Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][CH2:4][O:5][C:6](=[O:23])[C:7](=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[C:8](=O)[CH2:9][CH2:10][CH3:11])#[N:2].[NH2:24][C:25]([CH2:37][CH2:38][CH3:39])=[CH:26][C:27]([O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[O:28]>CCO>[CH2:30]([O:29][C:27]([C:26]1[CH:13]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:7]([C:6]([O:5][CH2:4][CH2:3][C:1]#[N:2])=[O:23])=[C:8]([CH2:9][CH2:10][CH3:11])[NH:24][C:25]=1[CH2:37][CH2:38][CH3:39])=[O:28])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CCCC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)C(=O)OCCC#N
Reactant: CCCC(N)=CC(=O)OCc1ccccc1
Solvent: CCO
Product: CCCC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(CCC)N1

Procedure:
A solution of 2-[(4-nitrophenyl)methylene]-3-oxohexanoic acid 2-cyanoethyl ester (9.80 g, 30 mmol) and benzyl 3-amino-2-hexenoate (7.24 g, 33 mmol) in 150 ml of EtOH was refluxed for 36 hrs. After the solvent was removed in vacuo, the residue was dissolved in 250 ml of CHCl3, washed with water (2×100 ml) and dried over Na2SO4. After filtration and evaporation of solvent, 5-benzyloxycarbonyl-3-(2-cyanoethoxy) carbonyl-1,4-dihydro-4-(4-nitrophenyl)-2,6-dipropylpyridine was obtained as a yellow oil (15.4 g, 97%).
Reaction SMILES: CSC.B(F)(F)F.CCOCC.[CH3:13][O:14][C:15](=[O:36])[C@@H:16]([O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([O:24]CC2C=CC=CC=2)=[CH:20][C:19]=1[Cl:32]>ClCCl>[CH3:13][O:14][C:15](=[O:36])[C@@H:16]([O:33][CH2:34][CH3:35])[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][C:19]=1[Cl:32]
Reactant: CCO[C@@H](Cc1ccc(OCc2ccccc2)cc1Cl)C(=O)OC
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Solvent: CSC
Product: CCO[C@@H](Cc1ccc(O)cc1Cl)C(=O)OC
Temperature: 25 °C
Reaction time: 5 h
Yield: 71.9 %

Procedure:
Dimethyl sulfide (5.8 ml, 79 mmol) and boron trifluoride diethyl etherate (46% purity, 4.3 ml, 16 mmol) were added to a ice cold solution of (2S)-3-(4-benzyloxy-2-chloro-phenyl)-2-ethoxy-propionic acid methyl ester (1.1 g, 3.2 mmol) in dichloromethane (34 ml) under an argon atmosphere. The mixture was stirred for 5 h at ambient temperature, poured into ice water/brine 1/1 and extracted two times with dichloromethane. The combined extracts were washed with ice water/brine 1/1 and dried over sodium sulfate. Removal of the solvent under reduced pressure gave a colorless oil which was purified by column chromatography (silica gel, cyclohexane/AcOEt) to yield 0.6 g (2.3 mmol, 74%) of the title compound as colorless oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=1)([CH:27]=O)[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:36]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:29]1[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=1)([C:27]#[CH:36])[CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(C=O)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Reactant: O=C([O-])[O-]
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Product: C#CC(CC(=O)OC(C)(C)C)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Step D (750 mg, 1.5 mmol) in MeOH (10 mL) was added K2CO3 (414 mg, 3 mmol) and dimethyl 1-diazo-2-oxopropylphosphonate (576 mg, 3 mmol). The mixture was stirred at room temperature for 2 h. After removing the organic solvent, the residue was added H2O (10 mL), extracted with ethyl acetate, and washed with brine (10 mL), dried over sodium sulfate, then filtered. The solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (EA/PE=1:8) to obtain the title compound as colorless solid. LC/MS m/z=495.2[M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]2[N:6]=[C:7]([C:9]#[N:10])[S:8][C:4]=2[C:3]=1[C:13]#[N:14].CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>>[C:9]([C:7]1[S:8][C:4]2[C:3]([C:13]#[N:14])=[C:2](/[N:1]=[CH:17]/[N:18]([CH3:20])[CH3:19])[CH:12]=[CH:11][C:5]=2[N:6]=1)#[N:10]
Reactant: COC(OC)N(C)C
Reactant: N#Cc1nc2ccc(N)c(C#N)c2s1
Product: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N

Procedure:
The thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib were prepared following scheme 1: N-Boc Protection of 2-amino-5-nitrobenzonitrile using di-tert-butyl dicarbonate in a suitable solvent, such as dichloromethane, in presence of suitable bases such as triethylamine and 4-(dimethylamino)pyridine and preferably at room temperature, provides tert-butyl (2-cyano-4-nitrophenyl)carbamate I in high yield. Reduction of the nitro intermediate I, for example by treatment with ammonium formate and a catalytic amount of 10% palladium charcoal preferably in ethanol under microwave irradiation for preferably 30 min at 600 W, provides tert-butyl 4-amino-2-cyanophenylcarbamate II in high yield. Treatment of intermediate II by a solution of bromine in dichloromethane in a suitable solvent, such as acetic acid, preferably at room temperature provides tert-butyl 4-amino-3-bromo-2-cyanophenylcarbamate III in a quantitative yield. Intermediate III is reacted with Appel's salt (4,5-dichloro-1,2,3-dithiazolium chloride) (Appel, R. et al., Chem. Ber., 1985, 118, 1632) preferably in dichloromethane at room temperature to afford (Z)-tert-butyl-3-bromo-4-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)-2-cyanophenylcarbamate IV. N-Boc deprotection of intermediate IV using di-tert-butyl dicarbonate in a suitable solvent, such acetic acid, preferably under microwave irradiation at 118° C. provides (Z)-6-amino-2-bromo-3-(4-chloro-5H-1,2,3-dithiazol-5-ylideneamino)benzonitrile V in a quantitative yield. Cyclization of intermediate V may be accomplished by treatment with copper iodide in a suitable solvent, such as pyridine, preferably under microwave irradiation at 400 W at 130° C. for 20 min to obtain 6-aminobenzo[d]thiazole-2,7-dicarbonitrile VI in good yield (Besson, T. et al., J. Chem. Soc., Perkin Trans. 1, 1998, 3925). Treatment of intermediate VI in a suitable solvent, such as dimethylformamide dimethylacetal, preferably under microwave irradiation at 70° C. (600 W) gives (E)-N′-(2,7-dicyanobenzo[d]thiazol-6-yl)-N,N-dimethylformimidamide VII in good yield. Cyclization of intermediate VII in thiazolo[5,4-f]quinazoline-2-carbonitriles VIIIaa-ib may be accomplished by a Dimroth rearrangement using the appropriate aniline or primary amine R3NH2 (preferably 1.5 equivalent) in a suitable solvent, such acetic acid and preferably under microwave irradiation at 118° C. (600 W) (Foucourt, A. et al., Tetrahedron, 2010, 66, 4495).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10]N(CC)CC)[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19].Cl.[CH2:22]([N:24]([CH2:29]C)[CH2:25][CH2:26]CCl)[CH3:23]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][CH2:10][CH2:29][N:24]([CH2:25][CH3:26])[CH2:22][CH3:23])[CH:5]=[CH:4][C:3]=1[C:16](=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCC(=O)c1ccc(OCCN(CC)CC)cc1Cl
Reactant: CCN(CC)CCCCl
Agent: Cl
Product: CCCC(=O)c1ccc(OCCCN(CC)CC)cc1Cl

Procedure:
This compound is prepared by essentially the same procedure as described in Example 1 Step A except that the 2-diethylaminoethyl chloride hydrochloride of Example 1 Step A is replaced by an equimolecular quantity of 3-diethylaminopropyl chloride hydrochloride. The product is obtained as a colorless oil upon distillation in vacuo (0.2 mm.).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[F:19])[N:5]=[CH:6][C:7]=1Cl.[CH3:21][NH:22][NH2:23]>CO>[Cl:1][C:2]1[C:3](=[O:20])[N:4]([C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][C:10]=2[F:19])[N:5]=[CH:6][C:7]=1[N:22]([CH3:21])[NH2:23]
Reactant: O=c1c(Cl)c(Cl)cnn1-c1cc(C(F)(F)F)ccc1F
Reactant: CNN
Solvent: CO
Product: CN(N)c1cnn(-c2cc(C(F)(F)F)ccc2F)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 41.8 grams of 4,5-dichloro-2-(2-fluoro-5-trifluoromethylphenyl)-pyridazin-3(2H)-one in 400 grams of methanol cooled to 15° C is added dropwise 18.4 grams of methylhydrazine. The reaction mixture is stirred at room temperature for 4 hours, and evaporated to dryness below 30° C. The resulting precipitate is dissolved in 300 grams of methylene dichloride and washed with 300 grams of water. The organic phase is separated and evaporated to dryness. The solid is crystallized from methanol to yield the title compound, m.p. 128° to 130° C (decomposition).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:13])=[C:6]([C:8](=O)[CH:9]([F:11])[F:10])[CH:7]=1.[CH3:14][C:15]([O:18][C:19](=[O:40])[N:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([CH3:17])[CH3:16].CCCCCC.C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[C:15]([O:18][C:19](=[O:40])/[N:20]=[C:8](/[C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:13])\[CH:9]([F:11])[F:10])([CH3:17])([CH3:16])[CH3:14]
Reactant: CC(C)(C)OC(=O)N=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=C(c1cc(Br)ccc1F)C(F)F
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)/N=C(/c1cc(Br)ccc1F)C(F)F
Temperature: 100 °C
Reaction time: 48 h
Yield: 51.1 %

Procedure:
A suspension of 1-(5-bromo-2-fluoro-phenyl)-2,2-difluoro-ethanone (16.0 g, 63.2 mmol) and N-(triphenylphosphoranylidene)-carbamic acid 1,1-dimethylethyl ester (CAS 68014-21-1) (26.3 g, 69.6 mmol) in 12 ml toluene was stirred at 100° C. for 2 days. The suspension became clear. After being cooled down somewhat, hexane was added till crystallization of triphenylphosphine oxide started. The mixture was filtered and the filtrate was purified by chromatography on silica gel with hexane/TBME 1-5% to give 11.37 g of the title compound as a yellow liquid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-])=O)=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:21]>CO.[Ni]>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([NH2:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:7][C:6]=1[CH3:21]
Reactant: COC(=O)Cc1ccc(Nc2ncccc2[N+](=O)[O-])cc1C
Agent: [Ni]
Solvent: CO
Product: COC(=O)Cc1ccc(Nc2ncccc2N)cc1C
Temperature: 25 °C
Reaction time: 6.5 h

Procedure:
A suspension of [2-methyl-4-(3-nitro-pyridin-2-ylamino)-phenyl]-acetic acid methyl ester (2.2 g, 7.30 mmol) and Raney Ni (˜220 mg) in MeOH (50 mL) is stirred for 6.5 h at rt, under a hydrogen atmosphere. The reaction mixture is filtered through a pad of celite and concentrated to afford the title compound: ES-MS: 272.1 [M+H]+; tR=2.53 min (System 1).
Reaction SMILES: [ClH:1].[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[CH:15]([CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[N:14](C(OC(C)(C)C)=O)[CH2:13][C:12]=2[S:11][C:10]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:8])([CH3:5])([CH3:4])[CH3:3]>C(OCC)(=O)C>[ClH:1].[C:2]([O:6][C:7]([C:9]1[C:17]2[CH:16]([N:18]=[C:19]=[O:20])[CH:15]([CH2:21][N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[NH:14][CH2:13][C:12]=2[S:11][C:10]=1[O:40][CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)=[O:8])([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)C(CN1C(=O)c3ccccc3C1=O)N(C(=O)OC(C)(C)C)C2
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(OCc2ccccc2)sc2c1C(N=C=O)C(CN1C(=O)c3ccccc3C1=O)NC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 90 %

Procedure:
To a solution of 1N hydrochloric acid in ethyl acetate (1.0 ml) was added 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3,6-dicarboxylic acid di-tert-butyl ester (52 mg, 0.08 mmol). The solution was stirred at room temperature for 48 h. A precipitate was filtered off which afforded 42 mg (90%) of 2-benzyloxy-carbonylamino-5-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-4,5,6,7-tetrahydro-thieno[2,3-c]pyridine-3-carboxylic acid tert-butyl ester hydrochloride as a solid.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1F)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21].C(N(CC)CC)C>C(#N)C>[F:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][C:16]=1[N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[N:13]([CH3:18])[C:12](=[O:19])[N:11]([OH:20])[C:10]2=[O:21]
Reactant: Cn1c(=O)n(O)c(=O)c2cc(F)c(F)cc21
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cn1c(=O)n(O)c(=O)c2cc(F)c(N3CCCC3)cc21
Yield: 38 %

Procedure:
Pyrrolidine (0.07 mL, 0.8 mmol) was added to a solution of 6,7-difluoro-3-hydroxy-1-methyl-1H-quinazoline-2,4-dione (Example L, 0.15 g, 0.66 mmol) and triethylamine (1.2 mL, 8.6 mmol) in 30 mL of acetonitrile. The solution was warmed to reflux for 18 hours, cooled, and filtered to give a solid. The solid was triturated with chloroform, filtered, and dried to give 0.07 g of the title compound as a solid, mp >250° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][NH:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][C:10]=1[NH:19][C:20](=O)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].Cl.N1C=CC=CC=1>N1C=CC=CC=1>[CH2:21]([C:20]1[N:8]([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][S:2][CH3:1])[C:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:12]=[CH:11][C:10]=2[N:19]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCC(=O)Nc1cnc2ccccc2c1NCCCCCSC
Agent: Cl
Solvent: c1ccncc1
Product: CCCCCCc1nc2cnc3ccccc3c2n1CCCCCSC
Yield: 94.4 %

Procedure:
A round bottom flask was charged with a magnetic stir bar, N-(4-{[5-(methylthio)pentyl]amino}quinolin-3-yl)heptanamide (4.44 g, 11.46 mmol), pyridine hydrochloride (0.13 g, 1.15 mmol), and anhydrous pyridine (50 mL) under a nitrogen atmosphere. The reaction was judged to be complete after stirring at reflux for 1.5 hours. The solution was cooled and partitioned between ethyl acetate and water. The layers were separated. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous sodium sulfate, filtered and then concentrated under reduced pressure to afford 2-hexyl-1-[5-(methylthio)pentyl]-1H-imidazo[4,5-c]quinoline (4.0 g, 10.82 mmol) as a brown oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N+:12]([O-])=[CH:11][N:10]([CH3:14])[C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1.CC1(C)C(=[S:26])C(C)(C)C1=O>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11](=[S:26])[N:10]([CH3:14])[C:9]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:4][CH:3]=1
Reactant: CC1(C)C(=O)C(C)(C)C1=S
Reactant: Cn1c[n+]([O-])c(-c2ccc(F)cc2)c1-c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cn1c(-c2ccncc2)c(-c2ccc(F)cc2)[nH]c1=S
Temperature: 0 °C
Reaction time: 1 h
Yield: 98 %

Procedure:
0.5 g of 5-(4-fluorophenyl)-4-(4-pyridyl)-3-methylimidazole N-oxide from example 1d were dissolved in 20 ml of CHCl3, and the reaction mixture was cooled in an ice-bath. An equimolar solution of 2,2,4,4-tetramethyl-3-thionocyclobutanone in CHCl3 was slowly added dropwise to the initial charge, and the mixture was then stirred in the ice-bath for 30 min. The ice-bath was removed, and stirring was continued at room temperature for 1 h. The solvent was then removed using a rotary evaporator, and the solid residue was triturated in diethyl ether. The precipitate was filtered off and dried under reduced pressure. The yield was 98%.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[C@H:10]([OH:21])[CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1>N1C=CC=CC=1.C(OC(=O)CCC)(=O)CCC.CN(C)C1C=CN=CC=1.C(OCC)C>[C:2]([O:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[C@H:10]([O:21][C:11](=[O:20])[CH2:10][CH2:9][CH3:8])[CH2:9]4)[CH2:6][CH2:5][C:4]=2[CH:3]=1)(=[O:1])[CH2:3][CH2:4][CH3:17]
Reactant: C[C@]12CC[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1C[C@@H](O)C2=O
Agent: CCCC(=O)OC(=O)CCC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CCCC(=O)Oc1ccc2c(c1)CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)[C@H](OC(=O)CCC)C[C@@H]12
Yield: 80.6 %

Procedure:
A solution of 2.0 g of 3,16α-dihydroxy-1,3,5(10)-estratrien-17-one in 10 ml of pyridine and 5 ml of butyric anhydride is allowed to stand at room temperature for 15 hours with the addition of 100 mg of 4-dimethylaminopyridine. The reaction mixture is diluted with diethyl ether, washed with water, dried over sodium sulfate, and evaporated. The residue is chromatographed on silica gel with a pentane-diethyl ether gradient (0-30% diethyl ether), yielding 1.2 g of 3,16α-dibutyryloxy-1,3,5(10)-estratrien-17-one as an oil.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH2:16]([O:18][C:19](=[O:31])[CH2:20][C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH3:17].[Cl:32][C:33]1[N:38]=[C:37]([Cl:39])[C:36]([CH2:40]I)=[CH:35][N:34]=1>O1CCCC1.C(OCC)(=O)C>[CH2:16]([O:18][C:19](=[O:31])[CH:20]([C:21]1[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=1[O:29][CH3:30])[CH2:40][C:36]1[C:37]([Cl:39])=[N:38][C:33]([Cl:32])=[N:34][CH:35]=1)[CH3:17]
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: CCOC(=O)Cc1cc(OC)ccc1OC
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(OC)ccc1OC
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 2,5-dimethoxyphenylacetic acid ethyl ester (2.24 g, 10.0 mmol) (Aldrich) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To the reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(2,5-dimethoxy-phenyl)-propionic acid ethyl ester as a colorless oil. (Yield 1.00 g, 51.9%).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-])=O)=[N:7]1)=[O:5])[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:18])[CH3:19])=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:32])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])=[N:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2[N+](=O)[O-])c2cc(C(=O)OC(C)(C)C)sc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)n1nc(NC(=O)c2ccccc2N)c2cc(C(=O)OC(C)(C)C)sc21
Reaction time: 10 h
Yield: 97.2 %

Procedure:
The suspension of 3-(2-Nitro-benzoylamino)-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (984 mg, 2.136 mmol) and Pd/C 10% (200 mg) in ethyl acetate (AcOEt, 35 mL) was shaken under hydrogen pressure (40 psi) for 10 hours. The solid was filtered on celite, washed with AcOEt and the filtrate was evaporated under vacuum to yield 894 mg (97%) of title compound.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:8]([OH:10])=O)(=[O:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:29]([O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])[CH:35]=1)[CH:30]([CH3:32])[CH3:31]>C(Cl)Cl.CN(C)C=O>[C:1]([O:4][C:5]1[CH:6]=[C:7]([C:8](=[O:10])[C:39]2[CH:38]=[CH:37][C:36]([O:40][CH2:41][CH:42]([CH3:44])[CH3:43])=[CH:35][C:34]=2[O:33][CH2:29][CH:30]([CH3:32])[CH3:31])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH:16]([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(C)COc1cccc(OCC(C)C)c1
Reactant: CC(=O)Oc1cc(C(=O)O)ccc1OCC(C)C
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(=O)Oc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.5 %

Procedure:
In 10 ml of methylene chloride is dissolved 1.00 g of 3-(acetyloxy)-4-isobutoxybenzoic acid. After adding 0.41 ml of oxalyl chloride and 20 μl of N,N-dimethylformamide successively at ambient temperature, the mixture thus obtained is stirred at ambient temperature for one hour. Then, 1.06 g of aluminum chloride and 1.15 g of 1,3-diisobutoxybenzene are successively added at 5-10° C., and the mixture is stirred at the same temperature as above for one hour. The reaction mixture is added to a mixture of methylene chloride and ice water, and the organic layer is separated. The organic layer is successively washed with water and saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography [eluent; n-hexane:ethyl acetate=5:1] to obtain 1.24 g of 5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl acetate as a yellow oily product.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C([BH3-])#N.[Na+].B(F)(F)F.CCOCC>CO>[OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2
Reactant: Oc1ccc2[nH]ccc2c1
Agent: FB(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCOCC
Product: Oc1ccc2c(c1)CCN2
Temperature: 25 °C
Yield: 71.5 %

Procedure:
5-Hydroxyindole (2 g, 15 mmol) was dissolved in methanol (60 ml) under argon. Sodium cyanoborohydride (1.89 g, 30 mmol) and trifluoroboron etherate (4.2 ml, 33 mmol) were added and the mixture was heated at reflux for 3 hours then left to cool to ambient temperature. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. Ammonia was added to adjust the pH to 10 and the aqueous phase was extracted with more ethyl acetate. The combined organic phases were washed with water, brine, dried (MgSO4), filtered and the solvent evaporated. The residue was purified by flash chromatography using dichloromethane/methanol (95/5) as solvent. Evaporation of the solvent gave 5-hydroxy-2,3-dihydro-1H-indole (1.45 g, 73%) as an off white solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[N-:26]=[N+:27]=[N-:28].[Na+].O>CN(C=O)C.CCOC(C)=O>[N:26]([CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])=[N+:27]=[N-:28]
Reactant: CS(=O)(=O)OCCOc1ccc(Br)cc1C(F)(F)F
Reactant: [N-]=[N+]=[N-]
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCOc1ccc(Br)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(4-Bromo-2-(trifluoromethyl)phenoxy)ethyl methanesulfonate (15.54 mmol, 5.643 g) and potassium carbonate (46.6 mmol, 6.44 g) were combined and stirred in DMF (50 ml). Sodium azide (46.6 mmol, 3.03 g) was added and the reaction stirred at room temperature overnight. Starting material remained. Reaction was heated to 60° C. for 5 hours. The reaction mixture was poured into water and diluted with EtOAc. The layers were separated and the organic dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by silica chromatography, eluting with a gradient of heptane—50/50 heptane/EtOAc to afford 1-(2-azidoethoxy)-4-bromo-2-(trifluoromethyl)benzene. (2.27 g)