Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:9]([NH2:14])[CH2:10][CH2:11][CH2:12][CH3:13]>C(Cl)Cl>[CH2:9]([NH:14][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCN
Reactant: CCCCCC(=O)Cl
Solvent: ClCCl
Product: CCCCCNC(=O)CCCCC
Reaction time: 4 h

Procedure:
275 g of caproyl chloride are added dropwise within 30 minutes to a solution of 500 ml of n-pentylamine in 1.41 of methylene chloride while cooling with ice and stirring. After standing at room temperature for 4 hours the reaction solution is washed in succession with 11 of 0.1N HCl, 11 of 0.1N NaOH and 1.51 of NaCl solution. The organic phase is concentrated on a rotary evaporator and dried in a high vacuum and gives 370 g of a crystalline mass (98% of theory). M.p. 37° C.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14](O)([CH3:16])[CH3:15].C[Si]([C:22]#[N:23])(C)C.[OH-:24].[NH4+]>>[Br:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]([NH:23][CH:22]=[O:24])([CH3:16])[CH3:15]
Reactant: CC(C)(O)c1ccc(F)cc1Br
Reactant: C[Si](C)(C)C#N
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: CC(C)(NC=O)c1ccc(F)cc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Add 98% sulfuric acid drop-wise (3 g, 31 mmol) to a mixture of 2-(2-bromo-4-fluoro-phenyl)-propan-2-ol (2.4 g, 10.30 mmol) and trimethylsilyl cyanide (2.04 g, 59 mmol) in a 25-mL round bottom flask under N2 at −20° C. Move the flask out of the cooling bath and stir the mixture at RT overnight. Dilute the mixture with ice-water and neutralize with ammonium hydroxide to pH=8. Extract the product with chloroform/IPA (3/1, 100 mL). Wash the organic phase with water/aqueous saturated sodium chloride, dry over sodium sulfate, and concentrate in vacuo to give the crude product. Purify by FCC (20% THF in DCM as elute) to give the title compound as a white solid (2 g, 75%). MS (ES) m/z 260/262 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[N:3]=1.Cl[CH2:10][CH:11]=O.Cl.C(OCC)(=O)C>O>[F:8][C:4]1[N:3]2[CH:10]=[CH:11][N:1]=[C:2]2[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(F)n1
Reactant: O=CCCl
Agent: Cl
Solvent: O
Solvent: CCOC(C)=O
Product: Fc1cccc2nccn12
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Amino-6-fluoropyridine (12 g) was completely dissolved in 120 mL of distilled water at 60° C. To the solution was added 35 mL (2 equivalents) of 40% chloroacetaldehyde. The mixture was stirred for 3 hours at 60° C. The reaction mixture was gradually cooled to room temperature, to which were added a 1N—HCl aqueous solution (50 mL) and ethyl acetate (150 mL). The ethyl acetate solution was subjected to extraction with a 1N—HCl aqueous solution (100 mL). The extract was mixed with the aqueous solution. To this aqueous solution was added NaHCO3 for neutralization (pH 0.35-7.30). To the neutralized aqueous solution was added a mixture of ethyl acetate and THF (4:1) (150 mL×3) to extract the product. The extract solutions were combined and dried over anhydrous magnesium sulfate, which was concentrated under reduced pressure to afford 5-fluoroimidazo[1,2-a]pyridine as a black liquid product (9.5 g, yield 65%).
Reaction SMILES: COC1C=CC(C(Cl)=O)=CC=1.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH2:15].[CH3:35][O:36][C:37]1[CH:42]=[CH:41][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:39][CH:38]=1>C1(C)C=CC=CC=1.C(O)C>[CH3:35][O:36][C:37]1[CH:38]=[CH:39][C:40]([C:43]([N:45]=[C:46]=[S:47])=[O:44])=[CH:41][CH:42]=1.[Cl:12][C:13]1[CH:19]=[C:18]([O:20][C:21]2[C:30]3[C:25](=[CH:26][C:27]([O:33][CH3:34])=[C:28]([O:31][CH3:32])[CH:29]=3)[N:24]=[CH:23][CH:22]=2)[CH:17]=[CH:16][C:14]=1[NH:15][C:46]([NH:45][C:43](=[O:44])[C:40]1[CH:41]=[CH:42][C:37]([O:36][CH3:35])=[CH:38][CH:39]=1)=[S:47]
Reactant: COc1cc2nccc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Agent: COc1ccc(C(=O)Cl)cc1
Agent: COc1ccc(C(=O)N=C=S)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(C(=O)NC(=S)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
4-Methoxy-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-methoxy-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-methoxy-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (36 mg, yield 46%).
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:23])([CH3:22])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20]#[N:21])[C:14]=2[CH:13]=[CH:12][N:11]=1)([CH3:4])[CH3:3].C(O)C.C(=O)(O)[O-].[Na+].Cl.[NH2:33][OH:34]>C(OCC)(=O)C>[CH3:4][C:2]([Si:5]([CH3:22])([CH3:23])[O:6][CH2:7][CH2:8][CH2:9][C:10]1[C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([C:20](=[NH:21])[NH:33][OH:34])[C:14]=2[CH:13]=[CH:12][N:11]=1)([CH3:1])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(C#N)cccc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](C)(C)OCCCc1nccc2c(C(=N)NO)cccc12
Temperature: 65 °C
Yield: 60.8 %

Procedure:
A round bottomed flask was charged with 1-(3-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}propyl)-5-isoquinolinecarbonitrile (D12; 417 mg, 1.28 mmol), ethanol (10 ml), sodium bicarbonate (107 mg, 12.8 mmol) and hydroxylamine hydrochloride (710 mg, 10.2 mmol). The vessel was fitted with a reflux condenser and warmed to 65° C. overnight. The resulting slurry was diluted with ethyl acetate and filtered through celite. The filtrate was concentrated in vacuo to give a yellow oil that was purified by flash column chromatography on silica using 0% to 100% ethyl acetate in cyclohexane as eluent. The relevant fractions were pooled and concentrated in vacuo to give the title compound as a yellow solid (280 mg).
Reaction SMILES: [CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9](Br)[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6].C(N(CC)CC)C.[CH3:31][Si:32]([C:35]#[CH:36])([CH3:34])[CH3:33].C(OCC)(=O)C>CCCCCC.[Cu]I.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>[CH3:1][C:2]([CH3:23])([CH3:22])[CH2:3][O:4][C:5]([C:7]1[CH:8]=[C:9]([C:36]#[C:35][Si:32]([CH3:34])([CH3:33])[CH3:31])[CH:10]=[C:11]2[C:16]=1[O:15][C:14]([CH3:18])([CH3:17])[CH2:13][C:12]2([CH3:20])[CH3:19])=[O:6]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)(C)COC(=O)c1cc(Br)cc2c1OC(C)(C)CC2(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)COC(=O)c1cc(C#C[Si](C)(C)C)cc2c1OC(C)(C)CC2(C)C
Yield: 70.6 %

Procedure:
Following General Procedure D and using 6-bromo-2,2,4,4-tetramethylchroman-8-carboxylic acid 2,2dimethylpropyl ester (Intermediate 46, 0.54 g, 1.4 mmol), triethyl amine (3 mL), copper(I)iodide (0.10 g, 0.52 mmol), trimethylsilyl acetylene (0.8 mL, 5.6 mmol) and dichlorobis(triphenylphosphine)palladium(II) (0.25 g, 0.35 mmol) followed by flash column chromatography over silica gel (230-400 mesh) using 10% ethyl acetate in hexane as the eluent, the title compound (0.396 g, 71%) was obtained as a yellow oil.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-:11])=[O:10])=[C:5]([Cl:12])[CH:4]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[Cl:12][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][C:6]=1[N+:9]([O-:11])=[O:10])[CH2:2][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]
Reactant: CCOP(OCC)OCC
Reactant: O=[N+]([O-])c1ccc(CBr)cc1Cl
Product: CCOP(=O)(Cc1ccc([N+](=O)[O-])c(Cl)c1)OCC
Temperature: 100 °C
Yield: 48 %

Procedure:
4-(Bromomethyl)-2-chloro-1-nitrobenzene (17.21 mmol, 4.31 g) and triethyl phosphite (25.8 mmol, 4.34 mL, 4.29 g) were combined and heated to 100° C. for 4 hours. The reaction mixture was quenched with water and extracted into ether. The organic phase was concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with dichloromethane-2% dichloromethane/methanol) to give the intermediate diethyl 3-chloro-4-nitrobenzylphosphonate (2.54 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[O:22])=[CH:16][CH:15]=1)[NH:5]C(OC(C)(C)C)=O.Cl.C(OCC)C>O1CCOCC1>[ClH:29].[CH3:1][O:2][C:3](=[O:31])[C@H:4]([CH2:13][C:14]1[CH:15]=[CH:16][C:17]([NH:20][C:21]([C:23]2[C:28]([Cl:29])=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:30])=[O:22])=[CH:18][CH:19]=1)[NH2:5]
Reactant: COC(=O)[C@H](Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COC(=O)[C@@H](N)Cc1ccc(NC(=O)c2c(Cl)cccc2Cl)cc1
Reaction time: 0.08 h

Procedure:
4-[[(2,6-Dichlorophenyl)carbonyl]amino]-N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanine methyl ester (1.86 g, 4.0 mmol) was treated with 4 N hydrochloric acid in dioxane (10 mL) at room temperature. After 5 minutes, the solids went into solution and the mixture was stirred for 1 h. Then, 25 mL of ethyl ether was added to precipitate the product. The solids were collected by filtration and washed with hexane. The resulting solid was very hydroscopic and became gummy. This material was dissolved in 50 mL of methanol and concentrated. After drying under high vacuum, 4-[[(2,6-dichlorophenyl)carbony]amino]-L-phenylalanine methyl ester hydrochloride salt. (1.64 g, 97%) was obtained as a light yellow solid: mp 158-161° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]([NH2:11])=[NH:10])=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1.C(=O)(O)[O-].[K+].Cl[CH2:20][C:21]([C:23]1[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=1)=O>C1COCC1.O>[Cl:2][C:3]1[C:8]([C:9]2[NH:11][CH:20]=[C:21]([C:23]3[N:24]([CH:28]([CH3:30])[CH3:29])[N:25]=[CH:26][N:27]=3)[N:10]=2)=[CH:7][N:6]=[C:5]([O:12][CH3:13])[CH:4]=1
Reactant: CC(C)n1ncnc1C(=O)CCl
Reactant: COc1cc(Cl)c(C(=N)N)cn1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(Cl)c(-c2nc(-c3ncnn3C(C)C)c[nH]2)cn1
Yield: 53.9 %

Procedure:
A suspension of 4-chloro-6-methoxy-nicotinamidine hydrochloride (50.9 mmol) and potassium bicarbonate (20.4 g, 202.5 mmol) in THF (128 mL) and water (21 mL) was heated to reflux and treated with a solution of 2-chloro-1-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-ethanone (9.55 g, 50.9 mmol) in THF (25 mL) added dropwise. The reaction mixture was heated at reflux for 24 h before removal of volatile solvent in vacuo. The resultant residue was diluted with water and extracted with ethyl acetate. The combined extracts were dried (Na2SO4), treated with charcoal (15 g), filtered and concentrated in vacuo to give a solid. The solid was triturated with 10% diethyl ether in pentane then dried at 50° C. in vacuo to give 4-Chloro-5-[4-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-1H-imidazol-2-yl]-2-methoxy-pyridine as a pale brown solid (8.74 g, 54%). LCMS RT=2.86 min, [M+H]+=319/321. 1H NMR 400 MHz (CDCl3) δ: 9.03 (1H, s), 7.89 (1H, s), 7.83 (1H, s), 7.26 (1H, s) 6.88 (1H, s), 4.01 (3H, s), 1.58 (6H, d, J=6.63 Hz).
Reaction SMILES: C([O-])(=O)C([O-])=O.[CH3:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[N+](CC)(CCC)CCC.[CH3:26][C:27]1C([N+]([O-])=O)=CC=C[C:28]=1[N+:36](CC)([CH2:40][CH2:41]C)[CH2:37][CH2:38][CH3:39].[OH-].[Na+]>C(OCC)(=O)C>[CH3:7][C:8]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:41][CH2:40][N:36]([CH2:37][CH2:38][CH3:39])[CH2:28][CH2:27][CH3:26]
Reactant: CCC[N+](CC)(CCC)c1cccc([N+](=O)[O-])c1C
Agent: O=C([O-])C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: CCCN(CCC)CCc1cccc([N+](=O)[O-])c1C

Procedure:
2-Methyl-3-nitro-N,N-Di-n-propyl phenyl ethyl ammonium oxalate (100 g) is added to solution of Sodium hydroxide (2000 ml 1.4%) and stir until the clear solution is obtained. Further, ethyl acetate (500 ml) is added and organic layer separated out, washed with brine solution and dried over Sodium sulphate (20 gm). Ethyl acetate is distilled out under vacuum at 50-60° C. to get residue of 2-Methyl-3-nitro-N,N-di-n-propyl phenyl ethyl amine as a free base (70-72 g)
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=C)=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].I([O-])(=O)(=O)=[O:32].[Na+].N1C(C)=CC=CC=1C>O1CCOCC1.O.[Os](=O)(=O)(=O)=O>[C:1]([C:3]1[C:4]([CH:19]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=2)[CH2:20][CH:21]=[O:32])=[C:5]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: C=CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)OCC)sc(N2CCOCC2)c1C#N
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: Cc1cccc(C)n1
Solvent: O
Product: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CC=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 43.5 %

Procedure:
To a suspension of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)but-3-en-1-yl]-5-(morpholin-4-yl)thiophene-2-carboxylate (247 mg, 0.531 mmol) in 1,4-dioxane (6.00 mL) and water (2.00 mL) was added sodium metaperiodate (454 mg, 2.12 mmol), 2,6-lutidine (246 uL, 2.12 mmol), and 4% osmium tetroxide in water (4:96, osmium tetraoxide:water, 64.9 uL, 0.0106 mmol). The reaction was vigorously stirred at rt for 5 hrs. The mixture was filtered over a celite pad and the filtered solid was rinsed with EtOAc. The filtrate was washed with NaHCO3(aq) saturated solution and the aqueous layer was extracted with EtOAc (×2). The combined organic layer was washed with 1N HCl soln and brine, dried, and concentrated. Purification on a silica gel column (gradient elution 5-50% EtOAc/hexanes) provided ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-oxopropyl]-5-(morpholin-4-yl)thiophene-2-carboxylate as a yellow syrup (108 mg, 43.5% yield). 1H NMR (400 MHz, CDCl3) δ 9.84-9.73 (d, J=1.3 Hz, 1H), 7.48-7.42 (d, J=2.1 Hz, 1H), 7.42-7.32 (d, J=8.4 Hz, 1H), 7.30-7.18 (m, 1H), 6.06-5.94 (t, J=7.7 Hz, 1H), 4.38-4.26 (q, J=7.1 Hz, 2H), 3.86-3.77 (t, J=4.9 Hz, 4H), 3.62-3.51 (dd, J=5.7, 4.0 Hz, 4H), 3.50-3.42 (m, 2H), 1.41-1.29 (m, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:10][O:11]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([OH:9])[C:3]=1[CH:10]=[O:11]
Reactant: COC(Cl)Cl
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C)c(C=O)c(O)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.1 %

Procedure:
3,5-Dimethylphenol (40.0 g; 330 mmole) was dissolved in dichloromethane (210 ml) and the solution was cooled to a temperature of 0° C. Titanium tetrachloride (105 g; 553 mmole) was added dropwise over a period of 5 minutes to the stirred solution and then the temperature of the solution was maintained at 0° C. for a period of 30 minutes while dichloromethyl methyl ether (31.6 g) was added dropwise. The solution was warmed to room temperature and stirred for a period of 30 minutes and then warmed to 35° C. and stirred for a further 15 minutes. The reaction mixture was poured onto ice (ca 300 g) and the aqueous mixture was extracted with dichloromethane. The organic phase was washed three times with water and the solvent was removed by evaporation under reduced pressure. The residue was steam distilled and the distillate was extracted with dichloromethane and the organic phase was separated, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give 2,4-dimethyl-6-hydroxybenzaldehyde (31.0 g; 63.0%) as a yellow solid mp <50° C. Proton magnetic resonance spectrum (CDC13 ; δ in ppm): 2.19 (3H, s); 2.42 (3H, s); 6.41-6.52 (2H, m); 10.05 (1H, s); 11.90 (1H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]1[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]1)=[O:28]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[S:27]([CH3:26])=[O:28])[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)c1ccccc1C1CCNCC1
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(c2ccccc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 143.1 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(2-methyl-3-oxo-2,3-dihydro-5-methoxy-1H-isoindol-1-yl)propionaldehyde (0.38 g) was coupled to 4-(2-methylsulfinylphenyl)piperidine (0.29 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in Example 8 to afford the title compound (0.447 g); mp 155°-178° C. (d); MS: m/z=585(M+1); NMR(CD3OD): 2.0-2.3 (m,4), 2.6 (m,2), 2.8-3.0 (m,3), 3.0-3.3 (m,7), 3.5-3.8 (m,4), 3.85 (s,3) 4.8 (d,1, J=4), 6.7-7.3 (m,5), 7.5-8.0 (m,5). Analysis for C31H34Cl2N2O3S.HCl.1.5 H2O: Calculated: C, 59.86; H, 5.67, N, 4.50; Found: C, 57.05; H, 5.64; N, 4.19.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][C@H:33]([CH3:42])[C:34]([N:36]1[CH2:39][C:38]([F:41])([F:40])[CH2:37]1)=[O:35].C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.C(N(CC)C(C)C)(C)C>CN(C=O)C>[F:41][C:38]1([F:40])[CH2:39][N:36]([C:34](=[O:35])[C@H:33]([NH:32][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=5)[N:8]([CH3:11])[N:7]=4)[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:31])[CH3:29])[CH:19]=2)=[O:23])[CH3:42])[CH2:37]1
Reactant: C[C@@H](N)C(=O)N1CC(F)(F)C1
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12)C(=O)N1CC(F)(F)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61.4 %

Procedure:
A round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (110 mg, 0.24 mmol), (R)-2-amino-1-(3,3-difluoro-azetidin-1-yl)-propan-1-one (98 mg, 0.60 mmol), HOBT (41 mg, 0.27 mmol) and EDC (51 mg, 0.27 mmol). DMF (1.1 ml) was added followed by N,N-diisopropylethylamine (0.10 ml, 0.57 mmol). The reaction mixture was stirred at room temperature for 48 h then quenched with water and extracted with diethyl ether (2×). The combined organic layers were washed twice with water and once with brine then dried over sodium sulfate, filtered and concentrated. The residue was chromatographed over silica gel with EtOAc/Hexanes (gradient 0-50% EtOAc) to afford 89 mg (61%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3,3-difluoro-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide as a light yellow solid.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[O:7][CH2:8][C:9](=[O:15])[C:10]=2[C:11]([O:13][CH3:14])=[O:12])[CH2:3][CH2:2]1.C(OC)(=O)CC(OC)=O.ClCC(Cl)=O.C1(CN)CC1.[NH:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][N:42]=2)[C:37]([CH:44]=O)=[CH:36]1.N1CCC[C@H]1C(O)=O>C(O)C>[NH:35]1[C:43]2=[N:42][CH:41]=[CH:40][CH:39]=[C:38]2[C:37]([CH:44]=[C:8]2[O:7][C:6]([NH:5][CH2:4][CH:1]3[CH2:3][CH2:2]3)=[C:10]([C:11]([O:13][CH3:14])=[O:12])[C:9]2=[O:15])=[CH:36]1
Reactant: COC(=O)C1=C(NCC2CC2)OCC1=O
Reactant: O=Cc1c[nH]c2ncccc12
Agent: NCC1CC1
Agent: O=C(Cl)CCl
Agent: O=C(O)[C@@H]1CCCN1
Solvent: COC(=O)CC(=O)OC
Solvent: CCO
Product: COC(=O)C1=C(NCC2CC2)OC(=Cc2c[nH]c3ncccc23)C1=O
Temperature: 25 °C
Yield: 13.7 %

Procedure:
To a solution of methyl 2-[(cyclopropylmethyl)amino]-4-oxo-4,5-dihydrofuran-3-carboxylate (0.30 g, 1.4 mmol) which similarly prepared according to the procedure described in the Example 4, First step using dimethyl malonate, chloroacetyl chloride and cyclopropylmethylamine, and 7-azaindole-3-carboxaldehyde (0.21 g, 1.4 mmol) in ethanol (10 mL), L-proline (0.016 g, 0.14 mmol) was added at ambient temperature. The mixture was refluxed for 3 days. Cooled to ambient temperature, the precipitate was collected by filtration, washed with methanol then dried to afford the titled compound as solid (0.065 g, y. 14%).
Reaction SMILES: [Cl-].ClC1[C:28](C)=[C:27]([O:30]C)[CH:26]=C(Cl)C=1C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[O:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1.C([Li])[CH2:39][CH2:40][CH3:41]>O>[C:34]([O:33][CH2:37][CH3:36])(=[O:30])[CH3:35].[CH:40]([O:30][CH:27]([CH3:28])[CH3:26])([CH3:41])[CH3:39]
Reactant: COc1cc(Cl)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(Cl)c1C
Reactant: C1CCOC1
Reactant: [Li]CCCC
Agent: [Cl-]
Solvent: O
Product: CC(C)OC(C)C
Product: CCOC(C)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
(2,6-Dichloro-3-methyl-4-methoxybenzyl) triphenyl phosphonium chloride (3.86 g., 7.7 mmol) was suspended in 50 ml. of tetrahydrofuran in a 100-ml. three-necked, round-bottomed flask fitted with an argon inlet, internal thermometer and septum. n-Butyllithium (2.3 M, 3.6 ml.) was added slowly at -70° C. thereto and the temperature was allowed to rise to about 30° C. until a clear solution was obtained. Methyl 2(E),4(E),6(Z)-3-methyl-6-fluoro-7-formyl-2,4,6-octatrienoate in 5 ml. of tetrahydrofuran was added at -70° C. thereto. The resulting mixture was stirred at 0° C. for 0.5 hours, poured into water and extracted with 200 ml. of ether-ethyl acetate (1:1 parts by volume). The organic layer was washed with 200 ml. of a saturated sodium chloride solution, dried with 50 g. of sodium sulfate, filtered and evaporated. The resulting material was filtered through 80 g. of silica gel with methylene chloride as elutant. The solvent was evaporated and two crystallizations of the residue from 40 ml. of ethyl acetate-isopropyl ether (1:1 parts of volume) gave 1.32 g. (47%) of methyl 2(E),4(E),6(Z),8(E)-3,7-dimethyl-6-fluoro-9-(2,6-dichloro-3-methyl-4-methoxyphenyl)-nona-2,4,6,8-tetraenoate.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([OH:9])[CH:6]=[C:5]([CH:10]([CH3:12])[CH3:11])[C:4]=1[OH:13])[CH3:2].[C:14](Cl)(=[O:16])[CH3:15].C(N(CC)CC)C.CCCCCC.[CH3:31][CH2:32][O:33]C(C)=O>ClCCl>[C:14]([O:13][C:4]1[C:5]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:7]([O:9][C:32](=[O:33])[CH3:31])=[CH:8][C:3]=1[CH2:1][CH3:2])(=[O:16])[CH3:15]
Reactant: CCOC(C)=O
Reactant: CCc1cc(O)cc(C(C)C)c1O
Reactant: CC(=O)Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1cc(OC(C)=O)cc(C(C)C)c1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of K2S2O8 (8.2 g) in 80 mL of water, was added at once a solution of the above 2-ethyl-6-isopropylphenol (2 g, 12.2 mmol in 25 mL 5% NaOH solution). The mixture was stirred for 3 h and extracted with hexane (3×60 mL). The organic extract was stirred with Na2S2SO4 solution (8.5 g, in 100 mL water) for one hour and the layers were separated. The organic layer was dried over Na2S2O4 and concentrated and dried under high vacuum to give 2-ethyl-6-isopropylbenzene-1,4-diol. To a solution of the crude 2-ethyl-6-isopropylbenzene-1,4-diol in dichloromethane (50 mL) was added acetyl chloride (2.9 g, 36 mmol) and then triethylamine (6 g, 60 mmol) slowly at 0° C. The mixture was stirred at room temperature for 2 h and diluted with hexane/EtOAc (4:1). The mixture was filtered and the filtrate was washed with water (3×80 mL) and dried over Na2SO4 and concentrated. The crude product was purified to afford 2-ethyl-6-isopropyl-1,4-phenylene diacetate as a yellow oil (750 mg).