Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.N1C=CC=CC=1.[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:31]=[CH:30][C:25]([CH2:26][C:27](Cl)=O)=[CH:24][CH:23]=1.Cl>ClCCl>[F:17][C:18]1[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[C:19]=1[CH2:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([CH2:26][CH2:27][C:4](=[O:5])[CH2:6][C:7]([O:9][CH2:2][CH3:10])=[O:8])=[CH:30][CH:31]=1
Reactant: O=C(Cl)Cc1ccc(OCc2c(F)cccc2F)cc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)CC(=O)CCc1ccc(OCc2c(F)cccc2F)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of Meldrum's acid (0.846 g, 5.8 mmol) in dichloromethane (5 ml) was added pyridine (2 ml) over a period of 10 minutes at 0° C. To this solution was added 4-(2,6-Difluorobenzyloxy)benzylcarbonyl chloride (Step D, 1.71 g, 5.7 mmol) in dichloromethane (5 ml), which resulted in an orange solution. The dark orange solution was stirred for 1 hour at 0° C., allowed to warm to room temperature and stirred for an additional hour. The reaction mixture was diluted with dichloromethane and poured onto 2M HCl and ice. The phases were separated and the aqueous phase was extracted twice with dichloromethane. The combined organic layers were washed twice with 2M HCl and brine, dried over Na2SO4, filtered and concentrated to a solid. The solid was suspended in abs EtOH (15 ml) and refluxed for 2.5 hours. The solvent was removed in vacuo to give a dark oil. The residue was purified by flash chromatography on silica gel column (hex:ethyl acetate, 2:1) to provide the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=2[CH:23]=O)[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1.[CH2:26]([NH2:28])[CH3:27].C([BH3-])#N.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[CH:6]=[C:7]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][C:14]=2[CH2:23][NH:28][CH2:26][CH3:27])[C:8]([O:11][CH3:12])=[CH:9][CH:10]=1
Reactant: CCN
Reactant: COC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCNCc1cc(C(F)(F)F)ccc1-c1cc(CC(=O)OC)ccc1OC
Temperature: 25 °C

Procedure:
To (2′-formyl-6-methoxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester (1.0 g, 2.89 mmol) and ethylamine (2M in THF; 3.6 mL, 7.23 mmol) in CH2Cl2 (10 mL) was added sodium cyanoborohydride (0.587 g, 8.6 mmol), followed by acetic acid (0.1 mL). The reaction was stirred at room temperature until deemed to be complete by analytical HPLC. The solution was neutralized with saturated aqueous NaHCO3 and extracted with CH2Cl2, and the combined organic layers were dried over MgSO4, filtered, and concentrated to give (6-methoxy-2′-ethylaminomethyl-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid methyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH:15]=O)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH2:1]([O:3][C:4]([C:6]1[S:10][C:9]2[CH:11]=[C:12]([CH2:15][NH:24][CH2:23][C:22]3[CH:25]=[CH:26][C:19]([O:18][CH3:17])=[CH:20][CH:21]=3)[CH:13]=[CH:14][C:8]=2[CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C=O)cc2s1
Reactant: COc1ccc(CN)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC(Cl)Cl
Product: CCOC(=O)c1cc2ccc(CNCc3ccc(OC)cc3)cc2s1

Procedure:
To a solution of 6-formyl-benzo[b]thiophene-2-carboxylic acid ethyl ester (1.05 g, 4.48 mmol) and 4-methoxy-benzylamine (0.76 mL, 5.86 mmol) in anhydrous dichloroethane (40 mL) were added sodium triacetoxyborohydride (2.87 g, 13.5 mmol) and acetic acid (0.25 mL, 4.4 mmol). After the reaction was complete, the reaction mixture was diluted with 60 mL of CH2Cl2 and 40 mL of saturated NaHCO3. The organic layer was separated, washed with 50 mL of water, 50 mL of brine and then dried over Na2SO4. After filtration, the filtrate was concentrated and the residue was purified by flash column chromatography to give 6-[(4-methoxy-benzylamino)-methyl]-benzo[b]thiophene-2-carboxylic acid ethyl ester as a white solid. MS (EI): cal'd 356.1 (MH+), exp 356.1 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[C:10](C#N)[C:9]2=[O:16])=[CH:4][CH:3]=1.[OH:17]S(O)(=O)=O.[CH3:22][OH:23]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:22]([OH:17])=[O:23])[C:9]2=[O:16])=[CH:4][CH:3]=1
Reactant: CO
Reactant: N#Cc1nccn(-c2ccc(F)cc2)c1=O
Reactant: O=S(=O)(O)O
Product: O=C(O)c1nccn(-c2ccc(F)cc2)c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 69 %

Procedure:
A mixture of 4-(4-fluorophenyl)-3-oxo-3,4-dihydropyrazine-2-carbonitrile (0.42 g, 1.95 mmol) and H2SO4 (4.16 mL, 78.1 mmol) was stirred at ambient temperature for 17 hours. Then the reaction mixture (amide intermediate) was added to MeOH (50 mL), and then the reaction was heated at 70° C. for 2.5 hours. The reaction mixture was quenched with ice-water and treated with aqueous 2N NaOH solution at 0° C. The mixture was acidified with aqueous 1N HCl, extracted with EtOAc, dried over MgSO4, and concentrated to afford 0.315 g of the desired product (69% for 3-step process in one pot reaction), which was rinsed with Et2O.
Reaction SMILES: [NH2:1][CH:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][CH:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14].C(N(CC)CC)C.[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35](Cl)=[O:36]>C(Cl)Cl>[CH:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][C:26]=1[C:35]([NH:1][C@H:2]1[C:6](=[O:7])[N:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:4][C@H:3]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:36]
Reactant: O=C(Cl)c1ccc2ccccc2c1
Reactant: CCCCCN1CC(C(=O)OCC)C(N)C1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCCN1C[C@@H](C(=O)OCC)[C@@H](NC(=O)c2ccc3ccccc3c2)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 87.6 %

Procedure:
To a solution of the aminopyrrolidinone of Example R (120 mg, 0.495 mmol) and triethylamine (0.35 ml, 2.48 mmol) in CH2Cl2 was added a solution of 2-naphthoyl chloride (94 mg, 0.495 mmol) in CH2Cl2 dropwise via syringe. After stirring for 12 h at room temperature the reaction mixture was evaporated in vacuo to give a residue which was chromatographed on silica gel eluting with EtOH/CH2Cl2 (2%-5%) to give the title compound (172 mg, 69%) as a colorless solid. MS M+1 calcd for C23H28N2O4 397; found 397.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[C:1]([C:4]1[CH:13]=[C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1cc(OCc2ccccc2)cc2c1CCC(=O)N2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: CC(=O)c1cc(OCc2ccccc2)cc2[nH]c(=O)ccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
13.0 g (44 mmol) 5-acetyl-7-benzyloxy-3,4-dihydro-1H-quinolin-2-one are suspended in 130 mL dioxane and combined with 15.0 g (66 mmol) of 2,3-dichloro-5,6-dicyanobenzoquinone. The mixture is refluxed for 30 minutes, cooled to ambient temperature and stirred for a further 2 hours. The solid is filtered off, washed with dioxane and dissolved in 600 mL dichloromethane/methanol (9:1). The solution is washed with sodium hydrogen carbonate solution, dried with sodium sulphate and evaporated down. Then the residue is suspended in methanol, filtered and dried.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][N:10]([C:13]2[S:14][C:15]([C:19]([OH:21])=O)=[C:16]([CH3:18])[N:17]=2)[C:9]1=[O:22])[C:2]1[CH:7]=CC=CC=1.CC1N=C(N2CCN(CCC)C2=O)SC=1C(O)=O.[NH2:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1>>[CH3:18][C:16]1[N:17]=[C:13]([N:10]2[CH2:11][CH2:12][N:8]([CH2:1][CH2:2][CH3:7])[C:9]2=[O:22])[S:14][C:15]=1[C:19]([NH:41][CH2:42][C:43]1[CH:44]=[N:45][CH:46]=[CH:47][CH:48]=1)=[O:21]
Reactant: Cc1nc(N2CCN(Cc3ccccc3)C2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Agent: CCCN1CCN(c2nc(C)c(C(=O)O)s2)C1=O
Product: CCCN1CCN(c2nc(C)c(C(=O)NCc3cccnc3)s2)C1=O
Yield: 46 %

Procedure:
Following the procedure as describe in Example 9, making variations as required to replace 2-(3-benzyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid with 4-methyl-2-(2-oxo-3-propylimidazolidin-1-yl)thiazole-5-carboxylic acid to react with 3-(aminomethyl)pyridine, the title compound was obtained as a white powder in 46% yield: mp 109-111° C. (ethyl acetate/hexanes); 1H NMR (300 MHz, CDCl3) δ 8.52-8.42 (m, 2H), 7.63 (d, J=7.8 Hz, 1H), 7.24-7.17 (m, 1H), 6.54 (t, J=6.0 Hz, 1H), 4.52 (d, J=6.0 Hz, 2H), 4.05-4.00 (m, 2H), 3.55-3.49 (m, 2H), 3.20 (t, J=7.5 Hz, 2H), 2.60 (s, 3H), 1.59-1.49 (m, 2H), 0.85 (t, J=7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 162.8, 157.5, 155.4, 153.5, 149.1, 148.6, 135.6, 134.1, 123.6, 116.7, 45.4, 42.1, 42.0, 41.2, 20.5, 17.2, 11.1; MS (ES+) m/z 360.3 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([NH:11][CH:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH:10]=1)[NH:7][C:6]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[CH:5]2.[C:24]1([N:30]=[C:31]=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:24]1([NH:30][C:31]([N:15]2[CH2:14][CH2:13][CH:12]([NH:11][C:9]3[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]4[C:8]=3[NH:7][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:5]4)[CH2:17][CH2:16]2)=[O:32])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: Clc1cc(NC2CCNCC2)c2[nH]c(-c3ccccc3)cc2c1
Reactant: O=C=Nc1ccccc1
Product: O=C(Nc1ccccc1)N1CCC(Nc2cc(Cl)cc3cc(-c4ccccc4)[nH]c23)CC1

Procedure:
(5-Chloro-2-phenyl-1H-indol-7-yl)-piperidin-4-yl-amine prepared in Example 93 and phenylisocyanate were reacted according to the same procedure as Example 22 to give the title compound.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C@@H:28]([NH2:31])[CH2:29][OH:30])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[F:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][C@@H:28]([NH:31][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:29][OH:30])=[CH:25][CH:26]=1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Reactant: N[C@@H](CO)Cc1ccc(F)cc1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(N[C@@H](CO)Cc2ccc(F)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
The similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, (R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamine and DIEA to give 2-[(R)-2-(4-fluoro-phenyl)-1-hydroxymethyl-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 408 (MH+).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[CH2:17]([NH2:21])[CH:18]([CH3:20])[CH3:19]>ClCCl.C([O-])(O)=O.[Na+]>[Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: O=C(Cl)c1ccc(SCCCl)c([N+](=O)[O-])c1
Reactant: CC(C)CN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNC(=O)c1ccc(SCCCl)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
To a biphasic solution of 4-(2-chloroethylthio)-3-nitrobenzoyl chloride (2.331 g, 8.32 mmol) in dichloromethane (75 mL) and saturated aqueous NaHCO3 (75 mL) was added isobutylamine (1.043 mL, 10.40 mmol). The reaction was allowed to stir for 16 hours. TLC and LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (4×50 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product, 4-(2-chloroethylthio)-N-isobutyl-3-nitrobenzamide, was used without further purification. Product yield was assumed to be 100% (2.64 g, 8.32 mmol) for future calculations. LCMS (+ESI) m/z=317.13 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C[O:18][C:19]([C:21]1[O:22][C:23]([CH2:26]Cl)=[CH:24][CH:25]=1)=[O:20]>>[N+:14]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([O:1][CH2:26][C:23]2[O:22][C:21]([C:19]([OH:20])=[O:18])=[CH:25][CH:24]=2)=[CH:3][CH:4]=1)([O-:16])=[O:15]
Reactant: COC(=O)c1ccc(CCl)o1
Reactant: O=[N+]([O-])c1ccccc1-c1ccc(O)cc1
Product: O=C(O)c1ccc(COc2ccc(-c3ccccc3[N+](=O)[O-])cc2)o1

Procedure:
5-(2′-Nitro-biphenyl-4-yloxymethyl)-furan-2-carboxylic acid was prepared using general procedure A from 4-hydroxy-2′-nitrobiphenyl (available from TCI America, Portland, Oreg.) and 5-chloromethylfuran-2-carboxylic acid methyl ester (available from Aldrich, Milwaukee, Wis., or from Maybridge plc, Tintagel, UK). Yield: 82 mg. Mass spectrum (ES) MH+=340.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[N:3]1.C(=O)([O-])[O-].[NH4+:15].[NH4+]>C(Cl)(Cl)Cl>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([S:7]([NH2:15])(=[O:9])=[O:8])=[N:3]1
Reactant: [NH4+]
Reactant: Cn1ccc(S(=O)(=O)Cl)n1
Agent: O=C([O-])[O-]
Solvent: ClC(Cl)Cl
Product: Cn1ccc(S(N)(=O)=O)n1

Procedure:
A mixture containing chloroform (100 ml), 13.6 g of 1-methylpyrazole-3-sulfonyl chloride and 13.6 g ammonium carbonate was heated to reflux for six hours, cooled, filtered and the solid was washed with water. The water-insoluble solid which was recrystallized from 50% ethanol-water melted at 149°-151° and showed absorption peaks in the infrared at 3100 and 3200 cm-1, consistent for the NH2 in the desired product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5](Cl)=[N:6][CH:7]=1.[OH:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C1C=CN=CC=1.CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[C:5]([O:12][CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CO
Reactant: O=[N+]([O-])c1cc(Br)cnc1Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ncc(Br)cc1[N+](=O)[O-]
Yield: 61.8 %

Procedure:
To a flask with 5-bromo-2-chloro-3-nitropyridine (73.B) (800 mg, 3.4 mmol) was added 78.D (mixed with 78.E, 445 mg, 3.4 mmol), cesium carbonate (2.2 g, 6.7 mmol) and N,N-dimethylpyridin-4-amine (82 mg, 0.67 mmol). DMF was used as the solvent. The reaction was heated for 2.5 hours. Standard aqueous workup with EtOAc as solvent and silica gel purification afforded 700 mg of 78.F mixed with some 78.E.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7](=O)[CH2:8][O:9][CH2:10]2)=[CH:5][CH:4]=1.[F:14][C:15]([F:22])([F:21])[C:16](OCC)=O.C[O-].[Na+].CO.[CH:28]1[C:33]([NH:34][NH2:35])=[CH:32][CH:31]=[C:30]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:29]=1.Cl>C(OCC)C.Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:7]3[N:34]([C:33]4[CH:28]=[CH:29][C:30]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:31][CH:32]=4)[N:35]=[C:16]([C:15]([F:14])([F:21])[F:22])[C:8]=3[O:9][CH2:10][C:11]=2[CH:12]=1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc2c(c1)COCC2=O
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: COc1ccc2c(c1)COc1c(C(F)(F)F)nn(-c3ccc(S(N)(=O)=O)cc3)c1-2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 7-methoxyisochroman-4-one (3.96 g, 22.2 mmol) and ethyl trifluoroacetate (2.90 mL, 5.8 mmol) was dissolved in 30 mL of diethyl ether and treated with a solution of 25% sodium methoxide in methanol (5.8 mL, 26.7 mmol). The solution was stirred at room temperature for 1 hour. The solution was diluted with 1N HCl and extracted with ethyl acetate, washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford a solid. The crude reaction product was dissolved in 50 mL of ethanol and treated with 4-sulfonamidophenylhydrazine hydrochloride (5.47 g, 24.4 mmol). This solution was heated to reflux for 3.5 hours, cooled to room temperature, diluted with 100 mL of 1N HCl. After cooling the solution to 0° C. for ca. 0.5 hour, crystals of pure 4-[1,5-dihydro-7-methoxy-3-(trifluoromethyl)-[2]benzopyrano[4,3-c]pyrazol-1-yl]benzenesulfonamide formed that were isolated by filtration and dried in vacuo to afford 7.56 g (80%): mp 275° C. (dec). 1H NMR (CDCl3 300 MHz) 7.91 (d, J=8.66 Hz, 2H), 7.54 (d, J=8.66 Hz, 2H), 6.69-6.54 (m, 5H), 5.07 (s, 2H), 3.63 (s, 3H). 19F NMR (CDCl3 282 MHz) -62.01(s). Anal. calc'd. for C18H14F3N3O4S: C, 50.82; H, 3.32; N, 9.88; S, 7.54. Found: C, 50.93; H, 3.38; N, 9.94; S, 7.57.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:20][C:21]1[CH:29]=[C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH:35]=2)=[O:31])[CH:27]=[C:26]([CH3:48])[C:22]=1[C:23](O)=[O:24].ClN1C(=O)CCC1=O.[CH3:57][O:58][C:59](=[O:68])[CH:60]([P:62]([O:66][CH3:67])([O:64][CH3:65])=[O:63])[NH2:61].COC(=O)C(P(OC)(OC)=O)NC(OCC1C=CC=CC=1)=O>ClCCl>[CH3:57][O:58][C:59](=[O:68])[CH:60]([P:62]([O:64][CH3:65])([O:66][CH3:67])=[O:63])[NH:61][C:23](=[O:24])[C:22]1[C:21]([CH3:20])=[CH:29][C:28]([C:30]([NH:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([O:40][Si:41]([C:44]([CH3:47])([CH3:46])[CH3:45])([CH3:43])[CH3:42])[CH:35]=2)=[O:31])=[CH:27][C:26]=1[CH3:48]
Reactant: Cc1cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc(C)c1C(=O)O
Reactant: COC(=O)C(N)P(=O)(OC)OC
Agent: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: O=C1CCC(=O)N1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)C(NC(=O)c1c(C)cc(C(=O)NCc2cccc(O[Si](C)(C)C(C)(C)C)c2)cc1C)P(=O)(OC)OC
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93 %

Procedure:
Triphenylphosphine (0.762 g, 2.9 mmol) was added to a suspension of 2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoic acid (Example 111; 1 g, 2.42 mmol) in dichloromethane (12 mL) at 25° C. The mixture was cooled to 0° C. and N-chlorosuccinimide (0.387 g, 2.9 mmol) was added. After stirring 15 min at 0° C., the mixture was stirred for an additional 15 min at 25° C. and then a solution of rac.-2-(dimethoxyphosphinyl)glycine methyl ester (Example 125) freshly prepared from rac.-N-(benzyloxycarbonyl)-2-(dimethoxyphosphinyl)glycine methyl ester (1.99 g, 6 mmol) in dichloromethane (2 mL) was added in one portion. The reaction was stirred for 5 h (a precipitate formed at 2 h), then was filtered and the solids were washed with dichloromethane and discarded. The filtrate was washed with 1N hydrochloric acid solution (50 mL), saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), then was dried (MgSO4) and concentrated under reduced pressure. The residue was flash chromatographed (silica gel, 10% ethyl acetate in petroleum ether) to yield rac.-N-[2,6-dimethyl-4-[[[3-[[(1,1-dimethylethyl)dimethylsilyl]oxy]benzyl]amino]carbonyl]benzoyl]-2-(dimethoxyphosphinyl)glycine methyl ester (1.33 g, 93% yield) as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.C1(P(C2C=CC=CC=2)C2[C:43]3[O:42]C4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)[C:34]=3C=CC=2)C=CC=CC=1.C(O)C[SH:67]>O1CCOCC1.O>[CH2:12]([O:11][C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH2:34][C:43]([OH:42])=[S:67])=[CH:3][CH:4]=1)=[O:10])[CH3:13]
Reactant: OCCS
Reactant: CCOC(=O)Cc1ccc(Br)cc1
Reactant: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOC(=O)Cc1ccc(CC(O)=S)cc1

Procedure:
Ethyl 4-bromophenylacetate (500 mg), diisopropylethylamine (700 μL), tris(dibenzylidenacetone)dipalladium(0) (46 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos) (58 mg) were dissolved in dioxane (5 mL). Then, thioglycol acid (140 μL) was added, and the mixture was heated under reflux for 4 hrs. The reaction mixture was poured into water, the aqueous phase was washed with ethyl acetate and acidified with 1 mol/L hydrochloric acid. Then, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (260 mg) as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]([C:14]([OH:16])=[O:15])[CH3:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:17]=[C:18]([CH3:20])[CH3:19].S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>O1CCOCC1.C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@@H:12]([C:14]([O:16][C:18]([CH3:20])([CH3:19])[CH3:17])=[O:15])[CH3:13])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)O
Reactant: C=C(C)C
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[C@@H](NS(=O)(=O)c1ccc(F)cc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 95 h

Procedure:
A solution of N-[(4-fluorophenyl)sulfonyl]-D-alanine from Example 3a (8.00 g, 32.4 mmol), isobutene (120 mL), and concentrated sulfuric acid (0.5 mL) in 1,4-dioxane (20 mL) and CH2Cl2 (60 mL) was added to a 500 mL high pressure bottle and sealed. The mixture was shaken at room temperature for 95 hours at a pressure of 18 psi. The mixture was poured into an aqueous solution containing 20 g of sodium bicarbonate, which was cooled by an ice bath. The aqueous solution was extracted with ethyl acetate and the combined organic layers were washed successively with water and brine, dried with MgSO4, and concentrated to a clear, yellow oil (6.06 g). Chromatography on silica gel (20% ethyl acetate in hexane) afforded N-[(4-fluorophenyl)sulfonyl]-D-alanine, 1,1-dimethylethyl ester, as a white solid (5.00 g, 51% yield): Anal. calc'd for C13H18NO4FS: C, 51.47; H, 5.98; N, 4.62. Found: C, 51.39; H, 5.82; N, 4.53.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4](I)[CH:3]=1.C([Mg]Cl)(C)C.CN(C)[CH:18]=[O:19].Cl>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH3:9])=[C:4]([CH:3]=1)[CH:18]=[O:19]
Reactant: CCc1ccc(Br)cc1I
Reactant: CN(C)C=O
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CCc1ccc(Br)cc1C=O
Temperature: -20 °C
Reaction time: 3 h
Yield: 96.6 %

Procedure:
To a solution of 4-bromo-1-ethyl-2-iodobenzene (31.8 g, 103 mmol) (described in WO 2008/071405) in anhydrous tetrahydrofuran (250 ml) at −20° C. is added isopropyl magnesium chloride (55 ml, 110 mmol, 2M solution in tetrahydrofuran) dropwise over 10 minutes. Once the addition is complete the reaction mixture is stirred at −20° C. for 3 hours, followed by dropwise addition of anhydrous N,N-dimethylformamide (16.0 ml, 200 mmol). The reaction mixture is stirred at room temperature for a further 2.5 hours, then left to stand overnight. 2M hydrochloric acid (90 ml) is added and the crude product is extracted into dichloromethane. Organics are combined, dried over magnesium sulfate then filtered and the filtrate evaporated under reduced pressure to afford 5-bromo-2-ethyl-benzaldehyde (21.20 g) as an orange liquid.