2 H), 1.56-1.34 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ219.8, 138.6, 128.4, 127.7, 127.6, 73.1, 70.3, 45.4, 38.7, 37.4, 35.7, 30.0, 29.7, 24.8. IR (neat): 2934, 2860, 1741, 1455, 1405, 1363, 1158, 1100, 737, 699 cm−1. HRMS m/z calcd for C16H22O2 246.1620, obsd 246.1615. [α]D25° C.−89° (c 1.4, CHCl3). Chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 94% ee.
Reaction SMILES: C[O:2][C:3](=[O:39])[CH:4]([O:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH:30]2[CH2:32][CH2:31]2)[C:14]2[S:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:33].[Li+].[OH-]>>[CH2:35]([O:34][CH:4]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH:13]([CH:30]2[CH2:31][CH2:32]2)[C:14]2[S:18][C:17]([C:19]3[CH:20]=[CH:21][C:22]([C:25]([F:27])([F:26])[F:28])=[CH:23][CH:24]=3)=[N:16][C:15]=2[CH3:29])=[CH:8][C:7]=1[CH3:33])[C:3]([OH:39])=[O:2])[CH2:36][CH2:37][CH3:38]
Reactant: CCCCOC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCCCOC(Cc1ccc(OC(c2sc(-c3ccc(C(F)(F)F)cc3)nc2C)C2CC2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], 2-butoxy-3-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-propionic acid methyl ester (mixture of two diastereomeric racemates) was treated with LiOH to obtain 2-butoxy-3-(4-{cyclopropyl-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methoxy}-2-methyl-phenyl)-propionic acid as a mixture of two diastereomeric racemates as yellow liquid.
Reaction SMILES: [CH:1]([C:4]1[C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=[CH:6][N:5]=1)([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:20])C=1>C(Cl)(Cl)Cl>[CH:1]([C:4]1[C:9]([CH2:10][Cl:11])=[CH:8][CH:7]=[CH:6][N+:5]=1[O-:20])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)c1ncccc1CCl
Solvent: ClC(Cl)Cl
Product: CC(C)c1c(CCl)ccc[n+]1[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
The 2-isopropyl-3-hydroxymethylpyridine (240 mg, 1.59 mmol) was dissolved in CH2Cl2 (15 mL) and cooled under nitrogen to 0° C. and thionyl chloride (1.0 mL) was slowly added and the reaction was stirred for 3 hours. The solvent was removed under reduced pressure and the residue was partitioned between CH2Cl2 and saturated sodium bicarbonate. The organic layer was dried with MgSO4, filtered and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine. The 2-isopropyl-3-chloromethylpyridine (65 mg, 0.383 mmol) was dissolved in CHCl3 (10 mL) and cooled under nitrogen to 0° C. and m-chloroperbenzoic acid (55%, 150 mg) was added in small portions. The reaction was stirred for 2 hours. The solution was extracted with saturated aqueous sodium bicarbonate (2×5 mL). The organic phase was dried with MgSO4, filtered, and the solvent removed under reduced pressure. The residue was chromatographed on silica gel packed in 99:1 CH2Cl2 :MeOH and eluted with same. The appropriate fractions were combined and the solvent removed under reduced pressure to give the desired 2-isopropyl-3-chloromethylpyridine-N-oxide.
Reaction SMILES: [CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]([OH:33])=O)[C:20]([CH:34]2[CH2:36][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3].C(O[N:41]([C@H]1CN(C(OC(C)(C)C)=O)[C@H](C(=O)N)C=C1C)S(C1C=CC=CC=1[N+]([O-])=O)(=O)=O)C=C>>[CH2:1]([O:4][N:5]([C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[C@H:21]([C:31](=[O:33])[NH2:41])[C:20]([CH:34]2[CH2:36][CH2:35]2)=[CH:19]1)[S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[N+:15]([O-:17])=[O:16])(=[O:8])=[O:7])[CH:2]=[CH2:3]
Reactant: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: C=CCON([C@H]1CN(C(=O)OC(C)(C)C)[C@H](C(N)=O)C=C1C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Product: C=CCON([C@@H]1C=C(C2CC2)[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1)S(=O)(=O)c1ccccc1[N+](=O)[O-]

Procedure:
The title compound was prepared from (2S,5R)-5-(N-(allyloxy)-2-nitrophenylsulfonamido)-1-(tert-butoxycarbonyl)-3-cyclopropyl-1,2,5,6-tetrahydropyridine-2-carboxylic acid (Intermediate 241, 2.28 g, 4.35 mmol) following the procedure described for Intermediate 20. The desired product was obtained as an orange foam (1.07 g, 47%).
Reaction SMILES: CN(C)C=O.[OH:6][C:7]1[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:12][S:13][CH3:14])[S:10][CH:11]=1.[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24](S(C)(=O)=O)[N:23]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:20][O:21][C:22]1[CH:27]=[C:26]([O:28][CH3:29])[N:25]=[C:24]([O:6][C:7]2[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:9]([CH2:12][S:13][CH3:14])[S:10][CH:11]=2)[N:23]=1
Reactant: CCOC(=O)c1c(O)csc1CSC
Reactant: COc1cc(OC)nc(S(C)(=O)=O)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(Oc2nc(OC)cc(OC)n2)csc1CSC
Reaction time: 2 h
Yield: 50.1 %

Procedure:
50 ml of N,N-dimethylformamide was added to 3.5 g (15.1 mmol) of ethyl 4-hydroxy-2-methylthiomethylthiophene-3-carboxylate, 3.3 g (15.1 mmol) of 4,6-dimethoxy-2-methylsulfonylpyrimidine and 2.1 g (15.2 mmol) of potassium carbonate, and the mixture was heated and stirred at from 90° to 100° C. for 2 hours. After cooling, the reaction solution was poured into water, extracted with ethyl acetate, washed with water and a saturated sodium chloride aqueous solution, and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography to obtain 2.8 g (yield: 50.0%) of the desired product.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:32])[F:31])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:34](O)(=[O:36])[CH3:35]>>[C:34]([N:17]1[CH2:18][CH2:19][C@H:20]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][C:30]([F:33])([F:31])[F:32])[CH:24]=2)[C@H:15]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:16]1)(=[O:36])[CH3:35]
Reactant: FC(F)(F)Oc1cccc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)c1
Reactant: CC(=O)O
Agent: Cl
Product: CC(=O)N1CC[C@H](OCc2cccc(OC(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (27.7 mg) obtained in Example 27 and acetic acid (6.9 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.