Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH2:9])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:16][O:17][CH2:18][CH2:19][CH2:20][C:21](Cl)=[O:22]>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:21](=[O:22])[CH2:20][CH2:19][CH2:18][O:17][CH3:16])=[N:6][CH:7]=1
Reactant: COCCCC(=O)Cl
Reactant: NCc1ccc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: COCCCC(=O)NCc1ccc(Br)cn1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 9.35 g of C-(5-bromopyridin-2-yl)methylamine [17399-23-0] in 200 ml of ethyl acetate is admixed with 300 ml of saturated aqueous sodium carbonate solution. The reaction mixture is cooled to 0° C. in an ice bath and subsequently admixed dropwise with a solution of 4-methoxybutanoyl chloride [61882-39-1] in 100 ml of ethyl acetate. The reaction mixture is stirred at 0° C. over 1 hour. The phases are separated and the aqueous phase is extracted with 300 ml of ethyl acetate (2×). The combined organic phases are washed with 300 ml of brine, dried over sodium sulphate and concentrated by evaporation. The title compound is identified on the basis of the Rf value from the residue by means of flash chromatography (SiO2 60 F).
Reaction SMILES: [CH2:1]([C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:7][C@@H:6]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:5]1)[CH:2]=[CH2:3].O.C([O-])(O)=[O:39].[Na+].OO>C1COCC1>[OH:39][CH2:3][CH2:2][CH2:1][C@@H:4]1[C@@H:8]([CH2:9][O:10][Si:11]([C:24]([CH3:27])([CH3:26])[CH3:25])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:7][C@@H:6]([N:28]2[CH:36]=[C:34]([CH3:35])[C:32](=[O:33])[NH:31][C:29]2=[O:30])[CH2:5]1
Reactant: O=C([O-])O
Reactant: C=CC[C@H]1C[C@H](n2cc(C)c(=O)[nH]c2=O)O[C@@H]1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cn([C@H]2C[C@H](CCCO)[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O2)c(=O)[nH]c1=O
Yield: 39.2 %

Procedure:
Compound 37 (0.74 g, 2 mmol) was treated with BH3Me2S (0.388 g, 5.12 mmol) in THF (10 ml). The reaction mixture was quenched with MeOH (0.7 mL). H2O (3 mL) and NaHCO3 (1.11 g, 13.3 mmol) were added to the reaction mixture followed by H2O2 (30%, 1.91 mL, 16.92 mmol). After work-up, the residue was purified by silica gel chromatography. The product was crystallized from ether/hexane to furnish 0.41 g of the product as white needles. mp 150°-151° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[I:15]I>FC(F)(F)C([O-])=O.[Ag+].C(Cl)Cl>[I:15][C:12]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:14])[N:9]2[CH3:13])=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COc1ccc2c(c1)CCC(=O)N2C
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClCCl
Product: COc1cc2c(cc1I)N(C)C(=O)CC2
Reaction time: 8 h
Yield: 47.8 %

Procedure:
Silver trifluoroacetate (2.32 g, 10.48 mmol) was added to a dry methylene chloride (100 ml) solution of 6-Methoxy-1-methyl-3,4-dihydro-1H-quinolin-2-one (1.0 g, 5.24 mmol) followed by the dropwise addition of methylene chloride (100 ml) solution of iodine (1.33 g, 10.48 mmol) over 15 minutes. The reaction mixture was stirred overnight and the precipitated silver iodide salts were filtered off. The filtrate was concentrated down to a residue which was chromatographed using 50% ethylacetate/hexane to yield the title compound (795 mg, 48% yield). 1H NMR (400 MHz, CDCl3) δ 2.57–2.61 (2H, m), 2.81–2.85 (2H, m), 3.27 (3H, s), 3.82 (3H, s), 6.62 (1H, s), 7.31 (1H, s). m/z (APCI+) 318 (M+1). HPLC (aqueous 200 Mm ammonium acetate buffer/acetonitrile gradient, 3.0 ml/min, Hewlett Packard ODS Hypersil 5 μM, 125×4 mm column), 4.959 min.
Reaction SMILES: Cl[C:2]1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[N:3]=1.[CH:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:15][C:14]([F:17])([F:16])[O:13][C:10]1[CH:11]=[CH:12][C:7]([N:4]2[CH2:5][CH2:6][C:2]([C:23]3[CH:24]=[CH:25][C:20]([CH:18]=[O:19])=[CH:21][CH:22]=3)=[N:3]2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(N2CCC(Cl)=N2)cc1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: O=Cc1ccc(C2=NN(c3ccc(OC(F)(F)F)cc3)CC2)cc1
Temperature: 150 °C
Yield: 34.9 %

Procedure:
A suspension of 3-chloro-1-(4-trifluoromethoxyphenyl)-4,5-dihydro-1H-pyrazole (114 mg, 0.43 mmol, 1.00 eq), 4-formylphenylboronic acid (97 mg, 0.65 mmol, 1.50 eq), bis(triphenylphosphine)palladium(II) dichloride (10 mg, 0.01 mmol, 0.03 eq), 2 M Na2CO3 (aq) (0.43 mL, 0.86 mmol, 2.0 eq), and 1,4-dioxane (5 mL) were heated at 150° C. in a microwave reaction vessel for 45 min. The cooled solution was then diluted with EtOAc (20 mL), filtered over Celite®, concentrated to dryness, and purified via chromatography (2:2:1, hexane:EtOAc:acetone) to afford the desired intermediate (50 mg, 0.15 mmol, 31%).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([NH:16][C:17]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][CH:22]=2)=[O:18])[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])[CH3:3]>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([CH2:20][NH:19][C:17]([NH:16][C:7]2[CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:10]([OH:11])=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:8]=2)=[O:18])=[CH:22][CH:23]=1
Reactant: CC(C)(C)c1cc(NC(=O)NCc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)NCc2ccc(N)cc2)cc(C(C)(C)C)c1O
Yield: 60 %

Procedure:
In a 100 ml autoclave, 0.55 g (1.38 mmole) of N-[3,5-bis-(1,1-dimethylethyl)-4-hydroxyphenyl]-N′-[(4-nitrophenyl)methyl]-urea is dissolved in a 2/1 mixture of ethanol and ethyl acetate, in the presence of 10% Pd/C. After hydrogenation for one and a half hours at 20° C., under 20 PSI, the mixture is filtered on celite and the filtrate is concentrated under vacuum. The evaporation residue is diluted in 20 ml of diethyl ether and the expected product crystallizes spontaneously. The crystals are filtered out and rinsed with 20 ml of diethyl ether. A white powder is obtained with a yield of 60% (0.31 g). Melting point: 194-195° C.
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([O:29]C)=[O:28])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:32]=[CH:31][C:26]([C:27]([OH:29])=[O:28])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:18])([F:20])[F:19])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc(NC(c2sc3cc(C(F)(F)F)cnc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Reaction time: 24 h
Yield: 89.3 %

Procedure:
To a mixture of methyl 4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]methyl}amino)benzoate (775 mg) synthesized above, tetrahydrofuran (10 mL) and ethanol (10 mL) was added 1N aqueous sodium hydroxide solution (10 mL), and the mixture was stirred for 1 day with heating under reflux, and concentrated under reduced pressure. The residue was dissolved in water (20 mL), and 1N hydrochloric acid (10 mL) was added at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (671 mg, 87%) as a pale-brown solid.
Reaction SMILES: [OH-].[K+].C([O:5][C:6](=[O:18])[CH:7]([NH:13][C:14](=[O:17])[CH2:15][Cl:16])[C:8]1[N:9]=[CH:10][S:11][CH:12]=1)C>O.C(O)C>[Cl:16][CH2:15][C:14]([NH:13][CH:7]([C:8]1[N:9]=[CH:10][S:11][CH:12]=1)[C:6]([OH:18])=[O:5])=[O:17]
Reactant: CCOC(=O)C(NC(=O)CCl)c1cscn1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(CCl)NC(C(=O)O)c1cscn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a solution of 2.5 g of potassium hydroxide in a mixture of 10 ml of water and 100 ml of ethanol is added 3.0 g of 2-chloroacetamido-4-thiazolyl acetic acid ethyl ester, and the mixture is stirred for one hour at room temperature. The solvent is evaporated under reduced pressure. To the residue is added 10 ml of water. The resulting aqueous solution is washed with ethyl acetate, and then adjusted to pH 2 with 10% hydrochloric acid, whereupon crystals separate out. The crystals are collected by filtration, washed with water, and dried to yield 2.2 g (84%) of 2-chloroacetamido-4-thiazolyl acetic acid, m.p. 193°-195° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([OH:15])=O)[N:12]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1.[NH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[S:9][CH:10]=[C:11]([C:13]([N:20]3[CH2:25][CH2:24][CH2:23][CH:22]([OH:26])[CH2:21]3)=[O:15])[N:12]=2)=[C:4]([NH:16][CH:17]([CH3:19])[CH3:18])[CH:3]=1
Reactant: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)O)cs1
Reactant: OC1CCCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Nc1cc(Cl)ncc1-c1nc(C(=O)N2CCCC(O)C2)cs1
Temperature: 25 °C

Procedure:
The 2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazole-4-carboxylic acid (23a) (100 mg, 0.336 mmol) was dissolved in DMF (5 mL), piperidin-3-ol (1.679 mmol) was added and stirred at room temperature. Added DIPEA (1.343 mmol), followed by addition of HATU (1.008 mmol) and stirred for 3 h. The reaction mixture was concentrated under reduced pressure to remove excess of DMF. The residue obtained was partitioned between water and EtOAc. The organic layer was separated, dried over Na2SO4, filtered and concentrated. The crude material obtained was purified by column chromatography through silica gel and MeOH: CHCl3 as eluent to afford the title compound, (2-(6-chloro-4-(isopropylamino)pyridin-3-yl)thiazol-4-yl)(3-hydroxypiperidin-1-yl)methanone.
Reaction SMILES: O.[NH2:2][NH2:3].[F:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:18]3[N:17]=[C:16](S)[NH:15][C:14]=3[CH:13]=[C:12]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:11]=2)=[CH:7][CH:6]=1>C(OCC)(=O)C>[F:4][C:5]1[CH:28]=[CH:27][C:8]([O:9][C:10]2[C:18]3[N:17]=[C:16]([NH:2][NH2:3])[NH:15][C:14]=3[CH:13]=[C:12]([O:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[CH:11]=2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(Oc2cc(Oc3cccnc3)cc3[nH]c(S)nc23)cc1
Reactant: NN
Solvent: O
Solvent: CCOC(C)=O
Product: NNc1nc2c(Oc3ccc(F)cc3)cc(Oc3cccnc3)cc2[nH]1
Temperature: 130 °C
Reaction time: 8 h

Procedure:
1.0 ml of hydrazine monohydrate was added to 130 mg of 4-(4-fluoro-phenoxy)-6-(pyridin-3-yloxy)-1H-benzimidazole-2-thiol, and the reaction liquid was stirred overnight at 130° C. The reaction liquid was diluted with ethyl acetate, washed with water and saturated saline in order, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through partitioning thin-layer chromatography (Kieselgel™ 60F254, Art 5744 (by Merck), hexane/ethyl acetate=1/1) to obtain the entitled compound.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]1.Cl[CH2:14][C:15]1[N:16]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[C:21]=2[F:30])[O:18][CH:19]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[F:30][C:21]1[C:22]([C:26]([F:29])([F:27])[F:28])=[CH:23][CH:24]=[CH:25][C:20]=1[C:17]1[O:18][CH:19]=[C:15]([CH2:14][N:3]2[CH:7]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:5]=[N:4]2)[N:16]=1
Reactant: Fc1c(-c2nc(CCl)co2)cccc1C(F)(F)F
Reactant: CCOC(=O)c1cn[nH]c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(Cc2coc(-c3cccc(C(F)(F)F)c3F)n2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a suspension of sodium hydride (60% in mineral oil, 0.08 g) in N,N-dimethylformamide (2 ml) was added ethyl 1H-pyrazole-4-carboxylate (0.21 g). After stirring at room temperature for 30 min, the compound (0.42 g) obtained in Example 105a was added to the reaction mixture. After stirring at room temperature for 2 hr, 10% aqueous citric acid solution and ethyl acetate were added to the reaction mixture. The ethyl acetate layer was separated, washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (carrier: silica gel, eluent: hexane-ethyl acetate) to give the title compound (0.44 g) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1cccc(-n2ccnn2)c1
Yield: 41.5 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (152 mg, 0.5 mmol) and 3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester (Example H2) (200 mg, 0.77 mmol) according to the general procedure K. Obtained as a yellow oil (107 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]1[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=1)[N:6]=[C:5]2O.[Cl:25]CCl.C(Cl)(C(Cl)=O)=O>CN(C)C=O>[Cl:25][C:5]1[C:4]2[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=2)[N:8]=[C:7]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[C:14]([O:22][CH3:23])[CH:13]=2)[N:6]=1
Reactant: ClCCl
Reactant: COc1cc(-c2nc(O)c3cc(F)ccc3n2)cc(OC)c1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: COc1cc(-c2nc(Cl)c3cc(F)ccc3n2)cc(OC)c1OC

Procedure:
Into a 500-mL round-bottom flask, was placed 6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazolin-4-ol (8.0 g, 24.22 mmol, 1.00 equiv), dichloromethane (200 mL) and N,N-dimethylformamide (0.5 mL). This was followed by the addition of (COCl)2 (23.74 g) dropwise with stirring. The resulting solution was stirred for 1 h at 40° C. in an oil bath. The resulting mixture was concentrated under vacuum. The residue was dissolved in 100 mL of dichloromethane. The resulting mixture was washed with 2×100 mL of NaHCO3 (sat.) and 1×100 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by ethyl acetate:petroleum ether in ratio of (1:5). This resulted in 5 g (59%) of 4-chloro-6-fluoro-2-(3,4,5-trimethoxyphenyl)quinazoline as a white solid. MS (ESI) m/z 349 ([M+H]+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[Br:16]Br>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:15])[C:5]([Br:16])([CH2:11][CH2:12][CH2:13][CH3:14])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2]
Reactant: BrBr
Reactant: CCCCC(C(=O)OCC)C(=O)OCC
Solvent: ClCCl
Product: CCCCC(Br)(C(=O)OCC)C(=O)OCC
Yield: 81.9 %

Procedure:
Diethyl-n-butylmalonate (32.2 gm) was dissolved in methylene chloride (200 ml) and treated, dropwise, with a solution of bromine (24.0 gm) dissolved in methylene chloride (25 ml). The resultant mixture was stirred (1 hour, room temperature) whereupon an orange coloration persisted. The solvent was removed under vacuum, and the residue distilled under high vacuum to give the desired product as a clear oil (boiling point temperature 105° C. to 110° C.; 36.0 gm). 1H NMR (CDCl3): δ=0.89-0.92 (t, 3H); 1.25-1.29 (t, 6H); 1.35-1.37 (m, 4H); 2.2-2.26 (m, 2H); 4.23-4.29 (q, 4H); m/z=295 and 297 (M+).
Reaction SMILES: [NH2:1][N:2]1[C:6](=[O:7])[CH2:5][S:4][C:3]1=[S:8].[O:9]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>C(O)C>[NH2:1][N:2]1[C:6](=[O:7])[C:5](=[CH:20][C:19]2[CH:22]=[CH:23][C:16]([O:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)=[CH:17][CH:18]=2)[S:4][C:3]1=[S:8]
Reactant: O=Cc1ccc(Oc2ccccc2)cc1
Reactant: NN1C(=O)CSC1=S
Solvent: CCO
Solvent: C1CCNCC1
Product: NN1C(=O)C(=Cc2ccc(Oc3ccccc3)cc2)SC1=S
Yield: 68.6 %

Procedure:
To a solution of 3-aminorhodanine (1.00 g) in ethanol (20 ml) were added 4-phenoxybenzaldehyde (1.47 g) and piperidine (57 mg), and the mixture was heated with reflux for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: chloroform) to give 3-amino-5-(4-phenoxybenzylidene)-2-thioxothiazolidin-4-one (1.52 g).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:11][N:12]=[C:13]=[S:14]>C(N(CC)CC)C>[CH3:11][NH:12][C:13]([NH:10][C:8]1[O:7][N:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:9]=1)=[S:14]
Reactant: CN=C=S
Reactant: CC(C)(C)c1cc(N)on1
Solvent: CCN(CC)CC
Product: CNC(=S)Nc1cc(C(C)(C)C)no1
Temperature: 75 °C
Yield: 52.7 %

Procedure:
A mixture of 3-t-butyl-5-aminoisoxazole (2.07 g), methyl isothiocyanate (1.40 g) and triethylamine (3 drops) is heated at 75° C. for 72 hours. The reaction mixture is chromatographed on a column of silica gel, whereby 1-methyl-3-(3-t-butyl-5-isoxazolyl)thiourea (1.66 g) is obtained as an oil. IR: 1622 cm-1 (CC14).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].Br[CH2:27][CH2:28][CH2:29][OH:30]>C(O)(C)C.[OH-].[Na+]>[OH:30][CH2:29][CH2:28][CH2:27][O:8][C:7]1[C:2]([CH3:1])=[CH:3][C:4]([CH2:10][CH2:11][C:12]([C:14]2[S:21][C:20]([CH3:22])=[C:19]3[C:15]=2[CH2:16][C@H:17]2[C:23]([CH3:25])([CH3:24])[C@H:18]23)=[O:13])=[CH:5][C:6]=1[CH3:9]
Reactant: OCCCBr
Reactant: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: Cc1cc(CCC(=O)c2sc(C)c3c2C[C@@H]2[C@H]3C2(C)C)cc(C)c1OCCCO
Temperature: 70 °C
Reaction time: 5 h
Yield: 73.1 %

Procedure:
A solution of 3-(3,5-dimethyl-4-hydroxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (3.00 g, 8.46 mmol, Intermediate 10) in isopropanol (80 mL) and 2 N aq. NaOH (30 mL) is treated with 3-bromopropanol (2.35 g, 16.9 mmol). The dark red reaction mixture is stirred at 70° C. for 5 h. The solvent is removed under reduced pressure and the residue is dissolved in EA and washed twice with water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 1:1 to give 3-[4-(3-hydroxy-propoxy)-3,5-dimethyl-phenyl]-1-((1aS,5aR)-1,1,2-tri methyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (2.55 g) as a yellow oil; LC-MS: tR=1.10 min, [M+1]+=413.33; 1H NMR (CDCl3): δ 6.87 (s, 2H), 3.99-3.90 (m, 4H), 3.04-2.85 (m, 5H), 2.81 (d, J=18.8 Hz, 1H), 2.39 (s, 3H), 2.27 (s, 6H), 2.10-2.01 (m, 2H), 1.93-1.88 (m, 2H), 1.13 (s, 3H), 0.72 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[C:17]([Cl:21])=[CH:16][C:15]=1O.C1CCC(N=C=NC2CCCCC2)CC1>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([O:12][C:15]2[CH:16]=[C:17]([Cl:21])[C:18]([Cl:20])=[CH:19][C:14]=2[Cl:13])=[O:11])[CH:5]=[CH:6][C:7]=1[OH:8]
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(Cc1ccc(O)c(Cl)c1)Oc1cc(Cl)c(Cl)cc1Cl
Reaction time: 8 h
Yield: 35.4 %

Procedure:
A solution of 4 g (21.6 mmol) of 3-chloro-4-hydroxyphenylacetic acid in 130 mL of ethyl acetate is slowly added to a solution of 4.7 g (23.6 mmol) of 2,4,5-trichlorophenol and 4.9 g (23.6 mmol) of DCC in 22 mL of dichloromethane and the reaction mixture is stirred overnight. The precipitate formed is separated by filtration and the solution is chilled to precipitate the rest of N,N-dicyclohexylurea. After a second filtration, the filtrate is washed three times with a solution of sodium bicarbonate, dried over MgSO4 and evaporated to dryness in a rotary evaporator. The resulting oil is chromatographed through silica gel eluting with hexanes and increasing amounts of dichloromethane. The desired product appears in the fraction eluted with 50% dichloromethane. After elimination of the solvent 2.8 g of product are isolated (34% yield), with the following analytical data: mp=77° C. Rf=0.33 (AcOEt/hexanes 3:7).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:3]=12.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]2[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:3]=12
Reactant: CNC
Reactant: Cc1nn(C)c2nc(-c3ccccc3)cc(Cl)c12
Product: Cc1nn(C)c2nc(-c3ccccc3)cc(N(C)C)c12
Temperature: 25 °C

Procedure:
15.5 gms. of 4-chloro-1,3-dimethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine (0.06 mol.) are added to 132 ml. of a solution of dimethylamine (40%). The reaction mixture is heated at 190°-200° C. for 16 hours in an autoclave and after cooling to room temperature is evaporated in vacuo. The residue is treated with water and extracted with ether. After evaporation of the extract, the 4-dimethylamino-1,3-dimethyl-6-phenyl-1H-pyrazolo[3,4-b]pyridine (15.6 gms. = 98%) is recrystallized from ligroin, m.p. 90°-91° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[S:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[S:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(C(O)=S)cc1
Solvent: CN(C)C=O
Product: Cc1ccc(C(=S)Cl)cc1

Procedure:
4-Methylthiobenzoic acid, 16.8 g (0.1 mole) is refluxed for 30 minutes in 50 ml of thionyl chloride (SOCl2) and 1 drop of dimethylformamide (DMF). The thionyl chloride is removed under vacuum and azeotroped with 50 ml of benzene to give 4-methylthiobenzoyl chloride as an oil.