Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([O:27]CC)=[O:26])=[CH:21][CH:20]=2)=[CH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(=O)([O-])[O-].[K+].[K+].Cl>CO>[C:1]1([C:7]([C:19]2[CH:31]=[CH:30][C:22]([O:23][CH2:24][C:25]([OH:27])=[O:26])=[CH:21][CH:20]=2)=[CH:8][C:9](=[O:18])[NH:10][CH2:11][C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)COc1ccc(C(=CC(=O)NCc2cccnc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(O)COc1ccc(C(=CC(=O)NCc2cccnc2)c2ccccc2)cc1
Yield: 85.8 %

Procedure:
100 mg of ethyl [4-[1-phenyl-2-[N-(3-pyridylmethyl)carbamoyl]ethenyl]phenoxy]acetate was mixed with 66 mg of potassium carbonate and 10 ml of 50% aqueous methanol, and then refluxed for 2 hours. The reaction mixture was adjusted to pH 6 with 3 mol/l hydrochloric acid, extracted with ethyl acetate, washed twice with water and once with brine, followed by drying over anhydrous magnesium sulfate. The drying agent was filtered off and the solvent was evaporated to give crude crystals (100 mg), which were then recrystallized from ethyl acetate to provide [4-[1-phenyl-2-[-(3-pyridylmethyl)carbamoyl]ethenyl]phenoxy]acetic acid (80 mg, yield: 86.7%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2Cl)=[CH:4][CH:3]=1.[CH2:13]([Mg]Cl)[CH2:14][CH2:15][CH3:16]>C(OCC)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[CH2:13][CH2:14][CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCCC[Mg]Cl
Reactant: Clc1nccc2ccc(Br)cc12
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCc1nccc2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.4 %

Procedure:
To a refluxing solution of 7-bromo-1-chloroisoquinoline (4.85 g, 23.28 mmol) in diethyl ether (75 mL) was added butylmagnesium chloride (17.8 mL, 2.0 M ether, 35.6 mmol) and the reaction maintained at reflux for 2 h. The reaction mixture was cooled to room temperature, carefully diluted with an equal volume of ethyl acetate, washed with saturated sodium bicarbonate, water, and saturated sodium chloride, dried (sodium sulfate), filtered, and concentrated under reduced pressure to give an brown oil. Purification by flash column chromatography (silica, 1-10% ether/hexanes) gave the desired 7-bromo-1-butylisoquinoline (1.50 g): ESI MS m/z 264 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[Cl:12][C:13]1[C:18]([N+:19]([O-:21])=[O:20])=[C:17](Cl)[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]=1[C:26]([F:29])([F:28])[F:27].Cl>O.CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:17]2[C:16]([N+:23]([O-:25])=[O:24])=[CH:15][C:14]([C:26]([F:27])([F:28])[F:29])=[C:13]([Cl:12])[C:18]=2[N+:19]([O-:21])=[O:20])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)c(Cl)c([N+](=O)[O-])c1Nc1ncc(Cl)cc1Cl
Reaction time: 2 h

Procedure:
In 20 ml. of dimethylformamide, 1.63 g. of 2-amino-3,5-dichloropyridine was dissolved and 0.73 g. of powdery potassium hydroxide was added with stirring. After the addition, 3.06 g. of 2,4-dichloro-3,5-dinitrobenzotrifluoride was added during 10 minutes. The reaction was continued for about 2 hours. After the reaction, the reaction mixture was poured into water and acidified with conc. HCl and the product was extracted with methylene chloride. The extracted layer was washed with water and dehydrated and the solvent was distilled off and the product was separated by a silica gel column with an eluent of toluene and then the solvent was distilled off to obtain 1.38 g. of the object compound having the melting point of 64° to 65° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].C(O)C.Cl.[C:16](=N)([O:18][CH2:19][CH3:20])[CH3:17]>O>[CH2:16]([O:18][C:19](=[N:11][NH:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:20])[CH3:17]
Reactant: NNc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(C)=N
Agent: Cl
Solvent: CCO
Solvent: O
Product: CCOC(C)=NNc1ccc([N+](=O)[O-])cc1
Yield: 85 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 15 parts of 1-(4-nitrophenyl)hydrazine and 160 parts of absolute ethanol were added 13.5 parts of ethyl ethanimidate hydrochloride. After stirring for 3 hours while cooling, the reaction mixture was poured into water. The precipitated product was filtered off, washed with water and dried, yielding 19 parts (85%) of 1-(1-ethoxyethylidene)-2-(4-nitrophenyl)hydrazine; mp. 101.8° C. (int. 18).
Reaction SMILES: C(N(CC)CC)C.Br[CH:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:11](=[O:12])[O:10]1>CC(C)=O>[C:11]1([C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9][O:10]1)=[O:12]
Reactant: O=C1OC(Br)c2ccccc21
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Product: O=C1OCc2ccccc21
Reaction time: 1 h

Procedure:
A solution of 6-tritylaminopenicillanic acid (9.8 g; 0.02M) in dry acetone (100 ml.) was cooled to 0°C, triethylamine (2.9 mg. 0.02 M) was added, followed by 3-bromophthalide (4.1 g; 0.02M) in dry acetone (20 ml.), and the reaction mixture kept at 0°C with stirring for 2 hours and finally at ambient temperatures for 1 hour. The triethylammonium bromide which precipitated was removed by filtration, the evaporated filtrate was dissolved in ethyl acetate (150 ml.) and after two washings with cold 2% aqueous sodium bicarbonate (2 × 150 ml.) and with ice-water (2 × 100 ml.) the ethyl acetate layer was dried over anhydrous magnesium sulphate to yield, on removal of solvent in vacuo, phthalide 6-tritylaminopenicillanate as a white amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[OH:10].[CH:11]([CH:13]=O)=O>CO>[Br:9][C:5]1[CH:4]=[C:3]([OH:10])[C:2]2[N:1]=[CH:11][CH:13]=[N:8][C:7]=2[CH:6]=1
Reactant: O=CC=O
Reactant: Nc1cc(Br)cc(O)c1N
Solvent: CO
Product: Oc1cc(Br)cc2nccnc12
Reaction time: 8 h

Procedure:
As shown in step 6-v of Scheme 6, 2,3-diamino-5-bromophenol (6.0 g, 29.5 mmol) was dissolved in methanol and to this solution was added glyoxal (3.77 g, 2.98 mL, 64.9 mmol) and stirred overnight. The reaction mixture was concentrated under reduced pressure to a minimum volume and the resulting tan solid collected by filtration and dried under high vacuum to produce 7-bromoquinoxalin-5-ol (compound 1017), which was used as is in subsequent reactions without further purification.
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[OH:20][CH2:21][CH2:22][NH2:23].CCN(C(C)C)C(C)C>>[OH:20][CH2:21][CH2:22][NH:23][C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1
Reactant: NCCO
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NCCO)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 2-hydroxy-ethylamine and DIEA to give 2-(2-hydroxy-ethylamino)-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 300 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:22]3[CH:21]=[CH:20][N:19]=[CH:18][C:17]=3[C:16]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:16]2[C:17]3[CH:18]=[N:19][CH:20]=[CH:21][C:22]=3[N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[N:15]=2)=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCC(n2nc(-c3ccc(Cl)cc3)c3cnccc32)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1ccc(-c2nn(C3CCNCC3)c3ccncc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 50.6 %

Procedure:
4-[3-(4-Chlorophenyl)-pyrazolo[4,3-c]pyridin-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol) was dissolved in DCM (5 mL) and TFA (5 mL) was added. The reaction mixture was stirred at room temperature for 30 min. The solvents were removed in vacuo and the residue was dissolved in 1 M aq Na2CO3 solution (50 mL) and extracted with DCM (3×50 mL). The combined organic layers were dried (MgSO4) and the solvents removed in vacuo. The residue was purified by reverse phase HPLC (YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 40% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water) to give 3-(4-chlorophenyl)-1-piperidin-4-yl-1H-pyrazolo[4,3-c]-pyridine (76 mg, 50.2%) as a white solid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[Br:17][CH2:18][C:19](Br)=[O:20]>C(OCC)(=O)C>[CH3:1][N:2]([C:19](=[O:20])[CH2:18][Br:17])[C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CNc1ccc(Cl)cc1Cc1ccccc1
Reactant: O=C(Br)CBr
Solvent: CCOC(C)=O
Product: CN(C(=O)CBr)c1ccc(Cl)cc1Cc1ccccc1
Reaction time: 1 h

Procedure:
The N-methyl 2-benzyl-4-chloroaniline (10.8 g) in solution in ethyl acetate is treated at 5° C. with 4.9 ml of bromoacetyl bromide. After 1 hour at room temperature, decantation and washing with water, the solution is concentrated. Upon crystallization, N-methyl 2'-benzyl-4'-chloro-bromoacetanilide is obtained (12.21 g). MP=78° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[C@@H:9](O)[C@H:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1)#[N:2].[OH-].[Na+].O1CCOCC1>O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:11][C:10]([CH2:14][F:15])([CH2:12][F:13])[CH:9]=[C:8]([N:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]3=[O:23])[C:7]=2[CH:24]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)[C@@H](n1ccccc1=O)[C@H](O)C(CF)(CF)O2
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc2c(c1)C(n1ccccc1=O)=CC(CF)(CF)O2

Procedure:
A mixture of 0.13 g of trans-6-cyano-2,2-bisfluoromethyl-3,4-dihydro-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran-3-ol, 0.13 g of sodium hydroxide on support and 2 ml of dioxane was refluxed for 45 minutes. Water was added thereto and the mixture was extracted with ethyl acetate. After the organic layer was washed with water and dried, the solvent was distilled off. The resultant residue was recrystallized from ethyl acetate to obtain 6-cyano-2,2-bisfluoromethyl-4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyran represented by the following formula having melting point of 174°-175° C.
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[C:4]([C:7]1([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13](Cl)[CH:12]=2)[CH2:10][CH2:9][CH2:8]1)(=O)[CH3:5].Cl>C(O)=O.O>[ClH:17].[CH2:1]([NH:3][CH:4]([C:7]1([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)[CH2:8][CH2:9][CH2:10]1)[CH3:5])[CH3:2]
Reactant: CCN
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: Cl
Solvent: O=CO
Solvent: O
Product: CCNC(C)C1(c2ccc(Cl)cc2)CCC1
Temperature: 140 °C

Procedure:
A mixture of 70% aqueous ethylamine (50 ml) and water (100 ml) was gradually mixed with a mixture of 98% formic acid (50 ml) and water (100 ml) to give a neutral solution which was evaporated at 100° C./100 mm Hg until 180 ml of water had been collected. The residue was heated to 140° C. and 1-acetyl-1-(4-chlorophenyl)cyclobutane (10.4 g) prepared in a similar manner to that described in Example 1 for 1-acetyl-1-(3,4-dichlorophenyl)cyclobutane and 98% formic acid (10 ml) were added. The mixture was heated on an oil bath at a temperature of 180°-200° C. for sixteen hours. The mixture was distilled until an internal temprature of 170° C. was obtained and this temperature was maintained for two hours. Any volatile material was removed by distillation at 160° C./20 mm and the residue heated under reflux with concentrated hydrochloric acid (15 ml) and industrial methylated spirit (IMS) (15ml) for three hours. The IMS was evaporated on a rotary evaporator and the residue washed with ether. The aqueous phase was brought to pH 12 with sodium hydroxide and extracted with ether. The ether extract was dried and on evaporation yielded a residue which was treated with aqueous hydrochloric acid to give N-ethyl-1-[1-(4-chlorophenyl)-cyclobutyl]ethylamine hydrochloride (m.p. 203°-205° C.) (Formula I R1 =Me; R2 =H; R3 =Et; R4 =H; R5 =4-Cl; R6 =H).
Reaction SMILES: Cl[CH2:2][CH:3]([OH:7])[CH2:4][CH2:5][Cl:6].[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1>>[Cl:6][CH2:5][CH2:4][CH:3]([OH:7])[CH2:2][O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: COc1ccc(O)cc1
Reactant: OC(CCl)CCCl
Product: COc1ccc(OCC(O)CCCl)cc1
Yield: 42 %

Procedure:
Utilizing the procedure of Preparation 21, 1,4-dichloro-2-butanol was reacted with 4-methoxyphenol to give white title compound, m.p. 65°-68° C. in 42% yield. The recrystallizing solvent was diethyl ether.
Reaction SMILES: C(=O)(O)[O-].[Na+].Cl.[NH2:7][OH:8].[CH3:9][C:10]([S:20]([CH3:23])(=[O:22])=[O:21])([CH2:16][CH2:17][CH:18]=O)[C:11]([O:13][CH2:14][CH3:15])=[O:12]>O.C(O)C>[OH:8][N:7]=[CH:18][CH2:17][CH2:16][C:10]([CH3:9])([S:20]([CH3:23])(=[O:22])=[O:21])[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: CCOC(=O)C(C)(CCC=O)S(C)(=O)=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(CCC=NO)S(C)(=O)=O
Reaction time: 15 h
Yield: 98 %

Procedure:
Sodium bicarbonate (2.29 g, 27.3 mmol, 1.05 equiv) was added to a solution of hydroxylamine hydrochloride (1.94 g, 27.3 mmol, 1.05 equiv) in water (100 mL) at room temperature. After the evolution of gas ceased (approx. 30 min), a solution of ethyl 2-methyl-2-(methylsulfonyl)-5-oxopentanoate (6.14 g, 26.0 mmol, 1.0 equiv) in ethanol (100 mL) was added dropwise over 30 min, and the reaction was allowed to stir overnight (approx. 15 h). The reaction mixture was concentrated under reduced pressure to half the volume (approx. 100 mL) and partitioned between dichloromethane (200 mL) and water (100 mL). The aqueous phase was extracted with dichloromethane (100 mL). The combined organic phases were dried over anhydrous magnesium sulfate and concentrated under reduced pressure to provide the title compound (6.4 g, 97%, approx. 1:1 mixture of E/Z isomers). MS (LCMS) m/z 252.1 (M+1). 1H NMR (400 MHz, CHLOROFORM-d) δ1.34 (td, J=7.12, 1.17 Hz, 6H) 1.56-1.72 (m, 6H) 2.11-2.19 (m, 2H) 2.19-2.29 (m, 1H) 2.44 (d, J=3.71 Hz, 4H) 2.51-2.63 (m, 1H) 3.06 (d, J=2.93 Hz, 6H) 4.30 (qd, J=7.12, 3.22 Hz, 4H) 6.66-6.88 (m, 1H) 7.43 (d, J=5.07 Hz, 1H).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:5][O:6][C:7]1[C:8]([N+:1]([O-:4])=[O:2])=[CH:9][C:10]([CH3:17])=[C:11]([NH:13][C:14](=[O:16])[CH3:15])[CH:12]=1
Reactant: O=[N+]([O-])O
Reactant: COc1ccc(C)c(NC(C)=O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COc1cc(NC(C)=O)c(C)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h
Yield: 56.8 %

Procedure:
Nitric acid (70%, 2.5 mL, 25.14 mmol) was added, dropwise, at a temperature ranging between 5 and 10° C., to a mixture of N-(5-methoxy-2-methyl-phenyl)-acetamide (3.0 g, 16.76 mmol) and concentrated sulfuric acid (10 mL) in glacial acetic acid (20 mL) and the resulting mixture was stirred for 3 hours. The reaction mixture was poured into ice-water and the solid formed was collected by filtration. The residue was dissolved in dichloromethane, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 2.135 g of N-(5-methoxy-2-methyl-4-nitro-phenyl)-acetamide as an off-white solid.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@@H](CO)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:30]1[CH2:54][O:53][C:32]2([CH2:37][CH2:36][C@H:35]3[C@H:38]4[C@H:48]([CH2:49][CH2:50][C@:33]23[CH3:34])[C@:46]2([CH3:47])[C@:41]([OH:52])([CH2:42][C:43](=[CH2:51])[CH2:44][CH2:45]2)[CH2:40][CH2:39]4)[O:31]1>>[CH2:54]1[CH2:30][O:31][C:32]2([CH2:37][CH2:36][C@H:35]3[C@H:38]4[C@H:48]([CH2:49][CH2:50][C@:33]23[CH3:34])[C@:46]2([CH3:47])[C@:41]([OH:52])([CH2:42][C@H:43]([CH2:51][OH:2])[CH2:44][CH2:45]2)[CH2:40][CH2:39]4)[O:53]1
Reactant: C[C@]12CCCCC1[C@H](CO)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C=C1CC[C@]2(C)[C@H]3CC[C@@]4(C)[C@@H](CCC45OCCO5)[C@@H]3CC[C@@]2(O)C1
Product: C[C@]12CC[C@H]3[C@@H](CC[C@@]4(O)C[C@H](CO)CC[C@]34C)[C@@H]1CCC21OCCO1
Yield: 98 %

Procedure:
Following the procedure described for the preparation of 3,3:17,17-bis(ethylendioxy)-6β-hydroxymethylandrostane (Prepn. 9) and starting from 17,17-(ethylendioxy)-3-methylenandrostane-5α-ol, 17,17-(ethylendioxy)-3α-hydroxymethylandrostane-5α-ol was obtained in 98% yield. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.44 (t, 1H), 3.81 (s, 1H), 3.76 (m, 4H), 3.58 (m, 1H), 3.39 (m, 1H), 1.91-0.97 (m, 22H), 0.87 (s, 3H), 0.74 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4](Cl)[N:3]=1.C(N(CC)CC)C.[NH2:17][C@@H:18]([CH3:21])[CH2:19][OH:20]>C(#N)C>[Cl:1][C:2]1[N:3]=[C:4]([NH:17][C@@H:18]([CH3:21])[CH2:19][OH:20])[CH:5]=[C:6]([Cl:8])[N:7]=1
Reactant: Clc1cc(Cl)nc(Cl)n1
Reactant: C[C@H](N)CO
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C[C@@H](CO)Nc1cc(Cl)nc(Cl)n1
Reaction time: 12 h

Procedure:
To a solution of 2,4,6-trichloropyrimidine (4.70 g, 25.6 mmol) and triethylamine (7.78 g, 77.0 mmol) in acetonitrile (150 mL) was added a solution of (S)-2-aminopropan-1-ol (2.31 g, 30.7 mmol) in acetonitrile (150 mL) at 0° C. The reaction mixture was allowed to room temperature and stirred for 12 h, then filtered and concentrated. Purification via column chromatography (elutriant: petroleum ether/ethyl acetate=4/1) afforded the title product.
Reaction SMILES: [CH:1]([OH:3])=O.[CH3:4][C:5]1[C:10](C#N)=[CH:9][N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[N:6]=1>[Ni].O>[CH3:4][C:5]1[C:10]([CH:1]=[O:3])=[CH:9][N:8]=[C:7]([NH:13][CH2:14][CH2:15][CH2:16][CH:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)[N:6]=1
Reactant: O=CO
Reactant: Cc1nc(NCCCC2CCN(C)CC2)ncc1C#N
Agent: [Ni]
Solvent: O
Product: Cc1nc(NCCCC2CCN(C)CC2)ncc1C=O
Temperature: 12.5 °C
Reaction time: 1 h

Procedure:
A vessel at room temperature was charged with formic acid (800 mL) and 4-methyl-2-(3-(1-methylpiperidin-4-yl)propylamino)pyrimidine-5-carbonitrile (100 g) and the resulting mixture stirred to yield a clear solution, then cooled to 10-15° C. Water (200 mL) was added and the resulting mixture cooled to −2 to 0° C. To the resulting mixture was then added RANEY® nickel (160 g) maintaining the temperature at −2 to 0° C. and then stirred at this temperature for 2-3 hours. The resulting mixture was then filtered to remove the RANEY® nickel and the filtercake washed with water (100 mL), The filtrate was cooled to 0-5° C. and then slowly treated with 50% sodium carbonate solution in water (3.0 L) to adjust the pH of the solution to pH˜10. Toluene (400 mL) was added and the resulting mixture stirred at room temperature for about 30 minutes, then allowed to settle for about 1 hour. The resulting layers were separated and the aqueous layer washed with toluene (400 mL×2). The combined toluene layer and washed were distilled at 55-60° C. to remove the toluene, to yield the title compound as an oily residue.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]([OH:12])([CH3:11])[CH3:10])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:13][C:14]([Cl:18])([Cl:17])[C:15]#[N:16].CO>C(OCC)C>[Cl:13][C:14]([Cl:18])([Cl:17])[C:15](=[NH:16])[O:12][C:9]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)([CH3:11])[CH3:10]
Reactant: CC(C)(O)c1ccccc1
Reactant: N#CC(Cl)(Cl)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CO
Product: CC(C)(OC(=N)C(Cl)(Cl)Cl)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
A suspension of 60% sodium hydride in mineral oil (0.42 g, 10.50 mmol) in diethyl ether (10 mL) was treated with the dropwise addition of a solution of 2-phenylpropan-2-ol (12.02 mL, 86 mmol) in diethyl ether (30 mL). Upon completion of addition, the mixture was stirred for 30 minutes, during which time a nearly clear solution was observed. After this time, the mixture was cooled to 0° C. and then treated with the dropwise addition of trichloroacetonitrile (8.18 mL, 82 mmol), which caused the mixture to turn dark brown. The reaction was allowed to warm to room temperature over 1 hour, and then was concentrated in vacuo to yield a residue. The residue was dissolved in hexanes (10 mL) and treated with methanol (0.424 mL, 10.48 mmol), and the resulting mixture was stirred vigorously for 5 minutes. The resulting black suspension was filtered through glass fiberglass filter paper, and the collected solids were rinsed 3× with hexanes. The combined filtrates were concentrated in vacuo to yield 2-phenylpropan-2-yl 2,2,2-trichloroacetimidate (23.8 g, 85 mmol, 99% yield) as an amber oil which was used as-is in the next step.
Reaction SMILES: [CH2:1]([N:8]([CH2:15][CH2:16]Cl)[CH2:9][C:10]1[CH:14]=[CH:13][O:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[OH-].[Na+]>O1CCCC1.CCCCCC>[CH2:1]([N:8]1[CH2:15][CH2:16][C:11]2[O:12][CH:13]=[CH:14][C:10]=2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClCCN(Cc1ccccc1)Cc1ccoc1
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: c1ccc(CN2CCc3occc3C2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 0.209 g (0.837 mmol) of N-benzyl-N-(3-furylmethyl)-2-chloroethylamine in 50 ml of tetrahydrofuran, 1.05 ml (1.67 mmol) of 1.6 M n-butyl lithium in hexane was added under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction mixture was poured into aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=9/1) to yield 5-benzyl-4,5,6,7-tetrahydrofuro[3,2-c]pyridine.
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:22]=[C:21]3[C:17]([CH2:18][CH2:19][N:20]3[S:23]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=3[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=2)=[O:13])=[CH:7][CH:6]=1)=[NH:4].N1C=CC=CC=1.C(C(CCCC)[CH2:44][O:45]C(Cl)=O)C>CN(C)C=O>[O:45]=[C:44]1[O:1][N:2]=[C:3]([C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]3[CH:22]=[C:21]4[C:17]([CH2:18][CH2:19][N:20]4[S:23]([C:26]4[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=4[O:33][CH3:34])(=[O:25])=[O:24])=[CH:16][CH:15]=3)=[O:13])=[CH:7][CH:6]=2)[NH:4]1
Reactant: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(C(=N)NO)cc3)cc21
Reactant: CCCCC(CC)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1ccc(Cl)cc1S(=O)(=O)N1CCc2ccc(C(=O)Nc3ccc(-c4noc(=O)[nH]4)cc3)cc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(N-hydroxycarbamimidoyl)-phenyl]-amide (254 mg, 0.51 mmol) in dimethylformamide (3.5 ml) was treated with pyridine (0.04 ml, 1 equiv.) and the mixture was cooled to 0° C. Chloroformic acid 2-ethylhexyl ester (98 mg, 0.51 mmol, 1 equiv.) was added dropwise. The reaction mixture was stirred at 0° C. for 30 min, then quenched with water. The slurry was extracted three times with ethyl acetate. The combined organic layers were dried with Na2SO4 and the solvent was evaporated. The crude compound was suspended in xylene and heated at reflux for 2 hours. After cooling to room temperature, the solid was filtered and dried under high vacuum, yielding 1-(5-chloro-2-methoxy-benzenesulfonyl)-2,3-dihydro-1H-indole-6-carboxylic acid [4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl]-amide as a white solid, 114 mg (43%). MS (ISP): m/e=525.2 (M−H), δH (300 MHz; d6-DMSO) 10.31 (1H, s), 7.55-7.80 (8H, m), 7.28 (1H, d), 7.16 (1H, d), 4.04 (2H, t), 3.60 (3H, s), 3.06 (2H, t).