Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[Mg].[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:21])[CH2:19][Cl:20])=[CH:14][CH:13]=1.[Cl-].[NH4+]>CCOCC.C1(C)C=CC=CC=1>[Cl:20][CH2:19][C:18]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)([OH:21])[CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=1[Cl:1]
Reactant: O=C(CCl)c1ccc(Cl)cc1
Reactant: ClCc1ccccc1Cl
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: OC(CCl)(Cc1ccccc1Cl)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 949.5 %

Procedure:
5.0 g (0.031 mol) of 2-chlorobenzyl chloride are added within 5 minutes at from 24° to 36° C. to 9.7 g (0.404 mol) of magnesium turnings in 20 ml of absolute ether. After the reaction has commenced, a solution of 200 ml of absolute ether and 50.2 g (0.31 mol) of 2-chlorobenzyl chloride is added dropwise. The mixture is subsequently refluxed for about a further 10 minutes, the excess magnesium is decanted off under nitrogen, and the Grignard solution is cooled to 0° C. 55.7 g (0.3 mol) of para-chloro-ω-chloroacetophenone dissolved in 350 ml of toluene are then added dropwise, and the reaction mixture is stirred at 0° C. for 1.5 hours and added dropwise at from about 2° to 6° C. to 1.5 l of concentrated ammonium chloride solution. Extraction with methyl tert.-butyl ether and subsequent conventional work-up gives 92.9 g (yield 99%, purity according to HPLC: 68.2%) of 1-chloro-2-(4-chlorophenyl)-3-(2-chlorophenyl)propan-2-ol as a crude oil, which can be further reacted directly. For characterization, the product was recrystallized from n-hexane.
Reaction SMILES: [N:1]1[C:9]([NH2:10])=[C:8]2[C:4]([N:5]=[CH:6][NH:7]2)=[N:3][CH:2]=1.[OH-].[CH2:12]([N+](CCCC)(CCCC)CCCC)CCC.CI.O>C(Cl)Cl.CO>[CH3:12][N:5]1[CH:6]=[N:7][C:8]2[C:4]1=[N:3][CH:2]=[N:1][C:9]=2[NH2:10]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [OH-]
Solvent: ClCCl
Solvent: CI
Solvent: O
Product: Cn1cnc2c(N)ncnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 43.2 g (0.23 mol) of adenine and 210 ml of 40% aqueous tetrabutylammonium hydroxide was stirred at room temperature for 30 minutes and 250 ml of methylene chloride was added. To this heterogenous mixture was added 40 ml (0.64 mol) of methyl iodide in 200 ml of methylene chloride. A further 450 ml of methylene chloride was added and the reaction was stirred vigorously for ten hours. The reaction was cooled to 10° and the liquid phase comprising methylene chloride and water was decanted from a milky precipitate which had formed. Methanol was added to the precipitate and the mixture warmed gently to 40°, cooled to 10° and the resulting granular solid filtered off. The solid was recrystallized from 350 ml of water to provide 20.9 g of 9-methyladenine.
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].Cl.[CH3:33][O:34][NH:35][CH3:36].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>ClCCl.C(N(CC)CC)C>[C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([N:35]([O:34][CH3:33])[CH3:36])=[O:29])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CNOC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccc(Cn2c(C(C)=O)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.4 %

Procedure:
To a solution of 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzoic acid (476 mg) in dichloromethane (10 ml) were added O,N-dimethylhydroxylamine hydrochloride (117 mg), 1-hydroxy-1H-benzotriazole (184 mg) and triethylamine (0.21 ml) and then 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (287 mg) was added at room temperature, and the mixture was stirred at room temperature for 15 hrs. Dichloromethane was added, and the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine and sodium sulfate was added to dry the mixture. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=1/1→1/9) to give the title compound (407 mg, 78%).
Reaction SMILES: [N:1]([CH:4]1[CH2:13][CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([OH:14])[CH2:10]2)[CH2:5]1)=[N+]=[N-].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[NH2:1][CH:4]1[CH2:13][CH2:12][CH:11]2[CH:6]([CH2:7][CH2:8][CH:9]([OH:14])[CH2:10]2)[CH2:5]1
Reactant: [N-]=[N+]=NC1CCC2CC(O)CCC2C1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: NC1CCC2CC(O)CCC2C1

Procedure:
A solution of 17 g (0.09 mole) of 2-azido-6-hydroxydecalin (XII) in 100 ml of absolute tetrahydrofuran was added dropwise, at 40°-50° C., to a suspension of 3.8 g (0.1 mole) of lithium aluminum hydride in 100 ml of absolute tetrahydrofuran. The mixture was then refluxed for 3 hours. Hydrolysis was carried out with dilute sodium hydroxide solution (20 ml), sodium sulfate was added and the mixture was filtered under suction. The filtrate was evaporated down under reduced pressure. The residue was purified via the hydrochloride.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[N:7](C(OCC(Cl)(Cl)Cl)=O)[C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]>CC(O)=O.[Zn]>[Br:1][C:2]1[C:3]([CH3:25])=[N:4][S:5][C:6]=1[NH:7][C@H:8]([C:13]([O:15][CH3:16])=[O:14])[CH2:9][CH:10]([CH3:12])[CH3:11]
Reactant: COC(=O)[C@H](CC(C)C)N(C(=O)OCC(Cl)(Cl)Cl)c1snc(C)c1Br
Agent: [Zn]
Solvent: CC(=O)O
Product: COC(=O)[C@H](CC(C)C)Nc1snc(C)c1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of methyl N-(4-bromo-3-methylisothiazol-5-yl)-N-[(2,2,2-trichloroethoxy)carbonyl]-L-leucinate (24.2 g, 48.8 mmol) in TBF (350 mL) and AcOH (90 mL) was added zinc dust (18.0 g, 275 mmol). The resulting grey suspension was sonicated for 30 min and then stirred at room temperature for 2 h. The reaction mixture was filtered on a pad of celite and concentrated in vacuo. The resulting residue was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography using Et2O in hexane to afford methyl N-(4-bromo-3-methylisothiazol-5-yl)-L-leucinate as a colorless oil which solidified upon standing for 1 h at room temperature under high vacuum to give a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:14])[F:13])[C:3]=1[C:4]([NH2:6])=O.N1C=CC=CC=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O>O1CCOCC1>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[C:7]([C:12]([F:15])([F:13])[F:14])[C:3]=1[C:4]#[N:6]
Reactant: NC(=O)c1c(C(F)(F)F)ccc(Cl)c1Cl
Solvent: C1COCCO1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: N#Cc1c(C(F)(F)F)ccc(Cl)c1Cl
Temperature: 8.5 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
409 g of 2,3-dichloro-6-trifluoromethylbenzamide was dissolved in 2 liters of dioxane, and 263 g of pyridine was further added to the resultant solution. To this solution, 349 g of trifluoroacetic anhydride was added dropwise over 30 minutes while maintaining the temperature from 7 to 10° C. After stirring the solution for 2 hours at 25° C., the reaction mixture was poured into ice water. The precipitated crystals generated were then collected by filtration and were dissolved in ethyl acetate. The solution was then washed with water and saturated saline solution in series and dried over anhydrous magnesium sulfate. The solvent was distilled under reduced pressure, and the crude product obtained was washed with n-hexane and filtered to obtain 358 g of the title compound(mp. 53-54° C.).
Reaction SMILES: [F:1][C:2]1[CH:32]=[C:31]([N+:33]([O-])=O)[CH:30]=[CH:29][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1/[CH:11]=[CH:12]/[C:13]([N:15]1[CH2:20][CH2:19][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][CH2:16]1)=[O:14].[NH4+].[Cl-]>[Fe]>[NH2:33][C:31]1[CH:30]=[CH:29][C:3]([O:4][C:5]2[CH:10]=[CH:9][N:8]=[CH:7][C:6]=2/[CH:11]=[CH:12]/[C:13]([N:15]2[CH2:16][CH2:17][CH:18]([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:25])([CH3:26])[CH3:27])[CH2:19][CH2:20]2)=[O:14])=[C:2]([F:1])[CH:32]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: CC(C)(C)OC(=O)NC1CCN(C(=O)/C=C/c2cnccc2Oc2ccc(N)cc2F)CC1

Procedure:
The title compound was prepared by the reduction of (E)-tert-butyl 1-(3-(4-(2-fluoro-4-nitrophenoxy)pyridin-3-yl)acryloyl)piperidin-4-ylcarbamate (100 mg, 0.21 mmol) in a manner similar to that of Step E of Example 35 using Fe powder (55 mg, 2.7 mmol), NH4Cl (280 mg, 5.3 mmol). The product (90 mg, 95%) was obtained as a light brown solid which was used directly in the subsequent step. MS(ESI+): m/z 457.18 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.N1C=CN=C1.[Cl-].[C:22]([SiH:26]([CH3:28])[CH3:27])([CH3:25])([CH3:24])[CH3:23]>O1CCCC1>[Si:26]([O:15][CH2:14][C:10]1[CH:9]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([NH2:1])=[N:7][CH:6]=2)[CH:13]=[CH:12][CH:11]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:28])[CH3:27]
Reactant: Nc1ccc(-c2cccc(CO)c2)cn1
Reactant: C[SiH](C)C(C)(C)C
Agent: [Cl-]
Agent: c1c[nH]cn1
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCc1cccc(-c2ccc(N)nc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.3 %

Procedure:
4.99 g of [3-(6-aminopyridin-3-yl)phenyl]methanol are placed in a round-bottomed flask and dissolved in 240 ml of tetrahydrofuran. 2.2 g of 1H-imidazole are added thereto, followed by 4.51 g of tert-butyldimethylsilane chloride, and the mixture is left to stir at ambient temperature for 48 hours. The reaction mixture is then hydrolysed with water, and the organic phase, which has been extracted with ethyl acetate, is separated, dried over magnesium sulphate and concentrated under reduced pressure. The residue obtained is purified by silica gel chromatography, elution being carried out with a heptane/ethyl acetate mixture. 7.0 g of compound are obtained.
Reaction SMILES: Cl.[CH:2]1([C:8]2([C:14]([OH:16])=[O:15])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[OH-].[Na+].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCOCC1>[C:24]1([CH2:23][O:22][C:20]([N:11]2[CH2:10][CH2:9][C:8]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]3)([C:14]([OH:16])=[O:15])[CH2:13][CH2:12]2)=[O:21])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)C1(C2CCCCC2)CCNCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC(C(=O)O)(C2CCCCC2)CC1
Temperature: 5 °C
Yield: 74286.4 %

Procedure:
A 2-L, three-necked, round-bottomed flask equipped with a mechanical stirrer and two addition funnels was charged with 4-cyclohexyl-4-piperidinecarboxylic acid hydrochloride (8-3) (157.9 g, 0.637 mol), 1 L of dioxane, and 255 mL of 5 N NaOH solution. The mixture was cooled at about 5° C., and then benzyl chloroformate (92 mL, 0.643 mmol) and 127 mL of 5 N NaOH solution were added dropwise simultaneously via two separate addition funnels while maintaining the temperature at or below 10° C. The reaction was monitored by TLC and, upon completion, the resulting mixture was diluted with 1 L of water and concentrated. The residue was diluted with 2 L of water and the pH was adjusted to about 12 using 5 N NaOH solution. The mixture was then extracted with 1 L of ethyl acetate. The aqueous layer was acidified to pH 1.5-2.0 using 2 N HCl solution, and extracted with three 1-L portions of ethyl acetate. The combined organic layers were washed with 1 L of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated to give 165 g of title compound 8-4 as a white solid.
Reaction SMILES: [CH2:1]([N:4]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6](=O)[C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([S:14](=[O:17])(=[O:16])[NH2:15])[CH:8]=1)[CH:2]=[CH2:3].P(=O)(O)(O)O.[OH2:30]>>[Cl:13][C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][N:4]2[C:1]3[C:21](=[CH:22][CH:23]=[CH:3][CH:2]=3)[CH2:20][CH:19]2[CH3:24])=[O:30])=[CH:8][C:9]=1[S:14](=[O:16])(=[O:17])[NH2:15]
Reactant: O
Reactant: C=CCN(NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1)c1ccccc1
Agent: O=P(O)(O)O
Product: CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1
Reaction time: 4 h

Procedure:
A mixture of 1-allyl-1-phenyl-2-(3-sulfamoyl-4-chlorobenzoyl)-hydrazine (36.6g, 0.1 mole) and orthophosphoric acid, 85% (100 ml) was stirred at 60° for a period of 4 hours. Dilution with water gave crude 1-(4-chloro-3-sulfamoylbenzamido)-2-methylindoline which was purified by recrystallization from isopropanol-n-hexane (60:40).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[C:36]([Cl:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:58])=[C:36]([Cl:48])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4ccccn4)c(Cl)c2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(Cl)c2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(pyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.37 g) was dissolved in dichloromethane (25 ml), and to the solution was added 3-chloroperbenzoic acid (0.2 g) under ice-cooling and the mixture was stirred overnight at room temperature. An aqueous solution of sodium thiosulfate was added to the mixture, the mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: ethyl acetate/hexane), to give 7-[4-(2-butoxyethoxy)phenyl]-N-[3-chloro-4-[hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.24 g) as pale red oil.
Reaction SMILES: [N+](C1C=CC(C[O:11][C:12]([C:14]2[N:15]3[CH:18]([CH:19]([CH3:35])[C:20]=2[S:21][CH:22]2[CH2:26][CH:25]([CH2:27][O:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[O:24][CH2:23]2)[CH:17]([CH:36]([OH:38])[CH3:37])[C:16]3=[O:39])=[O:13])=CC=1)([O-])=O.C(=O)(O)[O-].[Na+:44].O>[Pd].O1CCOCC1>[Na+:44].[OH:38][CH:36]([CH:17]1[C:16](=[O:39])[N:15]2[CH:18]1[CH:19]([CH3:35])[C:20]([S:21][CH:22]1[CH2:26][CH:25]([CH2:27][O:28][C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[O:24][CH2:23]1)=[C:14]2[C:12]([O-:13])=[O:11])[CH3:37]
Reactant: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(COc4ccccc4)C3)C(C)C12
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(O)C1C(=O)N2C(C(=O)[O-])=C(SC3COC(COc4ccccc4)C3)C(C)C12
Yield: 20.4 %

Procedure:
The title compound is prepared by the procedure of Example 18 using 0.320 g of product from Example 25, 0.054 g of sodium bicarbonate, 3.5 ml of water, 8.3 ml of dioxane and 0.166 g of 10% palladium/carbon to give 0.052 g of the desired product.
Reaction SMILES: [CH3:1][S:2]([O-:4])=[O:3].[Na+].Cl[C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:10][C:9](=[O:18])[CH:8]=1>CN(C=O)C.C(Cl)Cl>[CH3:1][S:2]([C:7]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][O:10][C:9](=[O:18])[CH:8]=1)(=[O:4])=[O:3]
Reactant: CS(=O)[O-]
Reactant: CCOC(=O)c1coc(=O)cc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1coc(=O)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.2 g of sodium methylsulfinate are introduced into a solution of 2.02 g of ethyl 4-chloro-2-oxo-2H-pyran-5-carboxylate in DMF, and the mixture is stirred for 2 hours at room temperature. The reaction mixture is diluted with CH2Cl2 and extracted with saturated aqueous NaCl solution. The organic phase is dried with Na2SO4 and evaporated. The distillation residue which has crystallized out is mixed with ether, filtered off with suction and washed with ether. Yield 1.4 g (56.9% of theory); melting point: 95°-97° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.Br[CH2:10][CH2:11][CH2:12][Cl:13].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Cl:13][CH2:12][CH2:11][CH2:10][O:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][CH:4]=1
Reactant: Oc1ccc(I)cc1
Reactant: ClCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: ClCCCOc1ccc(I)cc1
Temperature: 25 °C

Procedure:
A suspension of 4-iodophenol (20 g), 1-bromo-3-chloropropane (18 mL), and potassium carbonate (38 g) in acetone (250 mL) was heated at reflux for 16 h and allowed to cool to room temperature. The suspension was filtered, and the filtrate was evaporated in vacuo. Kugelrohr distillation of the residue (5–10 mm Hg, 210° C.) gave the title compound as a white crystalline solid (22 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([O:20]C)=[O:19])=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>C1COCC1.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([NH:12][C:13]2[CH:17]=[CH:16][S:15][C:14]=2[C:18]([OH:20])=[O:19])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)c1sccc1NC(=O)Cc1ccc(OC)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CC(=O)Nc2ccsc2C(=O)O)cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Methyl 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylate (5.7 g, 18.7 mmol) was dissolved in THF/H2O (40 mL, 4/1, v/v). Sodium hydroxide (2.24 g, 56.1 mmol) was added and the reaction mixture was stirred at 60° C. for 8 h. The resulting solution was acidified with 10% aqueous HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), filtered and concentrated under vacuum to give 3-(2-(4-methoxyphenyl)acetamido)thiophene-2-carboxylic acid. Retention time (min)=1.678, method [1], MS(ESI) 292.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[N:19]([Sn](C)(C)C)[N:18]=[N:17][N:16]=3)[CH:11]=[CH:10][C:9]=2[NH2:24])=[CH:4][CH2:3]1.[K+].[C:27]([C:29]1[N:30]=[C:31]([C:42]([O-])=[O:43])[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=1)#[N:28].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:1][C:2]1([CH3:25])[CH2:7][CH2:6][C:5]([C:8]2[CH:13]=[C:12]([CH2:14][C:15]3[NH:19][N:18]=[N:17][N:16]=3)[CH:11]=[CH:10][C:9]=2[NH:24][C:42]([C:31]2[N:32]([CH2:34][O:35][CH2:36][CH2:37][Si:38]([CH3:41])([CH3:40])[CH3:39])[CH:33]=[C:29]([C:27]#[N:28])[N:30]=2)=[O:43])=[CH:4][CH2:3]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CC1(C)CC=C(c2cc(Cc3nnnn3[Sn](C)(C)C)ccc2N)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CC=C(c2cc(Cc3nnn[nH]3)ccc2NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)CC1

Procedure:
The title compound was prepared from 2-(4,4-dimethyl-cyclohex-1-enyl)-4-(1-trimethylstannanyl-1H-tetrazol-5-ylmethyl)-phenylamine (as prepared in the previous step, 280 mg, 0.626 mmol), potassium 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate (as prepared in Example 11, step (d), 267 mg, 1.56 mmol), PyBroP (466 mg, 1.00 mmol) and DIEA (273 μL, 1.56 mmol) according to the procedure in Example 11, step (f) (128 mg, 38%). 1H-NMR (CDCl3; 400 MHz): δ9.72 (s, 1H), 8.27 (d, 1H, J=8.3 Hz), 7.76 (s, 1H), 7.19 (m, 1H), 7.12 (s, 1H), 5.94 (s, 2H), 5.70 (s, 1H), 4.29 (s, 2H), 3.66-3.64 (m, 2H), 2.27-2.25 (m, 2H), 2.07-2.06 (m, 2H), 1.56-1.51 (m, 2H), 1.09 (s, 6H), 0.99-0.94 (m, 2H), 0.01 (s, 9H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[O:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28](O)=[O:29])[CH:24]=[CH:25][CH:26]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C)C=O.CCOC(C)=O.O>[Cl:20][C:21]1[CH:22]=[C:23]([CH2:27][C:28]([N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]4[C:14]5[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=5[O:12][CH:11]=4)=[CH:7][CH:8]=3)[CH2:3][CH2:2]2)=[O:29])[CH:24]=[CH:25][CH:26]=1
Reactant: O=C(O)Cc1cccc(Cl)c1
Reactant: Nc1nccc2occ(-c3ccc4c(c3)CCN4)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1nccc2occ(-c3ccc4c(c3)CCN4C(=O)Cc3cccc(Cl)c3)c12
Temperature: 25 °C
Reaction time: 96 h
Yield: 67.3 %

Procedure:
A mixture of 3-(2,3-dihydro-1H-indol-5-yl)furo[3,2-c]pyridin-4-amine (150 mg, 0.440 mmol), 3-chlorophenylacetic acid (79 mg, 0.463 mmol), HATU (185 mg, 0.487 mmol), and Hunig's base (0.31 mL, 1.775 mmol) in N,N-Dimethylformamide (DMF) (3 mL) was stirred at room temperature for 4 days. Water (10 mL) was added, the mixture was stirred for about 4 hours, and the precipitate was collected by vacuum filtration. It was purified by flash chromatography (Analogix, 24 g SiO2, 25%-100% EtOAc in hexanes gradient over 30 minutes, then EtOAc for 10 minutes) to give 3-{1-[(3-chlorophenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}furo[3,2-c]pyridin-4-amine (126 mg, 0.296 mmol, 67.4% yield) as an off-white solid. LC/MS (ES) m/z=404, 406 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 3.25 (t, J=8.34 Hz, 2H), 3.93 (s, 2H), 4.25 (t, J=8.46 Hz, 2H), 5.54 (br. s., 2H), 6.93 (d, J=5.81 Hz, 1H), 7.24-7.46 (m, 6H), 7.86 (d, J=5.81 Hz, 1H), 7.92 (s, 1H), 8.16 (d, J=8.34 Hz, 1H).
Reaction SMILES: [O:1]1[C@@H:3]2[CH2:4][C@H:5]([C:22]3[CH:26]=[CH:25][O:24][CH:23]=3)[C@:6]3([CH2:8][CH2:9][C@H:10]4[C@H:19]([C@@:2]123)[CH2:18][CH2:17][C@H:16]1[C@:11]4([CH3:21])[CH2:12][CH2:13][C:14](=[O:20])[CH2:15]1)[CH3:7].C(O[Al](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[H-].O>O1CCCC1>[O:24]1[CH:25]=[CH:26][C:22]([C@H:5]2[CH2:4][C@H:3]3[O:1][C@@:2]43[C@H:19]3[C@H:10]([CH2:9][CH2:8][C@:6]24[CH3:7])[C@:11]2([CH3:21])[C@@H:16]([CH2:15][C@H:14]([OH:20])[CH2:13][CH2:12]2)[CH2:17][CH2:18]3)=[CH:23]1
Reactant: C[C@]12CCC(=O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Agent: CC(C)(C)O[Al](OC(C)(C)C)OC(C)(C)C
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](c3ccoc3)C[C@H]3O[C@]132
Temperature: 25 °C
Reaction time: 20 h
Yield: 95 %

Procedure:
To a solution of 4.5 g of 14β,15β-epoxy-17β-(3-furyl)-5β-androstan-3-one in 30 ml of dry tetrahydrofuran at -78° C., a solution of 9.8 g of tri-tert-butoxyaluminum-hydride in tetrahydrofuran was added dropwise. The mixture was stirred for 20 hrs, then 40 ml of water were added and the temperature raised to 25° C. The aluminum salts were filtered on a celite cake and washed with methanol. The solution was concentrated under reduced pressure and extracted with methylene chloride. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 4.3 g of the title compound (II-b) as a white solid.