Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][OH:36])=[CH:30][CH:29]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].C([O-])([O-])=O.[K+].[K+].[CH3:44][C:45]([CH3:47])=O>>[CH3:1][C:2]1[NH:3][C:4]([CH3:37])=[C:5]([C:21]([O:23][CH2:24][CH2:25][CH2:26][O:27][C:28]2[CH:29]=[CH:30][C:31]([CH2:34][CH2:35][O:36][CH2:44][CH2:45][CH3:47])=[CH:32][CH:33]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCCOc2ccc(CCO)cc2)C1c1cccc([N+](=O)[O-])c1
Reactant: CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCOCCc1ccc(OCCCOC(=O)C2=C(C)NC(C)=C(C(=O)OC)C2c2cccc([N+](=O)[O-])c2)cc1

Procedure:
A solution of 2,6-dimethyl-3-carbomethoxy-4-(3-nitrophenyl)-5-(3-[4-(2-hydroxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine (125 g, 0.252 moles) in acetone (700 mL) is stirred at reflux for 8 hours with K2CO3 (48 g, 0.35 mol) and n-bromopropane (61.5 g, 0.5 mol). After evaporation of the solvent, the crude product is purified by flash chromatography (solvent=93:7 CH2Cl2 :acetone) to yield 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(3-[4-(2-propoxyethyl)phenoxy]propoxycarbonyl)-1,4-dihydropyridine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1.[Cl-].[NH4+].C1C=CC2N(O)N=[N:42]C=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[Cl:1][C:2]1[C:3]([CH3:33])=[C:4]([N:8]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(=[O:24])=[O:25])[CH2:9][C:10]([NH:12][CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH2:42])=[O:20])=[CH:21][CH:22]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: On1nnc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(=O)O)cc2)c2cccc(Cl)c2C)cc1
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)N(CC(=O)NCc2ccc(C(N)=O)cc2)c2cccc(Cl)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.2 %

Procedure:
185 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid, 25 mg of ammonium chloride, and 62 mg of HOBt were dissolved in 2.00 mL of DMF, and 78 mg of WSC was added thereto, followed by stirring at room temperature overnight. To the reaction liquid was added water, followed by extraction with ethyl acetate, and the organic layer was washed with water, an aqueous sodium hydrogen carbonate solution, and water, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:80 to 0:100) to obtain a product, which was recrystallized from ethanol/water (95:5) to obtain 89 mg of 4-[({N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycyl}amino)methyl]benzoic acid amide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]([C:26]1[CH:27]=[C:28](OB(O)O)[CH:29]=[CH:30][CH:31]=1)=[O:25]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:14][O:15][CH:16]3[CH2:21][CH2:20][CH2:19][N:18]([C:30]4[CH:31]=[C:26]([CH:27]=[CH:28][CH:29]=4)[C:24]([O:23][CH3:22])=[O:25])[CH2:17]3)=[C:11]([CH3:13])[N:12]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)c1cccc(OB(O)O)c1
Reactant: Cc1nc(-c2ccc(Cl)cc2)sc1COC1CCCNC1
Product: COC(=O)c1cccc(N2CCCC(OCc3sc(-c4ccc(Cl)cc4)nc3C)C2)c1
Yield: 71.8 %

Procedure:
Using 3-[[2-(4-chlorophenyl)-4-methylthiazol-5-yl]methoxy]piperidine (60.2 mg, 0.186 mmol) and 3-(methoxycarbonyl)phenylboric acid (66.9 mg, 0.372 mmol), the same procedure was followed as in Example 2 to give 61.0 mg (72%) of the desired compound as a colorless oil.
Reaction SMILES: CO[CH:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[NH:5][C:4]1=[O:29].Br.[OH2:31]>>[OH:31][C:7]1[CH:8]=[CH:9][C:10]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:18][CH2:17]2)=[C:11]2[C:6]=1[NH:5][C:4](=[O:29])[CH2:3][CH2:12]2
Reactant: O
Reactant: COC1Cc2c(cccc2C(=O)CCN2CCN(c3ccccc3)CC2)NC1=O
Agent: Br
Product: O=C1CCc2c(C(=O)CCN3CCN(c4ccccc4)CC3)ccc(O)c2N1

Procedure:
To 19.7 g of methoxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril was added 300 ml of 47%-hydrobromic acid and the mixture was refluxed for 18 hours. The reaction mixture was concentrated under a reduced pressure to dryness. Then to the residue thus obtained was added water and again concentrated under a reduced pressure to dryness. Acetone was added to the crystalline residue and collected by filtration and were recrystallize from methanol. The crystals were suspended in 500 ml of water and the suspension was neutralized with 5%-sodium hydroxide aqueous solution and crystalline precipitates thus formed were collected by filtration and were washed with water. 17.1 Grams of 8-hydroxy-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril was obtained in amorphous-like crystals. Melting point: 287°-291° C.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([C:10]1[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=1)=[O:9].[F:17][CH:18]([F:30])[O:19][C:20]1[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:30][CH:18]([F:17])[O:19][C:20]1[CH:21]=[CH:22][C:23]([S:26]([N:6]2[CH2:5][CH2:4][N:3]([C:8]([C:10]3[CH:11]=[N:12][C:13]([CH3:16])=[CH:14][CH:15]=3)=[O:9])[C@@H:2]([CH3:1])[CH2:7]2)(=[O:28])=[O:27])=[CH:24][CH:25]=1
Reactant: Cc1ccc(C(=O)N2CCNC[C@@H]2C)cn1
Reactant: O=S(=O)(Cl)c1ccc(OC(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N2CCN(S(=O)(=O)c3ccc(OC(F)F)cc3)C[C@@H]2C)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 37.1 %

Procedure:
To a solution of (2S)-2-methyl-1-[(6-methyl-3-pyridinyl)carbonyl]piperazine (Description 13) (100 mg, 0.456 mmol) in DMF (10 ml) was added 4-[(difluoromethyl)oxy]benzenesulfonyl chloride (133 mg, 0.547 mmol). Finally DIPEA (0.239 ml, 1.368 mmol) was added and the reaction mixture was stirred at room temperature for 20 h. Solvent was removed by evaporation, the residue was dissolved in ethyl acetate and the solution washed with saturated aqueous NaHCO3. The organic layer was dried over MgSO4, filtered and evaporated to dryness and the residue was purified by MDAP to yield the title compound (72 mg) as a white powder.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22]>ClCCl.N1C=CC=CC=1>[CH3:23][C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:29][C:28]2[CH:30]=[CH:31][C:25]([C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:26][CH:27]=2)=[O:13])=[CH:30][CH:31]=1)([CH3:24])[CH3:22]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: CC(C)(C)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2SSc2ccccc2C(=O)Nc2ccc(C(C)(C)C)cc2)cc1
Temperature: 23 °C
Reaction time: 18 h
Yield: 12.1 %

Procedure:
A solution of 2,2'-dithiobisbenzoyl chloride (1.20 g, 3.50 mmol) in 25 mL of dichloromethane was added to a solution of 4-tert-butylaniline (1.04 g, 6.99 mmol) in 8 mL of pyridine at 23° C. The reaction mixture was stirred for 18 hours at 23° C. under nitrogen atmosphere. The mixture was concentrated, the residue triturated with 5% aqueous HCl, and the resulting solid was collected by filtration and washed with water to yield the crude product. The crude material was recrystallized from ethyl ether-ethanol to yield 0.24 g of the title compound, mp 135°-138° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[NH:10][C:9]2=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1.S(OC)(O[CH3:27])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[CH:12]=[C:11]([C:15]([F:17])([F:18])[F:16])[N:10]([CH3:27])[C:9]2=[O:19])=[C:4]([N+:20]([O-:22])=[O:21])[CH:3]=1
Reactant: COS(=O)(=O)OC
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc(Cl)cc2[N+](=O)[O-])c1=O
Temperature: 55 °C
Reaction time: 8 h
Yield: 73.6 %

Procedure:
A mixture of 3-(4-chloro-2-nitrophenyl)-6-trifluoromethyl-2,4(1H, 3H)-pyrimidinedione (3 g), dimethyl sulfate (1.7 g) and potassium carbonate (1.85 g) in N,N-dimethylformamide (100 ml) was stirred at 55° C. overnight. The resulting mixture was allowed to cool to ambient temperature and filtered through Celite to remove unsoluble precipitate. The filtrate was diluted with a mixed solvent of ethyl acetate and hexane (1:1, 200 ml), washed with brine (×2) and dried over anhydrous sodium sulfate. After removal of the solvent, the residue was solidified. The yellow solid was recrystallized from ethyl acetate and hexane to give desired compound (2.3 g).
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:6]=[C:7]([N:16]=[C:17]=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][S:12]([CH3:15])(=[O:14])=[O:13]>ClC1C=CC=CC=1>[Cl:4][C:5]1[CH:6]=[C:7]([NH:16][C:17]([N:2]([CH3:3])[CH3:1])=[O:18])[CH:8]=[CH:9][C:10]=1[O:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: CS(=O)(=O)Oc1ccc(N=C=O)cc1Cl
Reactant: CNC
Solvent: Clc1ccccc1
Product: CN(C)C(=O)Nc1ccc(OS(C)(=O)=O)c(Cl)c1

Procedure:
120 g of dimethylamine were introduced into a solution of 620 g of 3-chloro-4-methylsulfonyloxyphenylisocyanate (alternative name: methanesulfonic acid 2-chloro-4-isocyanatophenyl ester) in 2.5 liters of chlorobenzene at a temperature of 5°-22°C, whilst cooling. The crystals which thereupon formed were filtered off and dried. Yield: 714 g of N-(3-chloro-4-methylsulfonyloxyphenyl)-N',N'-dimethylurea, of melting point 130°-132°C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.Cl[Si:11]1([CH2:16][Cl:17])[CH2:15][CH2:14][CH2:13][CH2:12]1>>[Cl:17][CH2:16][Si:11]1([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: ClC[Si]1(Cl)CCCC1
Reactant: Fc1ccc([Mg]Br)cc1
Product: Fc1ccc([Si]2(CCl)CCCC2)cc1

Procedure:
In the same apparatus and procedures as Example 1 was reacted 62 ml of 4-fluorophenylmagnesiumbromide solution (1.0 M in diethylether) with 1-chloro-1-chloromethyl-1-silacyclopentane prepared from the above procedure i) for 1 hr at 60° C. In the same method as Example 1 was treated the reaction product to give 10.34 g of 1-chloromethyl-1-(4-fluorophenyl)-1-silacyclopentane (b.p. 98° C./0.5 mmHg).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([Cl:10])[N:5]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>CC(C)=O>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([NH:20][CH:17]([CH3:19])[CH3:18])[N:3]=[C:4]([NH:11][C:12]([C:15]#[N:16])([CH3:14])[CH3:13])[N:5]=1
Reactant: CC(C)(C#N)Nc1nc(Cl)c(C#N)c(Cl)n1
Reactant: CC(C)N
Solvent: CC(C)=O
Product: CC(C)Nc1nc(NC(C)(C)C#N)nc(Cl)c1C#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 48.6 %

Procedure:
To a stirred solution of 5.1 grams of 4,6-dichloro-2-(1-cyano-1-methylethylamino)-5-pyrimidinecarbonitrile in 100 ml of acetone, 2.3 grams of isopropylamine was added dropwise. The reaction mixture was then stirred at room temperature for 16 hours. The acetone was removed under reduced pressure, and the reaction mixture was extracted with a mixture of diethyl ether and water. The organic layer was separated and dried over magnesium sulfate. The solution was filtered, and the filtrate was evaporated under reduced pressure, yielding a residue. The residue was recrystallized from methylcyclohexane to give 2.7 grams of 4-chloro-2-(1-cyano-1-methylethylamino)-6-isopropylamino-5-pyrimidinecarbonitrile; mp, 144°-147°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:26][C:27](=[NH:33])[N:28]2[CH:32]=[CH:31][CH:30]=N2)=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1.NCCC[OH:38].C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]([CH2:23][C:24]([NH:26][C:27]([NH:28][CH2:32][CH2:31][CH2:30][OH:38])=[NH:33])=[O:25])=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH3:22])=[CH:15][CH:14]=2)[S:11][CH:12]=1
Reactant: NCCCO
Reactant: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)n2cccn2)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCOc1ccc(-c2scc(-c3ccccc3Cl)c2CC(=O)NC(=N)NCCCO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[imino(1H-pyrazol-1-yl)methyl]acetamide (0.240 g, 0.50 mmol) in CH2Cl2 (5 mL) was added 3-aminopropanol (0.112 g, 0.12 mL, 1.50 mmol) and diisopropyl ethylamine (0.193 g, 0.26 mL, 1.50 mmol). The solution was stirred overnight at RT. The solvent was removed and the product purified by flash chromatography (15:1 CHCl3:MeOH) to yield 2-[4-(2-chlorophenyl)-2-(4-propoxyphenyl)thien-3-yl]-N-[[(3-hydroxypropyl)amino](imino)methyl]acetamide as a white solid. mp 49-50° C.; MS (ES) m/z 486.09 ([M+H]+). MS (ES) m/z 971.26 ([2M+H]+). Anal. Calcd for C25H28ClN3O3S.0.10 C6H14: C, 62.16; H, 5.99; N, 8.49. Found: C, 62.41; H, 5.70; N, 8.45.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1.C1C(=O)N([Cl:25])C(=O)C1>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([C:9]2[NH:10][C:11]3[C:16]([C:17]=2[Cl:25])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH:3]=1
Reactant: Oc1ccc(Br)cc1-c1cc2ccccc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: Oc1ccc(Br)cc1-c1[nH]c2ccccc2c1Cl
Temperature: 25 °C
Yield: 97.4 %

Procedure:
To a solution of 4-bromo-2-(1H-indol-2-yl)phenol (100 mg, 0.35 mmol) in DMF (1 mL) was added NCS (46 mg, 0.35 mmol), it was allowed to stir at room temperature until LCMS showed the starting material was consumed completely. The reaction solution was extracted with EtOAc, and the combined organic layers were washed with H2O (3×10 mL), brine and dried over Na2SO4. The solvent was removed and the crude product was purified using prep-TLC to provide the desired product of 4-bromo-2-(3-chloro-1H-indol-2-yl)phenol (110 mg, yield: 98.2%). 1H-NMR (CDCl3, 400 MHz) δ 9.25 (s, 1H), 7.80 (d, J=2.4 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.40˜7.43 (m, 1H), 7.20˜7.30 (m, 2H), 7.12 (t, J=4.0 Hz, 1H), 6.86 (t, J=6.0 Hz, 1H), 5.93 (s, 1H). MS (M+H)+: 322/324.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH3:10].[Li]C(C)(C)C.[B:16](OC)([O:19]C)[O:17]C>C1COCC1>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([B:16]([OH:19])[OH:17])=[C:3]([O:9][CH3:10])[CH:4]=1
Reactant: COB(OC)OC
Reactant: COc1cc(Cl)ccc1Br
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(Cl)ccc1B(O)O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 89.4 %

Procedure:
4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester: To a solution of 2-bromo-5-chloroanisole (4.43 g, 20 mmol) in dry THF (100 mL) at −78° C. was added dropwise t-BuLi (14.1 mL, 1.7 M, 23.97 mmol). The mixture was stirred for 10 min at −78° C. and trimethyl borate (2.23 mL, 20 mmol) was added. The cooling bath was removed and the mixture was stirred for 30 min from −78° C. to room temperature and then for 3 h with a water bath. Hydrochloric acid (6N, 8 mL) and brine were added. The mixture was extracted with ethyl acetate, dried and evaporated to give 4-chloro-2-methoxyphenylboronic acid as a brown solid (3.33 g, 17.88 mmol) in 89.4% yield. This boronic acid was mixed with ethylene glycol (1.1 g, 17.88 mmol) and toluene (150 mL). The mixture was refluxed for 2 h under N2 with the help of a Dean-Stark trap to remove water generated. After being cooled to room temperature, the solution was transferred to another dry flask and rotary evaporated to provide 4-Chloro-2-methoxyphenylboronic acid ethylene glycol ester as a brown liquid (3.6 g, 16.97 mmol) in 84.8% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8](O)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:13][N:14](C=O)[CH3:15].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.CCN(C(C)C)C(C)C>O>[CH3:13][N:14]([CH3:15])[C:8](=[O:9])[C:7]1[CH:11]=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: CN(C)C=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 99 %

Procedure:
To a solution of 4-nitro-benzoic acid (20 g, 0.1196 mol) in DMF (300 mL) N,N-dimethylamine hydrochloride (11.7 g, 0.1436 mol), HOBt (20.9 g, 0.1554 mol), EDC.HCl (34.3 g, 0.1794 mol) and DIPEA (30.91 g, 0.2392 mol) were added. The reaction mixture was stirred at room temperature for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3×500 mL). The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound [23.0 g, 99%]; LC-MS (ESI): Calculated mass: 194.1; Observed mass: 195.1 [M+H]+ (RT: 1.70 min).
Reaction SMILES: C([CH:8]1[CH2:13][CH2:12][CH2:11][NH:10][C:9]1=O)(OC(C)(C)C)=O.[NH2:15][O:16][CH:17]1[CH2:22][CH2:21][N:20]([C:23]([O:25][CH:26]([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>C(O)C>[CH:26]([O:25][C:23]([N:20]1[CH2:19][CH2:18][CH:17]([O:16]/[N:15]=[C:8]2\[CH2:9][NH:10][CH2:11][CH2:12][CH2:13]\2)[CH2:22][CH2:21]1)=[O:24])([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)C1CCCNC1=O
Reactant: CC(C)OC(=O)N1CCC(ON)CC1
Solvent: CCO
Product: CC(C)OC(=O)N1CCC(O/N=C2/CCCNC2)CC1
Temperature: 65 °C
Reaction time: 0.75 h

Procedure:
3-Boc-piperidinone (0.83 mmol) and NaOAc.3H2O (30 mg) were combined in 1 mL of ethanol and heated to 65° C. for 15 minutes. 2b (167 mg, 0.83 mmol) was added and the mixture was heated at 65° C. for 18 h. The mixture was concentrated, taken up with DCM (5 mL), washed with aqueous NaHCO3 (5 mL) and the organic layer was separated and treated with TFA (5 mL). The mixture was stirred at room temperature for 45 minutes, concentrated, diluted with NaHCO3 (8 mL) and extracted with EtOAc (2×5 mL). The extracts were dried and concentrated to afford the crude 61a: LC-MS 284.2 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[F:15][C:16]([F:47])([F:46])[C:17]1[CH:18]=[C:19]([CH:39]=[C:40]([C:42]([F:45])([F:44])[F:43])[CH:41]=1)[C:20]([N:22]([CH:24]([CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1)[CH2:25][C:26](O)=[O:27])[CH3:23])=[O:21]>ClCCl>[C:2]1([NH:1][C:26](=[O:27])[CH2:25][CH:24]([N:22]([C:20](=[O:21])[C:19]2[CH:39]=[C:40]([C:42]([F:43])([F:44])[F:45])[CH:41]=[C:17]([C:16]([F:46])([F:15])[F:47])[CH:18]=2)[CH3:23])[CH2:29][C:30]2[C:38]3[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:32][CH:31]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)O)Cc1c[nH]c2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(CC(=O)Nc1ccccc1)Cc1c[nH]c2ccccc12
Reaction time: 24 h

Procedure:
Aniline (8.3 mg, 1.2 eq) is placed in dichloromethane (0.5 ml), and triethylamine (52 μl, 5 eq) and 3-[N'-(3,5-bistrifluoromethyl-benzoyl)-N'-methyl-amino]-4-(1H-indol-3-yl)-butanoic acid [Example 7(b)] (35 mg, 0.07 mmol) are added. Propanephosphonic acid anhydride (31.6 mg, 4 eq, in 0.5 ml of ethyl acetate/dichloromethane) is added and the mixture is left to stand at room temperature for 24 hours. The mixture is washed with 1N potassium carbonate solution (0.5 ml) and the solvent is concentrated by evaporation. The resulting title compound has an Rf value (ethyl acetate) of 0.69.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH2:11]I)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[C:13]([O-:16])(=[S:15])[CH3:14].[K+].O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1([CH2:11][S:15][C:13](=[O:16])[CH3:14])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4]
Reactant: CC([O-])=S
Reactant: COC(=O)C1(CI)CCCCC1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C1(CSC(C)=O)CCCCC1
Temperature: 10 °C
Reaction time: 18 h
Yield: 81.4 %

Procedure:
To a cold solution of crude 1261-B (109 mmol) in DMF (90 ml) was added Potassium thioacetate (1.2 equiv, 131 mmol, 15 g) maintaining temperature below 30° C. The reaction was stirred for 18 h then cooled to 10° C. and water (160 mL) was added. Reaction was extracted with EtOAc and washed with NaHCO3 sat., then brine. The dark organic layer was dried over MgSO4, filtered and concentrated down to a dark oil. Purification—HPFC (High Pressure Flash Chromatography) 75+M prepacked silica cartridge (1 to 5% EtOAc), UV collection. After concentration, 20.43 g of product 1261-C was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:27]=[CH:28]/[O:29]C)[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1.[I-].[Na+].C[Si](Cl)(C)C.O>C(#N)C>[F:1][C:2]1[CH:3]=[C:4]([CH2:27][CH:28]=[O:29])[C:5]([O:25][CH3:26])=[C:6]([C:8]2[S:12][C:11]([C:13]3[CH:14]=[CH:15][C:16]([CH2:21][CH:22]([CH3:24])[CH3:23])=[C:17]([CH:20]=3)[C:18]#[N:19])=[N:10][N:9]=2)[CH:7]=1
Reactant: CO/C=C/c1cc(F)cc(-c2nnc(-c3ccc(CC(C)C)c(C#N)c3)s2)c1OC
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COc1c(CC=O)cc(F)cc1-c1nnc(-c2ccc(CC(C)C)c(C#N)c2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.7 %

Procedure:
To a solution of 5-(5-{5-fluoro-2-(methyloxy)-3-[(E)-2-(methyloxy)ethenyl]phenyl}-1,3,4-thiadiazol-2-yl)-2-(2-methylpropyl)benzonitrile (D36) (130 mg) and sodium iodide (92 mg) in acetonitrile (20 mL) stirred under nitrogen at room temperature was added TMSCl (0.078 mL) dropwise. The reaction mixture was stirred at room temperature for 10 min. Water was added. The aqueous solution was extracted with EA for 3 times. The organic phase was washed with saturated Na2S2O3 solution and saturated brine, dried over sodium sulphate and evaporated in vacuo to afford the crude product 5-{5-[5-fluoro-2-(methyloxy)-3-(2-oxoethyl)phenyl]-1,3,4-thiadiazol-2-yl}-2-(2-methylpropyl)benzonitrile (D37) (75 mg) as a yellow oil. MS (ES): C22H20FN3O2S requires 409. found 410.2 (M+H+).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:24][CH2:23]4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH2:6]1)(=[O:4])=[O:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][S:2]([N:5]1[CH2:9][CH2:8][CH:7]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([CH:22]4[CH2:24][CH2:23]4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH2:6]1)(=[O:4])=[O:3]
Reactant: C[Si](C)(C)CCOCn1cc(C(=O)NC2CCN(S(C)(=O)=O)C2)c2nc(C3CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)N1CCC(NC(=O)c2c[nH]c3ncc(C4CC4)nc23)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.3 %

Procedure:
In a 10 mL round-bottomed flask, 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-yl)-amide (177 mg, 0.37 mmol) was dissolved in CH2Cl2 (3 mL). Trifluoroacetic acid (1.1 mL) was added and the light yellow reaction mixture was stirred at room temperature for 2 h then concentrated. The residue was taken up in toluene (5 mL), concentrated and then dried under high vacuum. The residue was dissolved in CH2Cl2 (2.5 mL) and ethylenediamine (1.5 mL) was added. The reaction mixture was stirred at room temperature overnight then diluted with MeOH and the solid precipitate was collected via filtration. The solid residue was rinsed with hot water and EtOAc then dried under high vacuum to afford 56 mg (43%) of 2-cyclopropyl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (1-methanesulfonyl-pyrrolidin-3-yl)-amide as a white solid. MS: (M+H)+=350; mp>300.