Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1.O.[Br:12]Br>CC(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[Br:12][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([B:8]([OH:10])[OH:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(B(O)O)cc1
Reactant: BrBr
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Solvent: CC(Cl)(Cl)Cl
Product: OB(O)c1ccc(CBr)cc1
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
A mixture of 4-methylphenylboronic acid (27.2 g; 0.2 mole) in methyl chloroform (250 ml) was heated at reflux with azeotropic removal of water until approximately 2.5 ml of water was collected and a crystalline slurry was formed. A solution of azo(bisisobutyronitrile) (1.0 g) and bromine (32 g) in methyl chloroform (25 ml) was added to the refluxing slurry over 2-3 hours. The mixture was then refluxed until the bromine colour was discharged. The reaction mixture was allowed to cool and stirred at 10°-15° C. for 30 minutes. The suspended solid was collected by filtration, washed with methyl chloroform (2×50 ml) and dried at ambient temperature to give the anhydride of 4-bromomethylphenylboronic acid (29 g) (Compound F) as a white, crystalline solid, which was used without further purification or characterisation.
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[NH2:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31]>>[CH3:1][C:2]([CH2:7][CH2:8][CH:9]=[C:10]([CH3:22])[CH2:11][CH2:12][CH:13]=[C:14]([CH3:21])[CH2:15][CH2:16][CH:17]=[C:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:23][CH2:24][CH:25]1[CH2:29][CH2:28][CH2:27][N:26]1[CH2:30][CH3:31])=[O:6]
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCCC(C)=CC(=O)O
Reactant: CCN1CCCC1CN
Product: CCN1CCCC1CNC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C
Yield: 93.9 %

Procedure:
The procedure of Example 9 was repeated except that 6.1 g of 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid and 3.8 g of 2-aminomethyl-1-ethylpyrrolidine were used as starting materials. 7.8 g (yield 94%) of the title compound was obtained as a brown oil.
Reaction SMILES: [BH4-].[Li+].[N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[CH:5][CH:4]=1.CO>O1CCCC1.CI>[NH:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH2:5][CH2:4]1
Reactant: c1ccc2nccnc2c1
Agent: [BH4-]
Agent: [Li+]
Solvent: CI
Solvent: CO
Solvent: C1CCOC1
Product: c1ccc2c(c1)NCCN2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Under a nitrogen atmosphere, to a solution of lithium borohydride (741 mg) in tetrahydrofuran (50 ml), methyl iodide (1.93 ml) was added dropwise under ice cooling and stirred at room temperature for 10 minutes. To this mixture, a solution of quinoxaline (1.32 g) in tetrahydrofuran (100 ml) was added dropwise over 15 minutes and then stirred at room temperature for 5 minutes. To the reaction mixture, methanol (10 ml) was added and stirred for 5 minutes, followed by addition of additional methanol (40 ml) and stirring at room temperature for 30 minutes. After the reaction mixture was concentrated, the resulting residue was dissolved again in methanol and evaporated under reduced pressure to remove the solvent. The resulting residue was diluted with 4M aqueous sodium hydroxide (100 ml) and extracted four times with chloroform. The combined organic layers were dried over anhydrous sodium sulfate and then filtered to remove the desiccant, followed by distilling off the solvent under reduced pressure. The resulting residue was converted into a powder form by addition of n-hexane, and then collected by filtration to give the titled compound, i.e., 1,2,3,4-tetrahydroquinoxaline (1.17 g) as a light-brown crystal.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[BH4-].[Na+]>CO>[CH2:18]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN1CCC(c2c[nH]c3ccc(NCc4ccccc4)nc23)CC1
Temperature: 40 °C
Reaction time: 5 h

Procedure:
A mixture of 0.25 gm (1.09 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine, 0.5 gm molecular sieves, and 0.22 mL (2.17 mMol) benzaldehyde in 10 mL methanol was stirred at 40° C. for 5 hours. The reaction mixture was then cooled to room temperature and then 0.124 gm (3.27 mMol) sodium borohydride were added. The reaction mixture was then stirred for 30 minutes at room temperature and then the reaction mixture quenched with 1N sodium hydroxide. The reaction mixture was concentrated under reduced pressure and then the aqueous residue was extracted well with 3:1 chloroform:isopropanol. The organic phases were combined, washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing 0-10% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:7][N:6]([N:8]=O)[C:5]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:4]=2[O:3]1.[OH-].[Na+]>CO.O>[NH2:8][N:6]1[C:5]2[CH:10]=[C:11]([N+:14]([O-:16])=[O:15])[CH:12]=[CH:13][C:4]=2[O:3][C:2]([CH3:17])([CH3:1])[CH2:7]1
Reactant: CC1(C)CN(N=O)c2cc([N+](=O)[O-])ccc2O1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(C)CN(N)c2cc([N+](=O)[O-])ccc2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 18.6 %

Procedure:
In 69 ml of methanol was dissolved 2.29 g of 3,4-dihydro-2,2-dimethyl-6-nitro-4-nitroso-2H-1,4-benzoxazine and the solution was cooled on an ice bath. After addition of a solution of 1.16 g of sodium hydroxide in 8.1 ml of water to the above solution, 3.13 g of formamidinosulfinic acid was gradually added. The mixture was stirred at room temperature overnight and, then, concentrated. The concentrate was subjected to column chromatography (eluent: hexane;ethyl acetate=9:1) to give 0.4 g of 4-amino-3,4-dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazine.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][S:6][C:7]1[S:11][C:10]([NH:12][C:13]([N:15]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:26])[CH3:25])[CH:17]=2)=[O:14])=[N:9][CH:8]=1)C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.NC1C=C(NC(=O)C(C)C)C=CC=1.C1(C=O)CCCC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH:29]1([CH2:28][N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:23](=[O:27])[CH:24]([CH3:25])[CH3:26])[CH:17]=2)[C:13](=[O:14])[NH:12][C:10]2[S:11][C:7]([S:6][CH2:5][C:4]([OH:34])=[O:3])=[CH:8][N:9]=2)[CH2:30][CH2:31][CH2:32][CH2:33]1
Reactant: CCOC(=O)CSc1cnc(NC(=O)N(CC2CCCC2)c2cccc(NC(=O)C(C)C)c2)s1
Agent: CC(C)C(=O)Nc1cccc(N)c1
Agent: CCOC(=O)CSc1cnc(N)s1
Agent: O=C(O)Cc1csc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)n1
Product: CC(C)C(=O)Nc1cccc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)c1

Procedure:
The title compound was prepared via {2-[3-cyclopentylmethyl-3-(3-isobutyrylamino-phenyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using N-(3-Amino-phenyl)-isobutyramide, cyclopentanecarbaldehyde and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:12])=[C:9](Cl)[N:8]([CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])[CH3:2].[Cl:17][C:18]1[CH:19]=[C:20]([SH:25])[CH:21]=[C:22]([Cl:24])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:10]([CH:11]=[O:12])=[C:9]([S:25][C:20]2[CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]([Cl:17])[CH:19]=2)[N:8]([CH:14]([CH3:16])[CH3:15])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1nn(C(C)C)c(Cl)c1C=O
Reactant: Sc1cc(Cl)cc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(C(C)C)c(Sc2cc(Cl)cc(Cl)c2)c1C=O
Temperature: 60 °C
Yield: 89.8 %

Procedure:
A solution containing 6 g of 5-chloro-4-formyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester in 10 ml of anhydrous dimethyl formamide was treated at room temperature with 5.28 g of 3,5-dichlorothiophenol and 4.07 g of potassium carbonate. The mixture was then heated at 60° C. for 1 h before being left to cool to room temperature. The solvent removed under reduced pressure and the residue partitioned between dichloromethane and water. The organic extract was washed with brine then dried over anhydrous magnesium sulphate, filtered and evaporated. The residue was purified by flash chromatography on silica gel using diethyl ether/petoleum ether (1:4 to 1:3) for the elution to give 8.53 g of 5-(3,5-dichlorophenylthio)-4-formyl-1-isopropyl-1H-pyrazole-3-carboxylic acid ethyl ester as a yellow oil. Mass spectrum (ESI) m/z [M+H]+.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH:19]=O)=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]1[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=1[N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[CH:8][C:7]([CH2:17][CH2:18][CH2:19][N:32]2[CH2:33][CH2:34][N:29]([C:23]3[CH:24]=[CH:25][CH:26]=[C:27]([CH3:28])[C:22]=3[CH3:21])[CH2:30][CH2:31]2)=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cccc(N2CCNCC2)c1C
Reactant: CC(C)(C)n1nc(CCC=O)cc1-c1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccc(N2CCN(CCCc3cc(-c4ccc(F)cc4)n(C(C)(C)C)n3)CC2)c1C

Procedure:
133 mg (75%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-3-yl)propanal (100 mg, 0.365 mmol), 1-(2,3-dimethylphenyl)piperazine (69 mg, 0.365 mmol), DIPEA (0.1 mL, 0.548 mmol) and NaBH(OAc)3 (232 mg, 1.095 mmol).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([Cl:22])=[CH:16][C:17]=2[CH3:21])[NH:12]1)=[O:10].I[CH2:24][CH2:25][CH2:26][CH3:27].[H-].[Na+]>CN(C=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][NH:8][C:9]([N:11]1[C:19](=[O:20])[C:18]2[C:13](=[N:14][C:15]([Cl:22])=[CH:16][C:17]=2[CH3:21])[N:12]1[CH2:24][CH2:25][CH2:26][CH3:27])=[O:10]
Reactant: CCCCI
Reactant: Cc1cc(Cl)nc2[nH]n(C(=O)NCCc3cccs3)c(=O)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCn1c2nc(Cl)cc(C)c2c(=O)n1C(=O)NCCc1cccs1

Procedure:
In analogy to example 2, 50 mg (0.148 mmol) of 6-chloro-4-methyl-3-oxo-1,3-dihydropyrazolo[3,4-b]pyridine-2-carboxylic acid (2-thiophen-2-ylethyl)amide were reacted with 41 mg (0.22 mmol) of 1-iodobutane in DMF with sodium hydride. Yield: 8 mg (14%), M+H+: 393.47
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([OH:26])[CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[NH2:17][C:18]1[CH:19]=[C:20]([CH:21]=[CH:22][C:23]=1[CH2:24][CH3:25])[O:26][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([NH:11][C:12]([CH:14]3[CH2:16][CH2:15]3)=[O:13])[N:10]=2)[N:7]=1
Reactant: O=C(Nc1cn2nc(I)ccc2n1)C1CC1
Reactant: CCc1ccc(O)cc1N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Temperature: 150 °C
Reaction time: 24 h
Yield: 69.8 %

Procedure:
A mixture of N-(6-iodoimidazo[1,2-b]pyridazin-2-yl)cyclopropanecarboxamide (984 mg, 3.0 mmol), 3-amino-4-ethylphenol (617 mg, 4.5 mmol), potassium carbonate (829 mg, 6.0 mmol) and N,N-dimethylformamide (9 mL) was stirred at 150° C. for 24 hr. The reaction mixture was diluted with water and extracted with a mixed solvent of ethyl acetate/tetrahydrofuran (3:1). The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=50/50→0/100) and recrystallized from a mixed solvent of ethyl acetate/diisopropyl ether to give the title compound (706 mg, yield 70%) as a khaki solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.[CH3:40][C:41]1([CH3:47])[CH2:46][CH2:45][CH2:44][NH:43][CH2:42]1>>[CH3:40][C:41]1([CH3:47])[CH2:46][CH2:45][CH2:44][N:43]([CH2:1][CH2:4][C:5]2[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]3[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=3[C@@H:21]3[CH2:30][CH2:29][C:28]4[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=4[CH2:22]3)=[CH:38][CH:39]=2)[CH2:42]1
Reactant: CC1(C)CCCNC1
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3CCCC(C)(C)C3)cc2)c1
Yield: 12.7 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 3,3-dimethylpiperidine (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (2.4 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[CH3:31])[CH:27]=[CH:26][C:3]=1[C:4]([NH:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH2:17][C:18]3[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=3)[CH:14]=2)[NH:9][N:8]=1)=[O:5].[NH:38]1[CH:42]=[CH:41][CH:40]=[C:39]1[C:43](Cl)=[O:44]>N1C=CC=CC=1>[F:24][C:22]1[CH:23]=[C:18]([CH:19]=[C:20]([F:25])[CH:21]=1)[CH2:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[NH:9][N:8]=[C:7]2[NH:6][C:4]([C:3]1[CH:26]=[CH:27][C:28]([N:30]([CH2:32][CH2:33][CH2:34][N:35]([CH3:36])[CH3:37])[CH3:31])=[CH:29][C:2]=1[NH:1][C:43]([C:39]1[NH:38][CH:42]=[CH:41][CH:40]=1)=[O:44])=[O:5]
Reactant: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(N)c1
Reactant: O=C(Cl)c1ccc[nH]1
Solvent: c1ccncc1
Product: CN(C)CCCN(C)c1ccc(C(=O)Nc2n[nH]c3ccc(OCc4cc(F)cc(F)c4)cc23)c(NC(=O)c2ccc[nH]2)c1
Yield: 65 %

Procedure:
2-Amino-N-[5-(3,5-difluoro-benzyloxy)-1H-indazol-3-yl]-4-[(3-dimethylamino-propyl)-methyl-amino]-benzamide (115 mg, 0.23 mmol) in pyridine (2.2 mL), cooled to 4° C., was treated with solid 1H-pyrrole-2-carbonyl chloride (34 mg, 0.27 mmol). The reaction was stirred until clear and left to room temperature over night. After removal of the volatiles, the crude was purified over silica gel to afford 90 mg of title compound in 66% yield.
Reaction SMILES: [CH2:1]([OH:6])/[CH:2]=[CH:3]\[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1.O>O1CCCC1>[CH2:1]([O:6][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)/[CH:2]=[CH:3]\[CH2:4][CH3:5]
Reactant: Clc1nsnc1-c1cccnc1
Reactant: CC/C=C\CO
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC/C=C\COc1nsnc1-c1cccnc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of cis-2-penten-1-ol (780 mg, 9 mmol) and sodium hydride (310 mg, 9 mmol) in dry tetrahydrofuran was added a solution of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (590 mg, 3 mmol) in dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 1 h. Water was added and the mixture was extracted with ether. The ether phase was dried and evaporated to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CC(C)=O>[CH2:23]([O:7][C:8]1[C:9]([CH3:22])=[C:10]([CH3:21])[C:11]2[O:15][C:14]([CH3:16])([CH3:17])[C:13](=[O:18])[C:12]=2[C:19]=1[CH3:20])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)C(C)(C)O2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(C)c2c(c(C)c1OCc1ccccc1)C(=O)C(C)(C)O2
Temperature: 50 °C
Reaction time: 3 h

Procedure:
Potassium carbonate (720 g) is added to a solution of 5-hydroxy-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-one (453 g, 2.1 mol) in acetone (2 L). A solution of benzyl bromide (423 g, 2.5 mmol) in acetone (200 mL) is added portionwise over a period of 10 min. A slight exotherm is observed. After 3 hrs, the mixture is heated to reflux. After 39 hrs, TLC shows complete conversion to product. The mixture is cooled to 50° C. and filtered using 1.5 L of ethyl acetate to remove the solids from the flask. The solids are washed with ethyl acetate (1.5 L). The filtrate is concentrated. The resulting solids are dissolved in ethyl acetate (7 L). This solution is washed with water, dried (magnesium sulfate) and concentrated. The resulting solids are placed on a tray for air-drying. After 2 days, 5-benzyloxy-2,2,4,6,7-pentamethyl-2,3-d3-onenzofuran-3-one is collected (638g, 99%). mp=114° C.-115° C.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH2:25][CH2:26][OH:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>C(Cl)Cl>[Si:33]([O:27][CH2:26][CH2:25][C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:24]=1)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 25 °C

Procedure:
2-(1-Trityl-1H-imidazol-4-yl)ethanol (20 g, 56.5 mmol) is dissolved in CH2Cl2 (500 mL). To this is added imidazole (11.5 g, 169 mmol) and tert-butyldimethylsilylchloride (10.2 g, 67.8 mmol). The solution is stirred at room temperature until LCMS indicated the reaction is complete. The solution is partitioned between CH2Cl2 and aqueous saturated NaHCO3. The organic layer is washed further with aqueous saturated NaHCO3 and brine.
Reaction SMILES: [CH3:1]C1(CC(O)=O)C2NC3C(C=2CCO1)=CC=CC=3.[CH3:19][O:20][C:21](=[O:37])[CH2:22][C:23]1([CH3:36])[C:28]2[NH:29][C:30]3[C:35]([C:27]=2[CH2:26][CH2:25][S:24]1)=[CH:34][CH:33]=[CH:32][CH:31]=3>>[CH3:19][O:20][C:21](=[O:37])[CH2:22][C:23]1([CH3:36])[C:28]2[N:29]([CH3:1])[C:30]3[C:35]([C:27]=2[CH2:26][CH2:25][S:24]1)=[CH:34][CH:33]=[CH:32][CH:31]=3
Reactant: CC1(CC(=O)O)OCCc2c1[nH]c1ccccc21
Reactant: COC(=O)CC1(C)SCCc2c1[nH]c1ccccc21
Product: COC(=O)CC1(C)SCCc2c1n(C)c1ccccc21

Procedure:
Similarly, the replacement of 1-methyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid by an equivalent amount of 1-methyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester, described in Example 3, affords 1,9-dimethyl-1,3,4,9-tetrahydrothiopyrano[3,4-b]indole-1-acetic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.C(O)(=O)[CH2:14][C:15]([OH:17])=[O:16].N1CCCCC1>N1C=CC=CC=1>[Cl:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([F:12])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:14]/[C:15]([OH:17])=[O:16]
Reactant: O=C(O)CC(=O)O
Reactant: COc1c(F)ccc(C=O)c1Cl
Solvent: C1CCNCC1
Solvent: c1ccncc1
Product: COc1c(F)ccc(/C=C/C(=O)O)c1Cl
Temperature: 90 °C
Reaction time: 3.67 h

Procedure:
To a mixture of 2-Chloro-4-fluoro-3-methoxybenzaldehyde (17.6 g, 93.3 mmol) and malonic acid (18.6 g, 179 mmol) was added pyridine (60 mL) followed by piperidine (1.6 mL, 19 mmol). The mixture was heated in a 90° C. oil bath giving a clear yellow solution. After 220 minutes, the hot solution was poured into 500 mL of ice cold 2.5N HCl with stirring. The resulting solid was isolated by filtration, washing thoroughly with water. Drying under vacuum gave (2E)-3-(2-chloro-4-fluoro-3-methoxyphenyl)acrylic acid as a yellow solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1.C[OH:16]>>[CH3:1][S:2]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:8]=1)=[O:16]
Reactant: CO
Reactant: COC(=O)CCc1ccc(SC)cc1
Product: COC(=O)CCc1ccc(S(C)=O)cc1
Temperature: 0 °C
Yield: 81 %

Procedure:
In a 250 mL round bottom flask, methyl 3-(4-(methylthio)phenyl)propanoate (0.50 g, 2.38 mmol) was dissolved in MeOH under a N2(g). The resulting solution was cooled to 0° C., then 0.5 M NaIO4 (4.76 mL, 2.38 mmol) was added dropwise to the cooled solution causing the formation of a white precipitate. The reaction was allowed to warm to room temperature. When HPLC indicated complete consumption of starting thioether, the reaction was filtered and the filtrate was concentrated. The resulting residue was taken up in CHCl3 (25 mL) then extracted with brine. The brine layer was subsequently extracted with CHCl3 (2×25 mL). The combined organic extracts were then dried over anhydrous Na2SO4(s), filtered and concentrated. The resulting sulfoxide was then purified by passing through a plug of silica using EtOAc/Hexanes as eluant affording methyl 3-(4-(methylsulfinyl)phenyl)propanoate (0.436 g, 81%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:3]=1[CH2:4][OH:5].[F:11][C:12]([F:18])([F:17])[S:13](Cl)(=O)=[O:14].C(N(CC)CC)C.COP(OC)OC>CCOCC>[F:11][C:12]([F:18])([F:17])[S:13]([O:5][CH2:4][C:3]1[C:6]([F:10])=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1])=[O:14]
Reactant: OCc1c(F)cccc1Cl
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: COP(OC)OC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=S(OCc1c(F)cccc1Cl)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 2-chloro-6-fluorobenzyl alcohol (0.50 g, 3.1 mmol) in ether (5 mL) at −10 C was added trifluoromethyl sulphonyl chloride, followed by a mixture of triethylamine (0.411 mL, 3.88 mmol) and trimethylphosphite (0.458 mLm, 3.88 mmol)) in ether (5 mL). The resulting mixture was stirred for 16 hours at room temperature and then partitioned between ether and water. The organic extract was washed with aq. HCl (0.5N), sat. aq. NaHCO3 and dried (MgSO4). The solvent was evaporated in vacuo to afford 2-chloro-6-fluorobenzyl trifluoromethanesulfinate as an oil. 1H NMR (400 MHz, CDCl3)2δ 7.38 (1H, dt, J=6 and 8 Hz) 7.28 (1H, d, J=8 Hz), 7.08 (1H, dt, J=1, 8 Hz), 5.53 (1H, dd, J=1.8 and 11.1 Hz), 5.30 (1H, dd, J=0.7 and 11.1 Hz) ppm.
Reaction SMILES: [CH:1]1([C:4](=[O:25])[CH2:5][C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1.[CH2:26]([O:28][CH:29](OCC)OCC)[CH3:27]>C(OC(=O)C)(=O)C>[CH:1]1([C:4](=[O:25])[C:5](=[CH:29][O:28][CH2:26][CH3:27])[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:15])([F:16])[F:17])=[CH:10][C:9]=2[S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: O=C(CC(=O)C1CC1)c1ccc(C(F)(F)F)cc1Sc1ccccc1
Reactant: CCOC(OCC)OCC
Solvent: CC(=O)OC(C)=O
Product: CCOC=C(C(=O)c1ccc(C(F)(F)F)cc1Sc1ccccc1)C(=O)C1CC1
Yield: 96.8 %

Procedure:
A mixture of 3-cyclopropyl-1-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (6.0 g) and triethylorthoformate (4.9 g) in acetic anhydride was stirred and heated at reflux for 3 hours. It was cooled and evaporated. The residue was treated with toluene and re-evaporated to dryness to give 1-cyclopropyl-2-ethoxymethylene-3-(2-phenylsulphenyl-4-trifluoromethylphenyl)propan-1,3-dione (6.7 g) as a red oil.