Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]=[C:12]1[NH:16][C@@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:14][S:13]1.[CH2:21](Br)[C:22]([CH3:25])([CH3:24])[CH3:23]>>[CH3:21][C:22]([CH3:25])([CH3:24])[CH2:23][N:11]([C:3]1[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[CH3:1])[C:12]1[S:13][CH2:14][C@H:15]([CH2:17][CH:18]([CH3:20])[CH3:19])[N:16]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CC(C)(C)CBr
Product: Cc1cc([N+](=O)[O-])ccc1N(CC(C)(C)C)C1=N[C@@H](CC(C)C)CS1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 2-Methyl-4-nitrophenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(2-methyl-4nitrophenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with neopentyl bromide according to Method D2a to afford (4S)-2-(N-(2,2-dimethylpropyl)-2-methyl-4-nitrophenylamino)-4-isobutyl-1,3-thiazoline.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH:6]([C:11]([O:13]C)=O)[C:7]([O:9]C)=O.[Na].F[B-](F)(F)F.[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([CH:39]=[CH:40][CH:41]=1)[C:36]([NH2:38])=[NH:37])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>CO>[CH2:25]([O:32][C:33]1[CH:34]=[C:35]([C:36]2[N:38]=[C:7]([OH:9])[C:6]([O:5][C:4]3[CH:15]=[CH:16][CH:17]=[CH:18][C:3]=3[O:2][CH3:1])=[C:11]([OH:13])[N:37]=2)[CH:39]=[CH:40][CH:41]=1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: N=C(N)c1cccc(OCc2ccccc2)c1
Reactant: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Agent: F[B-](F)(F)F
Agent: [Na]
Solvent: CO
Product: COc1ccccc1Oc1c(O)nc(-c2cccc(OCc3ccccc3)c2)nc1O
Reaction time: 0.5 h

Procedure:
6.3 g of dimethyl (2-methoxyphenoxy)malonate were added dropwise within 5 minutes under an argon atmosphere to a solution of 1.72 g of sodium in methanol (150 ml) at 5° C. Stirring was continued for 30 minutes (5° C.) then 7.85 g of m-benzyloxy-benzamidine tetrafluoroborate in methanol (50 ml) were added within 5 minutes at 5° C. and the mixture was then stirred for further 20 h at RT. The solvent was removed in vacuo and the residue partitioned between water and EtOAc (each 50 ml). The cold aqueous phase was acidified dropwise with conc. HCl the precipitate filtered off under suction, washed with water and dried under reduced pressure to give the desired 2-(3-benzyloxy-phenyl)-5-(2-methoxy-phenoxy)-pyrimidine-4,6-diol as an off-white solid, mp 192°-195° C.
Reaction SMILES: [CH:1](=O)[CH:2]([CH3:4])[CH3:3].[CH2:6]([SH:10])[CH2:7][CH2:8][SH:9].B(F)(F)F.CCOCC>ClCCl>[CH:2]([CH:1]1[S:10][CH2:6][CH2:7][CH2:8][S:9]1)([CH3:4])[CH3:3]
Reactant: CC(C)C=O
Reactant: SCCCS
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)C1SCCCS1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a mixture of isobutyraldehyde (9.1 mL, 100 mmol) and 1,3-propanedithiol (10 mL, 100 mmol) in dichloromethane at 0° C. was added boron trifluoride diethyl etherate (6.4 mL, 50 mmol). The resulting mixture was stirred at 0° C. for 30 min and at room temperature for 30 min. The reaction mixture was washed with brine, 5% NaHCO3, and brine again. The organic phase was separated and dried over Na2SO4, then concentrated to give 16 g (100%) of the title compound as a yellow liquid. This was carried to the next step without further purification. 1H NMR (CDCl3, 400 MHz): δ 1.057 (d, J=7.2 Hz, 3H), 1.059 (d, J=7.2 Hz, 3H), 1.80 (m, 1H), 1.97–2.08 (m, 2H), 2.82 (m, 4H), 4.00 (d, J=5.2 Hz, 1H).
Reaction SMILES: [Br:1]Br.[C:3]([C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)([CH3:6])([CH3:5])[CH3:4].C(Cl)(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[Br:1][C:11]1[CH:12]=[C:7]([C:3]([CH3:6])([CH3:4])[CH3:5])[CH:8]=[CH:9][C:10]=1[OH:13]
Reactant: CC(C)(C)c1ccc(O)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)c1ccc(O)c(Br)c1
Yield: 100.1 %

Procedure:
A solution of bromine (7.18 mL, 0.14 mol) in chloroform (25 mL) was added dropwise over 2 hours to a solution of 4-tert-butyl-phenol (20 g, 0.133 mol) in 1:1 v/v chloroform:carbon tetrachloride (64 mL) at 0° C. under nitrogen until a slight red coloration persisted (approximately 1 mL of bromine solution remained). The reaction mixture was then purged with nitrogen overnight. The resulting tan solution was diluted with dichloromethane (50 mL), washed with 1% aqueous sodium thiosulfate solution (100 mL) and saturated brine (100 mL), dried (MgSO4), filtered and concentrated under reduced pressure to give 2-bromo-4-(tert-butyl)phenol (30.5 g, quantitative yield) as a colorless oil.
Reaction SMILES: CS(O)(=O)=O.[NH2:6][CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[C:13](=[O:17])[N:12]([CH:18]1[CH2:23][CH2:22][C:21](=[O:24])[NH:20][C:19]1=[O:25])[CH2:11]2.[C:26]1([CH3:35])[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1.Cl>C(#N)C>[O:25]=[C:19]1[CH:18]([N:12]2[CH2:11][C:10]3[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][NH:6][C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([CH3:35])=[CH:27][CH:28]=4)=[O:34])[CH:9]=3)[C:13]2=[O:17])[CH2:23][CH2:22][C:21](=[O:24])[NH:20]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: Cc1ccc(N=C=O)cc1
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC#N
Product: Cc1ccc(NC(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 46.7 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methanesulfonate (0.37 g, 1.00 mmol) and p-tolyl-isocyanate (0.13 g, 1.00 mmol) in acetonitrile (30 mL) at 0° C. was added TEA (0.20 g, 2.0 mmol) dropwise over 10 min. The mixture was stirred at ambient temperature for 1.5 h and then 10% aqueous HCl solution (30 mL) was added. The solid precipitate was filtered, washed with water (20 mL) and dried in vacuo providing 1-[2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-3-p-tolyl-urea as a white solid (0.19 g, 46% yield); mp 267-269° C.; HPLC, Waters Symmetry C-18, 3.9×150 mm, 5 μm, 1 ml/min, 240 nm, 30/70 CH3CN/0.1% H3PO4, 4.30 (99.66%); 1H NMR (DMSO-d6) δ 1.91-2.08 (m, 1H, CHH), 2.21 (s, 3H, CH3), 2.28-2.47 (m, 1H, CHH), 2.53-2.68 (m, 1H, CHH), 2.80-3.02 (m, 1H, CHH), 4.31 (d, 1H, CHH), 4.36-4.52 (m, 3H, CH2 and CHH), 5.11 (dd, J=4.8, 13.1 Hz, 1H, CH), 6.69 (t, 1H, NH), 7.02 (d, 2H, Ar), 7.29 (d, J=8.1 Hz, 2H, Ar), 7.42 (d, 1H, Ar), 7.51 (s, 1H, Ar), 7.69 (d, 1H, Ar), 8.52 (s, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.28, 22.49, 31.20, 42.76, 45.72, 47.12, 51.56, 117.84, 121.86, 122.91, 126.89, 129.01, 129.84, 130.27, 137.81, 142.38, 144.93, 155.28, 167.95, 170.99, 172.85; LCMS: MH=407; Anal. Calcd for C22H22N4O4: C, 65.01; H, 5.46; N, 13.78. Found: C, 64.75; H, 5.48; N, 13.66.
Reaction SMILES: COC(OC)[CH2:4][N:5]([CH3:10])[C:6](=[O:9])[CH2:7][Cl:8].[CH3:13][CH:14]([OH:18])[CH:15]([OH:17])[CH3:16].C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:16][CH:15]1[CH:14]([CH3:13])[O:18][CH:4]([N:5]([CH3:10])[C:6](=[O:9])[CH2:7][Cl:8])[O:17]1
Reactant: CC(O)C(C)O
Reactant: COC(CN(C)C(=O)CCl)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: CC1OC(N(C)C(=O)CCl)OC1C
Temperature: 110 °C

Procedure:
N-(2,2-Dimethoxyethyl)-N-methyl-2-chloroacetamide (97.8 grams; 0.5 mole), 2,3-butanediol (45 grams) and 0.2 grams p-toluenesulfonic acid were charged into a glass reaction vessel fitted with a mechanical stirrer, thermometer, distilling head and condenser. The reaction mixture was heated at about 90° C. to 100° for period of 5 hours. Little reaction occurred as shown by the absence of methanol distilled. The reaction mixture was then heated at about 110° C., for about 2 hours at atmospheric pressure, then 1 hour at reduced pressure. Under these more rigorous conditions, methanol was formed and was distilled off. At the conclusion of the reaction, the reaction mixture was distilled and the fraction boiling at 127° C. to 130° C. at 0.55 mm Hg was the desired product N-(4,5-dimethyl-1,3-dioxolan-2-yl)-N-methyl-2-chloroacetamide. 1,3-dioxolan-2-yl)-N-methyl-2-chloroacetamide.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.[Cl-].[NH4+]>C(O)C.O1CCCC1.[Fe]>[CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][S:5][C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: CN(C)CCSc1ccc([N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: CN(C)CCSc1ccc(N)cc1
Temperature: 100 °C

Procedure:
To a solution of N,N-dimethyl-N-{2-[(4-nitrophenyl)thio]ethyl}amine (0.58 g, 3.0 mmol) in ethanol (45 mL), tetrahydrofuran (23 mL), and saturated aqueous ammonium chloride solution is added iron powder (1.1 g, 6.4 mmol). The mixture is heated in a 100° C. oil bath for one hour. While still hot, the reaction mixture is filtered through a pad of diatomaceous earth. The concentrated filtrate is partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude material is purified by reverse-phase high performance liquid chromatography to give 4-(2-dimethylamino-ethylsulfanyl)-phenylamine.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].C(N(CC)CC)C.[Cl:15][C:16]1[C:24]([CH3:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19]>ClCCl>[Cl:15][C:16]1[C:24]([CH3:25])=[C:23]([F:26])[CH:22]=[CH:21][C:17]=1[C:18]([N:4]1[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]1)=[O:19]
Reactant: Cc1c(F)ccc(C(=O)Cl)c1Cl
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1c(F)ccc(C(=O)N2CCNC(=O)C2)c1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-piperazinone (1 g, 9.99 mmol, commercially available from e.g. Sigma-Aldrich) was then dissolved in dichloromethane (DCM) (40 mL), and to this was added triethylamine (2.78 mL, 19.98 mmol). The solution was cooled to 0° C. before 2-chloro-4-fluoro-3-methylbenzoyl chloride, (2.072 g, 10.99 mmol), from Step 1, in DCM (10 mL) was added dropwise over 1 minute. The solution was then allowed to stir at room temperature for a further 30 minutes before the solvent was evaporated in vacuo. The remaining solid was then re-dissolved in DCM (80 mL) before being washed with water (30 mL), a saturated solution of sodium bicarbonate (30 mL), and brine (30 mL). The solution was then dried over anhydrous sodium sulphate, which was hen removed by filtration and the solvent was evaporated in vacuo. The remaining solid was then stirred in hexane at 55° C. for 30 minutes, before being filtered off to yield the product in 2.496 g.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16](=[O:44])[C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19](C3C=CC=C(C(F)(F)F)C=3)[CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[Br-:46]>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([C:17]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[CH:24]=3)[C:20]([OH:33])=[C:19]([Br:46])[CH:18]=2)=[O:44])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: O=C(NCCCCCCCCc1ccccc1)c1cc(-c2cccc(C(F)(F)F)c2)c(O)c(-c2cccc(C(F)(F)F)c2)c1
Agent: [K+]
Product: O=C(NCCCCCCCCc1ccccc1)c1cc(Br)c(O)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
The title compound was prepared as a white gum (0.976 g, 58%) from N-(8-phenyl-octyl)-3,5-bis(m-trifluoromethylphenyl)-4-hydroxy-benzamide using a procedure similar to Example 191. 1H NMR (DMSO-d6) δ 9.84 (s, 1H); 8.42 (t, 1H); 8.04 (d, 1H); 7.85–7.67 (m, 5H); 7.26–7.10 (m, 5H); 3.21 (dd, 2H); 2.52 (t, 2H); 1.50 (m, 4H); 1.26 (m, 8H); IR (KBr) 3330, 2950, 2850, 1620, 1550, 1495, 1470, 1330, 1220, 1170, 1120, 1100, 1080 cm−1; mass spectrum [(+)APCI], m/z 549 (M+H)+; Anal. Calcd. for C28H29F3NO2: C, 61.32; H, 5.33; N, 2.55. Found: C, 61.02; H, 5.29; N, 2.51.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([C:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH:21]=2)=[C:8]([NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])[CH:9]=1)(=[O:3])[CH3:2].[CH3:28][Mg]Cl.[NH4+].[Cl-]>C1COCC1.[Cl-].[Na+].O>[CH3:26][C:23]1([CH3:27])[CH2:24][CH2:25][C:20]([C:7]2[CH:6]=[CH:5][C:4]([C:1]([OH:3])([CH3:28])[CH3:2])=[CH:9][C:8]=2[NH:10][C:11]([C:13]2[NH:14][CH:15]=[C:16]([C:18]#[N:19])[N:17]=2)=[O:12])=[CH:21][CH2:22]1
Reactant: C[Mg]Cl
Reactant: CC(=O)c1ccc(C2=CCC(C)(C)CC2)c(NC(=O)c2nc(C#N)c[nH]2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(C(C)(C)O)cc2NC(=O)c2nc(C#N)c[nH]2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.5 %

Procedure:
To a solution of 4-cyano-1H-imidazole-2-carboxylic acid [5-acetyl-2-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-amide (as prepared in Example 31, step (d), 30.0 mg, 0.0828 mmol) in 2 mL of THF at −78° C. under Ar was added methyl magnesium chloride (58 μL, 0.17 mmol, 3.0 M in THF). The resulting mixture was warmed to RT and stirred for 0.5 h. Treated with 10 mL of saturated NH4Cl aqueous solution followed by 10 mL of brine, the mixture was extracted with EtOAc (2×20 mL). The combined organic layers were dried with Na2SO4. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography on silica gel (2-3% MeOH/DCM) to give 29.0 mg (93%) of the title compound as a white solid. 1H-NMR (DMSO-d6; 400 MHz): δ 14.22 (s, 1H), 9.76 (s, 1H), 8.32 (s, 1H), 8.12 (d, 1H, J=1.8 Hz), 7.25 (dd, 1H, J=8.1, 1.8 Hz), 7.14 (d, 1H, J=8.1 Hz), 5.65 (m, 1H), 2.16-2.29 (m, 2H), 1.87-1.98 (m, 2H), 1.47 (t, 2H, J=6.2 Hz), 1.43 (s, 6H), 0.99 (s, 6H). Mass spectrum (ESI, m/z): Calcd. for C22H26N4O2, 379.2 (M+H), found 379.0.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N:14]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:18]=[C:17]([CH3:19])[CH:16]=[CH:15][N+:14]=1[O-:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccnc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1cc[n+]([O-])c(Cl)c1
Yield: 464.3 %

Procedure:
40% meta-chloroperbenzoic acid (13.5 g, 31.4 mmol) was added at ambient temperature to a solution of 2-chloro-4-methyl-pyridine (2.0 g, 1.5 mmol) in chloroform (20 mL) and heated at reflux for 24 h. After allowing to cool, the mixture was washed with water followed by sodium bicarbonate solution. The separated organic phase was further washed with water and brine, dried over anhydrous sodium sulfate and concentrated to give a residue which was purified by column chromatography over silica gel (60-120 mesh) using 10% methanol in ethyl acetate as eluent to afford 2-chloro-4-methyl-pyridine 1-oxide (1.0 g, 45%) as a deep brown oily liquid.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4](I)[C:5]2[S:9][C:8]([NH:10][C:11]([NH:13][CH2:14][CH3:15])=[O:12])=[N:7][C:6]=2[CH:16]=1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:14]([NH:13][C:11]([NH:10][C:8]1[S:9][C:5]2[C:4]([C:20]3[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=3)=[CH:3][C:2]([I:1])=[CH:16][C:6]=2[N:7]=1)=[O:12])[CH3:15]
Reactant: OB(O)c1cccnc1
Reactant: CCNC(=O)Nc1nc2cc(I)cc(I)c2s1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(I)cc(-c3cccnc3)c2s1
Temperature: 120 °C

Procedure:
To a solution of 1-(5,7-diiodo-benzothiazol-2-yl)-3-ethyl-urea (0.20 g, 0.42 mmol) in DMF (5 mL) was added pyridine 3-boronic acid (0.076 g, 0.63 mmol) and K3PO4 (0.133 g, 0.63 mmol) under nitrogen atmosphere at room temperature. The reaction mixture was degassed for half an hour followed by the addition of bis(triphenylphosphine)palladium(II) dichloride (0.0044 g, 0.063 mmol). The reaction mixture was again degassed for half an hour and then heated at 120° C. for 1 h under nitrogen atmosphere. DMF was distilled off, added water and extracted with ethyl acetate (×3). The combined organic layer was dried over anhydrous Na2SO4, and evaporated to dryness under reduced pressure. The residue was purified by chromatography on silica (230-400 M) using DCM/Methanol (99:1) to provide 1-Ethyl-3-(5-iodo-7-pyridin-3-yl-benzothiazol-2-yl)-urea as an off white solid (0.025 g, 14%) and DCM/Methanol (98:2) to provide 1-Ethyl-3-(7-iodo-5-pyridin-3-yl-benzothiazol-2-yl)-urea as an off white solid (0.025 g, 14%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([SH:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:24][Si:25]([CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])([CH3:27])[CH3:26].Cl>CN(C)C=O>[C:12]([C:7]1[CH:8]=[C:9]([S:11][CH2:24][Si:25]([CH3:26])([CH3:27])[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]=1[OH:16])([CH3:15])([CH3:14])[CH3:13]
Reactant: CCCCCCCCCCCC[Si](C)(C)CCl
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCCCCCCC[Si](C)(C)CSc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mix 2,6-di-t-butyl-4-mercaptophenol (2.4 g, 10 mmol), potassium carbonate (1.7 g, 12.3 mmol), chloromethyldodecyldimethylsilane (2.8 g, 10 mmole) and dimethylformamide (50 mL) and stir overnight at room temperature under argon atmosphere. Dilute the mixture with ice-water, acidify with aqueous hydrochloric acid and extract with ethyl ether. Wash the ethereal layer with water, then brine, filter through fluorosil-Na2SO4 and evaporate to an orange semi-solid (4.0 g). Purify the product by first distilling (180°-200° C. @0.1 mm Hg) then subjecting to silica gel chromatography (CCl4) to obtain the title compound as a colorless oil which slowly crystallizes.
Reaction SMILES: [CH3:1][O:2][CH:3]([O:7][CH3:8])[C:4](=[O:6])[CH3:5].CO[CH:11]([N:14]([CH3:16])[CH3:15])OC>>[CH3:11][N:14]([CH3:16])/[CH:15]=[CH:5]/[C:4](=[O:6])[CH:3]([O:7][CH3:8])[O:2][CH3:1]
Reactant: COC(OC)C(C)=O
Reactant: COC(OC)N(C)C
Product: COC(OC)C(=O)/C=C/N(C)C
Temperature: 25 °C

Procedure:
A solution of 1,1-dimethoxypropan-2-one (12 g, 101.58 mmol, 1.00 equiv) and (dimethoxymethyl)dimethylamine (12 g, 100.70 mmol, 0.99 equiv) was stirred at 100° C. for 5 h. The reaction mixture was cooled to room temperature and used in the next step directly. LCMS (method D, ESI): RT=0.94 min, m/z=174.0 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:12])=[N:4][C:5]([F:11])=[C:6]([Cl:10])[C:7]=1[CH2:8][OH:9].[Cl:13][C:14]([C:24]([F:27])([F:26])[F:25])=[CH:15][C@@H:16]1[C@H:18]([C:19](Cl)=[O:20])[C:17]1([CH3:23])[CH3:22]>>[Cl:13][C:14]([C:24]([F:25])([F:26])[F:27])=[CH:15][C@@H:16]1[C@H:18]([C:19]([O:9][CH2:8][C:7]2[C:2]([Cl:1])=[C:3]([F:12])[N:4]=[C:5]([F:11])[C:6]=2[Cl:10])=[O:20])[C:17]1([CH3:23])[CH3:22]
Reactant: OCc1c(Cl)c(F)nc(F)c1Cl
Reactant: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Product: CC1(C)[C@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)OCc1c(Cl)c(F)nc(F)c1Cl

Procedure:
By The method of Example 2, 0.6 (0.002 mole) of 3,5-dichloro2,6-difluoro-4-hydroxymethylpyridine (Example 15) was reacted with 0.61 g (0.002 mole) of cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarbonyl chloride to produce, after purification using the Chromatotron, 0.5 g of (3,5-dichloro-2,6-difluoropyridin-4-yl)methyl cis-3-(2-chloro-3,3,3-trifluoropropenyl)-2,2-dimethylcyclopropanecarboxylate as a clear, white liquid, compound 21 in the Tables below.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1C=O>CCCCCC.O1CCCC1>[Cl:16][C:17]1[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=1[CH:8]1[O:7][C:1](=[O:6])[CH:2]=[C:3]([OH:4])[CH2:5]1
Reactant: O=Cc1ccccc1Cl
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C1C=C(O)CC(c2ccccc2Cl)O1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
The title compound was prepared as described in General Method 1 using 2.5 mL of methyl acetoacetate, 1.0 g of NaH 60% dispersion in oil, 12.5 mL of 2.0M n-butyl lithium in hexane, 3.3 mL of 2- chlorobenzaldehyde and 75 mL of tetrahydrofuran. After addition of the aldehyde, the reaction was stirred for 10 minutes at 0° C. then stirred for 2 hours at room temperature. The crude product was triturated from diethyl ether to afford a solid (m.p. 124°-125° C.). 1H NMR (CDCl3) δ 2.63 (dd, 1 H), 3.10 (dd, 1 H), 3.68 (dd, 2 H), 6.07 (dd, 1 H), 7.3-7.65 (m, 4 H).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([C:12]([OH:14])=O)[O:7][C:8]=1[CH:9]([CH3:11])[CH3:10])([CH3:3])[CH3:2].[NH2:15][C:16]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=1>>[CH:1]([C:4]1[CH:5]=[C:6]([C:12]([NH:15][C:16]2[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[CH:18][CH:17]=2)=[O:14])[O:7][C:8]=1[CH:9]([CH3:10])[CH3:11])([CH3:2])[CH3:3]
Reactant: CC(C)c1cc(C(=O)O)oc1C(C)C
Reactant: COC(=O)c1ccc(N)s1
Product: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)o2)s1
Yield: 54.3 %

Procedure:
In the same manner as that of Example 2, 4,5-diisopropylfuran-2-carboxylic acid (42 mg, 0.214 mmol) was condensed with methyl 5-aminothiophene-2-carboxylate (50 mg, 0.318 mmol), and the resultant was purified by silica gel chromatography (2% methanol-chloroform) to obtain methyl 5-[(4,5-diisopropylfuran-2-carbonyl)amino]thiophene-2-carboxylate (39 mg, 54%) as pale yellow prisms.
Reaction SMILES: [N+:1]([C:4]1[CH:58]=[CH:57][CH:56]=[CH:55][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:11]1[CH:14]([CH2:15][C:16](O)=[O:17])[CH:13]([CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[O:23])[CH3:20])[C:12]1=[O:35])=[O:9])([O-:3])=[O:2].C(Cl)(=O)C([Cl:62])=O>C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[CH:58]=[CH:57][CH:56]=[CH:55][C:5]=1[CH2:6][O:7][C:8]([CH:10]([PH:36]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[N:11]1[C@@H:14]([CH2:15][C:16]([Cl:62])=[O:17])[C@H:13]([CH:19]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])=[O:23])[CH3:20])[C:12]1=[O:35])=[O:9])([O-:3])=[O:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])C1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)C1CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(NC(=O)OCc1ccccc1[N+](=O)[O-])[C@@H]1C(=O)N(C(C(=O)OCc2ccccc2[N+](=O)[O-])[PH](c2ccccc2)(c2ccccc2)c2ccccc2)[C@H]1CC(=O)Cl
Reaction time: 0.08 h

Procedure:
1-(o-nitrobenzyloxycarbonyltriphenylphosphoranylmethyl)-3-(1-o-nitrobenzyloxycarbonylaminoethyl)-4-(carboxymethyl)-2-azetidinone (0.1320 g from the previous step) is dissolved in 5 ml CH2Cl2 and cooled to 0° under N2. Oxalyl chloride (0.040 ml, 0.44 mmole) is added dropwise over 5 minutes and then 1 drop of DMF is added. The mixture is stirred at 0° for 5 minutes and then at 25° C. for another 15 minutes. The solvent and excess oxalyl chloride are evaporated under reduced pressure. The residue is the desired acid chloride which is used without purification in the next step.