Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][CH:7]=1.Br[C:11]1[CH:16]=[CH:15][C:14]([CH:17]([OH:22])[C:18]([F:21])([F:20])[F:19])=[CH:13][CH:12]=1.C(O)(C(F)(F)F)=O>C1COCC1.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>[F:19][C:18]([F:20])([F:21])[CH:17]([C:14]1[CH:15]=[CH:16][C:11]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=2)=[CH:12][CH:13]=1)[OH:22]
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Reactant: Fc1cccc([Mg]Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: OC(c1ccc(-c2cccc(F)c2)cc1)C(F)(F)F
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
To Pd(PPh3)4 (2.1 g, 1.823 mmol) was added 3-fluorophenylmagnesium bromide (55 mls, 1.0 M in THF, 55 mmol) at 0° C. over 15 minutes. The ice bath was removed and the mixture was stirred for 30 minutes. 1-(4-Bromophenyl)-2,2,2-trifluoroethanol (4.65 g, 18.23 mmol) in THF (50 mls) was added over 10 minutes. The mixture was heated to reflux for 3 hours and was shown complete by LC (Sunfire column, TFA). The mixture was cooled, quenched with H2O, rotary evaporated to remove most of the THF, and extracted 3 times with CH2Cl2. The organics were combined washed with brine, dried over MgSO4, and concentrated. Chromatography (SiO2, CH2Cl2) gave 4.64 g of 2,2,2-trifluoro-1-(3′-fluorobiphenyl-4-yl)ethanol. Yield 94%.
Reaction SMILES: [CH:1]1([CH:7]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])=[O:29])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:18][CH2:17][S:16][CH2:15][CH2:14]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O1CCCC1.[OH-].[Na+]>C(O)C>[CH:1]1([CH:7]([NH:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]([NH:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])=[O:29])=[CH:26][CH:27]=2)[C:8]2[CH:12]=[C:11]([CH:13]3[CH2:14][CH2:15][S:16][CH2:17][CH2:18]3)[S:10][C:9]=2[CH2:19][CH3:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC(=O)c1ccc(NC(c2cc(C3CCSCC3)sc2CC)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CCc1sc(C2CCSCC2)cc1C(Nc1ccc(C(=O)NCCC(=O)O)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
To a mixture of ethyl 3-({[4-({cyclohexyl[2-ethyl-5-(tetrahydro-2H-thiopyran-4-yl)thiophen-3-yl]methyl}amino)phenyl]carbonyl}amino)propanoate (338 mg) synthesized above, tetrahydrofuran (5 mL) and ethanol (5 mL) was added 1N aqueous sodium hydroxide solution (1 mL), and the mixture was stirred at room temperature for 3 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title compound (296 mg, 93%) as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[C:4]=1[OH:13].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH:21]([CH3:23])[CH3:22]>CC(C)=O>[CH:21]([O:13][C:4]1[C:3]([O:2][CH3:1])=[CH:12][CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][CH2:9]2)([CH3:23])[CH3:22]
Reactant: CC(C)Br
Reactant: COc1ccc2c(c1O)CCCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: COc1ccc2c(c1OC(C)C)CCCC2
Yield: 92.6 %

Procedure:
33 (4.55 g, 25.5 mmol) was charged in a 250 mL round bottom flask, equipped with a reflux condenser, under nitrogen gas. 50 mL of anhydrous acetone was added followed by cesium carbonate (66.55 g, 204.3 mmol). 2-bromopropane (23.94 mL, 255.0 mmol) was added and the reaction mixture was refluxed for 12 h. The solvent was filtered and evaporated in vacuo and purified by flash column chromatography (silica gel, 1:99 EtOAc:Hexanes) to afford 5.2 g (93%) of 5-isopropoxy-6-methoxy-1,2,3,4-tetrahydronaphtalene (34). Rf value: 0.615 (15:85 EtOAc:Hexanes).
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].[Cl:12]C1C(C(F)(F)F)=CC=CC=1C(O)=O>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([Cl:12])=[O:5]
Reactant: O=C(O)c1cccc(Cl)c1Cl
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Product: O=C(Cl)c1cccc(Cl)c1Cl

Procedure:
Intermediate 14 was prepared in a similar manner as Intermediate 12 substituting 2,3-dichlorobenzoic acid for 2-chloro-3-(trifluoromethyl)benzoic acid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-:26])=[O:25])[C:18]=2Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[OH2:30]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([C:17]2[C:22]([Cl:23])=[CH:21][CH:20]=[C:19]([N+:24]([O-:26])=[O:25])[C:18]=2[OH:30])(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2Cl)CC1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc([N+](=O)[O-])c2O)CC1
Yield: 31.6 %

Procedure:
Following the general hydrolysis procedure outlined in example 15, 1-[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl-2,6-dichloro-3-nitrobenzene (200 mg, 0.45 mmol), 60% NaH (54 mg, 1.35 mmol) and water (8μL, 0.45 mmol) were reacted to form the desired product (60 mg, 32%). EI-MS (m/z) 420.1, 422.1 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:23][CH:22]=1)=[C:19]=[O:20]>>[C:24]1([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:23]=[CH:22][C:21]([NH:18][C:19]([NH:13][CH2:12][CH:8]2[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]3[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=3)[CH2:7]2)=[O:20])=[CH:26][CH:25]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Product: O=C(NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1)Nc1ccc(-c2ccccc2)cc1
Yield: 73.5 %

Procedure:
Example 32 was prepared in an analogous manner to Example 1 using a mixture of Intermediate 3 (0.025 g) and 4-isocyanato-1,1′-biphenyl (0.0266 g) to give the title compound (0.0314 g). LC-MS (System A): Rt 2.65 mins, Mass Spectrum m/z 470 [MH+].
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=O)[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:31][NH2:32]>CO>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](=[N:31][NH2:32])[CH2:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH3:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(=O)CCC2c1ccccc1OC
Reactant: NN
Solvent: O
Solvent: CO
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(=NN)CCC2c1ccccc1OC
Yield: 101.4 %

Procedure:
A solution of 166.6 g (0.424 mol) of methyl (3aRS,4SR,7aRS)-2-benzyl-4-(2-methoxyphenyl)-7-oxo-octahydroisoindole-3a-carboxylate and of 84.5 g (1.69 mol) of hydrazine hydrate in 2.8 dm3 of methanol is brought to reflux for two hours. After concentrating the methanol under reduced pressure, the residue was taken up in 2 dm3 of dichloromethane, washed with four times 1 dm3 of distilled water, dried over magnesium sulphate and concentrated under reduced pressure. 175.2 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-hydrazono-4-(2-methoxyphenyl)octahydroisoindole-3a-carboxylate were thus obtained in the form of a yellow oil, the characteristics of which were as follows:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].[C:20]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:32]([O:31][C:29](=[O:30])[CH:28]([CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)[C:20](=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH3:33]
Reactant: ClCc1ccc2c(c1)OCO2
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(Cc1ccc2c(c1)OCO2)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 76.5 %

Procedure:
5-Chloromethyl benzo[1,3]dioxol (11.2 g, 65.7 mmol) was dissolved in Dimethylformamide. Then, potassium carbonate (18.2 g, 131.4 mmol), sodium iodide (10.8 g, 72.27 mmol) and ethyl benzoylacetate (12.5 ml, 72.27 mmol) were added thereto and stirred for 5 hours at room temperature. The reaction mixture was extracted with ammonium chloride and ether, the organic layer was separated, dried over anhydrous magnesium sulfate, concentrated, and the resulting residue was purified by column chromatography to obtain 2-benzo[1,3]dioxol-5-ylmethyl-3-oxo-3-phenylpropionate ethyl ester (16.4 g, 76%).
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([OH:18])=O)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.S(Cl)([Cl:21])=O>ClCCl>[CH3:1][N:2]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:9]([C:16]([Cl:21])=[O:18])[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: CN1c2ccccc2C(C(=O)O)c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CN1c2ccccc2C(C(=O)Cl)c2ccccc21

Procedure:
A solution of 0.35 parts of 10-methylacridan-9-carboxylic acid (77) in 20 mL dichloromethane and 1.1 parts of thionyl chloride is treated as described in Example I, to give 10-Methylacridan-9-carboxylic acid chloride.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br>CO>[Br:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][N:2]([CH3:3])[CH3:1]
Reactant: CNC
Reactant: BrCc1ccccc1Br
Solvent: CO
Product: CN(C)Cc1ccccc1Br
Reaction time: 0.5 h

Procedure:
Dimethylamine (33% w/w in methanol) (25 ml) was added to 2-bromobenzylbromide (7.5 g 30 mmol) at 0° C. in methanol (35 ml), and the solution stirred for 30 min., evaporated, diluted with water and extracted twice with diethyl ether. The combined extracts were dried over sodium sulphate and evaporated to give product as a yellow oil (6.0 g). M+ 215/213; 360 MHz 1H n.m.r (CDCl3) 7.54 (1H, dd, J 1.2, 8.0 Hz), 7.42 (1H, dd, J 1.6, 7.6 Hz), 7.30-7.26 (1H, m), 7.11 (1H, dt, J 1.7, 7.7 Hz), 3.52 (2H, s), 2.30 (6H, s).
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.[C:10](Cl)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(N(CC)CC)C>C(Cl)(Cl)Cl.C(OCC)(=O)C.CN(C1C=CC=CN=1)C>[Cl:9][CH2:8][C:6]1[N:7]=[C:3]([NH:2][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[S:4][CH:5]=1
Reactant: Nc1nc(CCl)cs1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: ClCc1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 41.5 %

Procedure:
A solution of 2-amino-4-chloromethylthiazole hydrochloride (3.701 g), trityl chloride (11.15 g), triethylamine (10.5 ml) and dimethylaminopyridine (10 mg) in chloroform (150 ml) was stirred at room temperature. After 23 h the reaction mixture was diluted with chloroform (150 ml) and then washed with 5% aqueous sodium hydrogen carbonate solution (2×50 ml) and brine (50 ml), dried (MgSO4) and evaporated to an orange gum. The gum was triturated with diethyl ether to give a pale brown solid. The liquors from the trituration were diluted with ethyl acetate (250 ml) and washed with M-hydrochloric acid (3×60 ml), water (60 ml), and brine (30 ml) dried (MgSO4) and evaporated to a pale brown foam. The triturated solid was treated in the same manner as the liquors to give a pale brown foam. The two foams were combined and subjected to column chromatography on silica developing and eluting with ethyl acetate-petrol, 1:9 and gave an off white solid (3.241 g). A portion (240 mg) of the solid was crystallised twice from ethyl acetate-petrol to give off white crystals of the title thiazole (206 mg), m.p. 139°-140° C., λmax (EtOH) 267.5 nm (ε 8,050).
Reaction SMILES: [CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[NH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[CH3:19]C(C)([O-])C.[K+].IC.O>CS(C)=O>[CH2:1]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH:12]=2)[N:7]([CH3:19])[CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)[O-]
Reactant: CCCCc1c[nH]c2ccc(C(=O)OCC)cc12
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CCCCc1cn(C)c2ccc(C(=O)OCC)cc12
Temperature: 50 °C
Yield: 46.3 %

Procedure:
To a mixture of ethyl 3-butyl-1H-indole-5-carboxylate (0.6 g) in methylsulfoxide (10 mL) was added potassium t-butoxide (0.29 g) and iodomethane (2.0 mL). The mixture was stirred at 50° C. for 18 H, at which time the mixture was pored into water (50 mL). The solution was extracted with ethyl acetate and the organic extracts washed three times with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. Column chromatography on silica gel (100 mL) using 5% ethyl acetate in hexanes as eluent to give 0.294 g of the title compound: 1H NMR (CDCl3) δ 0.953, 1.44, 1.69, 2.77, 3.76, 4.40, 6.87, 7.26, 7.91, 8.35.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=O)[CH:7]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:6][CH2:5]2.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[C:13]1([CH:7]2[CH2:6][CH2:5][C:4]3[CH:3]=[C:2]([OH:1])[CH:11]=[CH:10][C:9]=3[CH2:8]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C1c2ccc(O)cc2CCC1c1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Oc1ccc2c(c1)CCC(c1ccccc1)C2
Temperature: 60 °C

Procedure:
To a solution of 6-hydroxy-2-phenyl-3,4-dihydro-2H-naphthalen-1-one (50 mg) in trifluoroacetic acid was added triethylsilane (98 mg). The mixture was heated at 60° C. for 3 h. Solvent was evaporated, water added to the residue and the mixture extracted with ethyl acetate. Organic extract was dried and evaporated. 1H NMR (400 MHz, d6-DMSO) δ: 9.02 (s, 1H), 7.18-7.32 (m, 5H), 6.87 (d, 1H, J 7.9), 6.50-6.53 (m, 2H), 2.68-2.92 (m, 5H), 1.94-1.99 (m, 1H), 1.81-1.89 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1.N1C=CN=C1.[Si:30](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31].O>CN(C)C=O>[Si:30]([O:1][CH2:2][CH2:3][S:4][C@H:5]1[CH2:22][CH2:21][C@@:20]2([CH3:23])[C:7](=[CH:8][CH2:9][C@@H:10]3[C@@H:19]2[CH2:18][CH2:17][C@@:15]2([CH3:16])[C@H:11]3[CH2:12][CH2:13][C:14]2=[O:24])[CH2:6]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H](SCCO)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCS[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]32)C1
Yield: 90.4 %

Procedure:
To a solution of 1.0 g of 3β-(2-hydroxyethylthio)-androst-5-en-17-one in 20 ml of dimethylformamide, 1.7 g of imidazole and 2.0 g of t-butyldimethylsilyl chloride were added at 0° C. After 12 hrs the mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.2 g of crude 3β-(2-tert-butyldimethylsilyloxyethythio)-androst-5-en-17-one.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8](Cl)=[O:9])[CH:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:20]=1[NH:19][C:18](=[O:21])[CH2:17]2.[Cl-].[Cl-].[Cl-].[Al+3]>CCOC(C)=O>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([C:8]([C:14]2[CH:15]=[C:16]3[C:20](=[C:12]([CH3:11])[CH:13]=2)[NH:19][C:18](=[O:21])[CH2:17]3)=[O:9])[CH:3]=1
Reactant: Cc1cccc2c1NC(=O)C2
Reactant: O=C(Cl)c1cc(Cl)ncn1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1NC(=O)C2
Temperature: 0 °C

Procedure:
1.92 g (10.9 mmol) 6-chloropyrimidine-4-carboxylic acid chloride, 1.60 g (10.9 mmol) 7-methyl-1,3-dihydro-indol-2-one and 7.33 g (55.0 mmol) aluminium trichloride were heated to 130° C. for 3 h with stirring. The mixture was combined first with ice water and then with EtOAc. The precipitate formed as black flakes was suction filtered and the phases were separated. The aqueous phase was extracted several times with EtOAc. The combined organic phases were dried on sodium sulphate, filtered and evaporated down i. vac.
Reaction SMILES: [CH:1]1[C:6](=[O:7])[C:5]([OH:8])=[CH:4][O:3][C:2]=1[CH2:9][OH:10].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23]Cl)=[CH:21][CH:20]=1>>[CH3:17][O:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][O:8][C:5]2[C:6](=[O:7])[CH:1]=[C:2]([CH2:9][OH:10])[O:3][CH:4]=2)=[CH:21][CH:20]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=c1cc(CO)occ1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1ccc(COc2coc(CO)cc2=O)cc1

Procedure:
42.6 9 of kojic acid is dissolved in 350 ml of N-dimethylformamide, then 82.8 g of anhydrous potassium carbonate and 55 g of p-methoxybenzyl chloride are added thereto, and reacted at 70°-75° C. for 1.5 hours. After the reaction, the reaction mixture is concentrated to about half the volume, and added dropwise to 700 ml of water with ice cooling. The formed precipitates are filtered off, washed with water and ethyl acetate and dried to obtain 59.9 g of 5-p-methoxybenzyloxy-2-hydroxymethyl-4-pyrone.
Reaction SMILES: [CH3:1][O:2][C:3](/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11]([OH:13])=O)=[O:8])=[O:4].C(Cl)(=O)C(Cl)=O.[CH:20]([O:23][C:24](=[O:28])[CH2:25][NH:26][CH3:27])([CH3:22])[CH3:21].C(N(C(C)C)CC)(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C)C=O>[C:3]([O:2][CH3:1])(=[O:4])/[CH:5]=[CH:6]/[C:7]([O:9][CH2:10][C:11](=[O:13])[N:26]([CH3:27])[CH2:25][C:24]([O:23][CH:20]([CH3:22])[CH3:21])=[O:28])=[O:8]
Reactant: COC(=O)/C=C/C(=O)OCC(=O)O
Reactant: CNCC(=O)OC(C)C
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)/C=C/C(=O)OCC(=O)N(C)CC(=O)OC(C)C
Yield: 26.8 %

Procedure:
Following general procedure B2, 2-[(2E)-3-(methoxycarbonyl)prop-2-enoyloxy]acetic acid (23) (0.50 g, 2.65 mmol) was activated with oxalyl chloride (0.30 mL, 0.40 g, 3.18 mmol) in dichloromethane (DCM) at ca. 0° C. and in the presence of a catalytic amount of N,N-dimethylformamide (DMF). A DCM solution of the freshly prepared crude acid chloride was reacted ca. 0° C. (ice bath) with sarcosine isopropyl ester (H-Sar-OiPr) (0.41 g, 3.18 mmol) and diisopropylethylamine (DIEA) (0.41 mL, 0.304 g, 2.35 mmol) in DCM and in the presence of 4-(N,N-dimethyl)aminopyridine (DMAP) (0.10 g, 0.82 mmol). After aqueous work-up and isolation, and purification by silica gel flash chromatography afforded 0.214 g (27% yield) of the title compound (35) as a pale-yellow solid. 1H NMR (CDCl3, 400 MHz, all rotamers): δ 6.94-6.90 (m, 2H), 5.09-4.99 (m, 1H), 4.89-4.79 (2s, 2H), 4.07-3.95 (2s, 2H), 3.78 (s, 3H), 3.04-2.98 (2s, 3H), 1.27-1.21 (m, 6H). MS (ESI): m/z 302.04 (M+H)+.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[N+:10]([O-])([OH:12])=[O:11].C(=O)(O)[O-].[Na+]>O>[N+:10]([C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[NH:1][CH:2]=1)([O-:12])=[O:11]
Reactant: O=[N+]([O-])O
Reactant: c1cnc2[nH]ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: O=[N+]([O-])c1c[nH]c2ncccc12
Temperature: 0 °C

Procedure:
3-nitro-7-azaindole 504 is prepared by adding 7-azaindole 1 to fuming nitric acid while cooling (e.g. 0° C.). After stirring for one to several hours, water is carefully added and the mixture neutralized with saturated sodium bicarbonate. The solids are collected by filtration and dried to provide 3-nitro-7-azaindole 504.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3](=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].C(O)=O.[CH3:16][N:17]([CH:19](OC)OC)[CH3:18].O>C1COCC1>[F:1][C:2]([F:11])([F:12])[C:3]([C:4](=[CH:16][N:17]([CH3:19])[CH3:18])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:10]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: COC(OC)N(C)C
Solvent: O
Solvent: O=CO
Solvent: C1CCOC1
Product: CCOC(=O)C(=CN(C)C)C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a stirred mixture of ethyl trifluoroacetoacetate (4.6 g, 0.025 mol) and formic acid (2.3 g, 0.05 mol) in 15 ml of THF, DMF dimethyl acetal (6.2 g, 0.05 mol) was added dropwise at a rate which maintained the reaction temperature below 35° C. After stirring the mixture at ambient temperature for 45 minutes to complete the reaction (TLC), it was poured into water and extracted with ether. The ether extract was washed with water, brine solution, then dried (MgSO4), and concentrated. The residual yellow oil was column-chromatographed on silica gel (Hexanes:Ethyl acetate/7:3) to give ethyl 2-trifluoroacetyl-3-(N,N-dimethylamino)-2-propenoate (Compound 2; Rf=0.3) as the major product; 3.2 g (53%). Ethyl 3-(N,N-dimethylamino)-2-propenoate (Compound 4, Rf=0.5) was obtained as the minor product in the form of an oil; 0.85 g (23.7%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([C:10]3[N:11]=[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:13]4[S:18][C:17]([C:19](O)=[O:20])=[CH:16][C:14]=4[N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH:28][C:29]1[CH:30]=[C:31]([CH:33]=[CH:34][CH:35]=1)[NH2:32]>>[OH:28][C:29]1[CH:30]=[C:31]([NH:32][C:19]([C:17]2[S:18][C:13]3[C:12]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)=[N:11][C:10]([C:5]4[CH:6]=[CH:7][CH:8]=[C:9]5[C:4]=4[CH:3]=[N:2][NH:1]5)=[N:15][C:14]=3[CH:16]=2)=[O:20])[CH:33]=[CH:34][CH:35]=1
Reactant: Nc1cccc(O)c1
Reactant: O=C(O)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1
Product: O=C(Nc1cccc(O)c1)c1cc2nc(-c3cccc4[nH]ncc34)nc(N3CCOCC3)c2s1

Procedure:
2-(1H-Indazol-4-yl)-4-morpholinothieno[3,2-d]pyrimidine-6-carboxylic acid 13 (30 mg) was coupled to 3-hydroxyaniline via General Procedure B. The product was purified via reverse phase HPLC to give 7.7 mg of 246. MS (Q1) 472.7 (M)+
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][C:13]1=[O:18].ClCCl.Cl[C:23]1[O:24][C:25]2[C:26](=[C:28]([C:40]#[N:41])[C:29]([CH3:39])=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:31]=2[F:32])[N:27]=1>C(Cl)(Cl)Cl>[F:32][C:31]1[C:30]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:29]([CH3:39])[C:28]([C:40]#[N:41])=[C:26]2[C:25]=1[O:24][C:23]([N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[C:13](=[O:18])[CH2:14]1)=[N:27]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CN1CCNCC1=O
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N3CCN(C)C(=O)C3)nc2c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.9 %

Procedure:
Diisopropylethylamine (232 μl, 1.36 mmol) and 1-methylpiperazin-2-one hydrochloride (103 mg, 0-682 mmol) were added to a dichloromethane (6 ml) solution of 2-chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (163 mg, 0.569 mmol), followed by stirring at room temperature for 30 minutes. Chloroform (50 ml) was added to the reaction liquid, followed by washing with saturated brine (50 ml). After drying over anhydrous sodium sulfate and concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (eluent, chloroform:methanol=20:1) to obtain the entitled compound (207 mg, 99.9%) as a colorless solid.