Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]([O:26][CH3:27])([O:24][CH3:25])[CH2:15][CH2:14]1)(=[O:12])=[O:11].[CH3:28][C:29]1([CH3:46])[O:33][C@H:32](CO[Si](C)(C)C)[C@@H:31](CO[Si](C)(C)C)[O:30]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][S:10]([CH:13]1[CH2:14][CH2:15][C:16]2([O:24][C@@H:25]([C@H:31]3[CH2:32][O:33][C:29]([CH3:46])([CH3:28])[O:30]3)[CH2:27][O:26]2)[CH:17]=[C:18]1[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:11])=[O:12]
Reactant: CCOC(=O)C1=CC(OC)(OC)CCC1S(=O)(=O)Nc1ccc(F)cc1Cl
Reactant: CC1(C)O[C@H](CO[Si](C)(C)C)[C@@H](CO[Si](C)(C)C)O1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)C1=CC2(CCC1S(=O)(=O)Nc1ccc(F)cc1Cl)OC[C@H]([C@H]1COC(C)(C)O1)O2
Yield: 24.4 %

Procedure:
300 mg (0.71 mmol) of ethyl 6-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-3,3-dimethoxy-1-cyclohexene-1-carboxylate obtained in Example (16a) and 436 mg (1.42 mmol) of (4R,5R)-2,2-dimethyl-4,5-bis[(trimethylsilyl)oxy]methyl[1.3]dioxolane were dissolved in 12 ml of dichloromethane and 26 μl (0.142 mmol) of trimethylsilyl trifluoromethanesulfonate was added thereto with stirring under ice-cooling, followed by stirring for 90 hours at room temperature. Saturated aqueous sodium hydrogencarbonate was added to the reaction solution and the mixture was extracted with dichloromethane. The organic layer was washed with water and dried over anhydrous magnesium sulfate, followed by concentration under reduced pressure. The residue was subjected to silica gel column chromatography (solvent; hexane:ethyl acetate=4:1) to give 90 mg of ethyl (2R)-8-[N-(2-chloro-4-fluorophenyl)sulfamoyl]-2-((4R)-2,2-dimethyl[1.3]dioxolan-4-yl)-1,4-dioxaspiro[4.5]dec-6-ene-7-carboxylate as an amorphous substance (yield: 24%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2].[C:29]1([C:35]#[CH:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(OC(=O)COC1C=CC(SC2C=C(C#CC3C=CC(CO)=CC=3)C=C(OCCC3C=CC(Cl)=CC=3)C=2)=CC=1C)C>>[CH2:1]([O:3][C:4](=[O:28])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:15]=[C:16]([C:36]#[C:35][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:17]=[C:18]([O:20][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:19]=2)=[CH:9][C:8]=1[CH3:27])[CH3:2]
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(OC3CCCC3)c2)cc1C
Reactant: C#Cc1ccccc1
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OC3CCCC3)c2)cc1C

Procedure:
The title product was prepared from [4-(3-Bromo-5-cyclopentyloxy-phenylsulfanyl)-2-methyl-phenoxy]-acetic acid ethyl ester (250 mg; 0.54 mmol), (phenyl acetylene (110 mg; 1.07 mmol) applying the procedure described for {4-[3-[2-(4-Chloro-phenyl)-ethoxy]-5-(4-hydroxymethyl-phenylethynyl)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester. The crude product was purified by preparative HPLC (method B). Yield: 186 mg (70%). HPLC-MS: m/z: 487.1 (M+H)+; Rt: 3.17 min.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:14][CH:13]([OH:15])[CH2:12][N:11]1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])=[O:9])([CH3:6])([CH3:5])[CH3:4].CI.[CH2:25](OCC)C>CN(C)C=O>[C:19]([O:18][C:16]([N:11]1[CH2:12][CH:13]([O:15][CH3:25])[CH2:14][N:10]1[C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])=[O:17])([CH3:22])([CH3:21])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CC(O)CN1C(=O)OC(C)(C)C
Reactant: CCOCC
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC1CN(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C1
Reaction time: 0.5 h

Procedure:
At 0°-5° C., 1.2 g of a sodium hydride dispersion (80 %) are added in portions to a solution of 8.6 g of 4-hydroxy-pyrazolidine-N,N'-dicarboxylic acid di-tert-butyl ester in 90 ml of N,N-dimethylformamide. After stiffing for 30 minutes at 0°-5° C., a solution of 2.5 ml of methyl iodide in 10 ml of N,N-dimethylformamide is added dropwise thereto. Stirring is then continued for 3 hours at 0°-5° C. and then 500 ml of diethyl ether are added thereto. The organic phase is washed with water, dried over sodium sulfate and concentrated to yield 8.0 g of the desired product, 4-methoxy-pyrazolidine-N,N'-dicarboxylic acid di-tertbutyl ester, in the form of a yellow oil.
Reaction SMILES: [H][H].[O:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][C:17]([N+:19]([O-])=O)=[CH:18][C:13]=2[S:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]>[Pd].C(O)C.O1CCCC1>[O:3]=[C:4]([C:10]1[C:14]2[CH:15]=[CH:16][C:17]([NH2:19])=[CH:18][C:13]=2[S:12][CH:11]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)C(=O)c1csc2cc([N+](=O)[O-])ccc12
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1csc2cc(N)ccc12

Procedure:
To a stirred suspension of 1.1 g of 5% palladium on carbon in 100 ml of ethanol under 60 psi of hydrogen was added in one portion a solution of 1.1 g of ethyl α-oxo-α-(6-nitro-3-benzothienyl)acetate in 25 ml of tetrahydrofuran. The reaction mixture was stirred at 25° C. under 60 psi of hydrogen for forty-five minutes, and then the mixture was filtered and the solvent was evaporated from the filtrate to give ethyl α-oxo-α-(6-amino-3-benzothienyl)acetate. Reaction with methoxylamine and subsequent hydrolysis and hydrogenation provides (6-amino-3-benzothienyl)glycine.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([C:17]([NH:19][C@@H:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C@@H:21]1[NH:26][C:27]([C:29]1[S:30][C:31]3[CH2:32][N:33]([CH3:38])[CH2:34][CH2:35][C:36]=3[N:37]=1)=[O:28])=[O:18])=[CH:11]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])O.[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl.O1CCCC1.CN(C)C=O.C(N(CC)CC)C>[CH3:38][N:33]1[CH2:34][CH2:35][C:36]2[N:37]=[C:29]([C:27]([NH:26][C@@H:21]3[CH2:22][CH2:23][CH2:24][CH2:25][C@@H:20]3[NH:19][C:17]([C:12]3[NH:13][C:14]4[C:10]([CH:11]=3)=[CH:9][C:8]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][CH:15]=4)=[O:18])=[O:28])[S:30][C:31]=2[CH2:32]1
Reactant: C#C[Si](C)(C)C
Reactant: CN1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NC(=O)c3cc4cc(Br)ccc4[nH]3)sc2C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3NC(=O)c3cc4cc(C#C[Si](C)(C)C)ccc4[nH]3)sc2C1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
Triethylamine (6 ml), N,N-dimethylformamide (5 ml), trimethylsilylacetylene (0.250 ml) and palladium acetate (20 mg) were added to a tetrahydrofuran solution (2 ml) of (±)-cis-N1-[(5-bromoindol-2-yl)carbonyl]-N2-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine (300 mg) and triphenylphosphine (70 mg) at room temperature. After stirring at 90° C. for 2 hours, the reaction mixture was allowed to cool to room temperature, and dichloromethane (20 ml) and a saturated aqueous solution (30 ml) of sodium hydrogencarbonate were added to conduct liquid separation. The resultant water layer was extracted with dichloromethane (3×10 ml), the organic layers were collected and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain residue. The resultant residue was purified by preparative thin-layer chromatography on silica gel (dichloromethane:acetone:methanol=10:10:1) to obtain a mixture mainly containing (±)-cis-N1-[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]-N2-[[5-(trimethylsilylethynyl)indol-2-yl]carbonyl]-1,2-cyclohexanediamine as a colorless solid. This product was dissolved in methanol (6 ml), potassium carbonate (120 mg) was added, and the mixture was stirred for 1 hour. Dichloromethane (20 ml) and water (20 ml) were added to the reaction mixture to conduct liquid separation. The resultant water layer was extracted with dichloromethane (2×15 ml), the organic layers were collected and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resultant residue was purified by preparative thin-layer chromatography on silica gel (dichloromethane:acetone:methanol=10:10:1) and dissolved in water-methanol-dichloromethane. The resultant solution was then concentrated to obtain the title compound (72 mg) as a pale yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][C:17]=3[Cl:19])[C:12](=[O:20])[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:10]2)=[CH:4][CH:3]=1.[Cl-].[CH3:27][Zn+].O>O1CCCC1.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>[Cl:19][C:17]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:18]=1[N:9]([CH2:8][C:5]1[CH:6]=[N:7][C:2]([CH3:27])=[CH:3][CH:4]=1)[N:10]=[C:11]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:12]2=[O:20]
Reactant: CCOC(=O)c1nn(Cc2ccc(Br)nc2)c2c(Cl)cccc2c1=O
Reactant: C[Zn+]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1nn(Cc2ccc(C)nc2)c2c(Cl)cccc2c1=O
Reaction time: 0.25 h

Procedure:
Ethyl 1-[(6-bromopyridin-3-yl)methyl]-8-chloro-4-oxo-1,4-dihydrocinnoline-3-carboxylate [(Example 69, Step 1), 0.11 g, 0.25 mmol] was dissolved in tetrahydrofuran (1.5 mL), sparged under nitrogen and treated with methylzinc chloride (0.18 mL, 2.0 M tetrahydrofuran solution, 0.35 mmol, 1.4 equiv) and 1,1′bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (10 mg, 0.013 mmol, 0.05 equiv). After stirring for 15 minutes, tetrakis(triphenylphosphine)palladium(0) (58 mg, 0.050 mmol, 0.2 equiv) were added and the mixture was stirred at ambient temperature for an additional 2 hours. The mixture was poured into water, extracted twice with ethyl acetate and the combined organic extracts were dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 0:100; hexanes:ethyl acetate), providing the titled compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:13](=[O:22])[N:14]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[N:15]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([CH:43]=1)[C:40](O)=[O:41])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]1[CH:36]=[CH:37][C:38]([CH3:44])=[C:39]([C:40]([N:19]2[CH2:20][CH2:21][CH:16]([N:14]3[C:13](=[O:22])[C:12]([CH2:25][CH3:26])([CH2:23][CH3:24])[C:11]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=4)=[N:15]3)[CH2:17][CH2:18]2)=[O:41])[CH:43]=1)[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: Cc1ccc(OCc2ccccc2)cc1C(=O)O
Reactant: CCC1(CC)C(=O)N(C2CCNCC2)N=C1c1ccc(OC)c(OC)c1
Product: CCC1(CC)C(=O)N(C2CCN(C(=O)c3cc(OCc4ccccc4)ccc3C)CC2)N=C1c1ccc(OC)c(OC)c1

Procedure:
The title compound is prepared analogously as described for GP2-WU2 using 5-(3,4-dimethoxyphenyl)-4,4-diethyl-2-piperidin-4-yl-2,4-dihydro-3H-pyrazol-3-one (compound B7) and 5-(benzyloxy)-2-methylbenzoic acid (compound F1) as starting compounds. The crude product is purified by chromatography (amino phase silica gel and DCM) and by a second chromatography (silica gel and cyclohexane/EA=1:1) to yield the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](Cl)(=[O:14])=[O:13])[CH:7]=1.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C([O-])(O)=O.[Na+]>O1CCOCC1.O>[CH3:1][O:2][C:3](=[O:16])[CH:4]=[CH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:14])(=[O:13])[NH:17][CH2:18][C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[CH:7]=1
Reactant: NCc1cccnc1
Reactant: COC(=O)C=Cc1cccc(S(=O)(=O)Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)C=Cc1cccc(S(=O)(=O)NCc2cccnc2)c1
Yield: 71.2 %

Procedure:
A solution of 3-(3-chlorosulfonylphenyl)acrylic acid methyl ester (3) (0.40 g, 1.53 mmol) in dioxane (5 ml) was added to a mixture of 3-(aminomethyl)pyridine (0.16 g, 1.48 mmol) in dioxane (1 ml) and NaHCO3 (0.37 g, 4.49 mmol) in water (3 ml), and the resultant solution was stirred at room temperature until the completion of the reaction (control by TLC). The reaction mixture was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed successively with water, saturated NaCl, and dried (Na2SO4). The solvent was removed and the residue was chromatographed on silica gel with dichloromethane-methanol (20:1, v/v) as eluent. The obtained product was washed with diethyl ether to give the title compound (0.35 g, 71%) as a white solid. 1H NMR (DMSO-d6, HMDSO), δ: 3.76 (3H, s); 4.09 (2H, d, J=6.0 Hz); 6.72 (1H, d, J=16.2 Hz); 7.29 (1H, dd, J=8.0 and 5.0 Hz); 7.51-8.12 (6H, m); 8.27 (1H, br t, J=6.0 Hz); 8.31-8.50 (2H, m).
Reaction SMILES: [F:1][C:2]([F:23])([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1)[CH2:3][NH:4][C:5]1[C:6](=[O:16])[N:7]([CH2:12][C:13]([OH:15])=O)[C:8]([CH3:11])=[CH:9][N:10]=1.[F:24][C:25]([F:34])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH2:27]>>[F:34][C:25]([F:24])([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[CH2:26][NH:27][C:13](=[O:15])[CH2:12][N:7]1[C:8]([CH3:11])=[CH:9][N:10]=[C:5]([NH:4][CH2:3][C:2]([F:1])([F:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[C:6]1=[O:16]
Reactant: NCC(F)(F)c1ccccn1
Reactant: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)O
Product: Cc1cnc(NCC(F)(F)c2ccccn2)c(=O)n1CC(=O)NCC(F)(F)c1ccccn1

Procedure:
5-1 was prepared from [3-(2,2-difluoro-2-pyridin-2-yl-ethylamino)-6-methyl-2-oxo-2H-pyrazin-1-yl]-acetic acid and 2,2-difluoro-2-(2-pyridyl)ethyl amine essentially according to the procedure of Example 1, Step K. Mass Spectrum: Found: (M+1)465.2.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH2:13].C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](Cl)=[O:30])=[CH:27][CH:26]=1>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[NH:13][C:29](=[O:30])[C:28]1[CH:32]=[CH:33][C:25]([O:24][C:23]([F:22])([F:34])[F:35])=[CH:26][CH:27]=1
Reactant: O=C(Cl)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc([N+](=O)[O-])cc1NC(=O)c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.7 %

Procedure:
To a solution of 2-amino-4-nitro-benzoic acid methyl ester (5.00 g, 25.5 mmol) in methylene chloride (75 mL) was added triethylamine (4.13 g, 40.8 mmol) followed by 4-trifluoromethoxy-benzoyl chloride (6.87 g, 30.6 mmol). This mixture was allowed to stir overnight at ambient temperature. The mixture was filtered, partitioned against brine, the layers were separated, and the aqueous layer was extracted with one portion of ethyl acetate. The organics were combined, dried over MgSO4, filtered and concentrated under reduced pressure. The crude material was recrystallized from ethyl acetate (250 mL) to give 4-nitro-2-(4-trifluoromethoxy-benzoylamino)-benzoic acid methyl ester (6.83 g, 70%) as pale-yellow crystals. 1H NMR (500 MHz, DMSO-d6); δ 11.53 (s, 1H), 9.20 (d, 1H), 8.19 (d, 1H), 8.10 (d, 2H), 8.07 (dd, 1H), 7.63 (d, 2H), 3.91 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])(=O)=O.[CH3:24][CH:25]([CH3:28])[C:26]#[CH:27]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CC#N.CCN(CC)CC.[Cu]I.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>[CH3:24][CH:25]([CH3:28])[C:26]#[C:27][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][C:8]=1[NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20]
Reactant: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1OS(=O)(=O)C(F)(F)F
Reactant: C#CC(C)C
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCC(=O)Nc1cc([N+](=O)[O-])ccc1C#CC(C)C
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
A mixture of 2-butyramido-4-nitrophenyl trifluoromethanesulfonate (Compound 118, 200 mg, 0.56 mmol), CuI (32 mg, 0.17 mmol), and n-Bu4NI (311 mg, 0.84 mmol) in CH3CN (5 ml) and Et3N (1 ml) was purged with N2 for 10 min and Pd(PPh3)4 (64 mg, 0.056 mmol) was added and the mixture was purged with N2 for another 5 min. The mixture was then cooled to 0° C. and 3-methyl-1-butyne (76 mg, 1.12 mmol) was added. After 5 min, the reaction was quenched with aqueous NaHCO3, extracted with EtOAc (×3). The combined organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→20% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([N:24]([C:29]3[CH:34]=[CH:33][C:32]([N+:35]([O-])=O)=[CH:31][C:30]=3[F:38])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:6][C:7]3[O:11][C:10]([C:12]4[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=4)=[C:9]([C:19]([NH:21][CH3:22])=[O:20])[C:8]=3[CH:23]=2)[CH2:3][CH2:2]1.O.O.[Sn](Cl)Cl>C(OCC)(=O)C.C(O)C>[NH2:35][C:32]1[CH:33]=[CH:34][C:29]([N:24]([C:5]2[C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:23][C:8]3[C:9]([C:19]([NH:21][CH3:22])=[O:20])=[C:10]([C:12]4[CH:13]=[CH:14][C:15]([F:18])=[CH:16][CH:17]=4)[O:11][C:7]=3[CH:6]=2)[S:25]([CH3:28])(=[O:27])=[O:26])=[C:30]([F:38])[CH:31]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc([N+](=O)[O-])cc3F)S(C)(=O)=O)c(C3CC3)cc12
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(c3ccc(N)cc3F)S(C)(=O)=O)c(C3CC3)cc12
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A suspension of 5-cyclopropyl-6-(N-(2-fluoro-4-nitrophenyl)methylsulfonamido)-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (420 mg, 0.77 mmol) and tin(II) chloride dihydrate (519 mg, 2.31 mmol) in ethyl acetate (15 mL) and ethanol (15 mL) was heated at 80° C. for 2 hours. The solution was cooled to room temperature and concentrated, diluted with ethyl acetate (50 mL) and washed with sodium carbonate solution. The organic layer was dried over sodium sulfate, filtered, concentrated to dryness, and purified by column chromatography to afford 6-(N-(4-amino-2-fluorophenyl)methylsulfonamido)-5-cyclopropyl-2-(4-fluorophenyl)-N-methylbenzofuran-3-carboxamide (360 mg, 0.7 mmol, 91% yield) as a yellow solid. LCMS (m/z, ES+)=512 (M+H+).
Reaction SMILES: C([O:8][CH2:9][C:10]1([O:23][CH3:24])[CH2:15][CH2:14][N:13]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:12][CH2:11]1)C1C=CC=CC=1.[H][H]>[OH-].[OH-].[Pd+2].CO>[OH:8][CH2:9][C:10]1([O:23][CH3:24])[CH2:11][CH2:12][N:13]([C:16]([O:18][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:17])[CH2:14][CH2:15]1
Reactant: COC1(COCc2ccccc2)CCN(C(=O)OC(C)(C)C)CC1
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: COC1(CO)CCN(C(=O)OC(C)(C)C)CC1
Yield: 78.5 %

Procedure:
20% palladium hydroxide on carbon (270 mg) was suspended in a MeOH (81 ml) solution of tert-butyl 4-[(benzyloxy)methyl]-4-methoxypiperidine-1-carboxylate (2.7 g), and stirred under a flow of hydrogen gas at room temperature for 4 hours. After filtering using Celite, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (EtOAc) to obtain tert-butyl 4-(hydroxymethyl)-4-methoxypiperidine-1-carboxylate (1.55 g).
Reaction SMILES: C([O:3][C:4](=[O:33])[C:5](=[O:32])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[C:20]([OH:27])=[C:19]([C:28]([CH3:31])([CH3:30])[CH3:29])[CH:18]=2)=[CH:8][CH:7]=1)C.[OH-].[Na+]>CO>[CH3:31][C:28]([C:19]1[CH:18]=[C:17]([S:16][CH2:15][CH2:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([C:5](=[O:32])[C:4]([OH:33])=[O:3])=[CH:11][CH:10]=2)[CH:22]=[C:21]([C:23]([CH3:24])([CH3:25])[CH3:26])[C:20]=1[OH:27])([CH3:29])[CH3:30]
Reactant: CCOC(=O)C(=O)c1ccc(OCCCSc2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)c1cc(SCCCOc2ccc(C(=O)C(=O)O)cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
As in Example 19, a solution of 4-[3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl] thio]propoxy]-alpha-oxobenzeneacetic acid ethyl ester (0.32 g) in methanol (15 mL) was treated with 2N sodium hydroxide (0.75 mL) was stirred at room temperature. After 3 hours, most of the methanol was removed in vacuo, then the mixture was acidified with 3N hydrochloric acid and extracted with dichloromethane-tetrahydrofuran (1:1). The dried (MgSO4) extracts were evaporated and the crude product was purified by flash chromatography over silica gel (toluene-ethyl acetate-acetic acid; 80:20:0.25 increasing to 74:25:1) to give 4-[3-[[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]thio]propoxy]-alpha-oxobenzeneacetic acid as an oil.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([P:23](Cl)(Cl)=[O:24])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([P:23]2(=[O:24])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH2:1][N:8]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(CNc2ccccc2)cc1
Reactant: COc1cccc(P(=O)(Cl)Cl)c1
Product: COc1cccc(P2(=O)c3ccccc3CN2c2ccccc2)c1
Yield: 27 %

Procedure:
The procedure of Example 1 was employed utilizing N-benzylaniline and 3-methoxyphenyl phosphonic dichloride. The reaction of the dilithio compound and the 3-methoxyphenyl phosphonic dichloride was conducted at 0° C. to yield 1-(3-methoxyphenyl)-2-phenyl-2,3-dihydro-1H-2,1-benzazaphosphole-1-oxide (2.75 g, 27% yield) as a solid having a melting point of 170°-172° C. and the following analysis:
Reaction SMILES: [Cl-].[CH3:2][O:3][CH:4]=C1C=CC=CC1[PH+](C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1.C([Li])CCC.[Cl:34][C:35]1[C:36]([N:45]2[C:49]([CH:50]=O)=[C:48]([C:52]#[N:53])[CH:47]=[N:46]2)=[N:37][N:38]([CH3:44])[C:39]=1[O:40][CH:41]([F:43])[F:42]>CCCCCC.C(OCC)(=O)C.O>[Cl:34][C:35]1[C:36]([N:45]2[C:49]([CH:50]=[CH:2][O:3][CH3:4])=[C:48]([C:52]#[N:53])[CH:47]=[N:46]2)=[N:37][N:38]([CH3:44])[C:39]=1[O:40][CH:41]([F:43])[F:42]
Reactant: COC=C1C=CC=CC1[PH+](c1ccccc1)c1ccccc1
Reactant: Cn1nc(-n2ncc(C#N)c2C=O)c(Cl)c1OC(F)F
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC=Cc1c(C#N)cnn1-c1nn(C)c(OC(F)F)c1Cl
Reaction time: 0.5 h

Procedure:
2.9 g (8.4 mmol) methoxymethylene-triphenylphosphonium chloride is added to 10 ml tetrahydrofuran and 5.6 ml (9.0 mmol) of a 1,6 molar solution of butyl lithium in hexane is slowly added dropwise at 0° C. The orange-coloured solution is stirred for another 30 minutes and then 1.0 g (3.3 mmol) 1-(4-chlor-5-difluormethoxy-1-methyl-3-pyrazolyl)-5-formyl-4-pyrazol-carbonitrile is slowly added dropwise. Stirring continues for 2 hours at room temperature. The reaction mixture is then added to water, shaken with ethyl acetate, dried over magnesium sulphate and concentrated. Purification is by column chromatography using a hexane/ethyl acetate mixture.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][C:13](=[NH:16])SC)=[O:11])=[N:4][C:5]([Cl:9])=[C:6]([NH2:8])[N:7]=1.[NH2:17][CH2:18][CH2:19][CH2:20]N>CC(O)C>[NH:17]1[CH2:18][CH2:19][CH2:20][NH:16][C:13]1=[N:12][C:10]([C:3]1[C:2]([NH2:1])=[N:7][C:6]([NH2:8])=[C:5]([Cl:9])[N:4]=1)=[O:11]
Reactant: NCCCN
Reactant: CSC(=N)NC(=O)c1nc(Cl)c(N)nc1N
Solvent: CC(C)O
Product: Nc1nc(N)c(C(=O)N=C2NCCCN2)nc1Cl
Temperature: 60 °C

Procedure:
1-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea (Intermediate A) (1.0 g, 2.58 mmol) is suspended in propan-2-ol (10 ml) and 1,3-diaminopropane (0.32 ml, 3.9 mmol) is added. The mixture is heated at 60° C. for 18 hours and then allowed to cool to room temperature and the solids present are collected by filtration. The solids are washed with THF and MeOH to yield the title compound as a yellow solid; [M+H]+ 270