Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][NH:19][CH2:20][CH2:21][CH2:22][N:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.[CH:30](=O)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN1C(=O)CCC1.CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:29])[N:6]2[CH2:16][CH2:17][CH2:18][N:19]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[CH2:20][CH2:21][CH2:22][N:23]1[CH2:24][CH2:25][O:26][CH2:27][CH2:28]1
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCCNCCCN3CCOCC3)c2n1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CO
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCN(CCCN3CCOCC3)Cc3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.7 %

Procedure:
6-Amino-2-butoxy-9-[3-(3-morpholin-4-yl-propylamino)-propyl]-7,9-dihydro-purin-8-one (0.1 g), Benzaldehyde (0.03125 g, 0.03005 ml) were combined in NMP (1.5 mL) and stirred at RT for 15 mins. Sodium triacetoxyborohydride (0.078 g) was added and the reaction mixture was stirred for 16 h. The reaction mixture was diluted with methanol and purified by RPHPLC to give the title compound (0.068 g)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[NH:6][CH2:5]2.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:12]([O-:14])=[O:13])[C:7](=[O:11])[NH:6][CH2:5]2
Reactant: Cc1ccc2c(c1)CNC2=O
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: Cc1cc2c(cc1[N+](=O)[O-])C(=O)NC2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
5-Methyl-2,3-dihydro-isoindol-1-one (1.00 g, 6.79 mmol) was taken up in sulfuric acid and cooled to 0EC. One equivalent of nitric acid was added to the solution and the mixture was allowed to slowly warm to room temp and stir for 12 h. The reaction mixture was poured into ice water and the aqueous layer was extracted four times with ethyl acetate and the combined organic layers were washed with water, brine and dried over anhydrous magnesium sulfate. The solution was filtered and the solvent removed under reduced pressure. Two products were isolated by flash chromatography. (10% methanol-ethyl acetate) Yield 813.40 mg of the 4-nitro and 100 mg of the 6-nitro. 1H NMR (300 MHz, d6-DMSO): 4-nitro δ 7.76 (s, 1H), 8.19 (s, 1H), 8.98 (bs, 1H); 6-nitro δ 7.69 (d, J=9 Hz, 1H), 7.84 (d, J=9 Hz), 8.91 (bs, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[CH3:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([CH2:27][C:28](OCC)=[O:29])=O)=[CH:21][N:20]=2)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1>>[CH3:9][C:10]1[N:11]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:27][C:28](=[O:29])[NH:8][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[N:1]=3)=[CH:21][N:20]=2)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][C:13]=2[N:18]=1
Reactant: Nc1ccccc1N
Reactant: CCOC(=O)CC(=O)c1ccc(-n2c(C)nc3cnccc32)nc1
Product: Cc1nc2cnccc2n1-c1ccc(C2=Nc3ccccc3NC(=O)C2)cn1
Yield: 14.3 %

Procedure:
The procedure of Example 1 was followed using 1,2-diaminobenzene (86 mg, 0.76 mmol) and ethyl 2-(2-methylimidazo[4,5-c]pyrid-1-yl)pyrid-5-oylacetate (260 mg, 0.80 mmol). The crude product was purified by flash chromatography (eluting with ethyl acetate/methanol =6:1), followed by recrystallisation from acetone to give the title compound (40 mg, 14%) as a buff solid, m.p. 208°-210° C..
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].[CH:11](=O)[C:12]1[C:13](=[CH:15][CH:16]=[CH:17][CH:18]=1)[OH:14].C(OCC)(=O)C>CCCCCC>[OH:14][C:13]1[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=1[CH:11]=[N:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(O)cc(C)c1N
Reactant: O=Cc1ccccc1O
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(O)cc(C)c1N=Cc1ccccc1O
Temperature: 55 °C
Reaction time: 19 h
Yield: 82 %

Procedure:
To a 500 milliliter round bottom flask equipped with a water condenser, magnetic stirrer and drying tube was added 13.72 grams (0.10 mole) of 4-amino-3,5-dimethylphenol, 12.21 grams (0.10 mole) of salicylaldehyde and 250 milliliters of ethyl acetate. The resulting reaction mixture was then heated to 55° C. and stirred for 19 hours at ambient pressure. After cooling the reaction mixture to room temperature, it was filtered and concentrated under reduced pressure to give a brown oil which solidified on standing. The resulting solidified material was slurried in hexane, collected by filtration and dried to yield 19.66 grams (0.082 moles) of 4-(2-hydroxybenzylideneamino)-3,5-dimethylphenol in the form of a yellow solid having a melting point of 145°-147° C.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][CH:3]([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]2[C:27]3[C:28]4=[C:29]5[C:24](=[CH:25][CH:26]=3)[CH:23]=[CH:22][CH:21]=[C:20]5[CH:19]=[CH:18][C:17]4=[CH:16][CH:15]=2)=[O:11])[S:2]1.[BH4-].[Na+]>O>[SH:2][CH:3]([CH2:4][CH2:5][SH:1])[CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][C:14]1[C:27]2[C:28]3=[C:29]4[C:24](=[CH:25][CH:26]=2)[CH:23]=[CH:22][CH:21]=[C:20]4[CH:19]=[CH:18][C:17]3=[CH:16][CH:15]=1)=[O:11]
Reactant: O=C(CCCCC1CCSS1)OCc1ccc2ccc3cccc4ccc1c2c34
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Product: O=C(CCCCC(S)CCS)OCc1ccc2ccc3cccc4ccc1c2c34
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thereafter, 500 mg of (1-pyrenyl)methyl 5-(1,2-dithiolan-3-yl)pentanoate was dissolved in DI water, 30 mg of NaBH4 was added, and the solution was stirred for 30 min at room temperature. The organic phase in the mixture solution was extracted by chloroform and dehydrated by anhydrous MgSO4, and then the organic solvent in the organic phase was removed leaving (1-pyrenyl)methyl 6,8-dimercaptooctanoate as a linking molecule. Because the 1H-NMR spectrum thereof was similar to that before the reduction reaction and the reverse reaction occurred readily, the product was not characterized but directly used to form covalent bonds with the quantum dots.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]#[C:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:4]([N+:20]([O-:22])=[O:21])[C:5](OS(C(F)(F)F)(=O)=O)=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[F:29][C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.O.C(=O)(O)[O-].[Na+]>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>[Cl:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[C:5]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([F:29])[CH:35]=2)=[C:4]([N+:20]([O-:22])=[O:21])[C:3]=1[C:23]#[C:24][Si:25]([CH3:26])([CH3:27])[CH3:28]
Reactant: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cc(Cl)c(C#C[Si](C)(C)C)c([N+](=O)[O-])c1-c1cccc(F)c1
Temperature: 80 °C
Yield: 87.5 %

Procedure:
A solution of methyl 5-chloro-3-nitro-2-{[(trifluoromethyl)sulfonyl]oxy}-4-[(trimethylsilyl)ethynyl]benzoate (9.3 g, 20 mmol) and (3-fluorophenyl)boronic acid (4.3 g, 30 mmol) in toluene (200 mL) was treated with water (200 mL) saturated with sodium bicarbonate (3.4 g, 40 mmol). The reaction mixture was degassed with nitrogen for 10 minutes, treated with tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol), degassed with nitrogen for 10 minutes, and heated at 80° C. for 6 hours. The reaction mixture was cooled to 20° C. and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered, and concentrated to a crude residue. The crude material was diluted with dichloromethane and adsorbed onto 36 g of silica gel. Purification by flash column chromatography using ethyl acetate in hexanes (0%-40%) gave the desired product (7.1 g, 86%). LCMS for C19H18ClFNO4Si (M+H)+: m/z=406.1; Found: 405.7.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([CH2:8]P(=O)(OCC)OCC)=[O:7])[CH3:4].[N+:17]([C:20]1[CH:33]=[CH:32][C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=O)=[CH:22][CH:21]=1)([O-:19])=[O:18]>COCCOC>[C:26]1([C:24]([C:23]2[CH:32]=[CH:33][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=2)=[CH:8][C:6]([O:5][CH2:3][CH3:4])=[O:7])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: O=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reaction time: 1.5 h

Procedure:
To a stirred suspension of sodium hydride, derived from 10.56 g. of a 50% suspension in mineral oil, in 400 ml. of 1,2-dimethoxyethane was added 51.6 g. of diethyl ethoxycarbonylmethylphosphonate, during 1 hour. When gas evolution ceased, a solution of 47.7 g. of 4-nitrobenzophenone in 400 ml. of 1,2-dimethoxyethane was added, dropwise, during 1.5 hours. Stirring was continued overnight and then the solvent was removed by evaporation in vacuo. The residue was partitioned between ethyl acetate and water. The layers were separated, and the water layer was extracted with fresh ethyl acetate. The combined ethyl acetate solutions were evaporated in vacuo to give the title compound as an oil, which slowly solidified.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:28])[CH:7]([CH3:27])[CH2:8][CH:9]([OH:26])[CH:10]([NH:18]C(=O)[O:20]C(C)(C)C)[CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[CH2:2][CH2:3][CH3:4].Cl.[NH4+].[OH-]>O1CCOCC1>[NH4+:5].[OH-:20].[NH2:18][CH:10]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)[CH:9]([OH:26])[CH2:8][CH:7]([CH3:27])[C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:28]
Reactant: CCCCNC(=O)C(C)CC(O)C(CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCCNC(=O)C(C)CC(O)C(N)CC1CCCCC1
Temperature: 25 °C
Yield: 231.1 %

Procedure:
A solution of the product from A [1S-(1R*,2R*, 4R*)][5-(butylamino)-1-(cyclohexylmethyl)-2-hydroxy-4-methyl-5-oxopentyl]carbamic acid, 1,1-dimethylethyl ester (0.23 g, 0.58 mmol) in dioxane (5 mL) at 0° C. was added a dioxane solution (15 mL) saturated with HCl(g) and allowed to stand two h and then warm to r.t. for 16 h. The reaction was made basic (pH=8) by the dropwise addition of conc. NH4OH and then extracted with CH2Cl2. The organic layer was washed with water, dried (Na2CO3), filtered and concentrated in vacuo. Silica gel chromatography (90:10:1 CH2Cl2 :MeOH:NH4OH) of the concentrate afforded the title compound (0.20 g, 98%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1.[C:29]([Cu])#[N:30].[C-]#N.[Na+]>CN(C=O)C>[C:29]([C:2]1[CH:3]=[C:4]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:5]=[CH:6][C:7]=1[CH2:8][C:9]1[N:10]([CH3:23])[C:11]([C:14](=[O:22])[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)#[N:30]
Reactant: Cc1ccc(C(=O)c2ccc(Cc3ccc(NS(C)(=O)=O)cc3Br)n2C)cc1
Reactant: N#C[Cu]
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)c2ccc(Cc3ccc(NS(C)(=O)=O)cc3C#N)n2C)cc1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
N-{3-Bromo-4-[5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-ylmethyl]phenyl}methane-sulfonamide (320 mg, 0.69 mmol) was dissolved in DMF. CuCN (120 mg, 1.38 mmol) was added and the suspension was refluxed for 4 h. The mixture was cooled to room temperature, and NaCN (2.0 g in 10 ml of water) was added. After 0.5 h the mixture was extracted with ethyl acetate and the extracts were washed with water, and brine, and dried over sodium sulfate. The solvent was removed in vacuo and the residue was purified by preparatory TLC (hexane-ethyl acetate) to give N-{3-cyano-4-[5-(4-methylbenzoyl)-1-methyl-1H-pyrrol-2-yl-methyl]phenyl}methanesulfonamide (190 mg, 67%) as a solid, mp 171-172° C.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13].Cl.Cl.[NH2:20][C:21]1[CH:53]=[CH:52][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:33]=[C:32]([CH2:34][O:35][C:36]4[CH:49]=[CH:48][C:39]([CH2:40][CH:41]5[S:45][C:44](=[O:46])[NH:43][C:42]5=[O:47])=[CH:38][CH:37]=4)[N:31]([CH3:50])[C:30]=3[CH:51]=2)=[CH:23][CH:22]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12]([NH:20][C:21]1[CH:22]=[CH:23][C:24]([O:25][C:26]2[CH:27]=[CH:28][C:29]3[N:33]=[C:32]([CH2:34][O:35][C:36]4[CH:37]=[CH:38][C:39]([CH2:40][CH:41]5[S:45][C:44](=[O:46])[NH:43][C:42]5=[O:47])=[CH:48][CH:49]=4)[N:31]([CH3:50])[C:30]=3[CH:51]=2)=[CH:52][CH:53]=1)=[O:13]
Reactant: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(N)cc3)cc21
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Oc3ccc(NC(=O)c4cccc(Cl)c4)cc3)cc21

Procedure:
A reaction was conducted by a similar procedure to that described in Example 52 using triethylamine (0.32 ml), 3-chlorobenzoyl chloride (0.09 ml), 5-[4-[6-(4-aminophenoxy)-1-methyl-1H-benzimidazol-2-ylmethoxy]benzyl]thiazolidine-2,4-dione dihydrochloride (400 mg) and anhydrous N,N-dimethylformamide (8 ml). The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate and then concentrated. The residue was chromatographed on a silica gel column using ethyl acetate:n-hexane=3:2→5:2 as the eluant to afford the title compound (232 mg, white powder, mp 238-239° C.).
Reaction SMILES: [C:1]([CH2:6][N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)([O:3][CH2:4][CH3:5])=[O:2].[CH3:19][O:20][C:21]1[CH:22]=[C:23]([C:29]([CH:36]([CH3:38])[CH3:37])([CH2:32][CH2:33][CH2:34]I)[C:30]#[N:31])[CH:24]=[CH:25][C:26]=1[O:27][CH3:28]>>[C:1]([CH:6]([N:7]=[CH:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([O:17][CH3:18])[CH:10]=1)[CH2:34][CH2:33][CH2:32][C:29]([C:23]1[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:21]([O:20][CH3:19])[CH:22]=1)([C:30]#[N:31])[CH:36]([CH3:38])[CH3:37])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: COc1ccc(C(C#N)(CCCI)C(C)C)cc1OC
Reactant: CCOC(=O)CN=Cc1ccc(OC)c(OC)c1
Product: CCOC(=O)C(CCCC(C#N)(c1ccc(OC)c(OC)c1)C(C)C)N=Cc1ccc(OC)c(OC)c1

Procedure:
The resulting imine of formula 24 is then deprotonated using a suitable strong base, and allowed to react with a compound of formula 22 to produce a compound of formula 25 (step 2). For example, 1-(carboethoxy)methyliminomethyl-3,4-dimethoxybenzene (24) is suspended in a solution of LiNiPr2 in THF/HMPA at -78° C., then reacted with 2-(3,4-dimethoxyphenyl)-2-isopropyl-2-(3-iodopropyl)acetonitrile (22) to produce N-[1-carboethoxy-5-(3,4-dimethoxyphenyl)-5-cyano-5-(isopropyl)pentyl]iminomethyl-3,4-dimethoxybenzene (25).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([NH2:11])[CH2:8][CH2:9][CH3:10])[CH:2]=1.[Cl:12][C:13]1[CH:18]=[C:17](Cl)[N:16]=[CH:15][N:14]=1.C(N(C(C)C)CC)(C)C>C(O)C>[Cl:12][C:13]1[N:14]=[CH:15][N:16]=[C:17]([NH:11][CH:7]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH2:8][CH2:9][CH3:10])[CH:18]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CCCC(N)c1cccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: CCCC(Nc1cc(Cl)ncn1)c1cccnc1
Reaction time: 72 h

Procedure:
To a solution of 1-pyridin-3-ylbutan-1-amine (100 mg, 0.67 mmol) in ethanol (4 mL) was added 4,6-dichloropyrimidine (109 mg, 0.73 mmol) and diisopropylethylamine (232 μL, 1.33 mmol). The solution was stirred for 3 days after which time the solvent was removed under reduced pressure. The residue was dissolved in ethyl acetate (25 mL) and washed with H2O (3×15 mL), brine (15 mL) and dried (Na2SO4). The residue remaining after concentration in vacuo was chromatographed using ethyl acetate-hexanes (4:6-9:1) as eluant to separate the desired product (28 mg).
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1[C:8]([CH2:9][C:10]([O:12]C)=[O:11])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH3:26])[N:5]=1>CO>[CH3:3][C:4]1[C:8]([CH2:9][C:10]([OH:12])=[O:11])=[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:6]([C:20]2[CH:21]=[N:22][CH:23]=[CH:24][C:25]=2[CH3:26])[N:5]=1
Reactant: COC(=O)Cc1c(C)nn(-c2cnccc2C)c1-c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccncc1-n1nc(C)c(CC(=O)O)c1-c1ccccc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
0.100 g (2.489 mmol) of 2 molar aqueous sodium hydroxide solution was added to 0.200 g (0.498 mmol) of methyl [3-methyl-1-(4-methylpyridin-3-yl)-5-phenyl-1H-pyrazol-4-yl]acetate in 5.00 ml of methanol, and the mixture was stirred at 20° C. for 1 h. The methanol was removed under reduced pressure, and the residue was poured onto a mixture of 10 ml of water and 15 ml of dichloromethane. The aqueous phase was extracted with 15 ml of dichloromethane, acidified with concentrated hydrochloric acid (pH=3) and extracted three times with in each case 15 ml of dichloromethane. Drying of the combined organic phases and removal of the solvent under reduced pressure give 0.108 g (71% of theory) of a yellow solid of melting point 246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:30][C:31]([CH3:38])([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32]O.[K+].[Br-].Cl>>[CH3:30][C:31]([CH3:38])([CH2:34][CH:35]([CH3:37])[CH3:36])[CH2:32][O:24][C:23]([C:18]1([C:20]([O:22][CH2:30][C:31]([CH3:38])([CH3:32])[CH2:34][CH:35]([CH3:37])[CH3:36])=[O:21])[O:17][C:16]2[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[OH:29])[CH3:28])=[CH:14][C:15]=2[O:19]1)=[O:25]
Reactant: CC(C)CC(C)(C)CO
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: CC(C)CC(C)(C)COC(=O)C1(C(=O)OCC(C)(C)CC(C)C)Oc2ccc(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)cc2O1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and 2,2,4-trimethylpentanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 0.65-0.9 (m, 24H, 8×CH3), 1.09 (d, J=6.4 Hz, 3H, CH3), 1.1-1.4 (m, 4H, CH2, CH2), 2.62 (m, 1H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 4.04 (s, 4H, OCH2, OCH2), 5.05 (m, 1H, CH), 6.34 (d, J=3.95 Hz, 1H, OH), 6.85 (dd, J=7.9, 1.32 Hz, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.5 (s, 1H, Ar--H), 8.7 (brs, 1H, NH), 9.1 (brs, 1H, NH); IR (KBr, cm-1) 3300 (OH), 2900 (NH), 1760 (CO); MS m/e 646 (M+H)+ ; Analysis for: C36H52ClNO7 ×HCl: Calc'd: C, 63.33; H, 7.83; N, 2.05; Found: C, 62.96; H, 7.71; N, 2.44.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1.[C:23](Cl)(=[O:27])[CH:24]([CH3:26])[CH3:25]>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[O:21][CH3:22])[CH2:3]1)(=[O:27])[CH:24]([CH3:26])[CH3:25]
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](OC(=O)C(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: 7.5 °C
Reaction time: 1 h
Yield: 86.1 %

Procedure:
A solution of 3α-hydroxy-17β-methoxy-5β-androstane (250 mg, 0.82 mmol) in dry pyridine (2 mL) was treated with isobutyryl chloride (0.12 mL, 1.15 mmol), and N,N-dimethylaminopyridine (5 mg) at 5° C. After stirring the mixture at 5-10° C. for 1 hr the mixture was quenched with HCl solution (0.5N, 25 mL). The mixture was extracted with EtOAc. The organic layer was washed with dil. HCl, water, and brine. After drying over anhyd. MgSO4 the solution was filtered and evaporated to yield the crude product. This crude product was then dissolved in a small amount of CH2Cl2 and poured on a column of silica gel. Elution with hexane:acetone mixture (9:1) gave 3α-isobutyryloxy-17β-methoxy-5β-androstane (266 mg); mp 82-87° C.; TLC Rf (hexane:acetone 9:1)=0.6.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1F)([O-:3])=[O:2].[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([SH:25])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15].C(N(CC)CC)C>CC(C)=O>[C:14]([NH:17][CH2:18][CH2:19][N:20]1[C:24]([S:25][C:5]2[CH:6]=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[N:23][N:22]=[N:21]1)(=[O:16])[CH3:15]
Reactant: CC(=O)NCCn1nnnc1S
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC(=O)NCCn1nnnc1Sc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Reaction time: 1 h

Procedure:
A solution of 9.3 g (0.050 mol) of 2,4-dinitrofluorobenzene in 50 ml of acetone was added to a solution of 9.35 g (0.050 mol) of 1-(2-acetamidoethyl)tetrazole-5-thiol and 6.85 ml (0.050 mol) of triethylamine in 100 ml of acetone and the reaction mixture was stirred for 1 hour. The solid material was collected by filtration and recrystallized from acetonitrile to give 1-(2-acetamidoethyl)-5-(2,4-dinitrophenylthio)tetrazole, mp 197°-198°.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]1[CH2:14][CH2:13][CH2:12][O:11][C:10]2[N:15]=[C:16](Cl)[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]=2[C:8]1=[O:26].[C:36]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)(=[O:38])[CH3:37]>>[C:36]([N:39]1[CH2:44][CH2:43][N:42]([C:16]2[CH:17]=[C:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:9]3[C:8](=[O:26])[N:7]([CH2:6][C:5]4[CH:4]=[C:3]([C:2]([F:35])([F:34])[F:1])[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=4)[CH2:14][CH2:13][CH2:12][O:11][C:10]=3[N:15]=2)[CH2:41][CH2:40]1)(=[O:38])[CH3:37]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C1c2c(-c3ccccc3)cc(Cl)nc2OCCCN1Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Product: CC(=O)N1CCN(c2cc(-c3ccccc3)c3c(n2)OCCCN(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)C3=O)CC1
Yield: 53.5 %

Procedure:
In a similar manner to Example 1, 5-[3,5-bis(trifluoromethyl)benzyl]-9-chloro-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (compound of Reference Example 15; 52.0 mg) was reacted with 1-acetylpiperazine (38.8 mg) to obtain 9-(4-acetylpiperazine-1-yl)-5-[3,5-bis(trifluoromethyl)benzyl]-6-oxo-7-phenyl-2,3,4,5-tetrahydro-6H-pyrido[2,3-b][1,5]oxazocine (32.8 mg, 54%).
Reaction SMILES: [F:1][CH2:2][CH:3]([O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:10]([NH:12][C:13]1[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=1)=[O:11])[CH2:4][F:5].Cl[C:24]1[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:5][CH2:4][CH:3]([O:6][C:7]1[CH:21]=[C:20]([O:22][C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH3:33])=[O:31])=[N:28][CH:29]=2)[CH:19]=[C:9]([C:10]([NH:12][C:13]2[CH:17]=[CH:16][N:15]([CH3:18])[N:14]=2)=[O:11])[CH:8]=1)[CH2:2][F:1]
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(OC(CF)CF)c2)n1
Reactant: COC(=O)c1cnc(Cl)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1cnc(Oc2cc(OC(CF)CF)cc(C(=O)Nc3ccn(C)n3)c2)cn1
Temperature: 120 °C
Reaction time: 3 h
Yield: 90.8 %

Procedure:
A mixture of 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (250 mg, 0.8 mmol), methyl 5-chloropyrazine-2-carboxylate (208 mg, 1.20 mmol) and potassium carbonate (222 mg, 1.61 mmol) in acetonitrile (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 120° C. for 3 hours. The solvent was removed in vacuo and the residue dissolved in ethyl acetate (50 mL) and water (50 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a yellow oil which was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound (0.325 g). 1H NMR δ (CDCl3): 3.71 (s, 3H), 3.96 (s, 3H), 4.56 (m, 2H), 4.68 (m, 3H), 6.73 (s, 1H), 6.95 (s, 1H), 7.22 (s, 1H), 7.27 (s, 1H), 7.36 (s, 1H), 8.46 (s, 1H), 8.67 (s, 1H), 8.67 (s, 1H); m/z 448 (M+H)+