Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1(=[O:15])[O:14][C:12](=[O:13])[CH2:11][CH2:10]1.CCN(CC)CC>C1COCC1>[CH2:1]([O:8][C:9](=[O:15])[CH2:10][CH2:11][C:12]([OH:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CCC(=O)O1
Reactant: OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(O)CCC(=O)OCc1ccccc1
Reaction time: 18 h
Yield: 82.8 %

Procedure:
To a solution of 4.13 mL (4.32 g, 40 mmol) of benzyl alcohol and 4.40 g (44 mmol) of succinic anhydride in 100 mL of THF at 0° C. was added at once 12.24 mL (8.90 g, 88 mmol) of Et3N. The mixture was allowed to come to room temperature and stirred for 18 h at which time it was concentrated under vacuum to a viscous oil and partitioned between 100 mL of 1 N HCl and 100 mL of EtOAc. The EtOAc layer was extracted with 84 mL of 5% NaHCO3 solution. The aqueous layer was acidified with concentrated HCl solution to pH 1 and extracted with two 50 mL portions of EtOAc. The EtOAc layers were combined and washed with brine, dried (MgSO4), filtered, and concentrated to give 6.9 g (83%) of 21 as a white chunky solid: 1H NMR (CDCl3) 2.70 (s, 4H), 5.22 (s, 2H), 7.38 (s, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[S:10][CH:11]=[C:12]([C:15]([CH3:17])=O)[C:13]=2[OH:14])[CH:5]=[CH:6][C:7]=1[Cl:8].[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=2)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1>CS(C)=O>[N:18]1([CH2:23][CH2:24][NH:25][C:26]([C:28]2[S:29][C:30]([C:33]([NH:35][N:36]=[C:15]([C:12]3[C:13]([OH:14])=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[S:10][CH:11]=3)[CH3:17])=[O:34])=[CH:31][CH:32]=2)=[O:27])[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: NNC(=O)c1ccc(C(=O)NCCN2CCCC2)s1
Reactant: CC(=O)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Solvent: CS(C)=O
Product: CC(=NNC(=O)c1ccc(C(=O)NCCN2CCCC2)s1)c1csc(-c2ccc(Cl)c(Cl)c2)c1O
Yield: 29 %

Procedure:
2-(3,4-Dichlorophenyl)-3-hydroxy-4-methylcarbonylthiophene (22 mg, 0.075 mmol) in dimethyl sulfoxide (2.0 mL) was heated with 5-(hydrazinocarbonyl)thiophene-2-carboxylic acid [2-(pyrrolidin-1-yl)ethyl]-amide (21 mg, 0.075 mmol) prepared in Reference Synthetic Example 1 at 100° C. for 24 hours. Evaporation of the solvent followed by recrystallization from chloroform (1 mL)-diethyl ether (2 mL) affored 12 mg of the desired product (yield 29%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6]O)[CH2:2]1.C(P(CCCC)CCCC)CCC.[Cl:21][C:22]1[N:23]=[C:24]([Cl:31])[C:25]2[CH:30]=[CH:29][NH:28][C:26]=2[N:27]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C(Cl)Cl>[Cl:21][C:22]1[N:23]=[C:24]([Cl:31])[C:25]2[CH:30]=[CH:29][N:28]([CH2:6][CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)[C:26]=2[N:27]=1
Reactant: Clc1nc(Cl)c2cc[nH]c2n1
Reactant: OCC1CCOC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Product: Clc1nc(Cl)c2ccn(CC3CCOC3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Tetrahydrofuran-3-ylmethanol (8 mL) and tributylphosphine (22 mL) were added to a suspension of 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (10 g) in CH2Cl2 (150 mL) at room temperature. 1,1′-(azodicarbonyl)dipiperidine (22 g) was added thereto under ice-cooling, and the mixture was stirred at room temperature overnight. After Hex (300 mL) was added to the reaction mixture, the mixture was stirred, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (Hex:EtOAc=9:1 to 6:4), whereby 2,4-dichloro-7-(tetrahydrofuran-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine (5.9 g) was obtained as a dark brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:19][C:20]([OH:22])=[O:21])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:28][CH2:29]O>>[CH2:28]([O:21][C:20](=[O:22])[CH2:19][C:11]1[CH:12]=[C:13]([C:15]([F:17])([F:18])[F:16])[CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[CH3:29]
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)Cc1cc(OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (3-benzyloxy-5-trifluoromethyl-phenyl)-acetic acid (1.5 g, 5.4 mmol) in EtOH (30 mL) was added sulfuric acid (1 mL), and the mixture was stirred overnight at room temperature. Once no starting material was seen by analytical LCMS, the reaction was worked up to give (3-Benzyloxy-5-trifluoromethyl-phenyl)-acetic acid ethyl ester.
Reaction SMILES: Cl[C:2]1[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=[C:18]([Cl:19])[C:4]=2[N:3]=1.[Cl:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([Cl:33])[CH:32]=1)[NH2:29].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[Cl:19][C:18]1[C:4]2[N:3]=[C:2]([NH:29][C:28]3[CH:27]=[C:26]([Cl:25])[CH:32]=[C:31]([Cl:33])[CH:30]=3)[N:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[C:5]=2[C:15]([CH:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:17]=1
Reactant: CCOC(=O)CCCn1c(Cl)nc2c(Cl)ccc(C(CC)CC)c21
Reactant: Nc1cc(Cl)cc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)CCCn1c(Nc2cc(Cl)cc(Cl)c2)nc2c(Cl)ccc(C(CC)CC)c21
Yield: 40.1 %

Procedure:
A mixture of ethyl 4-[2,4-dichloro-7-(1-ethylpropyl)-1H-benzimidazol-1-yl]butanoate (Reference Example 33; 500 mg, 1.35 mmol), 3,5-dichloroaniline (655 mg, 4.04 mmol) and p-toluenesulfonic acid monohydrate (257 mg, 1.35 mmol) in 1-methyl-2-pyrrolidinone (4 mL) was irradiated by microwave at 180° C. for 15 min. After cooling, aqueous sodium bicarbonate was added and the mixture was extracted with ethyl acetate. Organic layer was washed with water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 5-20% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give a residue, which was purified by preparative HPLC to give the title compound (270 mg, 0.542 mmol, 40%) as a colorless amorphous.
Reaction SMILES: [CH3:1][SiH:2]([CH3:11])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1.[Br:12]Br>>[CH3:1][Si:2]([CH3:11])([C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[C:5]([Cl:10])[CH:4]=1)[Br:12]
Reactant: BrBr
Reactant: C[SiH](C)c1ccc(Cl)c(Cl)c1
Product: C[Si](C)(Br)c1ccc(Cl)c(Cl)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
A glass reactor was charged with 19.1 g (0.093 mole) of dimethyl(3,4-dichlorophenyl)silane and 200 ml of petroleum ether. This mixture was cooled to -10° C., at which time a solution containing 14.9 g (0.093 mole) of bromine and 200 ml petroleum ether was gradually added, with agitation, to the reaction mixture. A decolorization of the bromine was observed. The cooling bath was removed as the bromine addition progressed. The resultant reaction mixture was stirred for 1 hour at ambient temperature following completion of the bromine addition. The volatile materials present in the reaction mixture were removed by evaporation under reduced pressure. The residue weighed 26.3 g, which is equivalent to a yield of 100 percent.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH2:10])([CH3:5])([CH3:4])[CH3:3].[CH2:12]([C:14]1[CH:19]=[C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:35])[CH3:34])=[CH:27][N:26]=3)[O:22][N:21]=2)[CH:17]=[C:16]([CH3:36])[C:15]=1[CH2:37][CH2:38][C:39](O)=[O:40])[CH3:13]>>[C:2]([O:6][C:7](=[O:11])[CH2:8][CH2:9][NH:10][C:39](=[O:40])[CH2:38][CH2:37][C:15]1[C:16]([CH3:36])=[CH:17][C:18]([C:20]2[N:24]=[C:23]([C:25]3[CH:30]=[C:29]([CH3:31])[C:28]([CH2:32][CH:33]([CH3:34])[CH3:35])=[CH:27][N:26]=3)[O:22][N:21]=2)=[CH:19][C:14]=1[CH2:12][CH3:13])([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCN
Reactant: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)O
Agent: Cl
Product: CCc1cc(-c2noc(-c3cc(C)c(CC(C)C)cn3)n2)cc(C)c1CCC(=O)NCCC(=O)OC(C)(C)C

Procedure:
3-(3-{2-Ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionylamino)-propionic acid tert-butyl ester is prepared in analogy to Example 37 by coupling 3-amino-propionic acid tert-butyl ester hydrochloride with 3-{2-ethyl-4-[5-(5-isobutyl-4-methyl-pyridin-2-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenyl}-propionic acid; LC-MS: tR=1.18 min, [M+H]+=535.33.
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[C:5](=[O:11])[NH:6]2.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH:35]([C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1)=[CH2:36]>C(O)C(O)C.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:43][C:40]1[CH:41]=[CH:42][C:37](/[CH:35]=[CH:36]/[C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2[C:4](=[O:12])[C:5](=[O:11])[NH:6]3)=[CH:38][CH:39]=1
Reactant: O=C1Nc2cccc(I)c2C1=O
Reactant: C=Cc1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CC(O)CO
Product: O=C1Nc2cccc(/C=C/c3ccc(O)cc3)c2C1=O
Temperature: 100 °C
Yield: 13 %

Procedure:
A mixture of 1.0 g (3.6 mmol) of 4-iodo-1H-indole-2,3-dione (Snow, et al., Journal of the American Chemical Society 1977, 99, 373444), 0.42 g (4.2 mmol) of TEA, 0.06 g (0.27 mmol) of palladium(II) acetate, 0.16 g (0.54 mmol) of trio-tolylphosphine and 5.0 g (4.2 mmol) of a 10% solution of 4-vinylphenol in propylene glycol was suspended in 15 mL of dry acetonitrile in a pyrex sealed tube and heated to 100° C. for 4 h. The mixture was cooled to rt, quenched with 50 mL of 10% hydrochloric acid and extracted with two 100 mL-portions of EtOAc. The combined extracts were dried over MgSO4 and concentrated to give a brown solid, which was subjected to chromatography on silica gel, eluting with hexane:EtOAc (3:1), to yield 0.125 g (13%) of trans4-[2-(4-hydroxyphenyl) vinyl]-1H-indole-2,3-dione as a red solid: 1H NMR (DMSO-d6): δ 6.6-7.6 (m, 8H), 7.77 (d, J=16.4 Hz, 1H), 9.85 (bs, 1H), 11.00 (bs, 1H); APCI−MS m/z 264 (M−1)−. Condensation of trans4-[2-(4-hydroxyphenyl)vinyl]-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G gave the title compound in 27% yield as an orange solid: 1H NMR (DMSO-d6): δ 6.78 (d, J=7.8 Hz, 1H), 6.88 (d, J=8.7 Hz, 2H), 7.26 (t, J=7.8 Hz, 1H), ), 7.29 (s, 2H), 7.36 (d, J=16.5 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.57 (d, J=8.7 Hz, 2H), ), 7.81 (d, J=8.7 Hz, 2H), 8.03 (d, J=16.5 Hz 1H), 9.78 (s, 1H), 11.17 (s, 1H), 13.02 (s, 1H); APCI−MS m/z 433 (M−1)−.
Reaction SMILES: [C:1]([C:6](=[CH:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30])[C:7]([O:9]CC)=O)(=[O:5])[CH2:2][CH2:3][CH3:4].C1(OC2C=CC=CC=2)C=CC=CC=1>CCCCCC>[C:1]([C:6]1[C:7](=[O:9])[C:19]2[C:14](=[C:15]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])[CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: CCCC(=O)C(=CNc1ccccc1N1C(=O)c2ccccc2C1=O)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCCCCC
Product: CCCC(=O)c1c[nH]c2c(N3C(=O)c4ccccc4C3=O)cccc2c1=O

Procedure:
Ethyl 2-butyryl-3-(2-phthalimidophenylamino)acrylate (83 g, 0.2 mol) was added portionwise to boiling diphenyl ether and heated under reflux for 45 mins. The mixture was cooled, diluted with hexane and the 3-butyryl-8-phthalimido-4(1H)quinolone (50 g, 67.5%) filtered off, washed with hexane and dried, m.p. 318°-20° C.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:25]>>[F:22][C:19]1[CH:20]=[CH:21][C:16]([CH2:15][O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:25])=[O:2])=[CH:9][CH:10]=2)=[CH:17][CH:18]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Agent: [OH-]
Product: NC(=O)CC(=O)Nc1ccc(OCc2ccc(F)cc2)cc1
Yield: 80 %

Procedure:
The title compound is prepared in analogy to example 3 from N-[4-(4-fluoro-benzyloxy)-phenyl]-malonamic acid methyl ester and ammonium hydroxide. Yield: 80%. Colorless solid. MS: m/e=303.2 (M++H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:18]=[C:19]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:20]=1[OH:21])[NH:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].O.[CH3:27]N(C)C=O>CI>[C:22]([C:19]1[CH:18]=[C:7]([CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:20]=1[OH:21])[N:8]([C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1)[CH3:27])([CH3:25])([CH3:24])[CH3:23]
Reactant: CC(C)(C)c1cc(Nc2ccc(C(=O)O)cc2)cc(C(C)(C)C)c1O
Reactant: CN(C)C=O
Solvent: O
Solvent: CI
Product: CN(c1ccc(C(=O)O)cc1)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1

Procedure:
A solution of 3.4 g (0.010 mole) of 4-(3,5-di-tertiary-butyl-4-hydroxyanilino)benzoic acid (prepared in Example 1) in 35 ml of N,N-dimethylformamide and 3.5 ml of methyl iodide was heated at 95° C. for about 48 hours under nitrogen. The reaction mixture was poured into cold water and the resulting solid was collected and then taken up in chloroform. The chloroform solution was filtered, washed with water, dried with magnesium sulfate and evaporated to give a tan solid. This material was recrystallized first from benzene and then from a mixture of ethanol and water to give 1.5 g of white crystalline 4-(3,5-di-tertiary-butyl-4-hydroxy-N-methylanilino)benzoic acid, m.p. 240°-244° C. Analysis: Calculated for C22H29NO3 : % C, 74.3; % H, 8.2; % N, 3.9. Found: % C, 74.4; % H, 8.3; % N, 3.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16](Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2].[C:34]([C:36]1[CH:41]=[CH:40][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:38][CH:37]=1)#[CH:35].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:33])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][C:21]3[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][N:22]=3)[CH:17]=[C:16]([C:35]#[C:34][C:36]3[CH:37]=[CH:38][C:39]([S:42]([CH3:45])(=[O:44])=[O:43])=[CH:40][CH:41]=3)[CH:15]=2)=[CH:9][C:8]=1[CH3:32])[CH3:2]
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Reactant: CCOC(=O)COc1ccc(Sc2cc(Br)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C
Agent: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(CO)cc3)cc(OCCc3ccc(Cl)cc3)c2)cc1C
Product: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccc(S(C)(=O)=O)cc3)cc(Oc3ccc(C(F)(F)F)cn3)c2)cc1C

Procedure:
The title product was prepared from {4-[3-Bromo-5-(5-trifluoromethyl-pyridin-2-yloxy)-phenylsulfanyl]-2-methyl-phenoxy}-acetic acid ethyl ester (250 mg; 0.46 mmol) and 1-Ethynyl-4-methanesulfonyl-benzene (249.2 mg; 1.38 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: 168 mg (57%). HPLC-MS: m/z: 642.1 (M+H)+; Rt: 2.75 min
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.Br[CH:15]1[CH2:20][CH2:19][CH:18]([C@H:21]2[CH2:26][CH2:25][C@H:24]([CH2:27][CH2:28][CH3:29])[CH2:23][CH2:22]2)[CH2:17][CH2:16]1>[Zn].[Ni](Cl)Cl.O1CCCC1>[CH2:27]([C@H:24]1[CH2:25][CH2:26][C@H:21]([C@H:18]2[CH2:19][CH2:20][C@H:15]([C:2]3[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][CH:3]=3)[CH2:16][CH2:17]2)[CH2:22][CH2:23]1)[CH2:28][CH3:29]
Reactant: FS(F)(F)(F)(F)c1ccc(Br)cc1
Reactant: CCC[C@H]1CC[C@H](C2CCC(Br)CC2)CC1
Agent: Cl[Ni]Cl
Agent: [Zn]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3ccc(S(F)(F)(F)(F)F)cc3)CC2)CC1

Procedure:
A mixture of 18.3 g of 4-bromophenyl-sulfur pentafluoride and 50 ml of tetrahydrofuran is added to a mixture of the organozinc compound prepared from 28.7 g of 1-bromo-4-(trans-4-propylcyclohexyl)-cyclohexane and 7 g of zinc, 13 g of nickel(II) chloride and tetrahydrofuran, and the mixture is heated at the boil for 5 hours. Working up in the customary manner gives 4-(trans-4-(trans-4-propylcyclohexyl)-cyclohexyl)-phenyl-sulfur pentafluoride.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N+:9]([O-])=[CH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][N:14]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[CH:12]=2.CS([Cl:29])(=O)=O>CN(C)C=O.C(OCC)(=O)C>[Cl:29][C:10]1[N:9]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH:17]=[C:16]2[C:11]=1[CH:12]=[C:13]([NH:18][C:19]([CH:21]1[CH2:23][CH2:22]1)=[O:20])[N:14]=[CH:15]2
Reactant: CS(=O)(=O)Cl
Reactant: O=C(Nc1cc2c[n+]([O-])c(-c3ccccc3Cl)cc2cn1)C1CC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1cc2c(Cl)nc(-c3ccccc3Cl)cc2cn1)C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.1 %

Procedure:
A mixture of 3-(2-chlorophenyl)-7-(cyclopropanecarboxamido)-2,6-naphthyridine 2-oxide (200 mg, 0.6 mmol) and methanesulfonyl chloride (0.47 mL, 5.9 mmol) in N,N-dimethylformamide (2.5 mL) was stirred at room temperature for 30 minutes. The reaction mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL) and then saturated sodium bicarbonate solution (20 mL). The organic layer was separated, dried over sodium sulfate, filtered, and evaporated in vacuo to afford a residue that was purified by flash chromatography (silica, 12 g, ISCO, 0-60% ethyl acetate in heptane) to provide the title compound as an off-white solid (170 mg, 80%). 1H NMR (400 MHz, CDCl3) δ 9.09 (s, 1H), 8.97 (s, 1H), 8.35 (s, 1H), 8.06 (s, 1H), 7.75 (dd, J=7.4, 2.0 Hz, 1H), 7.52 (m, 1H), 7.46-7.33 (m, 2H), 1.70-1.60 (m, 1H), 1.25-1.18 (m, 2H), 1.02-0.94 (m, 2H). LCMS (Method E): RT=5.562 min, M+H+=358.0.
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:28]=[C:27]([O:29][CH3:30])[C:26]([O:31][CH3:32])=[C:25]([O:33][CH3:34])[CH:24]=3)[O:19]2)[CH:10]=[C:11]([OH:17])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:6])=[O:5].[CH3:35][CH2:36][CH2:37]Br.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:1][CH2:2][CH2:3][S:4]([C:7]1[CH:8]=[C:9]([C@H:18]2[CH2:22][CH2:21][C@H:20]([C:23]3[CH:24]=[C:25]([O:33][CH3:34])[C:26]([O:31][CH3:32])=[C:27]([O:29][CH3:30])[CH:28]=3)[O:19]2)[CH:10]=[C:11]([O:17][CH2:35][CH2:36][CH3:37])[C:12]=1[O:13][CH2:14][CH2:15][CH3:16])(=[O:5])=[O:6]
Reactant: CCCBr
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CCO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc(S(=O)(=O)CCO)c1OCCC
Temperature: 75 °C

Procedure:
A mixture of trans-2-[3-(2-hydroxyethylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (366 mg, 0.74 mmol), n-propyl bromide (0.12 mL, 1.33 mmol) and potassium carbonate (255 mg, 1.85 mmol) in DMF (3 mL) was heated at 75° C. for 1 h. The reaction mixture was cooled and partitioned between ethyl ether and water, and the aqueous layer was re-extracted with ether (2 x). The organic extracts were combined, dried, and evaporated to dryness. The residue was purified by chromatography to give the title compound: Rf 0.43 (hexane-ethyl acetate; 1:2, v/v); NMR (CDCl3) δ 1.05 & 1.09 (2 t, J=7.5 Hz, 2 CH2CH2CH3), 2.85 (t, J=6.5 Hz, OH), 3.65 (m, SO2CH2), 3.95 (m, SO2CH2CH2); 4.03 & 4.15 (2 t. J=6.5 Hz, 2 CH2CH2CH3), 6.63 (s, 2 H, C5ArH), 7.27 & 7.49 (2 d, J=1.5 Hz, C2ArH).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([CH:7]([CH3:13])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(=[O:6])=[O:5].[Br:14][CH2:15][CH2:16]Br>CCCCCC.CN(C=O)C>[Br:14][CH2:15][CH2:16][C:7]([CH3:13])([S:4]([CH3:3])(=[O:5])=[O:6])[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: CCOC(=O)C(C)S(C)(=O)=O
Reactant: BrCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)(CCBr)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 2.33 g, 58.3 mmol) was washed with hexane (2×10 mL) in a 100 mL two neck round bottom flask under nitrogen then suspended in DMF (30 mL). The suspension was treated dropwise with ethyl 2-(methylsulfonyl)propanoate (10.0 g, 55.49 mmol) in DMF (10 mL). The mixture was stirred 30 min at RT, cooled to 0° C., and treated dropwise with 1,2-dibromoethane (5.17 mL, 58.8). The mixture was allowed to warm to room temperature while stirring overnight. The mixture was quenched with saturated ammonium chloride (100 mL) and the mixture was extracted with diethyl ether (4×50 mL). Combined organics were washed with 50% saturated sodium chloride (4×50 mL), dried (MgSO4), filtered and the filtrate concentrated in vacuo. Crude material was chromatographed over silica gel (350 g, 230-400 mesh) eluting with 10-20% EtOAc/hexane to afford the title compound as a pale yellow oil (7.9 g, 50%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.33 (t, J=7.05 Hz, 3H) 1.64 (s, 3H) 2.49-2.59 (m, 1H) 2.78 (ddd, J=13.89, 10.16, 6.64 Hz, 1H) 3.05 (s, 3H) 3.33-3.41 (m, 1H) 3.46-3.54 (m, 1H) 4.22-4.37 (m, 2H).
Reaction SMILES: I[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1/[C:4](=[CH:12]/[C:13]1[NH:14][CH:15]=[CH:16][CH:17]=1)/[C:5](=[O:11])[NH:6]2.C([O-])([O-])=O.[Na+].[Na+].[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1>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.COCCOC>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:10]=[CH:9][CH:8]=[C:7]3[C:3]=2/[C:4](=[CH:12]/[C:13]2[NH:14][CH:15]=[CH:16][CH:17]=2)/[C:5](=[O:11])[NH:6]3)=[CH:27][CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=C1Nc2cccc(I)c2/C1=C/c1ccc[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: O=C1Nc2cccc(-c3ccc(Cl)cc3)c2/C1=C/c1ccc[nH]1
Temperature: 25 °C

Procedure:
A solution of (Z)-1,3-dihydro-4-iodo-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (40 mg, 0.119 mmol) (Starting Material 1), 2M aqueous Na2CO3 solution (119 μL , 0.238 mmol), (Ph3P)4Pd (5 mg, 0.004 mmol) (Aldrich), and 4-chlorophenylboronic acid (21 mg, 0.134 mmol) (Aldrich) in 4 mL of a 3:1 mixture of 1,2-dimethoxyethane:distilled water was heated at reflux under a nitrogen atmosphere for 20 h. The reaction mixture was allowed to cool to room temperature and then directly purified by column chromatography. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 20% ethyl acetate-hexanes elution) provided a crude yellow solid. Recrystallization from chloroform-pentane yielded pure (Z)-4-(4-chlorophenyl)-1,3-dihydro-3-[(1H-pyrrol-2-yl)methylene]-2H-indol-2-one (34 mg, 89%) as a yellow solid (mp 188-190° C.).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:5]=[CH:6][C:7]=1[OH:8].Br[CH2:27][CH:28]1[CH2:30][C:29]1([F:32])[F:31].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[F:31][C:29]1([F:32])[CH2:30][CH:28]1[CH2:27][O:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[O:10][C:11]3[CH:17]=[C:16]([O:18][CH2:19][C@@H:20]([NH:22][C:23](=[O:25])[CH3:24])[CH3:21])[CH:15]=[CH:14][C:12]=3[N:13]=2)=[CH:3][C:2]=1[F:1]
Reactant: FC1(F)CC1CBr
Reactant: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(O)c(F)c3)oc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](C)COc1ccc2nc(-c3ccc(OCC4CC4(F)F)c(F)c3)oc2c1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 76.3 %

Procedure:
A suspension of N-((2S)-1-((2-(3-fluoro-4-hydroxyphenyl)-1,3-benzoxazol-6-yl)oxy)propan-2-yl)acetamide (290 mg), 1-bromomethyl-2,2-difluorocyclopropane (288 mg) and potassium carbonate (175 mg) in DMF (10 mL) was stirred at 70° C. for 1 hr and 30 min. The reaction mixture was diluted with ethyl acetate, and washed with saturated brine, and the organic layer was subjected to silica gel column chromatography (NH, ethyl acetate), and the solvent was evaporated. The obtained solid was washed with diethyl ether to give the title compound (279 mg).