Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:15][CH2:16][OH:17])[CH2:12][CH2:13][OH:14])[C:5]=2[O:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[S:25](Cl)([CH3:28])(=[O:27])=[O:26]>C(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([N:11]([CH2:15][CH2:16][O:17][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:12][CH2:13][O:14][S:25]([CH3:28])(=[O:27])=[O:26])[C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: OCCN(CCO)c1cccc2c1OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCCN(CCOS(C)(=O)=O)c1cccc2c1OCCO2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of II (39.6 g, 0.165 mol) and triethyl amine (69 mL, 0.5 mol) in methylene chloride (250 mL), chilled to 5° C. in an ice-bath, is added a solution of mesyl chloride (38 mL, 0.5 mol) in methylene chloride (50 mL). The addition is carried out over 0.5 h at temperature not exceeding 18° C. The ice-bath is removed and resulting suspension is stirred at ambient temperature for 1 h. At that time, TLC and HPLC showed disappearance of starting material. The reaction mixture is washed with water (1×150 mL) and 5% aqueous NaHCO3 solution (1×150 mL), dried with MgSO4 and concentrated to afford III as red oil, crude yield 67.0 g (102%). 1H NMR (CDCl3) δ 6.85 (m, 1H), 6.63 (m, 2H), 4.28 (m, 8H), 3.55 (t, J=7.5 Hz, 4H), 2.97 (s, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([NH2:14])[S:12][CH:13]=2)=[CH:5][CH:4]=1.[CH2:15]([C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1)[CH2:16][CH3:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[C:11]([NH:14][S:24]([C:21]3[CH:22]=[CH:23][C:18]([CH2:15][CH2:16][CH3:17])=[CH:19][CH:20]=3)(=[O:26])=[O:25])[S:12][CH:13]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2csc(N)n2)cc1
Reactant: CCCc1ccc(S(=O)(=O)Cl)cc1
Product: CCCc1ccc(S(=O)(=O)Nc2nc(-c3ccc(OC)cc3)cs2)cc1

Procedure:
The title compound was prepared from 4(4-methoxy-phenyl)-thiazol-2-ylamine and 4-n-propylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (32.2 mg) with purity >90%. MS (pos) m/z 389.2.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][NH2:10].C(N(CC)CC)C>ClCCl>[CH3:6][N:7]([CH3:12])[C:8](=[O:11])[CH2:9][NH:10][C:3](=[O:4])[CH2:2][Cl:1]
Reactant: CN(C)C(=O)CN
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)C(=O)CNC(=O)CCl
Reaction time: 0.5 h
Yield: 74.4 %

Procedure:
A solution of chloroacetyl chloride (1.7 g) in dichloromethane was stirred in an ice-bath, while a solution of N,N-dimethylglycinamide (1.8 g) and triethylamine (2.2 ml) in dichloromethane (20 ml) was added over 20 minutes. The reaction mixture was stirred for 30 minutes and was then washed with water (2×10 ml), and dried over MgSO4. The solution was evaporated under reduced pressure. Thus was obtained N,N-dimethyl chloroacetylglycinamide (2.0 g) as a brown oil, which was used directly, and without further purification.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][C:7]1[C:12]2[CH2:13][NH:14][CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1.Cl.C(N(CC)CC)C>ClCCl>[CH3:6][C:7]1[C:12]2[CH2:13][N:14]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][CH2:16][S:17][C:11]=2[CH:10]=[CH:9][CH:8]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc2c1CNCCS2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc2c1CN(S(C)(=O)=O)CCS2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methanesulphonyl chloride (1.69 g) in dichloromethane (20 ml) was added dropwise at room temperature to a stirred solution to 6-methyl-2,3,4,5-tetrahydro-1,4-benzothiazepine (2 g, prepared in a similar manner to its hydrochloride, Example 4 above) and triethylamine (1.51 g) in dichloromethane (30 ml). The reaction mixture was stirred at room temperature for one hour, washed with water, dried and the solvent was removed by evaporation. Purification of the residue by flash chromatography using dichloromethane as eluent gave 6-methyl-4-methylsulphonyl-2,3,4,5-tetrahydro-1,4-benzothiazepine, which was recrystallised from ethyl acetate/hexane. Yield 2.48 g (m.p. 128°-130° C.).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C:10](=[O:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCC(C)[BH-](C(C)CC)C(C)CC.[K+]>O1CCCC1.O>[CH2:1]([N:8]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]([OH:15])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H]1CC(=O)CN(Cc2ccccc2)C1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H]1C[C@H](O)CN(Cc2ccccc2)C1
Yield: 87.7 %

Procedure:
To a solution of (S)-1-benzyl-5-methyl-piperidin-3-one (1.1 g, 5 mmol) in dry tetrahydrofuran (15 ml) at −78° C. was added K-selectride (10.8 ml, 11 mmol, 1 M solution in tetrahydrofuran). After 2 h at −78° C. a few drops of water were cautiously added, the reaction allowed to reach room temperature, the tetrahydrofuran removed by evaporation and the residue the residue redissolved in dichloromethane, washed with sat. aq. sodium hydrogencarbonate solution, dried (Na2SO4) and concentrated. Purification by flash column chromatography (ethyl acetate/heptane 1:4) afforded the titled product as a crystalline solid (0.9 g, 43%). MS (ISP)=204.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[NH2:10].[C:18](OCC)(OCC)(OCC)[CH:19]([CH3:21])[CH3:20]>C(#N)C.Cl.CCOCC>[ClH:17].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:9]2[CH2:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=[C:18]([CH:19]([CH3:21])[CH3:20])[NH:10]2)=[CH:12][CH:13]=1
Reactant: Nc1ccccc1CN(N)c1ccc(Cl)cc1
Reactant: CCOC(OCC)(OCC)C(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)C1=Nc2ccccc2CN(c2ccc(Cl)cc2)N1
Yield: 122.8 %

Procedure:
To a mixture of 3 g (0.012 m) of 1-[(2-aminophenyl)methyl]-1-(4-chlorophenyl)hydrazine of Example 12b and 3.56 g (0.024 m) of triethyl orthoisobutyrate in 50 ml of acetonitrile, sufficient ethereal HCl was added to make the mixture acidic. The mixture was refluxed overnight (about 16 hours), cooled and the product filtered off as the hydrochloride salt. Recrystallization by suspending the product in ethanol, adding sufficient methanol to afford a solution and diluting with anhydrous ether gave 2.5 g (62%) of 4,5-dihydro-4-(4-chlorophenyl)-2-(isopropyl)-3H-1,3,4-benzotriazepine hydrochloride, m.p. 255°-258° C.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]#[CH:17])=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([Li])CCC.[F:23][C:24]([F:30])([F:29])[C:25]([CH2:27][F:28])=[O:26].C(OCC)C>O1CCCC1>[F:23][C:24]([F:30])([F:29])[C:25]([OH:26])([CH2:27][F:28])[C:17]#[C:16][C:13]1[CH:12]=[CH:11][C:10]([S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[CH:15][CH:14]=1
Reactant: O=C(CF)C(F)(F)F
Reactant: C#Cc1ccc(S(=O)(=O)c2ccccc2)cc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=S(=O)(c1ccccc1)c1ccc(C#CC(O)(CF)C(F)(F)F)cc1
Reaction time: 0.08 h

Procedure:
To a cooled (-78° C.) solution of 4-phenylsulfonylphenylethyne (1.68 g) in anhydrous tetrahydrofuran (70 mL) was added n-butyl lithium (3.06 mL of a 2.5 M solution in hexanes). The solution was stirred for 15 minutes at -78° C. before 1,1,1,3-tetrafluoroacetone (2.96 mL of a 40% diethyl ether solution) was added. The reaction mixture was kept at -78° C. for five minutes before quenching with 2N hydrochloric acid. Diethyl ether was added and the aqueous layer extracted further with diethyl ether. The combined organic layers were dried, evaporated and the product purified by chromatography, with diethyl ether:chloroform (1:9) as eluent. This yielded the title compound as a white solid (1.64 g) mp 119-120.8; (300 MHz) (CDCl3): 3.77 (s,1, OH), 4.55-4.79 (m,2, CH2F), 7.48-7.61 (m,5, Ar), 7.86-7.94 (m,4, Ar); MS: m/z=373 (M+1). Analysis for C17H12F4O3S: Calculated: C, 54.84; H, 3.25; Found: C, 54.70; H, 3.37.
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)[N:11]([C@@H:29]([CH2:32][CH3:33])[CH:30]=[O:31])[C:10]1=[O:34])[CH:7]=[CH2:8]>C1COCC1>[CH2:6]([C@@:9]1([CH3:35])[CH2:14][C@H:13]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[CH:16]=2)[C@@H:12]([C:22]2[CH:23]=[CH:24][C:25]([Cl:28])=[CH:26][CH:27]=2)[N:11]([C@@H:29]([CH2:32][CH3:33])[CH:30]([CH:1]2[CH2:3][CH2:2]2)[OH:31])[C:10]1=[O:34])[CH:7]=[CH2:8]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O
Reactant: Br[Mg]C1CC1
Solvent: C1CCOC1
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(O)C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Cyclopropylmagnesium bromide (0.5 M solution in THF, 2.0 mL, 1.013 mmol) was added dropwise via syringe over a period of 1 min to a stirred solution of (S)-2-((3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-1-yl)butanal (Example 91, Step C, 150 mg, 0.338 mmol) in THF (1.7 mL) at rt. The reaction mixture was stirred at rt for 20 minutes and then quenched with NH4Cl (30 mL, saturated aqueous solution) and diluted with EtOAc (50 mL). The organic layer was dried over MgSO4, filtered and evaporated in vacuo. Purification by column chromatography (24 g SiO2, Hexanes:EtOAc, 1:0 to 4:1) gave the title compound as a mixture of diastereomers.
Reaction SMILES: [C:1]([C:9]1[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][CH:14]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:19][NH2:20]>C(O)C>[C:2]1([C:1]2[C:9]3[CH:14]=[CH:13][CH:12]=[N:11][C:10]=3[C:15](=[O:17])[NH:19][N:20]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(c1ccccc1)c1cccnc1C(=O)O
Reactant: NN
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(-c2ccccc2)c2cccnc12
Temperature: 25 °C
Yield: 69.7 %

Procedure:
To a round bottomed flask containing 3-benzoylpicolinic acid (2.00 g, 9 mmol) was added 50 mL of ethanol. Hydrazine hydrate (0.6 ml, 11 mmol) was added and the mixture was heated to reflux for 3 h. After cooling to rt, the solvent was removed in vacuo. The resulting yellow solid was recrystallized from 30 mL of boiling 1-propanol to afford 5-phenylpyrido[2,3-d]pyridazin-8(7H)-one 70 (1.4 g, 71% yield) as a white solid. 1H-NMR (400 MHz, CDCl3): δ 10.55 (br s, 1H), 9.16 (dd, J=8.6, 1.6 Hz, 1H), 7.73 (dd, J=8.6, 4.7 Hz, 1H), 7.56 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])[CH2:16]2)(=[O:12])=[O:11].[CH:23]1([N:26]2[CH2:31][CH2:30][N:29]([CH2:32][C:33]3[C:34]([CH3:41])=[C:35]([CH:39]=O)[NH:36][C:37]=3[CH3:38])[CH2:28][CH2:27]2)[CH2:25][CH2:24]1>>[CH:23]1([N:26]2[CH2:27][CH2:28][N:29]([CH2:32][C:33]3[C:34]([CH3:41])=[C:35](/[CH:39]=[C:16]4\[C:17](=[O:22])[NH:18][C:19]5[C:15]\4=[CH:14][C:13]([S:10]([CH2:9][C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])(=[O:12])=[O:11])=[CH:21][CH:20]=5)[NH:36][C:37]=3[CH3:38])[CH2:30][CH2:31]2)[CH2:24][CH2:25]1
Reactant: Cc1[nH]c(C=O)c(C)c1CN1CCN(C2CC2)CC1
Reactant: O=C1Cc2cc(S(=O)(=O)Cc3c(Cl)cccc3Cl)ccc2N1
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4c(Cl)cccc4Cl)cc32)c(C)c1CN1CCN(C2CC2)CC1

Procedure:
5-(2,6-Dichloro-phenylmethanesulfonyl)-1,3-dihydro-indol-2-one (178 mg) was condensed with 4-(4-cyclopropyl-piperazin-1-ylmethyl)-3,5-dimethyl-1H-pyrrole-2-carbaldehyde (125 mg) to give the titled compound.
Reaction SMILES: C(O)[C@H]1[O:7][C@H:6]([O:8][C@:9]2(CO)O[C@H:12](CO)[C@@H:11](O)[C@@H:10]2O)[C@H:5]([OH:20])[C@@H:4](O)[C@@H:3]1O.C1C2C(=CC=CC=2)C=CC=1.C(OCCCC)(=O)C(C)O>C(O)CCC>[OH:20][CH:5]([CH:4]=[CH2:3])[C:6]([O:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:7]
Reactant: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Agent: CCCCOC(=O)C(C)O
Solvent: c1ccc2ccccc2c1
Solvent: CCCCO
Product: C=CC(O)C(=O)OCCCC
Temperature: 160 °C
Yield: 25 %

Procedure:
An autoclave (50 cc microclave) is charged with 8.0 g of 1-butanol, 0.2249 g of sucrose (0.6569 mmol), 121.0 mg naphthalene (internal standard) and finally with 160.5 mg Sn-BEA (prepared according to U.S. Pat. No. 6,306,364). The autoclave is closed, charged with 20 bar of argon and heated to 160° C. After the temperature reaches 100° C., the mechanical stirrer is started (500 rpm) and the mixture is heated for 20 hours under these conditions. GC-analysis of the reaction mixture shows that 0.68 mmol of n-butyl lactate is formed (26%) together with 0.164 mmol n-butyl 2-hydroxy-3-butenoate (8%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][OH:5].[N+:6]([C:9]1[CH:14]=[CH:13][C:12]([SH:15])=[CH:11][CH:10]=1)([O-:8])=[O:7].[OH-].[Na+]>O>[OH:5][CH2:4][CH2:3][CH2:2][S:15][C:12]1[CH:13]=[CH:14][C:9]([N+:6]([O-:8])=[O:7])=[CH:10][CH:11]=1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: OCCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=[N+]([O-])c1ccc(SCCCO)cc1
Temperature: 80 °C
Yield: 98.4 %

Procedure:
3-Chloropropanol (6.0 g, 63.5 mmol) was added dropwise to a solution of 4-nitrothiophenol (8.2 g, 52.9 mmol) and sodium hydroxide (3.2 g) in water (120 ml) stirred and heated at 80° C. under nitrogen and the mixture heated at 80° C. for 205 minutes. The mixture was allowed to cool and then extracted with EtOAc (2×100 ml). The extracts were combined, washed with water (50 ml) and brine (50 ml), dried and evaporated to give the title compound (11.1 g, 98%). NMR (CDCl3) 1.99 (m, 2H), 3.18 (t, 2H), 3.81 (m, 2H), 7.35 (d, 2H), 8.13 (d, 2H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:17]=[C:16]([N+:18]([O-])=O)[CH:15]=[C:14]([C:21]#[N:22])[CH:13]=2)[O:9][N:8]=1.O.O.[Sn](Cl)Cl.ClCCl>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:21]#[N:22])[CH:15]=[C:16]([NH2:18])[CH:17]=2)[O:9][N:8]=1
Reactant: N#Cc1cc(-c2nc(-c3ccccn3)no2)cc([N+](=O)[O-])c1
Agent: Cl[Sn]Cl
Solvent: ClCCl
Solvent: CCO
Solvent: O
Product: N#Cc1cc(N)cc(-c2nc(-c3ccccn3)no2)c1
Yield: 10.6 %

Procedure:
3-(2-Pyridyl)-5-(3-cyano-5-nitrophenyl)-1,2,4-oxadiazole (30 mg, 0.10 mmol) and tin(II) chloride dihydrate (115 mg, 0.51 mmol) in ethanol (1 mL) were sealed in a glass vial and then heated at 78 oC for 2 hours. The reaction was cooled and dichloromethane was added to the reaction mixture. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. Silica gel chromatography of the residue using hexanes:ethyl acetate:dichloromethane 1:3:4 followed by recrystallization using methanol afforded 2.8 mg (10%) of 3-(2-Pyridyl)-5-(3-amino-5-cyanophenyl)-1,2,4-oxadiazole: 1H NMR (CDCl3), δ (ppm): 8.85 (d, 1H), 8.22 (d, 1H), 7.91 (m, 2H), 7.78 (s, 1H), 7.48 (m, 1H), 7.11 (s, 1H), 4.17 (bs, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]([C:20]([OH:22])=[O:21])=[C:8]([CH3:23])[NH:7][C:6]=1[CH3:24])=[O:4].Br[CH2:26][CH2:27][Cl:28].C(N(CC)CC)C>C(OCC)(=O)C.CO.N>[CH3:23][C:8]1[NH:7][C:6]([CH3:24])=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:10]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:9]=1[C:20]([O:22][CH2:26][CH2:27][Cl:28])=[O:21]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: ClCCBr
Agent: N
Solvent: CO
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCl)C1c1cccc([N+](=O)[O-])c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 19 %

Procedure:
A mixture of 3-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid (3.32 g, 0.01 mole), 1-bromo-2-chloroethane (1.43 g, 0.01 mole) and triethylamine (1.01 g, 0.01 mole) is stirred at 120° C. for 8 hours. The reaction mixture is dissolved in a mixture of ethyl acetate/methanol/ammonia (80:30:3) and subjected to chromatography on a silica gel column (2×35 cm). Thus, there are obtained chloroethyl methyl 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate (0.75 g, 19.8%) and the dimeric ethylene glycol-di-/2,6-dimethyl-4-(m-nitrophenyl)-5-methoxycarbonyl-1,4-dihydropyridyl-3/dicarboxylate (0.1 g, 1.5%) as oily substance.
Reaction SMILES: [N:1]([C@@H:4]([C@H:8]([C:16]1[CH:24]=[CH:23][C:19]2[O:20][CH2:21][O:22][C:18]=2[CH:17]=1)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1)[C:5](O)=[O:6])=[N+]=[N-].[NH2:25][C:26]1[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=1[CH2:28][CH2:29][C@H:30]1[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:44])([F:43])[F:42])[N:32](C(OC(C)(C)C)=O)[CH2:31]1>>[O:20]1[C:19]2[CH:23]=[CH:24][C:16]([C@H:8]([C:9]3[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=3)[C@@H:4]([C:5]([NH:25][C:26]3[CH:56]=[CH:55][CH:54]=[C:53]([F:57])[C:27]=3[CH2:28][CH2:29][C@H:30]3[O:35][CH2:34][C@@H:33]([CH2:36][O:37][C:38](=[O:45])[NH:39][CH2:40][C:41]([F:43])([F:44])[F:42])[NH:32][CH2:31]3)=[O:6])[NH:1][C:21]([O:20][CH3:19])=[O:22])=[CH:17][C:18]=2[O:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CCc2c(N)cccc2F)OC[C@H]1COC(=O)NCC(F)(F)F
Reactant: [N-]=[N+]=N[C@H](C(=O)O)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2
Product: COC(=O)N[C@H](C(=O)Nc1cccc(F)c1CC[C@@H]1CN[C@H](COC(=O)NCC(F)(F)F)CO1)[C@@H](c1ccc(Cl)cc1)c1ccc2c(c1)OCO2

Procedure:
The title compound was prepared from (2S,3S)-2-azido-3-(benzo[d][1,3]dioxol-5-yl)-3-(4-chlorophenyl)propanoic acid (Example 1010, step 1) and the product of step 4 of Example 99 using the procedures given in steps 2 and 3 of Example 93 and steps 1 and 2 of Example 91. MS (ES) m/z=739 (M+H)+.
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH2:13][CH3:14])=[C:9]([CH3:12])[C:10]=1[CH3:11])(OCC)=O.[CH3:15]C1OC(C)OC(C)O1>>[CH2:13]([C:8]1[NH:7][C:6]([CH2:1][CH3:15])=[C:10]([CH3:11])[C:9]=1[CH3:12])[CH3:14]
Reactant: CCOC(=O)c1[nH]c(CC)c(C)c1C
Reactant: CC1OC(C)OC(C)O1
Product: CCc1[nH]c(CC)c(C)c1C

Procedure:
2-Carbethoxy-3,4-dimethyl-5-ethyl-pyrrole was reductively alkylated with paraldehyde to yield 2,5-diethyl-3,4 dimethyl-pyrrole. ##STR84##
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH2:10][C@H:9]1[C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:15]([NH2:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[CH2:15]([NH:25][C:12]([C@@H:9]1[CH2:10][CH2:11][N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[O:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: CCCCCCCCCCN
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCNC(=O)[C@@H]1CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 96 h

Procedure:
N-(tert-Butoxycarbonyl)-(S)-(−)-2-azetidinecarboxylic acid (1) (90 mg; 0.447 mmol) is dissolved in methylene chloride (3 mL) at ambient temperature. n-Decylamine (72 mg; 0.470 mmol), N,N-diisopropylethylamine (116 mg; 0.895 mmol) and PyBOP (244 mg; 0.470 mmol) are added sequentially. The reaction is stirred for 4 days at room temperature, then concentrated under reduced pressure. The crude product is purified via silica gel chromatography using a gradient elution (10%→60% ethyl acetate in hexanes) affording the desired product (285). ISMS: MH+ 341.4
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.[Cl:12][C:13]1[CH:14]=[C:15](I)[C:16]([NH2:19])=[N:17][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[Cl:12][C:13]1[CH:14]=[C:15]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[S:2][CH3:1])[C:16]([NH2:19])=[N:17][CH:18]=1
Reactant: Nc1ncc(Cl)cc1I
Reactant: CSc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CSc1ccccc1-c1cc(Cl)cnc1N
Temperature: 25 °C
Yield: 46.8 %

Procedure:
Mixture of 2-(methylthio)phenylboronic acid (5.0 g, 29.8 mmol), 5-chloro-3-iodopyridin-2-amine (7.56 g, 29.8 mmol), sodium carbonate (9.0 g, in 50 mL of water), Pd(PPh3)4 (621 mg) and 100 mL of toluene was refluxed overnight under N2. reaction mixture was cooled down to room temperature, organic layer was separated and concentrated in vacuum. The residue was subjected to column chromatography on silica gel with hexane/ethyl acetate gradient mixture as eluent, providing 3.5 g of 5-chloro-3-(2-(methylthio)phenyl)pyridin-2-amine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][S:23][CH2:22]1>C(#N)C.[I-].[K+]>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[O:12][CH2:20][CH:21]1[CH2:26][CH2:25][CH2:24][S:23][CH2:22]1
Reactant: O=[N+]([O-])c1cc(O)c(Cl)cc1F
Reactant: BrCC1CCCSC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1cc(OCC2CCCSC2)c(Cl)cc1F
Temperature: 25 °C
Yield: 28.8 %

Procedure:
47.9 g (250 mmol) of 2-chloro-4-fluoro-5-nitrophenol, 34.6 g (250 mmol) of potassium carbonate, 1 g of potassium iodide and 58.5 g (300 mmol) of 3-bromomethyltetrahydrothiopyran in 500 ml of acetonitrile were refluxed for 5 hours. The mixture was cooled to 25° C. and filtered, the solvent was removed from the filtrate, the residue was taken up in methylene chloride, and the solution was washed with water, dried and concentrated. 22 g (29%) of 2-chloro-4-fluoro-5-nitro-1-(3-tetrahydrothiopyranylmethoxy)benzene (melting point 100° to 103° C.) were obtained.
Reaction SMILES: [OH-].[Na+].[CH2:3]1[O:5][C@@H:4]1[CH2:6]Cl.[F:8][C:9]([F:21])([C:17]([F:20])([F:19])[F:18])[CH2:10][CH2:11][CH2:12][S:13][CH2:14][CH2:15][OH:16]>S([O-])(O)(=O)=O.C([NH3+])(C)(C)C>[O:5]1[CH2:3][CH:4]1[CH2:6][O:16][CH2:15][CH2:14][S:13][CH2:12][CH2:11][CH2:10][C:9]([F:21])([F:8])[C:17]([F:18])([F:19])[F:20]
Reactant: ClC[C@@H]1CO1
Reactant: OCCSCCCC(F)(F)C(F)(F)F
Agent: CC(C)(C)[NH3+]
Agent: O=S(=O)([O-])O
Agent: [Na+]
Product: FC(F)(F)C(F)(F)CCCSCCOCC1CO1
Temperature: 0 °C
Yield: 62.7 %

Procedure:
A mixture of 50% acqueous NaOH (1.85 ml), S-epichlorohydrin (1.142 g, 12.34 mmole) and t-butylammonium hydrogen sulfate (24 mg) was vigorously stirred at 0° C., for half an hour and allowed to reach room temperature. To this mixture was added 2-(4,4,5,5,5-pentafluoropentylthio)ethan-1-ol (735 mg, 3.08 mmole) at room temperature. The reaction mixture was stirred for 18 hours and quenched with water. The aqueous phase was extracted with ethyl acetate. Then, the organic layer was washed with water and saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel (n-hexane:ethyl acetate=7:1) to give the title compound (568 mg, yield 63%) as a colorless oil.