Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:14]([CH2:19][Br:20])[CH:15](Br)[S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(OCCCCCCCC(C)C)(OCCCCCCCC(C)C)OCCCCCCCC(C)C>C(OCC)C>[C:1]([NH:9][CH:10]1[C:28](=[O:29])[N:12]2[C:13]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[C:14]([CH2:19][Br:20])[CH2:15][S:16](=[O:17])[C@H:11]12)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)C1=C(CBr)C(Br)S(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Agent: CC(C)CCCCCCCOP(OCCCCCCCC(C)C)OCCCCCCCC(C)C
Solvent: CCOCC
Product: CC(C)(C)OC(=O)C1=C(CBr)CS(=O)[C@@H]2C(NC(=O)c3ccccc3)C(=O)N12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 44.6 %

Procedure:
The remainder of the solution of the 2-bromo-3-bromomethyl compound obtained was used as such in the following debromination process. To this solution which contained at most 14.4 mmoles of t-butyl 7-benzamido-2-bromo-3-bromomethyl-3-cephem-4-carboxylate 1-oxide, were added 14 ml (approximately 25 mmoles) of triisodecyl phosphite and the mixture was stirred for 30 minutes at room temperature. The reaction mixture was then washed with water, dried over magnesium sulfate and filtered. The filtrate was evaporated to dryness and upon addition of a small quantity of acetone, a brown precipitate was formed. Upon addition of diethyl ether, the brown precipitate was decolored almost completely and after standing for one night in the refrigerator, the precipitate was filtered off to obtain 3.0 g (44.6%) of t-butyl 7-benzamido-3-bromomethyl-3-cephem-4-carboxylate 1-oxide.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9].C(N(CC)C(C)C)(C)C.CN(C)CCCN=C=NCC.[C:39]([O:43][C:44]([N:46]1[CH2:51][CH2:50][CH2:49][CH:48]([C:52](O)=[O:53])[CH2:47]1)=[O:45])([CH3:42])([CH3:41])[CH3:40].ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([NH:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:52]([CH:48]3[CH2:49][CH2:50][CH2:51][N:46]([C:44]([O:43][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:45])[CH2:47]3)=[O:53])[CH2:15][CH2:14]2)=[O:12])[CH:6]=[CH:7][C:8]=1[Cl:9]
Reactant: CC(C)(C)OC(=O)N1CCCC(C(=O)O)C1
Reactant: O=C(Nc1ccc(Cl)c(Cl)c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCCC(C(=O)N2CCN(C(=O)Nc3ccc(Cl)c(Cl)c3)CC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a mixture of N-(3,4-dichlorophenyl)piperazine-1-carboxamide hydrochloride (1.0 g) in dichloromethane (100 mL) was added N,N-di-iso-propylethylamine (0.56 mL) at room temperature. After 10 minutes N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide (617 mg) was added followed by 1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (671 mg) and 1-hydroxybenzotriazole (435 mg). The reaction was stirred overnight at room temperature. The reaction mixture was partitioned between dichloromethane and water and the organic layer was washed with brine. The organic extract was dried over magnesium sulfate and evaporated. The residue was purified by silica column chromatography, eluting with a gradient of 0 to 15% ethyl acetate in hexane to give the title compound as a white foam (1.4 g, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:17])([CH3:16])[C:9]([NH:11][CH2:12][CH:13]([CH3:15])[CH3:14])=[O:10])=[CH:4][CH:3]=1.[N:18]1[CH:23]=[C:22](B(O)O)[CH:21]=[N:20][CH:19]=1>>[CH2:12]([NH:11][C:9](=[O:10])[C:8]([CH3:17])([C:5]1[CH:6]=[CH:7][C:2]([C:22]2[CH:23]=[N:18][CH:19]=[N:20][CH:21]=2)=[CH:3][CH:4]=1)[CH3:16])[CH:13]([CH3:15])[CH3:14]
Reactant: OB(O)c1cncnc1
Reactant: CC(C)CNC(=O)C(C)(C)c1ccc(Br)cc1
Product: CC(C)CNC(=O)C(C)(C)c1ccc(-c2cncnc2)cc1

Procedure:
Prepared in a similar manner to Example 1 from 2-(4-bromophenyl)-N-isobutyl-2-methylpropanamide (example 1a) and pyrimidin-5-ylboronic acid. Yeld: 64%. 1H NMR (400 MHz, dMSO): δ 0.75-0.77 (d, 6H), 1.49 (s, 6H), 1.69-1.72 (m, 1H), 2.84-2.87 (t, 2H), 7.41 (t, 1H), 7.45-7.47 (d, 3H), 7.77-7.79 (d, 2H), 9.14 (s, 2H), 9.18 (s, 1H); MS+H (297.7).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[Cl:16][CH2:17][CH2:18][CH2:19][C:20]1([C:25]2[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=2)OCC[O:21]1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl>C(O)CCC.O.C(OCC)(=O)C.CO>[ClH:16].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:17][CH2:18][CH2:19][C:20]([C:25]3[CH:30]=[CH:29][C:28]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:27][CH:26]=3)=[O:21])[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: CS(=O)(=O)Nc1ccc(C2(CCCCl)OCCO2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: O
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CS(=O)(=O)Nc1ccc(C(=O)CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)cc1
Reaction time: 5 h

Procedure:
A mixture of 4-fluorophenyl-4-piperidinyl methanone (3.1 g, 15.0 mmol) and 2-(3-chloropropyl)-2-(4-methanesulfonamidophenyl)-1,3-dioxolane (4.70 g, 14.7 mmol) was prepared in n-butanol (50 mL), treated with potassium carbonate (2.00 g, 14.5 mmol) and a catalytic amount of potassium iodide, and refluxed for 18 hours. The cooled mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried (MgSO4), filtered, and evaporated to an oil. The oil was dissolved in methanol (200 mL), treated with HCl (25 mL of a 10% solution in water), and stirred for 5 hours. The solution was concentrated, made basic with aqueous 5% sodium bicarbonate, and extracted twice with chloroform. The combined organic layers were washed with water, brine, dried (MgSO4), filtered, and evaporated to a yellow solid. The solid was chromatographed on silica gel, eluting with acetone. The appropriate fractions were combined and evaporated to afford a yellow solid. The solid was dissolved in methanol and treated with a slight excess of HCl in methanol. The solution was concentrated and the resulting solid was recrystallized from methanol/butanone to yield the desired product as a tan powder: mp 205°-210° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][OH:39])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1.[C:42](Cl)(=[O:44])[CH3:43].C(N(CC)CC)C.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH2:9][NH:10][CH2:11][CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][NH2:23])[CH:6]=[CH:5][C:4]=1[OH:24].[Cl:25][C:26]1[N:31]=[C:30]([NH:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:42](=[O:44])[CH3:43])[CH:29]=[C:28]([CH2:40][CH3:41])[N:27]=1
Reactant: CC(=O)Cl
Reactant: CCc1cc(NCCCCCCO)nc(Cl)n1
Agent: COc1cc(CNCCCNCCCCNCCCN)ccc1O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(NCCCCCCOC(C)=O)nc(Cl)n1
Yield: 65.4 %

Procedure:
In 10 ml of dichloromethane were dissolved 1.00 g of dl-5-chloro-6-ethyl-4-(6-hydroxyhexyl)aminopyrimidine and 0.40 g of acetyl chloride, and under stirring, 0.50 g of triethylamine was added to the solution and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was neutralized with an aqueous sodium carbonate solution and extracted with dichloromethane. After the organic layer was dried over anhydrous sodium sulfate, the solvent was removed under reduced pressure. The resulting oily product was isolated through a column chromatography (Wako gel C-200, trade name, eluent; toluene:ethyl acetate=4:1) to give 0.70 g of the title compound as pale yellow oily product. nD19.6 1.5228.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([OH:17])=O)=[O:12])[C:4]=2[CH:3]=1.CN1CCOCC1.[NH2:31][C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[O:6][C:7]3[CH:21]=[CH:20][CH:19]=[CH:18][C:8]=3[CH2:9][N:10]([C:11]([NH:13][CH2:14][C:15]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=3)=[O:17])=[O:12])[C:4]=2[CH:3]=1
Reactant: Nc1ccncc1
Reactant: O=C(O)CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: O=C(CNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21)Nc1ccncc1
Yield: 15.3 %

Procedure:
By the method described in Example 5, the title compound of Example 4 (0.5 g, 1.5 mmol) in 20 mL of CH2Cl2 was converted to its mixed anhydride with NMM (0.16 mL, 1.5 mmol) and IBCF (0.2 mL, 1.5 mmol). This intermediate was condensed with 4-aminopyridine (0.21 g, 2.25 mmol) to produce the title compound (94 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:7][C:6]([N+:15]([O-])=O)=[CH:5][N:4]=1>C(O)C.[Pd]>[CH3:1][O:2][C:3]1[N:4]=[CH:5][C:6]([NH2:15])=[CH:7][C:8]=1[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ncc([N+](=O)[O-])cc1-c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: COc1ncc(N)cc1-c1ccccc1
Reaction time: 16 h

Procedure:
A mixture of 2-methoxy-5-nitro-3-phenylpyridine (0.43 mmol, 0.1 g) and Pd/C 10% (0.14 mmol, 0.015 g) in ethanol (2 ml) was stirred for 16 hours under hydrogen atmosphere. The catalyst was filtered off and the solid thoughtfully washed with warm ethanol. The filtrate was evaporated affording 0.085 g (98% of yield) of the expected product.
Reaction SMILES: [F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([F:29])=[C:26]([OH:28])[CH:27]=2)=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15].[C:37]([O:41][CH2:42][CH3:43])(=[O:40])[CH2:38]O>>[F:1][C:2]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:3]=1[CH2:4][N:5]([CH2:16][C:17]1[CH:31]=[CH:30][C:20]([O:21][C:22]2[CH:23]=[CH:24][C:25]([F:29])=[C:26]([CH:27]=2)[O:28][CH2:38][C:37]([O:41][CH2:42][CH3:43])=[O:40])=[CH:19][CH:18]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:7]=1[CH3:15]
Reactant: Cc1c(N(Cc2ccc(Oc3ccc(F)c(O)c3)cc2)Cc2ccc(F)cc2F)cccc1[N+](=O)[O-]
Reactant: CCOC(=O)CO
Product: CCOC(=O)COc1cc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)ccc1F

Procedure:
The product from Example 305G and ethyl glycolate were processed as described in Example 62A to provide the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27]>CN(C=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cnc2cc(Br)ccc2c1Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cnc2cc(Br)ccc2c1NCCCO
Temperature: 0 °C
Yield: 129.3 %

Procedure:
To a round-bottomed flask containing 7-bromo-4-chloro-3-nitroquinoline (60 g, 209.1 mmol) was added DMF (390 mL) and triethylamine (44 mL, 313.6 mmol) and the solution was stirred at 0° C. in an ice-bath. To this cooled solution was added 3-aminopropan-1-ol (17.6 mL, 230.0 mmol) and the reaction was stirred at ambient temperature overnight. The solvent was removed under reduced pressure and the resultant orange solid was recrystallized from ethyl acetate (800 mL). The product was separated by filtration and the solids were washed with diethyl ether and dried under reduced pressure to afford crude 3-[(7-bromo-3-nitroquinolin-4-yl)amino]propan-1-ol (88.15 g) as a brown solid.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[CH:11]2)[CH2:2][CH2:3][CH3:4].[H-].[Na+].I[CH3:21]>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:17])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH3:21])[CH:12]=[CH:11]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)Cc1ccc2[nH]ccc2c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)Cc1ccc2c(ccn2C)c1
Reaction time: 1 h
Yield: 43 %

Procedure:
A solution of N-butylindole-5-acetamide (1.0 g) in dimethylformamide (15 ml) was added to a slurry of sodium hydride (0.11 g) in dimethylformamide (7 ml) at 0° under a nitrogen atmosphere, stirred for 1 hr at 0° and treated with iodomethane (0.3 ml). The reaction was quenched with saturated ammonium chloride solution and diluted with water. The precipitate that formed was collected by filtration, washed with water, and dried under vaccum to give N-butyl-1-methyl-indole-5-acetamide (0.46 g, 43%) as a pale yellow powder: NMR (250 MHz, CDCl3): 0.84(t, 3H, N(CH2)3CH3), 1.38-1.17(m, 4H, NCH2 (CH2)2), 3.16(q, 2H, NCH2), 3.67(s, 2H, ArCH2), 3.80(s, 3H, NCH3), 5.43(br, 1H, NH), 6.45(d, 1H, H2 -indole).
Reaction SMILES: FC(F)(F)C(O)=O.C(O[C:13]([N:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:25]=[CH:24][C:23]([S:26]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][N:33]=[CH:32]4)(=[O:28])=[O:27])=[CH:22][CH:21]=2)[CH2:16]1)=O)(C)(C)C>C(Cl)Cl>[CH3:13][N:15]1[CH2:19][CH2:18][C@@H:17]([C:20]2[CH:21]=[CH:22][C:23]([S:26]([C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[NH:34][N:33]=[CH:32]4)(=[O:27])=[O:28])=[CH:24][CH:25]=2)[CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](c2ccc(S(=O)(=O)c3ccc4[nH]ncc4c3)cc2)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CC[C@@H](c2ccc(S(=O)(=O)c3ccc4[nH]ncc4c3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.8 %

Procedure:
Trifluoroacetic acid (3.4 mL) was added to a solution of (S)-3-[4-(1H-indazole-5-sulfonyl)-phenyl]-pyrrolidine-1-carboxylic acid tert-butyl ester (193.4 mg, 0.452 mmol) in DCM (3.4 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the residue was dissolved in acetonitrile (4 mL). Formaldehyde (37% in water, 0.181 mL) was added, under nitrogen atmosphere, to this material followed by sodiumcyanoborohydride (85 mg). The reaction mixture was stirred for 1.5 hour, and then a saturated solution of Na2CO3 was then added. The mixture was extracted with DCM, and the combined organic extracts were dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude material was dissolved in HCl (2 M, 10 mL) and the resulting mixture was stirred for 8 hours. Solvent was evaporated under reduced pressure and the crude residue was purified via flash chromatography (DCM/MeOH/NH4OH) to give 89.2 mg of 5-[4-((S)-1-methyl-pyrrolidin-3-yl)-benzenesulfonyl]-1H-indazole which was treated with 1,4-dioxane (2 mL) and transformed into 83.3 mg of the corresponding hydrochloride salt by addition of HCl (4 M in 1,4-dioxane, 0.84 mL). MS (M+H)=342.
Reaction SMILES: C([N:4]1[C:8]2[C:9]([Br:13])=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:5]1=[O:20])(=O)C.Cl>C(O)C>[Br:13][C:9]1[C:8]2[NH:4][C:5](=[O:20])[N:6]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:7]=2[CH:12]=[CH:11][CH:10]=1
Reactant: CCOC(=O)Cn1c(=O)n(C(C)=O)c2c(Br)cccc21
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cn1c(=O)[nH]c2c(Br)cccc21
Reaction time: 2 h

Procedure:
Ethyl (3-acetyl-4-bromo-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl)acetate (500 mg, 1.47 mmol) was dissolved in ethanol (10 mL) and 6 M aqueous HCl (20 mL) and heated at reflux. After 2 h, the reaction was concentrated and redissolved in ethanol (10 mL). The mixture was treated with concentrated H2SO4 (0.5 mL) and heated at reflux. After 1 h, the cooled reaction mixture was partitioned between saturated aqueous NaHCO3 and CH2Cl2. The organic layer was dried over sodium sulfate, filtered, and concentrated to give the title compound. MS: m/z=301 (M+1).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[C:3]#[CH:4].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10](Br)[C:9]=1[OH:15]>N1C=CC=CC=1.CCOC(C)=O>[Br:7][C:8]1[C:9]2[O:15][C:3]([C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:4][C:10]=2[CH:11]=[CH:12][CH:13]=1
Reactant: C#CC(C)(C)C
Reactant: Oc1c(Br)cccc1Br
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(C)(C)c1cc2cccc(Br)c2o1
Temperature: 55 °C
Reaction time: 8 h
Yield: 25.7 %

Procedure:
3,3-Dimethylbut-1-yne (1.6 g, 20 mmol) was added to a solution of 2,6-dibromophenol (5.0 g, 20 mmol) and Cu2O (1.7 g, 12 mmol) in dry pyridine (50 mL) under N2, then the mixture was heated to about 55° C. and stirred overnight. The mixture was filtered and the filtrate was concentrated to give a residue, which was dissolved in EtOAc. This solution was washed with brine and dried over Na2SO4. The solvent was removed and the residue was purified by column chromatography to afford 7-bromo-2-tert-butyl-benzofuran (1.3 g, 26%). 1H NMR (CDCl3): 1.40 (S, 9H), 6.41 (s, 1H), 7.04 (t, 1H), 7.38 (d, 1H), 7.42 (d, 1H).
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1.[Cu](C#N)[C:15]#[N:16]>CN1CCCC1=O.O1CCCC1>[C:15]([C:2]1[C:7]([CH3:8])=[CH:6][C:5]([S:9]([NH2:12])(=[O:11])=[O:10])=[C:4]([CH3:13])[CH:3]=1)#[N:16]
Reactant: Cc1cc(S(N)(=O)=O)c(C)cc1Br
Reactant: N#C[Cu]C#N
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: Cc1cc(S(N)(=O)=O)c(C)cc1C#N
Temperature: 200 °C

Procedure:
To a solution of 4-bromo-2,5-dimethylbenzenesulfonamide (4.6 g, 22 mmol, the product of Step A) in N-methylpyrrolidinone (30 mL) was added copper cyanide (2.5 g, 28 mmol), and the reaction mixture was heated at 200° C. for 30 min. The reaction was then allowed to cool and poured into 200 mL of crushed ice to precipitate a solid. To this mixture was added dichloromethane (500 mL), and the mixture was warmed to dissolve the white solid. The mixture was then filtered to remove any undissolved solids, the phases were separated, and the dichloromethane was washed with water (2×100 mL), dried over magnesium sulfate, and evaporated under reduced pressure to obtain an oil. The oil was dissolved in tetrahydrofuran (30 mL) and water (30 mL), and the solution was concentrated under reduced pressure to precipitate a solid. This solid was isolated by filtration and washed with water to afford 2.5 g of the title compound. 1H NMR (CDCl3) δ 7.98 (s, 1H), 7.56 (s, 1H), 4.89 (br s, 2H), 2.66 (s, 3H), 2.58 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13]Br)[CH2:3]1.[OH:25][C:26]1[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[OH:1][C@@H:2]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:19]2[CH2:18][CH2:17][C@@:16]2([CH3:24])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:12](=[O:15])[CH2:13][O:25][C:26]2[CH:27]=[N:28][CH:29]=[CH:30][CH:31]=2)[CH2:3]1
Reactant: Oc1cccnc1
Reactant: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)CBr)CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@]12CC[C@@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](C(=O)COc3cccnc3)CC[C@@H]12
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 3α-hydroxy-21-bromo-5β-pregnan-20-one (300 mg, 0.76 mmol) in DMF (5 mL) was added 3-hydroxypyridine (215 mg, 2.27 mmol) and K2CO3 (313 mg, 2.27 mmol) and the mixture obtained was sired at 25° C. for 0.5 h. The reaction mixture was then poured into a separatory funnel containing water (30 mL) and the mixture was extracted with EtOAc (3×35 mL). The combined extracts were washed with water (2×25 mL) and then dried over Na2SO4. Removal of the solvent in vacuo resulted in the crude product which was purified by flash chromatography over silica gel to yield the pure 3α-hydroxy-21-(pyrid-3-yl)oxy-5β-pregnan-20-one (50 mg); mp 63-66° C.; TLC Rf (MeOH:CH2Cl2 5:95)=0.15.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@@H:9]([C@@H:15]1[C@@:19]2([CH3:35])[CH2:20][CH2:21][C@@H:22]3[C@@:27]4([CH3:33])[CH2:28][CH2:29][C@@H:30]([OH:32])[CH2:31][C@H:26]4[CH2:25][C@H:24](O)[C@H:23]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:10][CH2:11][C:12](O)=[O:13].C(Cl)(=O)C(C)(C)C.[NH2:43][CH2:44][CH2:45][S:46]([OH:49])(=[O:48])=[O:47]>O1CCOCC1.[OH-].[Na+].C(Cl)(Cl)Cl.CO.CC(O)=O>[CH3:8][C@@H:9]([C@@H:15]1[C@@:19]2([CH3:35])[CH2:20][CH2:21][C@@H:22]3[C@@:27]4([CH3:33])[CH2:28][CH2:29][C@@H:30]([OH:32])[CH2:31][C@H:26]4[CH2:25][CH2:24][C@H:23]3[C@@H:18]2[CH2:17][CH2:16]1)[CH2:10][CH2:11][C:12]([NH:43][CH2:44][CH2:45][S:46]([OH:49])(=[O:48])=[O:47])=[O:13]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3[C@@H](O)C[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: NCCS(=O)(=O)O
Agent: CC(C)(C)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: C[C@H](CCC(=O)NCCS(=O)(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 10 °C
Reaction time: 3 h

Procedure:
2.5 g (24.75 mmol) of triethylamine are added dropwise at a temperature of 20° C. to a suspension of 9.6 g (24.45 mmol) of ursodeoxycholic acid in 60 ml of dioxane. Once solubilized, the mixture is cooled to 10° C., 2.98 g (24.70 mmol) of pivaloyl chloride are added slowly and the temperature is then allowed to rise spontaneously to 20° C. The salts formed are filtered off and the precipitate is washed with dioxane, the washings being added to the solution. 3.84 g (30.72 mmol) of taurine dissolved in 24 ml of 1N NaOH are added to the solution obtained and the mixture is stirred for 3 hours at 15° C. The reaction can be followed by thin layer chromatography using CHCl3 /MeOH/AcOH=70/30/5 as the eluent.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH:15]=[C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C@H:18]([OH:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[N:6]=1.Br>>[NH2:1][C:2]1[O:3][CH:4]=[C:5]([C:7]2[C@:8]3([CH2:25][CH2:24][C@H:23]4[C@@H:13]([CH2:14][CH:15]=[C:16]5[C@:21]4([CH3:22])[CH2:20][CH2:19][C:18](=[O:26])[CH2:17]5)[C@@H:10]3[CH2:11][CH:12]=2)[CH3:9])[N:6]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3coc(N)n3)=CC[C@@H]12
Agent: Br
Product: C[C@]12CCC(=O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3coc(N)n3)=CC[C@@H]12

Procedure:
In an analogous manner to example 2 the title compound is prepared from (3β)-17-(2-amino-4-oxazolyl)-androsta-5,16-dien-3-ol.HBr prepared in example 5.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][C:9]1[CH:14]=CC=CN=1.SCC[OH:18]>N1C=CC=CC=1.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7][S:8][CH:9]([OH:18])[CH3:14]
Reactant: c1ccc(SSc2ccccn2)nc1
Reactant: OCCS
Solvent: CO
Solvent: c1ccncc1
Product: CC(O)SSc1ccccn1
Reaction time: 8 h

Procedure:
2.25 g of bis(2-pyridyl)disulfide are dissolved in 100 ml of pyridine:methanol (1:99). β-mercaptoethanol (700 μl, 1 eq.) is added dropwise to the solution. An immediate yellow color is observed. The medium is stirred overnight. The following day, starting product is no longer observed, and the solution is evaporated. The residue is passed over two silica columns, so as to obtain 770 mg of the expected product (column prepared with dichloromethane with a slight ethyl acetate gradient). Only the cleanest fractions are evaporated.