Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([N+:17]([O-:19])=[O:18])([CH2:15][OH:16])[CH2:13][OH:14])[CH:6]=[CH:5]2.C(Cl)Cl.CO[C:25](OC)([CH3:27])[CH3:26].B(F)(F)F.CCOCC>CCOC(C)=O.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([N+:17]([O-:19])=[O:18])[CH2:15][O:16][C:25]([CH3:27])([CH3:26])[O:14][CH2:13]1)[CH:6]=[CH:5]2
Reactant: O=[N+]([O-])C(CO)(CO)c1ccc2cc(Br)ccc2c1
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CC1(C)OCC(c2ccc3cc(Br)ccc3c2)([N+](=O)[O-])CO1
Reaction time: 0.25 h
Yield: 82 %

Procedure:
2-(6-Bromo-naphthalen-2-yl)-2-nitro-propane-1,3-diol (32.6 g, 0.100 mol) was dissolved in methylene chloride (150 mL, 2.3 mol; Acros, anhydrous) and 2,2-dimethoxypropane (180 mL, 1.5 mol; Aldrich), cooled with an ice bath. Boron trifluoride etherate (10.1 mL, 0.0800 mol; Aldrich) was added slowly. The mixture was stirred for 15 min and large amount of solid precipitated. The cooling bath was removed and the mixture was stirred at r.t. for 4 hours. The mixture was quenched with aqueous saturated NaHCO3 (˜600 mL) to pH˜8, extracted with EtOAc (600 mL, 300 mL, 2×100 mL). The EtOAc layer was washed with water, brine, dried over Na2SO4, filtered. The solvent was evaporated to ˜100 mL. The resulted solid product was collected by filtration and the mother liquid was concentrated further to afford the second crop of product. Rf of product=0.4(EtOAc/hexane=1/4). Total product weighed 30.0 g (yield 82%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]2[C:9](=[O:19])[NH:10][C:11]3([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:12]=2[OH:13])[CH:7]=1.[Cl:21][C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][C:23]=1[F:31].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.S([O-])([O-])(=O)=O.[Mg+2]>COCCOC.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([C:8]3[C:9](=[O:19])[NH:10][C:11]4([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)[C:12]=3[OH:13])[CH:7]=2)=[CH:24][C:23]=1[F:31]
Reactant: Cc1ccc(Br)cc1C1=C(O)C2(CCCCC2)NC1=O
Reactant: OB(O)c1ccc(Cl)c(F)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(Cl)c(F)c2)cc1C1=C(O)C2(CCCCC2)NC1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under argon, 36.4 mg (0.05 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium complex were added to 150 mg (0.45 mmol) of the compound from Example 13A in 15 ml of degassed 1,2-dimethoxyethane. The mixture was stirred at room temperature for 5 minutes, and 117 mg (0.67 mmol) of (4-chloro-3-fluorophenyl)boronic acid and a solution of 509 mg (1.56 mmol) of cesium carbonate in 0.9 ml of degassed water was then added. Under microwave irradiation, the reaction mixture was heated at 150° C. for 10 minutes. After cooling, 0.3 ml of concentrated aqueous hydrogen chloride solution were added, magnesium sulfate was added, the mixture was filtered through silica gel, the filter cake was washed with ethyl acetate and the mixture was concentrated. Purification of the crude product by HPLC chromatography (C18 phase, mobile phase: water/acetonitrile gradient/0.1% formic acid) gave 43.7 mg (25% of theory) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11]Cl)(=[O:10])=[O:9])=[CH:6][CH:7]=1.[CH2:13]=[C:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CC#N>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]2[C:14]3([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Reactant: C=C1CCCCC1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC23CCCCC3)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.3 %

Procedure:
To a stirred suspension of dried Chloramine-T (5.10 g, 20.76 mmol) in CH3CN (100 mL) under a nitrogen atmosphere was added methylenecyclohexane (9.98 g, 104 mmol). Phenyltrimethylammonium tribromide (7.80 g, 20.76 mmol) was added in three portions over 10 min. The mixture was stirred at room temperature for 16 hours. The solvent was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was dried over Na2SO4 and the solvent was evaporated. The residue was chromatographed on silica gel with an ISCO Combiflash using EtOAc/hexanes (5-30% gradient) to afford the title compound as a white solid (2.66 g).
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15](=[O:31])[C:16]([OH:30])=[CH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[NH:22][CH:21]=2)=[O:19])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:34][N:35]([CH3:39])[C:36](Cl)=[O:37].[Cl-].[NH4+]>C1COCC1>[C:1]1([CH:7]([O:14][C:15](=[O:31])[C:16]([OH:30])=[CH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([C:36](=[O:37])[N:35]([CH3:39])[CH3:34])[CH:21]=2)=[O:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)C(=O)Cl
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C(O)=CC(=O)c1c[nH]c2ccc(Cl)cc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)OC(c2ccccc2)c2ccccc2)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 77.5 %

Procedure:
To a solution of 0.432 g (1 mmol) of diphenylmethyl ester obtained in Example 91 in THF (5 ml) was added under ice-cooling, 88 mg (2.2 mmol) of sodium hydride (60% dispersion in mineral oil). The mixture was stirred for 30 minutes at room temperature. Subsequently, to the mixture was added 110 μl (1.2 mmol) of dimethylcarbamoyl chloride under ice-cooling and stirred for 1 hour at room temperature. The reaction mixture was poured into aqueous ammonium chloride and extracted with ethyl acetate. The extract was washed with water and dried. The solvent was removed and the residue was crystallized from ether. The crystal was collected by filtration and washed with ether to give 0.39 g of the titled compound. Yield: 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[CH2:9]([O:11][C:12](=[O:26])[CH:13]([C:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:14][C:15](=O)[CH3:16])[CH3:10].CC1C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:9]([O:11][C:12]([C:13]1[CH:14]=[C:15]([CH3:16])[N:5]([C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[C:18]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:26])[CH3:10]
Reactant: Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(CC(C)=O)C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(C)n(-c2cccc(Cl)c2)c1-c1ccccc1

Procedure:
m-Chloroaniline (5 mmol, 0.6 g), 2-benzoyl-4-oxo-pentanoic acid ethyl ester (5 mmol, 1.2 g), and tosic acid (0.1 g) were combined in ethanol, then heated under reflux. Upon completion of the reaction, the crude solid was recrystallized from ethanol to provide the named product (m.p. 93.2° C.-94.6° C.).
Reaction SMILES: [CH3:1][C:2]([CH3:13])([O:4][C:5]([NH:7][C@H:8]([C:10]([OH:12])=O)[CH3:9])=[O:6])[CH3:3].CN1CCOCC1.C(OC(Cl)=O)C(C)C.Cl.[CH3:30][NH:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].CNCC(O)=O>C(OCC)(=O)C.CCCCCC.C(Cl)(Cl)Cl>[CH3:13][C:2]([CH3:1])([O:4][C:5]([NH:7][C@H:8]([C:10]([N:31]([CH3:30])[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:12])[CH3:9])=[O:6])[CH3:3]
Reactant: CCOC(=O)CNC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CNCC(=O)O
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Solvent: CCCCCC
Product: CCOC(=O)CN(C)C(=O)[C@H](C)NC(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
A mixture of N-[(1,1-dimethylethoxy)-carbonyl]-L-alanine (2.48 g., 13.1 mmole) and dry chloroform (20 ml.) at -20° under argon is treated with N-methylmorpholine (1.47 ml., 1.0 eq.) and isobutylchloroformate (1.8 ml., 1.0 eq.) and stirred for 20 minutes. N-Methylglycine, ethyl ester, hydrochloride (2.0 g., 1.0 eq.) and N-methyl morpholine (1.47 ml.) are added. After one hour, the ice-bath is removed and the reaction mixture is stirred for an additional 3 hours. The mixture is then partitioned between ethyl acetate/5% potassium bisulfate, and the organic phase is washed with 5% potassium bisulfate, saturated sodium bicarbonate, dried (Na2SO4), and evaporated to give 3.7 g. of crude N-[N-(1,1-dimethylethoxy)carbonyl]-L-alanyl]-N-methylglycine, ether ester as an oil. Tlc (ethyl acetate/hexane, 1:2) shows a major spot at Rf =0.22.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[NH:10][CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[CH:16]=2)[C:3]1=[O:25].[C:26]([C:28]1[CH:33]=[CH:32][C:31](I)=[CH:30][CH:29]=1)#[N:27].P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>O1CCOCC1.[Cu]I>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[N:10]([C:31]3[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=3)[CH:11]=[CH:12][CH:13]=2)=[C:5]([CH3:14])[N:4]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[CH:16]=2)[C:3]1=[O:25]
Reactant: Cc1c(-c2ccc[nH]2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: N#Cc1ccc(I)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1c(-c2cccn2-c2ccc(C#N)cc2)c(=O)n(C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 31.8 %

Procedure:
A solution of 3,6-dimethyl-5(1H-pyrrol-2-yl)-1-(3-trifluoromethylphenyl)pyrimidin-2,4(1H,3H)-dione (prepared in Reference Example 201) (20.0 mg), 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) in 1,4-dioxane (2.0 ml) was stirred with heating under reflux for fifteen hours. Thereto were added 4-cyanoiodobenzene (39.4 mg), copper(I) iodide (1.0 mg), cyclohexyldiamine (0.6 mg) and potassium phosphate (36.4 mg) and the resulting mixture was stirred with heating under reflux for four hours. To the reaction mixture was added water (10 ml) and the resulting mixture was extracted with ethyl acetate (10 ml×2). The organic layer was washed with saturated saline (20 ml), dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate) and further purified by silica gel column chromatography (eluent: hexane/acetone/methanol) to afford 4-[2-[3,6-dimethyl-2,4-dioxo-1-(3-trifluoromethylphenyl)-1,2,3,4-tetrahydropyrimidin-5-yl]-1H-pyrrol-1-yl]benzonitrile (8.2 mg).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([CH3:17])[CH:3]=1.Br[CH2:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(Cl)Cl.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:10]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:20][CH2:19]2)=[O:16])=[C:4]([CH3:17])[CH:3]=1
Reactant: BrCCBr
Reactant: CCOC(=O)CC(=O)Nc1ccc(Br)cc1C
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccc(Br)cc2C)CC1
Reaction time: 192 h
Yield: 75.9 %

Procedure:
Into a 100 milliliter three-necked round-bottom reaction flask equipped with a mechanical stirrer, thermometer and nitrogen inlet and outlet was added 5.0 grams (17.0 mmol) of ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate prepared as in Example A, 1.7 milliliters (20.0 mmol) of 1,2-dibromoethane and 0.33 grams (0.83 mmol) of Aliquat® 336 in 25 milliliters of methylene chloride. The resulting solution was stirred at ambient temperature under a nitrogen atmosphere as 0.2 milliliters of water and 4.60 grams (33.0 mmol) of potassium carbonate was added to the reaction flask. The resulting mixture was stirred for a total of 8 days and the reaction was monitored by high pressure liquid chromatography throughout this period (after one day, an additional 0.2 milliliters of water was added and, after 2 days, an additional 0.33 grams (0.83 mmol) of Aliquat® 336 and 1.7 milliliters (20.0 mmol) of 1,2-dibromoethane were added). After the 8 day reaction period, the reaction mixture was diluted with 125 milliliters of water and extracted with methylene chloride. The combined organic extracts were washed with 125 milliliters of 3N aqueous HCl and 125 milliliters of saturated aqueous sodium bicarbonate. After drying over anhydrous magnesium sulfate and evaporation, a yellow solid residue was obtained which was flash chromatographed on silica gel with an 85:15 volume/volume hexane-ethyl acetate eluent to give 4.20 grams (12.9 mmol) of ethyl 1-(4-bromo-2-methylphenylaminocarbonyl)cyclopropanecarboxylate as a pale yellow solid having a melting point of 87.5° C.-89.0° C. The total yield was 80 percent based on a 96.7 weight percent assay of the starting ethyl 3-[(4-bromo-2-methylphenyl)amino]-3-oxopropanoate. NMR analysis of the product indicated the following:
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[N:8]([C@@H:11]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=1)([O-])=O.N.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O1CCOCC1.O.[Cl-].[Na+].O>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[N:8]([C@@H:11]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH:9]=[N:10][C:6]=2[CH:5]=1
Reactant: COC(=O)C[C@H](c1ccccc1)n1cnc2cc([N+](=O)[O-])ccc21
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Cl-]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)C[C@H](c1ccccc1)n1cnc2cc(N)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude mixture of methyl (3R)-3-(5-nitro-1H-benzimidazol-1-yl)-3-phenylpropanoate and the corresponding 2-ethoxyethanol ester (714 mg, ca. 2.2 mmol) in a mixture of 1,4-dioxane (10 mL) and water (10 mL) was added concentrated ammonia solution (0.3 mL) and sodium dithionite (3.06 g, 17.6 mmol). The solution was stirred at room temperature for 3 hours, then diluted with brine, and extracted with ethyl acetate. The combined ethyl acetate extracts were dried over anhydrous magnesium sulfate, filtered, and evaporated in vacuo. The residue was purified by flash column chromatography on silica gel, gradient eluting with a mixture of dichloromethane and methanol (95:5, then 9:1), to afford a mixture of the title compound and the corresponding 2-ethoxyethanol ester, which was used directly without any additional purification. [LCMS (Method C, Mobile Phase I) RT=1.95 mins, MH+ 296 (Me-ester) and RT=2.13 mins, MH+ 354 (EtOCH2CH2-ester)].
Reaction SMILES: C(=O)([O-])[O-].[Ca+2:5].[Ca].[OH-].[Ca+2].[OH-].[B:10]([OH:13])([OH:12])[OH:11]>CCCCCC.C1(C)C(C)=CC=CC=1>[B:10]([O-:13])([O-:12])[O-:11].[Ca+2:5].[B:10]([O-:13])([O-:12])[O-:11].[Ca+2:5].[Ca+2:5]
Reactant: OB(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Agent: [Ca]
Solvent: CCCCCC
Solvent: Cc1ccccc1C
Product: [O-]B([O-])[O-]
Temperature: 60 °C

Procedure:
A solution or 323.2 g of a calcium carbonate overbased alkylsalicylate (TBN 205 mgKOH/g, calcium content; 8.5 wt. %) (the calcium content of this starting material being the same as the total calcium content of the starting materials (A) and (B) in Example 1 or in each of Comparative Examples 1 and 2) and 400 g of xylene were put in a 1000-ml four-necked flask fitted with a condenser and heated to 60° C. while agitating. To this mixture was added 43.4 g of orthoboric acid, and the resulting mixture was heated up to a refluxing temperature (66° C.) under agitation and reacted for 4 hours to obtain a reaction product. The reaction product was further heated to 140° C. for 1.5 hours to distill out the reaction water and xylene. Finally the reaction product was diluted twofold with hexane and filtered to remove any residual solids present, and the hexane was distilled out to obtain a calcium borate overbased alkylsalicylate.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13].Cl[CH2:21][CH2:22][O:23][CH2:24][CH2:25]Cl.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8]([N:10]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:7]=[CH:6][C:5]=1[O:11][Si:12]([C:15]([CH3:16])([CH3:18])[CH3:17])([CH3:13])[CH3:14]
Reactant: COC(=O)c1cc(N)ccc1O[Si](C)(C)C(C)(C)C
Reactant: ClCCOCCCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cc(N2CCOCC2)ccc1O[Si](C)(C)C(C)(C)C
Yield: 17.8 %

Procedure:
A solution of 5-amino-2-(tert-butyl-dimethyl-silanyloxy)benzoic acid methyl ester (4.5 g, 16 mmol), 2-chloroethyl ether (1.9 mL, 16.2 mmol), and diisopropylethylamine (5.6 mL, 32.1 mmol) in DMF (50 mL) was stirred at 100° C. for 48 h. The reaction mixture was poured into 10% aqueous NaHCO3 (100 mL) and extracted with ether (200 mL). The organic layer was washed with water (5×100 mL) and brine (100 mL), dried over magnesium sulfate (MgSO4), and concentrated to a red syrup. The residue was purified by flash chromatography (silica gel, 4×15 cm, eluted with 9/1 hexanes/EtOAc) to yield 2-(tert-butyl-dimethyl-silanyloxy)-5-morpholin-4-yl-benzoic acid methyl ester (1.0 g, 18%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][N:5]([C:12]1[N:13]=[C:14]3[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]3=[N:16][CH:17]=1)[C:6]2=[O:11].C(N(CC)CC)C.[NH2:39][C@H:40]([CH:49]1[CH2:51][CH2:50]1)[C:41]([N:43]1[CH2:46][CH:45]([C:47]#[N:48])[CH2:44]1)=[O:42].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[C:47]([CH:45]1[CH2:46][N:43]([C:41](=[O:42])[C@H:40]([NH:39][C:21]([C:20]2[C:14]3[C:15](=[N:16][CH:17]=[C:12]([N:5]4[CH2:4][C:3]5[C:7](=[CH:8][CH:9]=[CH:10][C:2]=5[Cl:1])[C:6]4=[O:11])[N:13]=3)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:29])([CH3:31])[CH3:30])[CH:19]=2)=[O:23])[CH:49]2[CH2:50][CH2:51]2)[CH2:44]1)#[N:48]
Reactant: N#CC1CN(C(=O)[C@H](N)C2CC2)C1
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CC(C#N)C2)C2CC2)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Reaction time: 16 h
Yield: 39.8 %

Procedure:
To a solution of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (80 mg, 0.17 mmol) in DMF (2.4 mL) was added triethylamine (73 μl, 0.52 mmol), 1-((R)-2-amino-2-cyclopropyl-acetyl)-azetidine-3-carbonitrile (31.2 mg, 0.17 mmol) and PyBOP (109 mg, 0.21 mmol) at room temperature. The reaction mixture was stirred for 16 h at the same temperature then poured into EtOAc (50 mL) and washed with water (4×50 mL). The organic extracts were dried (Na2SO4) and evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 23 g, Hex:EtOAc, 0% to 6:4, in 35 min) to afford 42 mg (39%) of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.
Reaction SMILES: [S:1]([C:5]1[CH:11]=[C:10]([SH:12])[C:9]([Cl:13])=[CH:8][C:6]=1[NH2:7])(=[O:4])(=[O:3])[NH2:2].[C:14](Cl)(=O)[CH3:15]>O1CCOCC1>[CH3:14][C:15]1[NH:2][S:1](=[O:3])(=[O:4])[C:5]2[CH:11]=[C:10]([SH:12])[C:9]([Cl:13])=[CH:8][C:6]=2[N:7]=1
Reactant: Nc1cc(Cl)c(S)cc1S(N)(=O)=O
Reactant: CC(=O)Cl
Solvent: C1COCCO1
Product: CC1=Nc2cc(Cl)c(S)cc2S(=O)(=O)N1

Procedure:
A mixture of 2-sulfamoyl-4-mercapto-5-chloroaniline, prepared as described in Example 13, Step A-3 (0.02 mole) and acetyl chloride (0.022 mole) in 75 ml. of dioxane is heated under reflux for 24 hours. The solution is concentrated to dryness in vacuo and the residue dissolved in 75 ml. of ethanol and treated with 75 ml. of concentrated ammonium hydroxide in the cold. Thereafter the solution is heated under reflux for three hours and concentrated to dryness in vacuo. The residue is suspended in 100 ml. of water acidified with hydrochloric acid and the product, following recrystallization from dimethylformamide-water, melts at 304°-305° C.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([OH:32])=O)[S:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:33]1[CH2:38][CH2:37][CH:36]([N:39]2[C:47]3[C:42](=[N:43][CH:44]=[CH:45][CH:46]=3)[NH:41][C:40]2=[O:48])[CH2:35][CH2:34]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O.O>[N:1]1([CH2:7][CH2:8][NH:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH:17]2[N:21]([CH2:22][CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:20](=[O:28])[C@H:19]([CH2:29][C:30]([N:33]3[CH2:34][CH2:35][CH:36]([N:39]4[C:47]5[C:42](=[N:43][CH:44]=[CH:45][CH:46]=5)[NH:41][C:40]4=[O:48])[CH2:37][CH2:38]3)=[O:32])[S:18]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: CC(C)(C)CCN1C(=O)[C@H](CC(=O)O)SC1c1cccc(F)c1NCCN1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)CCN1C(=O)[C@H](CC(=O)N2CCC(n3c(=O)[nH]c4ncccc43)CC2)SC1c1cccc(F)c1NCCN1CCCCC1

Procedure:
2-((5S)-2-(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetic acid (319.0 mg, 0.685 mmol), 1-(piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (398.9 mg, 1.370 mmol), EDC (262.6 mg, 1.370 mmol), HOBt (209.8 mg, 1.370 mmol) and DIEA (354.1 mg, 477.2 μL, 2.740 mmol) in DMF (4 mL) were stirred at RT overnight. The mixture was transferred to a separatory funnel with water and EtOAc. The aq. layer was extracted with EtOAc, the organics washed with sat bicarb, brine, dried over Na2SO4, concentrated and purified by reverse phase semiprep chromatography (CH3CN/water) to give 1-(1-(2-((5S)-2-(2-(2-(piperidin-1-yl)ethylamino)-3-fluorophenyl)-3-(3,3-dimethylbutyl)-4-oxothiazolidin-5-yl)acetyl)piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one. LC/MS: 666.37 (M+1) Rt=2.06 min (10-90% 3/5 min (grad/run) w/formic acid).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([NH:15][C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[CH2:8]([N:15]([C@H:16]([CH2:20][CH3:21])[C@H:17]([OH:19])[CH3:18])[C:24](=[O:25])[CH2:23][Cl:22])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C(Cl)CCl
Reactant: CC[C@@H](NCc1ccccc1)[C@@H](C)O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC[C@H]([C@@H](C)O)N(Cc1ccccc1)C(=O)CCl
Temperature: -40 °C
Reaction time: 1 h

Procedure:
Triethylamine (0.43 mL, 3.4 mmol) was added to a −40° C. solution of (2R,3R)-3-(benzylamino)pentan-2-ol (220 mg, 1.1 mmol) in dichloromethane (100 mL), followed by the addition of 2-chloroacetyl chloride (0.10 mL, 1.1 mmol) dropwise. The reaction mixture was stirred at −40° C. for 1 hour and then quenched with saturated NaHCO3 solution. The layers were separated, and the aqueous layer was extracted with dichloromethane (3×10 mL). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. Purification of the residue on a silica gel column (0 to 50% EtOAc/hexanes) afforded N-benzyl-2-chloro-N-((2R,3R)-2-hydroxypentan-3-yl)acetamide. MS APCl calc'd for C14H20ClNO2 [M+H]+ 270. found 270.