Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[C:11](=[O:25])[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][C:16]=1[O:23][CH3:24])=[O:14].[BH4-].[Na+].C(O)(=O)C>C(O)CC>[CH3:24][O:23][C:16]1[CH:17]=[C:18]([O:21][CH3:22])[CH:19]=[CH:20][C:15]=1[CH:13]([OH:14])[CH2:12][CH:11]([C:4]1[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=1[O:2][CH3:1])[OH:25]
Reactant: COc1ccc(C(=O)CC(=O)c2ccc(OC)cc2OC)c(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCCO
Product: COc1ccc(C(O)CC(O)c2ccc(OC)cc2OC)c(OC)c1

Procedure:
1,3-Bis(2,4-dimethoxyphenyl)-propan-1,3-dione (8) (5 mg) was dissolved in 1-propanol (1 ml), followed by the addition of sodium borohydride (3 mg) and the mixture was allowed to react at room temperature for 3 hours. Upon completion of the reaction, 20% acetic acid (0.2 ml) was added to neutralize the excess sodium borohydride. The mixture was then separated on a pre-packed C18 column eluting with a MeOH/H2O gradient to provide 1,3-bis(2,4-dimethoxyphenyl)-propan-1,3-diol (9).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:19])[C:14]([N:16]([CH3:18])[NH2:17])=[O:15])[CH3:2].[F:20][C:21]([F:28])([F:27])[C:22](=O)[CH2:23][S:24][CH3:25].O>C1(C)C=CC=CC=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([C:3]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[C:5]([CH2:11][CH3:12])[C:4]=1[C:13](=[O:19])[C:14]([N:16]([CH3:18])[N:17]=[C:22]([CH2:23][S:24][CH3:25])[C:21]([F:28])([F:27])[F:20])=[O:15])[CH3:2]
Reactant: CSCC(=O)C(F)(F)F
Reactant: CCc1cc(CC)c(C(=O)C(=O)N(C)N)c(CC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCc1cc(CC)c(C(=O)C(=O)N(C)N=C(CSC)C(F)(F)F)c(CC)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
To a 100 ml volume three-necked flask, 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-1-methylhydrazine ((12-2)-(11)-40) (3.01 g) was added, and to the mixture was added dropwise a solution of 1,1,1-trifluoro-3-methylsulfanyl-2-propanone (7-0-2) (2.10 g) in toluene (27 g), followed by the addition of para-toluenesulfonic acid monohydrate (0.030 g). The resulting mixture was stirred under reflux for 40 minutes. Then, the reaction mixture was cooled to room temperature, poured into water (30 ml), and extracted with ethyl acetate (50 ml) 3 times. The resulting organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and subjected to silica gel column chromatography (chloroform) to give 2.31 g of 1-[2-(2,4,6-triethylphenyl)-2-oxoacetyl]-2-(1,1,1-trifluoro-3-methylsulfanyl-2-propylidene)-1-methylhydrazine ((4-46)-(1)-40).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].Br[CH2:20][CH2:21][CH2:22][Cl:23]>CN(C)C=O>[Cl:23][CH2:22][CH2:21][CH2:20][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: ClCCCBr
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCCCl)Cc1ccc(C(F)(F)F)cc1
Yield: 50.8 %

Procedure:
Using 0.22 g of (4-(trifluoromethyl)benzyl)malononitrile, 3 ml of N,N-dimethylformamide, 0.05 g of sodium hydride (60% in oil), and 0.31 g of 1-bromo-3-chloropropane, and according to the process described in the Production Example 1, there was obtained 0.15 g of 2-(3-chloropropyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (85)).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][C:3]=1[Cl:11].[CH:12]([NH:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)([CH3:14])[CH3:13]>O1CCCC1>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:15]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:12]([CH3:14])[CH3:13])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: CC(C)NC1CCCCC1
Reactant: O=C(Cl)c1ccc(Br)c(Cl)c1
Solvent: C1CCOC1
Product: CC(C)N(C(=O)c1ccc(Br)c(Cl)c1)C1CCCCC1
Reaction time: 1 h

Procedure:
To a stirred, cold (0° C.) solution of 4-bromo-3-chlorobenzoyl chloride (6.14 g, 24.2 mmol) in tetrahydrofuran (20 ml) is added dropwise a solution of isopropyl cyclohexyl amine (6.841g, 48.4 mmol) in THF (7 mL). After stirring for 1 hr. at 0° C., the reaction is stirred at room temperature for 3 hr. and refluxed for 3 hr. The reaction is concentrated in vacuo and the residual mass is dissolved in ethyl ether and water. The layers are separated and the organic layer washed once with water, twice with 0.5N HCl, once more with water, twice with 5% aqueous NaHO3 solution, and once with water. After drying over sodium sulfate, the organic layer is filtered, and the filtrate concentrated in vacuo to give the crude product. This material is purified by chromatography on silica gel using mixtures of EtOAc, and hexane as eluents to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=2[NH:16][C:17]2[C:18]3[C:25]([CH3:26])=[C:24]([C:27]([OH:29])=O)[S:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:4][CH2:3]1.[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH2:36]>>[CH3:31][N:32]([CH3:37])[CH2:33][CH2:34][CH2:35][NH:36][C:27]([C:24]1[S:23][C:19]2[N:20]=[CH:21][N:22]=[C:17]([NH:16][C:10]3[CH:11]=[CH:12][C:13]([F:15])=[CH:14][C:9]=3[O:8][CH:5]3[CH2:6][CH2:7][C:2]([CH3:30])([CH3:1])[CH2:3][CH2:4]3)[C:18]=2[C:25]=1[CH3:26])=[O:29]
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCC(C)(C)CC3)c12
Reactant: CN(C)CCCN
Product: Cc1c(C(=O)NCCCN(C)C)sc2ncnc(Nc3ccc(F)cc3OC3CCC(C)(C)CC3)c12

Procedure:
Prepared analogously to 29.3 from 0.150 g 4-[2-(4,4-dimethyl-cyclohexyloxy)-4-fluoro-phenylamino]-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (cpd. 31.2) and 0.044 ml N,N-dimethyl-propane-1,3-diamine.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:15]([CH3:25])[CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:4][CH:3]=1.[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37](B3OC(C)(C)C(C)(C)O3)=[CH:36][CH:35]=2)[CH2:33][CH2:32]1)=[O:30])[CH3:27]>>[CH2:26]([O:28][C:29]([C:31]1([C:34]2[CH:39]=[CH:38][C:37]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[NH:14][CH:15]([CH3:25])[CH2:16][C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=4)=[CH:4][CH:3]=3)=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:30])[CH3:27]
Reactant: COc1ccc(CC(C)Nc2c(C)noc2-c2ccc(Br)cc2)cc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(C)Cc4ccc(OC)cc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 7, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amine and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)[CH2:11][CH2:10]1)C1C=CC=CC=1>CO.[Pd]>[N:15]1([C@H:12]2[CH2:11][CH2:10][C@H:9]([NH2:8])[CH2:14][CH2:13]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: c1ccc(CN(Cc2ccccc2)[C@H]2CC[C@H](N3CCCCC3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: N[C@H]1CC[C@H](N2CCCCC2)CC1

Procedure:
1.7 g (4.8 mmol) of trans-dibenzyl-4-piperidino-cyclohexylamine are dissolved in 35 mL MeOH and hydrogenated on 350 mg Pd/C (10%) at 20° C. The solvent is eliminated in vacuo and the residue is crystallised from ethanol and conc. HCl.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2.[ClH:22].[H][H]>CO.[Pd]>[ClH:22].[ClH:22].[CH3:1][N:2]([CH3:21])[C:3]1[CH:8]=[C:7]([NH2:9])[CH:6]=[CH:5][C:4]=1[C:12]1[NH:13][C:14]2[C:15]([N:20]=1)=[N:16][CH:17]=[CH:18][CH:19]=2
Reactant: CN(C)c1cc([N+](=O)[O-])ccc1-c1nc2ncccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN(C)c1cc(N)ccc1-c1nc2ncccc2[nH]1

Procedure:
An amount of 2.83 gm of 2-(2'-dimethylamino-4'-nitrophenyl)-imidazo[4,5-b]pyridine was hydrogenated in a mixture of 100 ml of methanol, 10 ml of concentrated methanolic hydrochloric acid, and 1 gm of palladium/charcoal for 4.5 hours at ambient temperature with hydrogen gas at 5 bar. The catalyst was then removed by filtration, the filtrate was concentrated by evaporation, and the residue was triturated with acetone to form crystals, filtered, and then washed with a mixture of ether and acetone.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:13][CH:12]2[C:14](=[O:15])[CH:8]([CH2:9][S:10][CH2:11]2)[CH2:7]1)=[O:5])C.O.[OH-].[Na+]>C1COCC1>[O:15]=[C:14]1[CH:8]2[CH2:7][CH:6]([C:4]([OH:5])=[O:3])[CH2:13][CH:12]1[CH2:11][S:10][CH2:9]2
Reactant: CCOC(=O)C1CC2CSCC(C1)C2=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)C1CC2CSCC(C1)C2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.4 %

Procedure:
To a solution of 9-oxo-3-thia-bicyclo[3.3.1]nonane-7-carboxylic acid ethyl ester (5 g, 22 mmol) in a THF (55 ml)/water (30 ml) mixture at 0° C. was added dropwise a 1N sodium hydroxide solution (24 ml, 24 mmol). The reaction mixture was stirred at room temperature overnight, then heated to 60° C. for 1 hour before THF was evaporated. The remaining aqueous layer was washed with ethyl acetate, acidified with 1N HCl, the resulting precipitate was filtered and dried to yield 9-oxo-3-thia-bicyclo[3.3.1]nonane-7-carboxylic acid (2.22 g) as a solid.
Reaction SMILES: [CH3:1][CH2:2][CH:3]([C:51]([O-:53])=[O:52])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH:5]1[CH3:50].[Na+]>C(OCC)(=O)C.O1CCOCC1>[CH3:1][CH2:2][CH:3]([C:51]([OH:53])=[O:52])[CH:4]1[O:9][CH:8]([CH:10]([CH:12]([OH:48])[CH:13]([C:15]([CH:17]([CH:20]2[O:25][C:24]3([O:30][C:29]4([O:34][C:33]([CH:36]5[O:41][CH:40]([CH3:42])[C:39]([OH:45])([CH2:43][CH3:44])[CH2:38][CH2:37]5)([CH3:35])[CH2:32][CH2:31]4)[CH2:28][CH:27]=[CH:26]3)[CH:23]([CH3:46])[CH2:22][CH:21]2[CH3:47])[CH2:18][CH3:19])=[O:16])[CH3:14])[CH3:11])[CH:7]([CH3:49])[CH2:6][CH:5]1[CH3:50]
Reactant: CCC(C(=O)[O-])C1OC(C(C)C(O)C(C)C(=O)C(CC)C2OC3(C=CCC4(CCC(C)(C5CCC(O)(CC)C(C)O5)O4)O3)C(C)CC2C)C(C)CC1C
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCC(C(=O)O)C1OC(C(C)C(O)C(C)C(=O)C(CC)C2OC3(C=CCC4(CCC(C)(C5CCC(O)(CC)C(C)O5)O4)O3)C(C)CC2C)C(C)CC1C
Yield: 71.8 %

Procedure:
20-Deoxynarasin sodium salt (200 mg) was dissolved in ethyl acetate (10 ml). This solution was washed with 0.1 N HCl (10 ml) and then twice with water (5 ml). The resulting organic layer was evaporated to dryness to give a residue which was redissolved in dioxane and lyophilized to give 139.6 mg of 20-deoxynarasin free acid as a white solid.
Reaction SMILES: Cl.[NH2:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1.C(N(CC)C(C)C)(C)C.[Cl:21][CH2:22][CH2:23][N:24]=[C:25]=[O:26]>C(#N)C>[Cl:21][CH2:22][CH2:23][NH:24][C:25]([NH:2][CH:3]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4]1)=[O:26]
Reactant: O=C=NCCCl
Reactant: NC1Cc2ccccc2C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C(NCCCl)NC1Cc2ccccc2C1
Yield: 46.8 %

Procedure:
Synthesized according to general procedure 40. The reaction was set up with 2-aminoindan hydrochloride (5.0 g, 29.5 mmol), N,N-diisopropylethylamine (10.3 mL, 58.9 mmol), acetonitrile (100 mL), and 2-chloroethylisocyanate (2.52 mL, 29.5 mmol). Purification via silica gel chromatography using 50% EtOAc in hexanes gave the desired urea as a white solid (3.3 g, 13.8 mmol, 47% yield). 1H NMR (400 MHz, DMSO-d6) δ 7.23-7.18 (m, 2H), 7.15-7.11 (m, 2H), 6.38 (d, J=7.3 Hz, 1H), 6.03 (t, J=5.7 Hz, 1H), 4.36-4.28 (m, 1H), 3.57 (t, J=6.2 Hz, 2H), 3.38-3.29 (m, 2H), 3.12 (dd, J=7.1, 15.8 Hz, 2H), 2.68 (dd, J=5.5, 15.8 Hz, 2H).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][CH2:9][O:10][C:11]2[C:21]3[CH2:20][CH2:19][C:18]4[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=4[C:16](=[O:26])[C:15]=3[CH:14]=[CH:13][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH2:30].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C1(C)C=CC=CC=1>CC([O-])=O.CC([O-])=O.[Pd+2].C(O)(C)(C)C>[F:27][C:28]1[CH:34]=[C:33]([F:35])[CH:32]=[CH:31][C:29]=1[NH:30][C:23]1[CH:24]=[CH:25][C:17]2[C:16](=[O:26])[C:15]3[CH:21]=[C:11]([O:10][CH2:9][CH2:8][CH2:7][N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[CH:12]=[CH:13][C:14]=3[CH2:20][CH2:19][C:18]=2[CH:22]=1
Reactant: O=C1c2ccccc2CCc2c(OCCCN3CCOCC3)cccc21
Reactant: Nc1ccc(F)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CC(C)(C)O
Solvent: Cc1ccccc1
Product: O=C1c2ccc(Nc3ccc(F)cc3F)cc2CCc2ccc(OCCCN3CCOCC3)cc21
Yield: 43 %

Procedure:
In accordance with general method AA, 0.67 g (1.8 mmol) of 2-chloro-7-(3-morpholin-4-yl-propoxy-10,11-dihydrodibenzo[a,d]-cyclohepten-5-one (36i), 0.25 g (1.9 mmol) of 2,4-difluoroaniline, 0.05 g (0.22 mmol) of Pd(OAc)2, 0.10 g (0.21 mmol) of 2-(dicyclohexylphosphino)-2′-,4′-,6′-triisopropyl-biphenyl, 0.60 g (6.2 mmol) of Na—O-tert-butylate, 5 ml of toluene and 1 ml of tert-BuOH are used. Reaction time: 1 h. Purification is carried out via flash chromatography (SiO2, hexane/ethyl acetate 7+3). C28H28F2N2O3 (Mr=478.54); yield 43%; m.p. 114° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12](Br)[CH:11]=1)=[O:5])[CH3:2].[CH2:21]([N:28]1[CH:36]=[C:35]2[C:30]([CH:31]=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:33]=[CH:34]2)=[N:29]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.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>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[CH2:9][C:10]1[N:18]2[C:13]([C:14]([NH2:19])=[N:15][CH:16]=[N:17]2)=[C:12]([C:32]2[CH:33]=[CH:34][C:35]3[C:30]([CH:31]=2)=[N:29][N:28]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:36]=3)[CH:11]=1)=[O:5])[CH3:2]
Reactant: CC1(C)OB(c2ccc3cn(Cc4ccccc4)nc3c2)OC1(C)C
Reactant: CCOC(=O)C1CC1Cc1cc(Br)c2c(N)ncnn12
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: CN(C)C=O
Product: CCOC(=O)C1CC1Cc1cc(-c2ccc3cn(Cc4ccccc4)nc3c2)c2c(N)ncnn12
Yield: 54 %

Procedure:
To a solution of 2-(4-amino-5-bromo-pyrrolo[2,1-f][1,2,4]triazin-7-ylmethyl)-cyclopropanecarboxylic acid ethyl ester (1.33 g, 4 mmol) in degassed DMF (6.6 mL) was added 2-benzyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2H-indazole (2.1 g, 6.3 mmol), Pd(PPh3)4, and 2N Na2CO3 solution (5.3 mL). The reaction was irradiated in a microwave reactor at 150° C. for 10 min. After cooling the mixture was partitioned between EtOAc and H2O. The organic phase was separated and dried over Na2SO4, filtered, and evaporated in vacuo. The crude was purified by Biotage® (50-100% EtOAc/hexane) to give the title product as an off white solid, 1.0 g (yield 54%). 1H NMR (300 MHz, DMSO-d6) δ 8.60 (s, 1 H), 8.05 (d, 2 H), 8.0 (s, 1 H), 7.90 (d, 1 H), 7.70 (s, 1 H), 7.60-7.40 (m, 7 H), 7.25 (d, 1 H), 7.20 (s, 1 H), 5.70 (s, 2 H), 4.0 (m, 2 H), 3.0 (m, 2 H), 1.70 (m, 2 H), 1.2-1.0 (m, 5 H); ES-MS m/z 5467.27 [M+H]+, HPLC RT (min) 2.79.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([CH2:9][S:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[N:8]=1)=[O:2].[Cl:17]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:17][C:6]1[S:5][C:4]([NH:3][CH:1]=[O:2])=[N:8][C:7]=1[CH2:9][S:10][C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1
Reactant: O=CNc1nc(CSc2ccncc2)cs1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: O=CNc1nc(CSc2ccncc2)c(Cl)s1
Reaction time: 16 h
Yield: 46.7 %

Procedure:
A mixture of 2-formylamino-4-(4-pyridylthiomethyl)thiazole (1.6 g) and N-chlorosuccinimide (1.5 g) in acetic acid (25 ml) was heated at 40°-50° C. for 5 hours with stirring and then the mixture was allowed to stand at room temperature for 16 hours. The reaction mixture was concentrated under reduced pressure and the residue was triturated with aqueous sodium bicarbonate. The precipitates were collected by filtration washed with water and dried in vacuo to give 5-chloro-2-formylamino-4-(4-pyridylthiomethyl)thiazole (0.85 g, yield: 46.8%). mp: 200°-203° C. (dec.) IR (Nujol): 1680, 1665, 1587, 1300 cm-1
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:24])[Cl:23])[CH:16]=[C:15]([CH2:25][CH3:26])[C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][CH2:11][CH:12]=[N:13][OH:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.CN(C)C=O>O>[CH2:33]([O:14][N:13]=[CH:12][CH2:11][O:10][CH2:9][CH2:8][CH2:7][CH2:6][O:5][C:4]1[C:15]([CH2:25][CH3:26])=[CH:16][C:17]([O:19][CH2:20][CH:21]=[C:22]([Cl:23])[Cl:24])=[CH:18][C:3]=1[CH2:1][CH3:2])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NO
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1cc(OCC=C(Cl)Cl)cc(CC)c1OCCCCOCC=NOCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.6 %

Procedure:
First, 0.27 g of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde oxime, 0.10 g of potassium carbonate, 0.16 g of benzyl bromide, and 10 ml of N,N-dimethylformamide were placed in a reaction vessel. After stirring at room temperature for 24 hours, the reaction mixture was poured into water, and extracted twice with diethyl ether. The diethyl ether layers were combined, washed with water, dried over anhydrous magnesium sulfate, and concentrated to give a crude product. This crude product was subjected to silica gel chromatography, which afforded 0.21 g (yield, 56%) of 4-(2,6-diethyl-4-(3,3-dichloro-2-propenyloxy)phenoxy)butyloxyacetaldehyde O-benzyloxime, nD22.5 1.5402.
Reaction SMILES: C([O:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1>[OH:5][C@@H:6]1[C@:14]2([CH2:15][CH3:16])[C@H:9]([C@@H:10]3[CH2:24][CH2:23][C:22]4[CH:21]=[C:20]([O:25][CH3:26])[CH:19]=[CH:18][C:17]=4[C@H:11]3[CH2:12][CH2:13]2)[CH2:8][CH2:7]1
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Yield: 103.4 %

Procedure:
A solution of 0.4 g (1.12 mmoles) of (+)-17β-tert.butoxy-13 β-ethyl-3-methoxygona-1,3,5(10)-triene and 0.1 g of p-toluenesulfonic acid monohydrate in 10 ml of toluene was stirred and heated at reflux for 1 hr. The resulting solution was cooled and treated with saturated aqueous sodium bicarbonate solution then extracted twice with ether. The combined organic extracts were dried, filtered and concentrated in vacuo giving 0.348 g of (+)-17β-hydroxy-13β-ethyl-3-methoxygona-1,3,5(10)-triene as a colorless solid.
Reaction SMILES: I[CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4].[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[OH:41])(=[O:37])[CH3:36].[H-].[Na+].O>C(Cl)Cl>[C:35]([O:38][C@@H:39]1[C@@H:45]([O:46][C:47](=[O:49])[CH3:48])[C@H:44]([O:50][C:51](=[O:53])[CH3:52])[C@@H:43]([CH2:54][O:55][C:56](=[O:58])[CH3:57])[O:42][C@H:40]1[O:41][CH2:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:7]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=1)=[O:4])(=[O:37])[CH3:36]
Reactant: CC(=O)OC[C@H]1O[C@@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: O=C(CI)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](OCC(=O)c2cc(OCc3ccccc3)c(OCc3ccccc3)c(OCc3ccccc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Iodo-3′,4′,5′-tribenzyloxyacetophenone (20) (5.64 g, 10 mmol) and β-D-glucose-2,3,4,6-tetraacetate (8) (4.18 g, 12 mmol) was dissolved in dry DCM (50 mL) and sodium hydride (0.48 g, 20 mmol) (0.8 g 60% NaH suspension in oil)) was added in small portions. The reaction mixture was allowed to be stirred at room temperature overnight. Excess of sodium hydride was decomposed by addition of suitable amount water. Dichloromethane was removed under vacuum in order to simplify the work up. Water (100 mL) was added and the water phase extracted with diethyl ether (4×75 mL). The organic layers were combined and washed with water (2×50 mL), dried (MgSO4) and evaporated to give a dark viscous oil. The product was isolated by dry flash chromatography (PE/EtOAc 6:4). Recrystallisation from a mixture of methylcyclohexane and ethyl acetate afforded the desired compound as white crystals, m.p. 156-158° C. Yield 5.1 g (65%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([OH:24])=[CH:11][CH:10]=3)[CH3:2].[OH-].[K+].[CH2:27]([CH:29]1[O:31][CH2:30]1)Cl>CS(C)=O>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([NH:16][CH2:17][CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]4)=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([O:24][CH2:27][CH:29]1[O:31][CH2:30]1)=[CH:11][CH:10]=3)[CH3:2]
Reactant: CCn1ncc2c(NCC3CCCCC3)c3cc(O)ccc3nc21
Reactant: ClCC1CO1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCn1ncc2c(NCC3CCCCC3)c3cc(OCC4CO4)ccc3nc21
Reaction time: 0.5 h

Procedure:
A mixture of 1-ethyl-6-hydroxy-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine (6 g), KOH (5 g), and DMSO (70 ml) was stirred for 30 minutes and then epichlorohydrin (1.5 ml) was added. The reaction mixture was stirred overnight and then was partitioned between CH2Cl2 and water. The organic layer was then separated, dried and evaporated to dryness. The residue was purified by column chromatography on silica gel eluting with ethyl acetate, followed by crystallization from hexane/ether to afford 1.0 g of 1-ethyl-6-(2,3-epoxypropoxy)-N-(cyclohexylmethyl)-1H-pyrazolo[3,4-b]quinolin-4-amine, m.p. 160°-163° C.