Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15]CC3C=CC=CC=3)=[CH:12][CH:13]=2)[N:8]([CH3:23])[CH:7]=1)=O.O.[PH2]([O-])=O.[Na+]>O1CCOCC1.O.[Pd]>[CH3:1][O:2][C:3](=[O:24])[CH2:4][C:6]1[C:14]2[C:9](=[CH:10][C:11]([OH:15])=[CH:12][CH:13]=2)[N:8]([CH3:23])[CH:7]=1
Reactant: COC(=O)C(=O)c1cn(C)c2cc(OCc3ccccc3)ccc12
Agent: [Pd]
Agent: O=[PH2][O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)Cc1cn(C)c2cc(O)ccc12
Temperature: 100 °C
Reaction time: 16 h
Yield: 52.1 %

Procedure:
To a solution of (6-benzyloxy-1-methyl-1H-indol-3-yl)-oxo-acetic acid methyl ester (0.68 g, 2.10 mmol) in 1,4-dioxane (12 mL) is added a slurry of Pd/C (10%, 0.25 g). The flask is evacuated and re-filled with N2 three times. The mixture is heated to 100° C. and a solution of sodium hypophosphite, hydrate (5.0 g, 47 mmol) in water (5 mL) is added dropwise. The mixture is stirred at 100° C. for 16 hours and cooled to room temperature. The mixture is filtered through a pad of diatomaceous earth and the filtrate is concentrated under reduced pressure. The residue is purified via silica gel chromatography eluting with 25-50% EtOAc/Hexanes to provide the title compound (0.24 g, 52%). ES/MS m/e 220.0 (M+1), 218.0 (M−1).
Reaction SMILES: [K+].[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH-:12])(=[O:11])=[O:10])=[N:7][CH:8]=1.[Cl:13][C:14]1[C:19]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])=[C:18](Cl)[N:17]=[C:16]([CH3:30])[N:15]=1.O>CS(C)=O>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([S:9]([NH:12][C:18]2[C:19]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[O:27][CH3:28])=[C:14]([Cl:13])[N:15]=[C:16]([CH3:30])[N:17]=2)(=[O:11])=[O:10])=[N:7][CH:8]=1
Reactant: Cc1ccc(S([NH-])(=O)=O)nc1
Reactant: COc1ccccc1Oc1c(Cl)nc(C)nc1Cl
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccccc1Oc1c(Cl)nc(C)nc1NS(=O)(=O)c1ccc(C)cn1
Temperature: 25 °C
Reaction time: 48 h
Yield: 76.6 %

Procedure:
At room temperature 2.95 g of 5-methyl-2-pyridine sulfonamide potassium salt (Example 3c) was added to a suspension of 2 g of 4,6-dichloro-5-(o-methoxyphenoxy)-2-methyl-pyrimidine (Example 7b) in 30 ml DMSO. The mixture was stirred at room temperature for 48 h and was then poured onto 300 ml of water. The aqueous solution was extracted twice with 200 ml of diethyl ether. The organic layers were extracted with water and the aqueous layers were combined and acidified with 3 ml of acetic acid to pH 4. Precipitation of the product was enhanced by adding 100 ml of saturated aqueous sodium chloride and cooling the mixture to 0° C. Eventually, the precipitate was filtered off, washed with cold water and dried under high vacuum to give 2.26 g of 5-methyl-N-[6-chloro-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-2-pyridine sulfonamide as a beige powder. LC-MS: tR=4.79 min, [M+1]+=421.42, [M−1]−=419.46.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([CH2:11][N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH:13]2[CH2:25]O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[K+]>C(Cl)(Cl)(Cl)Cl.O>[Cl:3][CH2:25][CH:13]1[CH2:14][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:16][CH2:17][N:12]1[CH2:11][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: OCC1CN(Cc2ccccc2)CCN1Cc1ccccc1
Reactant: O=S(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClC(Cl)(Cl)Cl
Solvent: O
Product: ClCC1CN(Cc2ccccc2)CCN1Cc1ccccc1

Procedure:
To a solution of 10.1 ml of thionyl chloride in 50 ml of carbon tetrachloride was added, with stirring, a solution of 22.15 g of 1,4-bis(phenylmethyl)-2-piperazinemethanol in 120 ml of carbon tetrachloride. This mixture was stirred in an oil bath at 70° C. for one hour, then cooled in an ice bath and a solution of 17.1 g of potassium hydroxide in 50 ml of water was added. The mixture was extracted several times with dichloromethane. The extracts were combined, filtered through hydrous magnesium silicate and evaporated. The residual gum was dissolved in warm heptane, filtered and evaporated to an oil which crystallized on standing, giving 17.94 g of 2-chloromethyl-1,4-bis(phenylmethyl)piperazine, mp 54°-56° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16](I)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH:25]=[CH:24][N:23]=[N:22]1.C(C)(C)C>>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([N:22]2[N:23]=[CH:24][CH:25]=[N:21]2)[CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1Cc1cccc(I)c1
Reactant: c1c[nH]nn1
Agent: CC(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1Cc1cccc(-n2nccn2)c1

Procedure:
(S)-2-(3-[1,2,3]Triazol-2-yl-benzyl)-pyrrolidine-1-carboxylic acid tert-butyl ester was prepared from (S)-2-(3-iodo-benzyl)-pyrrolidine-1-carboxylic acid tert-butyl ester and 1H-1,2,3-triazole in analogy to the procedure described for A-13. LC-MS A: tR=0.97 min; [M+H-tBu]+=273.16.
Reaction SMILES: O.[NH2:2][NH2:3].N[O:5][C:6](=O)[CH2:7][N:8]1[CH2:12][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:10][C:9]1=[O:16]>CCO.[Cl-].[Na+].O>[O:16]=[C:9]1[CH2:10][CH:11]([CH2:13][CH2:14][CH3:15])[CH2:12][N:8]1[CH2:7][C:6]([NH:2][NH2:3])=[O:5]
Reactant: NN
Reactant: CCCC1CC(=O)N(CC(=O)ON)C1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCC1CC(=O)N(CC(=O)NN)C1
Temperature: 25 °C
Yield: 91.6 %

Procedure:
In a 250 ml three necked flask fitted with a magnetic stirrer, hydrazine hydrate (5.78 g, 0.18 mol, 3 eq) is added to a solution of 1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one x40 (11.99 g, 60.29 mmol) in EtOH (125 ml). The mixture is heated 4 h at reflux, cooled down to room temperature, diluted with brine and extracted with CH2Cl2. The combined organic phases are dried over MgSO4, filtered and evaporated to afford 11.0 g of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide x41.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19](Cl)[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1.C(N(CC)CC)C>CN(C=O)C>[Cl:14][C:15]1[C:20]([N+:21]([O-:23])=[O:22])=[C:19]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[C:18]([CH3:25])=[C:17]([CH3:26])[N:16]=1
Reactant: CC(C)(C)OC(=O)NCCCCN
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCCCNC(=O)OC(C)(C)C)c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.6 %

Procedure:
A solution of tert-butyl 4-aminobutylcarbamate (8.50 g, 45.2 mmol) in DMF (20 mL) in an addition funnel was added over 1 hour to a stirred solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (10.0 g, 45.2 mmol) and triethylamine (9.30 mL, 67.8 mmol) in DMF (100 mL). The addition funnel was rinsed with DMF (17 mL) and the solution was added to the reaction vessel. After the reaction solution was stirred overnight at room temperature, additional tert-butyl 4-aminobutylcarbamate (0.1 equivalent) was added. The solution was allowed to stir an additional 2 hours, then was concentrated under reduced pressure. The resulting oil was partitioned between ethyl acetate (400 mL) and water (100 mL). The organic phase was washed with water (4×50 mL), then was dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by flash chromatography (silica gel, elution with 33% ethyl acetate in hexanes followed by 66% ethyl acetate in hexanes) to afford 9.2 g of tert-butyl 4-[(2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)amino]butylcarbamate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.CCN(CC)CC.[CH3:16][Si:17](Cl)([CH3:20])[CH2:18][CH3:19]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:19][CH2:18][SiH:17]([CH3:20])[CH3:16]
Reactant: CC[Si](C)(C)Cl
Reactant: Oc1cccc(Br)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[SiH](C)CCOc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 3-bromophenol (0.60 g, 3.47 mmol) in dry THF (15 mL) under nitrogen was added Et3N (0.48 mL, 3.47 mmol). A clear yellow solution formed immediately; after cooling to 0° C., dimethylethylsilyl chloride (0.43 g, 0.49 mL, 3.47 mmol) was added by syringe over a period of 10 minutes. The yellow color disappeared in 10 min, and a white cloudy solution formed. After 3 hr the thick reaction mixture was filtered, washed with 15 mL of hexane, and filtered again. Concentration gave a clear oil (quantitative weight recovery) that was used in the next step without any purification.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]([NH2:17])=O)(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(Cl)(Cl)C(Cl)=O>C(Cl)Cl>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([O:13][CH3:14])=[CH:10][CH:11]=2)[CH2:6][CH:5]1[C:15]#[N:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)CC(C(N)=O)N2C(C)=O
Agent: O=C(Cl)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc2c(c1)CC(C#N)N2C(C)=O
Temperature: 25 °C

Procedure:
To a suspension of intermediate (22) (0.022 mole) in DCM (150 ml), cooled in an ice bath under argon, was added triethylamine (0.066 mole) then trichloroacetyl chloride (0.033 mole). The mixture was allowed to slowly warmed to room temperature overnight. The mixture was washed with water, 2N HCl, and saturated NaHCO3. The organic phase was dried, concentrated and triturated in ether and the solid collected, yielding 1-acetyl-2,3-dihydro-5-methoxy-1H-indole-2-carbonitrile (intermediate 23, mp. 108-110° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:19][C:18]([F:20])([F:21])[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:12][CH:13]=1)[OH:22]
Reactant: Fc1cccc([Mg]Br)c1
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: OC(c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To Pd(PPh3)4 (2.1 g, 1.823 mmol) was added 3-fluorophenylmagnesium bromide (55 mls, 1.0 M in THF, 55 mmol) at 0° C. over 15 minutes. The ice bath was removed and the mixture was stirred for 30 minutes. 1-(4-Bromophenyl)-2,2,2-trifluoroethanol (4.65 g, 18.23 mmol) in THF (50 mls) was added over 10 minutes. The mixture was heated to reflux for 3 hours and was shown complete by LC (Sunfire column, TFA). The mixture was cooled, quenched with H2O, rotary evaporated to remove most of the THF, and extracted 3 times with CH2Cl2. The organics were combined washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) gave 4.64 g of 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol. Yield 94%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1(C)[O:23]C(=O)C[C:20](=O)[O:19]1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>C(Cl)Cl>[CH2:1]([O:8][C:9]([NH:11][CH2:12][CH2:13][C:14](=[O:16])[CH2:17][C:18]([O:19][CH3:20])=[O:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C(O)CCNC(=O)OCc1ccccc1
Agent: CCOP(=O)(C#N)OCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)CC(=O)CCNC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
3-(Benzyloxycarbonylamino)propanoic acid [N-Cbz-β-alanine] (5.0 g, 22.4 mmoles) is suspended in methylene chloride (100 mL) and 2,2-dimethyl-1,3-dioxane-4,6-dione (3.3 g, 22.9 mmoles), triethylamine (8.5 mL, 61.0 mmoles) and diethyl cyanophosphonate (3.7 mL, 22.8 mmoles) are added. All solids dissolve quickly, and the reaction quickly turns yellow. The solution is stirred for 16 hours at ambient temperature. The reaction mixture is then diluted with methylene chloride (100 mL) and carefully washed three times with aqueous hydrochloric acid (3 M, 50 mL each), three times with water (50 mL each) and once with saturated aqueous sodium chloride (50 mL). The reaction mixture is then dried over anhydrous sodium sulfate, filtered and evaporated to an orange syrup. The syrup is dissolved in anhydrous methanol (200 mL) and heated to reflux for 16 hours. The methanol is evaporated and the crude product purified on silica gel (150 mL bed volume) eluting with methylene chloride (500 mL) then methylene chloride:methanol (99.5:0.5 [v/v], 500 mL then 99:1 [v/v], 1000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow oil. The oil is dried well in vacuo. The yield is 4.5 g (68%).
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][NH:20]2)[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:18])[O:16][CH3:17])=[CH:10][CH:9]=1.[CH3:34][C:35]([O:38][C:39]([NH:41][C:42]([C:44]1[CH:52]=[CH:51][C:47]([C:48](O)=[O:49])=[CH:46][CH:45]=1)=[NH:43])=[O:40])([CH3:37])[CH3:36]>>[Cl:2][C:3]1[N:4]=[C:5]([C@@H:19]2[CH2:23][C@H:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH2:26][CH2:25]3)[CH2:21][N:20]2[C:48]([C:47]2[CH:46]=[CH:45][C:44]([C:42]([NH:41][C:39](=[O:40])[O:38][C:35]([CH3:36])([CH3:34])[CH3:37])=[NH:43])=[CH:52][CH:51]=2)=[O:49])[NH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([O:16][CH3:17])=[O:18])=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NC(=N)c1ccc(C(=O)O)cc1
Reactant: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3)nc2Cl)cc1
Agent: Cl
Product: COC(=O)Nc1ccc(-c2[nH]c([C@@H]3C[C@H](C4CCN(S(C)(=O)=O)CC4)CN3C(=O)c3ccc(C(=N)NC(=O)OC(C)(C)C)cc3)nc2Cl)cc1

Procedure:
The compound prepared in Example 67 was treated with the compound prepared in Example 18 following the procedure described in Example 8 to give the title compound as a white solid.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.S(Cl)([Cl:12])=O>>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([Cl:12])=[O:9])[N:6]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1nc(C(=O)O)cs1
Product: Cc1nc(C(=O)Cl)cs1
Temperature: 80 °C

Procedure:
To 2-methyl-1,3-thiazole-4-carboxylic acid (1 g) was added thionyl chloride (5 ml). The mixture was heated at 80° C. for 8 h. Thionyl chloride (5 ml) was added and the mixture heated for 2 h at 80° C. Further thionyl chloride (5 ml) was added and the mixture heated for 2 h. The mixture was concentrated in vacuo and azeotroped with toluene to give the title compound (1.12 g) as a brown solid
Reaction SMILES: [C:1]1(=O)[NH:6][CH:5]=[CH:4][N:3]2[CH:7]=[CH:8][CH:9]=[C:2]12.P(Cl)(Cl)([Cl:13])=O.C(=O)(O)[O-].[Na+]>>[Cl:13][C:1]1[C:2]2[N:3]([CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:5][N:6]=1
Reactant: O=c1[nH]ccn2cccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: Clc1nccn2cccc12
Reaction time: 16 h
Yield: 71 %

Procedure:
To pyrrolo[1,2-a]pyrazin-1(2H)-one (0.35 g, 2.61 mmol) was added phosphorous oxychloride (4.0 g, 26.1 mmol). The reaction mixture was agitated for approximately 16 hours. The reaction mixture was then made alkaline by the addition of sodium bicarbonate. The reaction mixture was then extracted with hexane, washed with a saturated sodium bicarbonate solution, dried over MgSO4 and evaporated. The product was purified by recrystallization in hexane and cooled with a mixture of dry ice and acetone to give the title compound, 1-chloropyrrolo[1,2-a]pyrazine (71%), m.p. 56°-57° C.
Reaction SMILES: [CH2:1]([C:4]1[C:13]([OH:14])=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3].[CH3:19][S:20]([C:23]1[CH:28]=[CH:27][C:26](F)=[CH:25][CH:24]=1)(=[O:22])=[O:21].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.[Cu]I>[CH2:1]([C:4]1[C:13]([O:14][C:26]2[CH:27]=[CH:28][C:23]([S:20]([CH3:19])(=[O:22])=[O:21])=[CH:24][CH:25]=2)=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[C:15]([O:17][CH3:18])=[O:16])[CH:2]=[CH2:3]
Reactant: C=CCc1c(O)cc(C(=O)OC)cc1C(=O)OC
Reactant: CS(=O)(=O)c1ccc(F)cc1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C=CCc1c(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)OC)cc1C(=O)OC
Yield: 77.4 %

Procedure:
A mixture of dimethyl 4-allyl-5-hydroxyisophthalate (2.0 g, 7.99 mmol), 4-fluorophenyl methyl sulfone (2.1 g, 12 mmol), Cs2CO3 (5.2 g, 16 mmol) and CuI (400 mg, 2.1 mmol) in DMF (20 mL) was heated to for 4 hours. The solvent was removed under reduced pressure. The residue was poured into water (20 mL) and extracted with EtOAc (50 mL×2). The combined organic layer was washed with brine (20 mL×2), dried over Na2SO4 and concentrated. The product was purified via silica gel gradient chromatography eluted with EtOAc in hexanes (10/90 to 30/90) to afford the title compound (2.5 g, 78%) as a white solid. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.83 (dd, J=6.69, 1.60 Hz, 2 H) 3.03-3.16 (m, 3 H) 3.93 (d, 6 H) 6.14-6.34 (m, 1 H) 6.63 (dd, J=16.11, 1.60 Hz, 1 H) 6.88-6.98 (m, 1 H) 6.97-7.09 (m, 2 H) 7.79 (d, J=1.70 Hz, 1 H) 7.87-8.01 (m, 2 H) 8.29 (d, J=1.70 Hz, 1 H); LC-MS (ESI)+m/z =405.00 (M+H)+.
Reaction SMILES: [O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26](=[O:28])[CH3:27])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH2:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:32](=O)[C:33]1[O:37][CH:36]=[CH:35][CH:34]=1>>[O:1]([C:8]1[C:16]([S:17](=[O:30])(=[O:29])[NH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[NH:25][C:26](=[O:28])[CH3:27])=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[NH:31][CH2:32][C:33]1[O:37][CH:36]=[CH:35][CH:34]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccco1
Reactant: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(N)c1Oc1ccccc1
Product: CC(=O)Nc1ccccc1NS(=O)(=O)c1cc(C(=O)O)cc(NCc2ccco2)c1Oc1ccccc1
Reaction time: 16 h

Procedure:
The starting material is prepared as follows: The mixture of 3.5 g of 4-phenoxy-3-amino-5-(2-acetamidophenylsulfamoyl)-benzoic acid and 30 ml of furfural is heated to 100° for five hours and allowed to stand at room temperature for 16 hours. It is evaporated under reduced pressure, the residue triturated with diethyl ether and dissolved in 75 ml of ethanol. Thereupon 2 g of sodium borohydride are added while stirring and cooling followed by another 0.5 g thereof after 4 hours and another 0.5 g thereof after 16 hours and stirring is continued for one hour. Thereupon 100 ml of water are added, the mixture filtered and the filtrate acidified with hydrochloric acid to a pH of 2-3. The precipitate formed is filtered off and recrystallized from 30% aqueous ethanol to yield the 4-phenoxy-3-furfurylamino-5-(2-acetamidophenylsulfamoyl)-benzoic acid melting at 207°-210° with decomposition.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])(=[O:3])[CH3:2].B(Cl)([C@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1)[C@H]1[C@@H](C)[C@H]2C(C)(C)[C@H](C2)C1>>[OH:3][C@H:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][N:11]=1)[C:7]#[N:8])[CH3:2]
Reactant: CC(=O)c1cc(C#N)ccn1
Agent: C[C@@H]1[C@H](B(Cl)[C@@H]2C[C@H]3C[C@@H]([C@@H]2C)C3(C)C)C[C@H]2C[C@@H]1C2(C)C
Product: C[C@H](O)c1cc(C#N)ccn1
Yield: 78.5 %

Procedure:
The title compound (1.13 g, 7.63 mmol) was prepared according to General Method E1 starting from 2-acetyl-isonicotinonitrile (1.42 g, 9.72 mmol) and (−)-DIPCl (4.67 g, 14.57 mmol).
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[C:19]1([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[O:29][C:28]([CH3:30])=[N:27][C:26]=2[C:31](O)=[O:32])[CH:20]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:31]([C:26]3[N:27]=[C:28]([CH3:30])[O:29][C:25]=3[C:21]3[CH:20]=[C:19]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[CH:24]=[CH:23][CH:22]=3)=[O:32])=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: Cc1nc(C(=O)O)c(-c2cccc(-c3ccccc3)c2)o1
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Product: CC(=O)c1ccc(Cn2ccc(NC(=O)c3nc(C)oc3-c3cccc(-c4ccccc4)c3)n2)o1

Procedure:
Following general procedure B followed by T, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and 5-biphenyl-3-yl-2-methyl-oxazole-4-carboxylic acid. LC-MS-conditions 02: tR=1.11 min; [M+H]+=467.31.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[CH:7][CH:6]=1.[Br:14]Br>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([S:11][CH3:12])=[C:7]([Br:14])[CH:6]=1
Reactant: BrBr
Reactant: COC(=O)Cc1ccc(SC)cc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)Cc1ccc(SC)c(Br)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.2 %

Procedure:
A solution of (4-methylsulfanyl-phenyl)-acetic acid methyl ester (5.11 g, 26.03 mmol) in carbon tetrachloride (130 mL) was slowly treated with bromine (1.74 mL, 33.84 mmol). The reaction mixture was stirred at 25° C. for 4 h, at which time, thin layer chromatography still indicated the presence of a substantial amount of starting material. The reaction mixture was treated with more bromine (1.74 mL, 33.84 mmol). The reaction mixture was stirred an additional 4 h at 25° C. and then quenched with a 10% aqueous sodium bisulfite solution (150 mL). The reaction mixture was concentrated in vacuo to remove carbon tetrachloride. The resulting aqueous layer was extracted with ethyl acetate (3×150 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 70-230 mesh, 9/1 hexanes/ethyl acetate) afforded (3-bromo-4-methylsulfanyl-phenyl)-acetic acid methyl ester (6.10 g, 85%) as a light yellow oil: EI-HRMS m/e calcd for C10H11BrO2S (M+) 273.9663, found 273.9661.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[N:18][CH:17]=[C:16](Br)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26][OH:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[C:19]([NH2:20])=[N:18][CH:17]=[C:16]([O:27][CH2:26][C:25]3[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=3)[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(Br)cnc2N)CC1
Reactant: OCc1cccc(Cl)c1
Product: CC(C)(C)OC(=O)N1CCN(c2nc(OCc3cccc(Cl)c3)cnc2N)CC1

Procedure:
3′-Amino-6′-(3-chloro-benzyloxy)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3s was prepared from 3′-Amino-6′-bromo-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-carboxylic acid tert-butyl ester I-3r (1.0 g, 2.8 mmol) and 3-chlorobenzyl alcohol (0.36 mL, 3.1 mmol) in a manner analogous to compound I-1b in example 1. The title compound I-3s was obtained as a red viscous oil (394 mg, 34% yield).
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].Cl.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>>[CH2:9]([N:11]([CH2:12][CH3:13])[C:1]([CH2:2][CH2:3][C:4]#[CH:5])=[O:7])[CH3:10]
Reactant: C#CCCC(=O)O
Reactant: CCNCC
Agent: Cl
Product: C#CCCC(=O)N(CC)CC
Yield: 94.7 %

Procedure:
The title compound (370 mg, 95%) was prepared from 4-pentynoic acid (250 mg, 2.55 mmol) and diethylamine hydrochloride (310 mg, 2.83 mmol) by the procedure similar to that described in Example 51(1).