Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.[ClH:9].[NH2:10][N:11]1[CH2:15][CH:14]([CH3:16])[N:13]([CH3:17])[C:12]1=[O:18]>CO>[ClH:9].[CH3:17][N:13]1[CH:14]([CH3:16])[CH2:15][N:11]([N:10]=[CH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:12]1=[O:18]
Reactant: CC1CN(N)C(=O)N1C
Reactant: O=Cc1cccnc1
Agent: Cl
Solvent: CO
Product: CC1CN(N=Cc2cccnc2)C(=O)N1C
Yield: 84.1 %

Procedure:
2.3 g of pyridine-3-carbaldehyde are added at room temperature to a solution of 3.6 g of 1-amino-3,4-dimethylimidazolidin-2-one hydrochloride in 25 ml of methanol. The solution is concentrated by evaporation and the residue is stirred with tetrahydrofuran. 4.6 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-imidazolidin-2-one hydrochloride having a melting point of 232-236° are obtained. 2.3 g of triethylamine are added to a suspension of 4.4 g of 3,4-dimethyl-1-(pyridin-3-ylmethyleneamino)-imidazolidin-2-one hydrochloride in 100 ml of tetrahydrofuran and after 20 minutes under reflux the reaction mixture is filtered while hot. 300 ml of hexane are added to the filtrate. The crystals that have precipitated are filtered off with suction and dried. 2.5 g of the title compound having a melting point of 126-129° are obtained.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1C=C(N)C(C2C=CC([N+:32]([O-:34])=[O:33])=CC=2C2C=CC=C(Cl)C=2Cl)=CN=1.NC1N=C(N)C(C2C=C([N+]([O-])=O)C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: Nc1cc(N)c(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)cn1
Agent: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: [NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH2:3][CH2:4][CH3:5].C1CCC(NC2CCCCC2)CC1.[NH2:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].Cl.C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)(Cl)Cl>[NH:1]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[C@H:2]([C:6]([NH:29][C@H:30]([C:35]([O:37][CH3:38])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33])=[O:8])[CH2:3][CH2:4][CH3:5]
Reactant: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: COC(=O)[C@@H](N)CC(C)C
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: C1CCC(NC2CCCCC2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(C)C)C(=O)OC
Reaction time: 8 h
Yield: 75 %

Procedure:
BOC-Nva-OH, liberated from 8.0 g (20 mmoles) of the DCHA salt as described in Step 1 of Example 4, and 3.82 g (21 mmoles) of H-Leu-OMe.HCl are dissolved in 60 ml of chloroform, and 2.94 ml (21 mmoles) of triethylamine are added. The solution is cooled with ice, and a solution of 4.33 g (21 mmoles) of DCC in 40 ml of chloroform is added with stirring. The reaction mixture is allowed to stand at 5° C. overnight, the separated DCU is removed by filtration, the filtrate is washed thrice with 30 ml of n hydrochloric acid, each, thrice with 30 ml of n sodium hydrocarbonate solution, each, and finally with 30 ml of water, dried over anhydrous sodium sulfate, and then evaporated. The crystalline residue is triturated with n-hexane, filtered off, and the resulting 6.65 g of crude product is recrystallized from a mixture of 5 ml of ethyl acetate and 20 ml of petroleum ether. 5.20 g (75%) of BOC-Nva-Leu-OMe are obtained; m.p.: 100°-101° C., Rf2 =0.84, [α]D25 =-47.5° (c=1%, in methanol).
Reaction SMILES: [N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1.[CH3:35][O-:36].[Na+].C1(C)C=CC=CC=1>ClCCl>[N:1]1([C:6]2[CH:34]=[CH:33][C:9]([CH2:10][C:11]3[C:12]([O:36][CH3:35])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([C:22]([C:24]3[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[CH:26][CH:25]=3)=[O:23])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: N#Cc1ccc(C(=O)c2ccc3nc(Cl)c(Cc4ccc(-n5cncn5)cc4)c(Cl)c3c2)cc1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1nc2ccc(C(=O)c3ccc(C#N)cc3)cc2c(Cl)c1Cc1ccc(-n2cncn2)cc1
Temperature: 110 °C
Reaction time: 0.75 h

Procedure:
A heterogeneous mixture containing 4-(3-(4-(1H-1,2,4-triazol-1-yl)benzyl)-2,4-dichloroquinoline-6-carbonyl)benzonitrile (583 mg, 1.20 mmol, Intermediate 16: step d), sodium methoxide (780 mg, 14.4 mmol), and toluene (17 mL) was heated to 110° C. After 45 minutes, the flask was allowed to cool to 23° C. Dichloromethane (100 mL) was added to the flask and then the mixture was filtered through Celite®, rinsing with dichloromethane. Silica gel (5 g) was added to the filtrate and the solvent was removed by rotary evaporation to provide a free-flowing powder. The powder was loaded onto a column of silica gel for flash chromatography purification. Elution with hexanes initially, grading to 80% ethyl acetate-hexanes afforded the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16](N3C=CN=C3)=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[OH:40].CN(C)C=O>O>[Cl:1][C:2]1[C:7]2[C:8](=[O:26])[N:9]3[CH2:25][CH2:24][CH2:23][C@H:10]3[C:11]3[N:12]([CH:13]=[N:14][C:15]=3[C:16]([O:40][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[Cl:33])=[O:17])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C1c2c(Cl)cccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Reactant: Oc1ccccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Oc1ccccc1Cl)c1ncn2c1[C@@H]1CCCN1C(=O)c1c(Cl)cccc1-2
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture of 3.0 g (8.2 mmol) of 1-[[(S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[ 2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole, 1.59 g (11.5 mmol) of powdered potassium carbonate, 1.3 ml (11.5 mmol) of 2-chlorophenol and 20 ml of dry dimethylformamide is stirred at room temperature for 5 days, then poured into 60 ml of water and extracted three times with methylene chloride. The organic extracts are washed twice with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. The crude product is chromatographed on silica gel, the elution being carried out successively with ethyl acetate/n-hexane (1:1), ethyl acetate/n-hexane (3:2) and ethyl acetate/n-hexane (7:3). After recrystallization from ethyl acetate, there is obtained o-chlorophenyl (S)-8-chloro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylate of melting point 214°-215°.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[CH:4]([OH:12])[C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH:29]([N:42]1[CH2:45][CH:44](O)[CH2:43]1)([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C=CC=CC=1>[CH:29]([N:42]1[CH2:45][CH:44]([O:12][CH:4]([C:5]2[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=2)[C:3]2[CH:13]=[CH:14][C:15]([Cl:17])=[CH:16][C:2]=2[Cl:1])[CH2:43]1)([C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: OC1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: OC(c1ccc(Cl)cc1)c1ccc(Cl)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1ccc(C(OC2CN(C(c3ccccc3)c3ccccc3)C2)c2ccc(Cl)cc2Cl)cc1
Yield: 49.7 %

Procedure:
A solution of 2,4,4′-trichlorobenzhydrol (2) (174 mmol), p-toluenesulfonic acid (174 mmol) and 1-benzhydryl-3-azetidinol (1) (87 mmol) in toluene (700 mL) was heated at reflux under Dean-Stark conditions for 30 minutes. The solution was cooled, washed with sodium hydrogen carbonate (saturated aqueous solution, 700 mL), dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography [SiO2; (10% ethyl acetate:isohexane)] to furnish the product as a yellow oil (22.0 g, 50%).
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[N-:27]=[N+]=[N-].[Na+].[N-]=[N+]=[N-].[ClH:34]>CN(C=O)C.C(O)C.[Pd]>[NH2:27][CH2:11][CH:12]1[O:25][C:16]2=[C:17]3[C:21](=[CH:22][CH:23]=[C:15]2[O:14][CH2:13]1)[NH:20][C:19](=[O:24])[CH2:18]3.[ClH:34]
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Pd]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCO
Product: NCC1COc2ccc3c(c2O1)CC(=O)N3
Temperature: 45 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (3.0 g, 8.0 mmole) and sodium azide (1.6 g, 24.0 mmole) were placed in 300 ml of DMF and the reaction mixture was heated at 45° C. for 15 hours. Most of the DMF was removed and the residue was partitioned between dichloromethane and water. The dichloromethane layer was separated, dried over anhydrous magnesium sulfate and concentrated. The residue was pure enough without further purification and was identified as the desired product, (S)-2-azidomethyl-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one. An aliquot amount of the azide (0.8 g, 3.2 mmole) in ethanol (50 ml) was hydrogenated with 10% palladium on carbon (100 mg) for 15 hours. The resulting mixture was acidified with 4 N isopropanolic HCl until pH<3. The catalyst was then filtered off and the filtrate was concentrated. The residue was dissolved in 90% aqueous ethanol and precipitated with diethyl ether to give the (S) enantiomer of the title compound as a white solid hydrochloride, 1.25 hydrate, (0.7 g, 85%), m.p. 278-280° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([Cl:23])=[CH:11][C:10]=1[C:24]1[O:28][N:27]=[C:26]([CH2:29][NH2:30])[C:25]=1[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1)C1C=CC=CC=1.[C:38](OC(=O)C)(=[O:40])[CH3:39].C(N(CC)CC)C.B(Cl)(Cl)Cl>C(Cl)Cl>[Cl:23][C:12]1[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:24]2[O:28][N:27]=[C:26]([CH2:29][NH:30][C:38](=[O:40])[CH3:39])[C:25]=2[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=2)[CH:11]=1
Reactant: NCc1noc(-c2cc(Cl)c(OCc3ccccc3)cc2OCc2ccccc2)c1-c1ccc(F)cc1
Reactant: CC(=O)OC(C)=O
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)NCc1noc(-c2cc(Cl)c(O)cc2O)c1-c1ccc(F)cc1
Yield: 14 %

Procedure:
To a solution of C-[5-(2,4-Bis-benzyloxy-5-chloro-phenyl)-4-(4-fluoro-phenyl)-isoxazol-3-yl]-methylamine (100 mg, 0.19 mmol) in DCM was added acetic anhydride (130 μl, 7.0 equiv.) and triethylamine (81 μl, 3.0 equiv.). The solution was stirred at room temperature until the amine was consumed. The solvent was removed in vacuo to leave the yellow tinged oily crude benzyl protected product. This was deprotected using the standard procedure with boron trichloride described above and purified by preparative TLC and soxhlet extraction of the silica by ether gave the pure compound as a colourless solid (10 mg, 14% yield).
Reaction SMILES: Cl.[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][NH:19][CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1.[F:23][C:24]([F:35])([F:34])[O:25][C:26]1[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:2]1([C:5]2[N:6]=[CH:7][C:8]([O:11][C@H:12]3[CH2:22][N:15]4[C:16](=[O:21])[CH2:17][CH2:18][N:19]([CH2:30][C:29]5[CH:32]=[CH:33][C:26]([O:25][C:24]([F:23])([F:34])[F:35])=[CH:27][CH:28]=5)[CH2:20][C@H:14]4[CH2:13]3)=[N:9][CH:10]=2)[CH2:4][CH2:3]1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Reactant: O=C1CCNC[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCN(Cc2ccc(OC(F)(F)F)cc2)C[C@H]2C[C@@H](Oc3cnc(C4CC4)cn3)CN12
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
(8R,9aR)-8-[(5-Cyclopropylpyrazin-2-yl)oxy]octahydro-5H-pyrrolo[1,2-a][1,4]diazepin-5-one hydrochloride (60 mg, 0.185 mmol, prepared as described in Example 55, Part B) was suspended in dichloromethane (1.0 mL) in a 4-mL scintillation vial. 4-(Trifluoromethoxy)benzaldehyde (45.7 mg, 0.240 mmol, 1.3 equivalents) was added followed by triethylamine (0.051 mL, 0.369 mmol, 2.0 equiv). After stirring for 10 minutes, sodium triacetoxyborohydride (94 mg, 0.443 mmol, 2.4 equivalents) was added, and the reaction was stirred at room temperature for an additional four hours. The suspension was loaded directly onto a 4 g silica gel column and eluted with ethyl acetate (flow rate=18 mL/minute) over 20 minutes to give the title compound as a light yellow oil (42 mg, 50%). 1H NMR (400 MHz, CDCl3) δ ppm 8.03 (d, J=1.2 Hz, 1H), 7.93 (d, J=1.3 Hz, 1H), 7.35 (d, J=8.6 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 5.44-5.24 (m, 1H), 4.10 (td, J=9.3, 4.5 Hz, 1H), 3.88 (dd, J=13.2, 5.2 Hz, 1H), 3.74 (dd, J=13.2, 2.0 Hz, 1H), 3.59 (s, 2H), 2.91 (dd, J=12.6, 6.8 Hz, 1H), 2.86-2.71 (m, 2H), 2.71-2.50 (m, 2H), 2.50-2.31 (m, 2H), 2.08-1.82 (m, 2H), 1.00-0.88 (m, 4H); MS (ESI+) m/z 463.1 (M+H)+; [a]D23.6=0.08 (c=0.17, CH3OH).
Reaction SMILES: [C-:1]#[N:2].[Na+].CS(C)=O.[CH3:8][O:9][C:10]([NH:12][C:13]1[N:14]=[C:15]2[CH:20]=[CH:19][C:18]([S:21][C:22]3[CH:27]=[CH:26][C:25](OC(=O)C)=[CH:24][CH:23]=3)=[CH:17][N:16]2[CH:32]=1)=[O:11].CS(C)([O-])=O>O>[C:1]([C:25]1[CH:24]=[CH:23][C:22]([S:21][C:18]2[CH:19]=[CH:20][C:15]3[N:16]([CH:32]=[C:13]([NH:12][C:10]([O:9][CH3:8])=[O:11])[N:14]=3)[CH:17]=2)=[CH:27][CH:26]=1)#[N:2]
Reactant: [C-]#N
Reactant: COC(=O)Nc1cn2cc(Sc3ccc(OC(C)=O)cc3)ccc2n1
Agent: C[SH](C)(=O)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COC(=O)Nc1cn2cc(Sc3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3.7 g. of cuprous cyanide and 2.6 g. of finely powdered sodium cyanide in 20 ml. of dimethyl sulfoxide is treated dropwise with a solution of 4.12 g. (0.01 mole) of the diazonium tetrafluoroborate salt of 6-(aminophenylthio)-2-(methoxycarbonylamino) imidazo [1,2-a] pyridine obtained in Example 15 in 10 ml. of dimethyl sulfinate. An exotherm is observed and external cooling is necessary. The reaction mixture is stirred at room temperature for one hour, diluted with water and the solids collected by filtration. The solids are washed with water, dried and recrystallized from dimethylformamide-ethanol (50/50) to yield 6-(p-cyanophenylthio)-2-(methoxycarbonylamino) imidazo [1,2-a] pyridine.
Reaction SMILES: Cl.[NH2:2][OH:3].[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH3:12])=[CH:7][CH:6]=1.C(C1C=CC=CC=1)(=O)C>N1C=CC=CC=1>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:2][OH:3])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(=O)c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CC(=O)c1ccccc1
Solvent: c1ccncc1
Product: CC(=NO)c1ccc(O)cc1

Procedure:
1.1 equivalents of hydroxylamine hydrochloride are added to a solution of para-hydroxyacetophenone in pyridine (16% dilution). The reaction mixture is maintained at reflux until the starting acetophenone has disappeared, and is then poured into ice-cold water. The medium is extracted with ethyl acetate. After drying, the organic phase is removed and the corresponding oxime is obtained quantitatively. The elemental analysis is in accordance with the structure.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[NH2:34][CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][NH:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Reactant: NCc1ccccn1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(Cn2c3ccccc3c3c(OCCNCc4ccccn4)cccc32)cc1
Yield: 80.9 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.0622 g, 0.1635 mmol), diisopropylethylamine (0.0211 g, 0.1635 mmol), 2-(2-aminomethylpyridine (0.0531 g, 0.4907 mmol), and DMF (0.5 mL) is stirred at 100° C. for 30 min. After cooling, the solvent is removed and the residue partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel (40 mL) using CH3OH—CH2Cl2 (2/98) gave 0.0539 g (81%) of the title compound; IR (drift) 1586, 1457, 1342, 1269, 1237, 1153, 1145, 1118, 1047, 782, 776, 753, 745, 718, 710 cm−1; 1H NMR (CDClCH3) δ3.32, 4.13, 4.44, 5.51, 6.70, 6.99, 7.12, 7.2-7.4, 7.66, 8.39, 8.60. Anal. Calcd for C27H25N3O: C, 79.58; H, 6.18; N, 10.31. Found: C, 79.66; H, 6.41; N, 10.28.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14](=[O:17])[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2].[Si]([O:29][C:30](=[CH2:36])/[CH:31]=[CH:32]/N(C)C)(C(C)(C)C)(C)C.C(Cl)(=O)C>CC(O)CC>[CH:1]([O:4][C:5]1[CH:19]=[CH:18][C:8]([C:9]([N:11]2[CH2:16][CH2:15][C:14]3([O:17][CH:32]=[CH:31][C:30](=[O:29])[CH2:36]3)[CH2:13][CH2:12]2)=[O:10])=[CH:7][C:6]=1[O:20][CH3:21])([CH3:3])[CH3:2]
Reactant: C=C(/C=C/N(C)C)O[Si](C)(C)C(C)(C)C
Reactant: COc1cc(C(=O)N2CCC(=O)CC2)ccc1OC(C)C
Solvent: CCC(C)O
Solvent: CC(=O)Cl
Product: COc1cc(C(=O)N2CCC3(CC2)CC(=O)C=CO3)ccc1OC(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 591.2 %

Procedure:
A suspension of 1-(4-isopropoxy-3-methoxy-benzoyl)piperidin-4-one (12.8 g, 44.0 mmol) in 2-butanol (100 mL) was purged with argon gas for 5 minutes. (1E)-3-[tert-butyl(dimethyl)silyl]oxy-N,N-dimethyl-buta-1,3-dien-1-amine (10.0 g, 4.0 mmol) was added dropwise at room temperature under argon gas. The reaction mixture was stirred at room temperature overnight. The mixture turned to a dark brown clear solution. Solvent was removed. The residue was redissolved in THF (200 mL) and cooled to −78° C. Acetyl chloride (3.75 mL, 52.8 mmol) was added dropwise. The mixture was stirred at −78° C. for 30 min. The reaction was quenched with saturated sodium bicarbonate (25 mL). The organic layer was separated. The aqueous layer was extracted with diethyl ether (3×). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by column chromatography (40-60% ethyl acetate-Hex) to provide 3-(4-isopropoxy-3-methoxy-benzoyl)-11-oxa-3-azaspiro[5.5]undec-9-en-8-one (8.5 g) as a light yellow thick oil. 1H NMR (400 MHz, CDCl3) δ 7.28 (d, J=6.1 Hz, 1H), 6.99 (d, J=1.9 Hz, 1H), 6.94 (dd, J=8.2, 1.9 Hz, 1H), 6.87 (d, J=8.3 Hz, 1H), 5.44 (d, J=6.1 Hz, 1H), 4.57 (dt, J=12.2, 6.1 Hz, 1H), 4.25-4.00 (m, 2H), 3.87 (s, 3H), 3.34 (s, 2H), 2.56 (s, 2H), 2.15 (d, J=14.1 Hz, 2H), 1.62 (s, 2H), 1.39 (t, J=5.3 Hz, 6H). ESI-MS m/z calc. 359.17, found 360.3 (M+1)+; Retention time: 1.18 minutes (3 minute run).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=1[Br:19].C([O-])(=O)C.[Na+].[N:34]#[C:35]Br.O>C(O)C>[Br:19][C:10]1[CH:11]=[CH:12][C:13]([C:15]([F:16])([F:17])[F:18])=[CH:14][C:9]=1[CH2:8][N:7]([CH2:6][C:5]1[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=[C:3]([C:2]([F:27])([F:1])[F:28])[CH:4]=1)[C:35]#[N:34]
Reactant: FC(F)(F)c1cc(CNCc2cc(C(F)(F)F)ccc2Br)cc(C(F)(F)F)c1
Reactant: N#CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)Cc1cc(C(F)(F)F)ccc1Br
Reaction time: 0.33 h

Procedure:
To the product of step B (873 g, 1.82 mol) in ethanol (4.6 L) was added sodium acetate (452 g, 5.46 mol). The resulting mixture was stirred for 20 minutes and then cyanogen bromide (386 g, 3.64 mol) was added. This mixture was stirred for 2 hours at which point the reaction was complete as evidenced by LC analysis. Water (4 L) was added and volatiles were removed in vacuo. Toluene (4 L) was added and the mixture was stirred until 2 clear layers formed, The layers were separated and the aqueous layer was washed with toluene (2 L). The combined organics were washed with brine (1 L), dried over sodium sulfate, filtered, and concentrated (910 g yield). 1H-NMR (CDCl3) 7.83 (s, 1H), 7.71 (m, 3H), 7.54 (d, 1.7 Hz, 1H), 7.46 (dd, 2.1 Hz, 8.3 Hz, 1H), 4.38 (s, 2H), 4.34 (s, 2H). Mass Spec (ESI): M+1=505.0
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1I.[NH2:10][C:11]1[C:37]([Br:38])=[CH:36][C:14]2[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:16]([Sn](CCCC)(CCCC)CCCC)[O:17][C:13]=2[CH:12]=1>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:10][C:11]1[C:37]([Br:38])=[CH:36][C:14]2[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:16]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])[O:17][C:13]=2[CH:12]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1oc2cc(N)c(Br)cc2c1C(=O)OCC
Reactant: Fc1ccc(I)c(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccc(F)cc2F)oc2cc(N)c(Br)cc12
Temperature: 60 °C
Reaction time: 8 h
Yield: 9 %

Procedure:
2,4-difluoro-1-iodobenzene (2.09 g, 8.72 mmol) and Pd(PPh3)4(20 mg) were added into a solution of ethyl 6-amino-5-bromo-2-(tributylstannyl)benzofuran-3-carboxylate (5 g, 8.72 mmol, prepared from ethyl 6-amino-5-bromobenzofuran-3-carboxylate with LDA and Bu3SnCl) in toluene (10 mL) under N2, then the mixture was stirred at 60° C. overnight. The reaction mixture was cooled to room temperature and filtered. The filtrate was washed with H2O, brine, dried over Na2SO4. After concentrated, the resulting residue was purified using column chromatography (petroleum ether:EtOAc=6:1) to provide the product of ethyl 6-amino-5-bromo-2-(2,4-difluorophenyl)benzofuran-3-carboxylate (310 mg, yield: 9%). 1H-NMR (CDCl3, 400 MHz) δ 8.10 (s, 1H), 7.66 (d, J=8.0 Hz, 1H), 6.95˜7.01 (m, 2H), 6.92 (d, J=8.0 Hz, 1H), 4.37 (q, J=7.6 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H). MS (M+H)+: 396/398.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[C:30]([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)#N>>[CH:30]([C@@H:32]1[CH:49]2[C@:44]([CH3:51])([CH2:45][CH2:46][C:47](=[O:50])[CH2:48]2)[C@@H:43]2[C@H:34]([C@H:35]3[C@@:39]([CH2:41][CH2:42]2)([CH3:40])[C:38](=[O:52])[CH2:37][CH2:36]3)[CH2:33]1)=[O:2]
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Reactant: C[C@]12CCC(=O)CC1[C@@H](C#N)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
6α-Formylandrostane-3,17-dione was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane (Prepn. 11) by the procedure described above for the preparation of 6α-cyanoandrostane-3,17-dione (II-ac, Prepn. 3). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 6α-formylandrostane-3,17-dione. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 9.50 (d, 1H), 2.56-0.82 (m, 21H), 1.16 (s, 3H), 0.88 (s, 3H).