Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1.[OH-].[Li+]>CO>[CH3:14][N:13]([CH3:15])[CH2:12][CH2:11][O:10][C:7]1[CH:8]=[CH:9][C:4]([C:3]([OH:16])=[O:2])=[CH:5][CH:6]=1
Reactant: COC(=O)c1ccc(OCCN(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: CN(C)CCOc1ccc(C(=O)O)cc1
Temperature: 22 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
To a solution of 4-[2-(dimethylamino)-ethoxy]-benzoic acid methyl ester (3 mmol) in methanol (10 mL) is added a lithium hydroxide solution (2 M, 20 mL). The reaction mixture is stirred at 22° C. for 15 min. After removal of the solvent, the residue is re-dissolved in methanol, passed through a SCX column, washed with methanol, and eluded with 2M ammonia in methanol. After solvent is evaporated, a white solid is obtained (500 mg, 80% yield, ES−(m/z) 208.2 [M−H]).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[CH:13]3[CH2:17][CH2:16][CH2:15][CH2:14]3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(N(CC)CC)C>ClCCl>[CH2:22]([O:21][C:19]([N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)/[C:6](=[CH:12]/[CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17]2)/[C:7]1=[O:11])=[O:20])[CH3:23]
Reactant: O=C1Nc2cc(Cl)ccc2/C1=C/C1CCCC1
Reactant: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)N1C(=O)/C(=C\C2CCCC2)c2ccc(Cl)cc21
Yield: 58.6 %

Procedure:
In a manner similar to the method described in example 4b, E/Z-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one (0.8 g, 3.2 mmol) was reacted with ethyl chloroformate (0.46 mL, 4.9 mmol) and triethylamine (0.9 mL, 6.4 mmol) in dichloromethane to give E/Z-6-chloro-3-cyclopentylmethylene-2-oxo-2,3-dihydro-indole-1-carboxylic acid ethyl ester as brown oil (Yield 0.6 g, 58%).
Reaction SMILES: [CH2:1]([N:3]1[C:12](=[O:13])[C:11]2[NH:10][CH:9]=[N:8][C:7]=2[N:6]([CH3:14])[C:4]1=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32][N:10]3[C:11]4[C:12](=[O:13])[N:3]([CH2:1][CH3:2])[C:4](=[O:5])[N:6]([CH3:14])[C:7]=4[N:8]=[CH:9]3)=[CH:30][CH:29]=2)=[O:27])=[CH:36][CH:37]=1
Reactant: CCn1c(=O)c2[nH]cnc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c(=O)c2c(ncn2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 14 h
Yield: 24.7 %

Procedure:
In DMF (10 ml) was dissolved 1-ethyl-3-methylxanthine (385 mg), a production process for which is described in Journal of American Chemical Society 75, 114, 1953. To this solution were added potassium carbonate (415 mg) and 4-(4-chlorobenzoyl)benzyl bromide (619 mg) and the mixture was stirred at room temperature for 14 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate and the solvent was distilled off. The residue was purified by silica gel column chromatography (hexane: ethyl acetate=1:4) and recrystallized (ethyl acetate-ether-hexane) to provide the title compound as white powder (207 mg, 25%).
Reaction SMILES: [CH2:1]([C:3]1[O:4][CH2:5][CH2:6][N:7]=1)[CH3:2].[C:8]1([OH:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[O:14]([CH2:5][CH2:6][NH:7][C:3](=[O:4])[CH2:1][CH3:2])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCC1=NCCO1
Reactant: Oc1ccccc1
Product: CCC(=O)NCCOc1ccccc1
Yield: 90 %

Procedure:
Adding 2-ethyl-2-oxazoline to hot (150°) phenol and maintaining heating at about 175° for 16 additional hours. The oil is then quenched in water to give N-(2-phenoxyethyl)propionamide (IV) in approximately 90% yield.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH3:16])[N:8]2[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][N:3]=1.[C-]#N.[Na+].C1N2CC[N:22](CC2)[CH2:21]1>CS(C)=O.O>[CH3:13][C:12]([CH3:15])([CH3:14])[CH2:11][N:8]1[C:7]([CH3:16])=[N:6][C:5]2[C:9]1=[N:10][C:2]([C:21]#[N:22])=[N:3][CH:4]=2
Reactant: Cc1nc2cnc(Cl)nc2n1CC(C)(C)C
Reactant: C1CN2CCN1CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1nc2cnc(C#N)nc2n1CC(C)(C)C

Procedure:
6.1 g of 2-chloro-9-(2,2-dimethyl-propyl)-8-methyl-9H-purine, 1.25 g of NaCN and 0.57 g of DABCO were heated for 6 hours to 80° C. in 60 ml DMSO/H2O=90:10. The crude mixture was extracted with ethyl acetate and saturated NaHCO3 solution and the organic phases were dried over sodium sulfate and evaporated to dryness. After chromatography on silicagel with ethyl acetate/hexanes=1:1 9-(2,2-dimethyl-propyl)-8-methyl-9H-purine-2-carbonitrile was isolated as a pale brown powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([OH:9])=O.Cl.[NH2:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[C:6]([CH:10]=1)[C:7]([NH:21][C@H:22]([C:24]1[CH:33]=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][CH:25]=1)[CH3:23])=[O:9]
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Reactant: O=C(O)c1cc(Cl)ccc1COc1cccc(F)c1
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)ccc2COc2cccc(F)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 6 of Example 1 from 5-chloro-2-[(3-fluorophenoxy)methyl]benzoic acid (step 2) and methyl 4-[(1S)-1-aminoethyl]benzoate hydrochloride (step 5 of Example 1):
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].S(=O)(=O)(O)O.[Cl-].[Na+].[C:32](OC(=O)C)(=[O:34])[CH3:33]>C1(C)C=CC=CC=1>[C:32]([O:1][C:2]1[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1O
Agent: O=S(=O)(O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C#Cc2ccc(S(=O)(=O)Cl)cc2)ccc1OC(C)=O

Procedure:
Ethyl 2-hydroxy-5-[(4-chlorosulfonylphenyl]ethynyl]benzoate (16 g, 44 mmol) was dissolved in acetic anhydride (40 ml) at 120° C. Sulfuric acid (about 0.4 ml) was added dropwise. After 5 min the solution was diluted with toluene (about 100 ml) and added to saturated sodium chloride solution with vigorous stirring. The phases were separated, the toluene solution dried and evaporated. More toluene was added and the evaporation repeated. The oily product crystallized. The product was sufficiently pure for the next step. Yield 17.0 g (95%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N+:11]([O-])=[CH:10][CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:20]#[N:21])(C)C.CN(C)C>C(#N)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([C:20]#[N:21])[CH:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc2c(ccc[n+]2[O-])c1
Reactant: C[Si](C)(C)C#N
Agent: CN(C)C
Solvent: CC#N
Product: CC(C)(C)c1ccc2nc(C#N)ccc2c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 91.1 %

Procedure:
A mixture of 6-tert-butylquinoline 1-oxide (310 mg, 1.54 mmol), trimethylsilylcyanide (458 mg, 4.62 mmol), trimethylamine (312 mg, 3.08 mmol) in acetonitrile (3 ml) was stirred for 15 minutes at 120° C. under microwave irradiation. The mixture was applied to a silica gel column chromatography and eluted with hexane/EtOAc (20:1) to furnish the title compound (295 mg, 91% yield) as a white solid. 1H NMR (300 MHz, CDCl3) δ ppm 1.44 (9H, s), 7.68 (1H, d, J=8.8 Hz), 7.79 (1H, d, J=2.2 Hz), 7.94 (1H, d, J=2.2, 8.8 Hz), 8.11 (1H, d, J=8.8 Hz), 8.26 (1H, d, J=8.8 Hz) MS (ESI): m/z 211 (M+H)+.
Reaction SMILES: C(O[C:9]([N:11]([C:13]1[CH:14]=[CH:15][C:16]2[O:20][C:19]([C:21]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=3)=[O:22])=[C:18]([NH:31][C:32]([C@H:34]3[CH2:39][CH2:38][C@H:37]([N:40]([CH3:42])[CH3:41])[CH2:36][CH2:35]3)=[O:33])[C:17]=2[CH:43]=1)C)=O)C1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[CH3:42][N:40]([CH3:41])[C@H:37]1[CH2:36][CH2:35][C@H:34]([C:32]([NH:31][C:18]2[C:17]3[CH:43]=[C:13]([NH:11][CH3:9])[CH:14]=[CH:15][C:16]=3[O:20][C:19]=2[C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)=[O:22])=[O:33])[CH2:39][CH2:38]1
Reactant: CN(C(=O)OCc1ccccc1)c1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: CNc1ccc2oc(C(=O)Nc3ccc(Cl)cn3)c(NC(=O)[C@H]3CC[C@H](N(C)C)CC3)c2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To trans-5-[N-(benzyloxycarbonyl)-N-methylamino]-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 22 is added 30% hydrogen bromide in acetic acid (2 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution is added diethyl ether (20 ml), and the precipitates are collected by filtration, and suspended in a saturated aqueous sodium hydrogen carbonate solution, and extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and the solvent is evaporated under reduced pressure to give trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-methylamino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. Subsequently, this product is dissolved in ethanol, and treated with 4N hydrogen chloride in ethyl acetate to give the title compound (88 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=O)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:21]=1[NH2:22].C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.O1CCOCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:20]([O:19][CH3:18])([C:15]([CH2:14][C:11]2[CH:10]=[CH:9][C:8]([C:5]3[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=3)=[CH:13][CH:12]=2)=[O:17])[CH:21]([CH:23]=1)[NH2:22]
Reactant: COc1ccc(Cl)cc1N
Reactant: O=C(O)Cc1ccc(-c2ccc(O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: COC1(C(=O)Cc2ccc(-c3ccc(O)cc3)cc2)C=CC(Cl)=CC1N
Yield: 70 %

Procedure:
A solution of 10 gm (44 millimols) of 4-hydroxy-4'-biphenyl-acetic acid (see W. H. Linnell and H. J. Smith, J. Chem. Soc. 1959,557) in a mixture of 33 ml of tetrahydrofuran and 162 ml of absolute dioxane were added at 0° C to a solution of 4.63 gm (29.4 millimols) of 2-methoxy-5-chloroaniline (m.p. 83°-85° C) in 40 ml of absolute dioxane, and the mixed solution was subsequently admixed with a solution of 9.1 gm (44 millimols) of N,N'-dicyclohexyl-carbodiimide in 20 ml of dioxane. After 20 hours of reaction time at 0° C, the dicyclohexylurea was filtered off and the solvent was distilled off. The residue was dissolved in 700 ml of chloroform, the solution was washed several times with 2N hydrochloric acid and water, dried over sodium sulfate, and the organic phase was evaporated in vacuo. The light brown, viscous crude product was purified on a silicagel column with toluene/acetic acid (4:1 ) as the eluant. Yield: 70% of theory; m.p. 165°-168° C.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]1[CH:31]=[N:30][N:29]=[C:28]1[SH:32]>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:32][C:28]3[N:27]([CH3:26])[CH:31]=[N:30][N:29]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Reactant: Cn1cnnc1S
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nncn3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70) where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 4-methyl-4H-1,2,4-triazole-3-thiol was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.48-1.65 (m, 8H) 1.96 (m, 2H) 2.65 (d, J=15.1 Hz, 1H) 2.87 (d, J=17.7 Hz, 1H) 3.16 (s, 1H) 3.64 (s, 3H) 3.80 (s, 3H) 7.02 (d, J=8.8 Hz, 1H) 7.16 (dd, J=8.5, 2.20 Hz, 1H) 7.27 (d, J=1.9 Hz, 1H) 8.56 (s, 1H). MS (APCI) calcd for C22H26ClN3O4S: 463.98; found M=464.9.
Reaction SMILES: [CH2:1](Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:9][CH2:10][C@H:11]1[CH2:13][C@@H:12]1[CH2:14][C:15]([OH:17])=[O:16].C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[OH:9][CH2:10][C@H:11]1[CH2:13][C@@H:12]1[CH2:14][C:15]([O:17][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:16]
Reactant: BrCc1ccccc1
Reactant: O=C(O)C[C@H]1C[C@@H]1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C(C[C@H]1C[C@@H]1CO)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 79.1 %

Procedure:
Benzyl bromide (539 μL, 4.53 mmol) was added to a mixture of 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetic acid (536 mg, 4.12 mmol), potassium carbonate (626 mg, 4.53 mmol) and DMF (8 mL) at room temperature, and the mixture was stirred at room temperature for 15 hr. The reaction mixture was poured into water (80 mL), and the mixture was extracted with ethyl acetate (×3). The organic layer was washed with water and brine, and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent gradient; 33→53% ethyl acetate/hexane) to give benzyl 2-((1R,2S)-2-(hydroxymethyl)cyclopropyl)acetate (718 mg, 3.26 mmol, 79%) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:7]2O)[CH3:2].O=P(Cl)(Cl)[Cl:22]>>[Cl:22][C:7]1[C:6]2[C:11](=[CH:12][CH:13]=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=2)[N:10]=[CH:9][C:8]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OCC)cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cnc2ccc(OCC)cc2c1Cl

Procedure:
Prepared as in Example 1b from ethyl 6-ethoxy-4-hydroxyquinoline-3-carboxylate (Example 13c) and POCl3 as pale yellow solid (100%). 1H NMR (400 MHz, DMSO-d6) δ 1.34-1.42 (m, 6H), 4.21 (q, J=7.2 Hz, 2H), 4.40 (q, J=7.2 Hz, 2H), 7.52 (d, J=2.8 Hz, 1H), 7.56-7.59 (m, 1H), 8.02 (d, J=8.8 Hz, 1H), 8.94 (s, 1H). MS 280, 282 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[C:17]([C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1)#[N:18]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([C:22]3[CH:21]=[CH:20][C:19]([C:17]#[N:18])=[CH:24][CH:23]=3)(=[O:27])=[O:26])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(S(=O)(=O)Nc2cncc(-c3ccc(C#N)c(Cl)c3)c2)cc1
Yield: 39.4 %

Procedure:
According to General Sulfonylation Procedure 2 in example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added 4-cyano-benzenesulfonyl chloride (19.3 mg, 96 μmol, 1.1 eq). The product was purified by preparative TLC, the plate was eluted with dichloromethane/methanol 95/5, to give (15.5 mg, >95% purity, yield: 39.4%).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:4]=[N:5][C:6]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)=[CH:7][C:8]=1[C:9]1(CO)[CH:17]([CH:18]=[CH2:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10]1>[Pd]>[CH2:18]([C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]=1[C:8]1[CH:7]=[C:6]([C:22]2[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=2)[N:5]=[N:4][C:3]=1[O:2][CH3:1])[CH3:19]
Reactant: C=CC1c2ccccc2NC1(CO)c1cc(-c2ccncc2)nnc1OC
Agent: [Pd]
Product: CCc1c(-c2cc(-c3ccncc3)nnc2OC)[nH]c2ccccc12
Reaction time: 4 h

Procedure:
12 mg Palladium, 10% on charcoal are added to a solution of 70 mg 2-(3-Methoxy-6-pyridin-4-yl-pyridazin-4-yl)-3-vinyl-1H-indole methanol, and the reaction mixture is stirred under an hydrogen atmosphere for 4 hours. The catalyst is removed by filtration and the solvent by evaporation yielding the product which was used without further purification.
Reaction SMILES: [C:1]([C:4]1[C:5](=O)[C:6]2[C:14](=[CH:15][CH:16]=1)[C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH:7]=2)([OH:3])=[O:2].C(O)COCCO.[OH-].[Na+].O.NN>O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)C1=CC=C2C(=Cc3ccccc32)C1=O
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCO
Product: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 125 °C
Reaction time: 3 h

Procedure:
2-Carboxyfluorenone (12.3 g, 0.05 mole) and diethylene glycol were added to a 500 mL round bottom flask. Sodium hydroxide (7.65 g, 0.19 mole) and hydrazine hydrate (9.16 mL, 0.23 mole) were added to the solution. The temperature of the reaction was increased to 125° C. Heating was continued for three hours and then the vessel was cooled to room temperature. Distilled water (1.5 L) was added. The product was precipitated with concentrated hydrochloric acid. The product was filtered and rinsed with distilled water (2 L). The solids were dissolved in 0.5 M sodium hydroxide (2.8 L) and heated to 70° C. The product was precipitated with concentrated hydrochloric acid (pH approximately 2). The product was filtered and washed with distilled water (1.5 L). The 2-carboxyfluorene was dried overnight under reduced pressure with phosphorus pentoxide present. NMR confirmed the structure by the appearance of two new protons at δ4.01 ppm.
Reaction SMILES: Cl[S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[NH2:16][C:17]1[S:18][C:19]([Cl:22])=[CH:20][N:21]=1.Cl>N1C=CC=CC=1>[Cl:22][C:19]1[S:18][C:17]([NH:16][S:2]([C:5]2[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=2)(=[O:4])=[O:3])=[N:21][CH:20]=1
Reactant: COC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ncc(Cl)s1
Agent: Cl
Solvent: c1ccncc1
Product: COC(=O)c1ccc(S(=O)(=O)Nc2ncc(Cl)s2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Methyl 4-(chlorosulfonyl)benzoate (Preparation 2, 8.0 g, 34 mmol, 1 eq) was added portionwise to a solution of 2-amino-5-chlorothiazole hydrochloride (23.3 g, 136 mmol, 4 eq) in pyridine (80 ml) and the reaction mixture stirred at room temperature for 1 hour. The solution was added to a stirred solution of 6M HCl (300 ml) and the resulting precipitate collected by filtration and washed with water. The title compound was obtained as a dark brown solid (3.35 g, 0.01 mmol, 30%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:25])[CH2:6]1)[C@:19]1([CH3:20])[C:14](=[CH:15][C:16](=[O:24])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)(=[O:3])[CH3:2].[CH3:26]OC(OC)(C)C.[NH+]1C=CC=CC=1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([O:4][C@@H:5]1[C@H:10]2[C@H:11]3[C@H:21]([CH2:22][CH2:23][C@:8]2([CH3:9])[C:7](=[O:25])[CH2:6]1)[C@:19]1([CH3:20])[C:14]([CH:15]=[C:16]([O:24][CH3:26])[CH2:17][CH2:18]1)=[CH:13][CH2:12]3)(=[O:3])[CH3:2]
Reactant: COC(C)(C)OC
Reactant: CC(=O)O[C@H]1CC(=O)[C@@]2(C)CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43C)[C@H]12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COC1=CC2=CC[C@H]3[C@@H]4[C@@H](OC(C)=O)CC(=O)[C@@]4(C)CC[C@@H]3[C@@]2(C)CC1
Reaction time: 5 h

Procedure:
10.0 g of 15α-acetoxy-4-androstene-3,17-dione is stirred under reflux with 60 ml of dimethoxypropane and 1.0 g of pyridinium-4-toluenesulfonate. After 5 hours, 1 ml of pyridine is added, the mixture is diluted with ethyl acetate, washed neutral with water, and dried. The crude product is recrystallized from hexane/acetone. Yield: 9.6 of 15α-acetoxy-3-methoxyandrosta-3,5-dien-17-one, mp 209° C.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].CO[C:13](=O)[CH2:14][O:15][CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[F:24][C:20]1[CH:19]=[C:18]([CH2:17][CH2:16][O:15][CH2:14][C:13]2[NH:6][C:4](=[O:5])[C:3]3[CH:7]=[CH:8][CH:9]=[N:10][C:2]=3[N:1]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: COC(=O)COCCc1cccc(F)c1
Reactant: NC(=O)c1cccnc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1[nH]c(COCCc2cccc(F)c2)nc2ncccc12
Yield: 54.9 %

Procedure:
A suspension of 2-amino-nicotinamide (250 mg, 1.82 mmol) and [2-(3-fluoro-phenyl)-ethoxy]-acetic acid methyl ester (464 mg, 2.18 mmol) in THF (5 ml) was treated with LiHMDS (1M THF solution, 4.6 ml) overnight at ambient temperature. The yellow suspension was filtrated, the filtrate was brought to dryness and the residue was purified by column chromatography (amino-phase silica gel, CH2Cl2/MeOH, 19/1) to give 2-[2-(3-fluoro-phenyl)-ethoxymethyl]-3H-pyrido[2,3-d]pyrimidin-4-one (303 mg, 1 mmol; 55%) as white solid. MS (m/e): 300.2 [M+H]+
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:4]([CH3:21])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2>[Pd].C(O)C>[ClH:1].[NH2:2][C:3]1[N:4]([CH3:21])[C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: Cn1c(N)c(-c2ccc([N+](=O)[O-])cc2)c2ccccc21
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: Cn1c(N)c(-c2ccc(N)cc2)c2ccccc21
Yield: 53 %

Procedure:
The compound is obtained by hydrogenating at room temperature and atmospheric pressure in the presence 10% Pd on charcoal an ethanol solution of the hydrochloride of 2-amino-1-methyl-3-(p-nitrophenyl) indole. Yield 53%, m.p. 258°-261° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH:21]([CH3:25])[CH2:22][CH2:23][OH:24])[CH:9]=2)=[CH:4][CH:3]=1.CC(C)=[O:28].OS(O)(=O)=O.O=[Cr](=O)=O>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[N:11]=[C:10]([CH:21]([CH3:25])[CH2:22][C:23]([OH:28])=[O:24])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc(-n2nc(C(C)CCO)cc2-c2ccc(Cl)cc2)cc1
Reactant: CC(C)=O
Agent: O=[Cr](=O)=O
Agent: O=S(=O)(O)O
Product: COc1ccc(-n2nc(C(C)CC(=O)O)cc2-c2ccc(Cl)cc2)cc1
Reaction time: 1.5 h
Yield: 92 %

Procedure:
To a solution of compound 50 (0.65 g, 1.8 mM) in acetone (50 ml) was added Jones Reagent (1.85 ml, 3.7 mM) and the reaction stirred for 1.5 hr, the acetone decanted and the chromium residues washed exhaustively with acetone. The combined acetone layers were then evaporated in vacuo, the residue dissolved in EtOAc (100 ml), washed (H2O), dried (Na2SO4) and concentrated to give an oil which was chromatographed on Silica (EtOAc/MeOH, 30% as eluent) to afford 3-[5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-pyrazolyl]-3-methylpropanoic acid (0.62 g, 92%) as a yellow semi-solid which was used without further purification and following the procedure of Example 11 was converted to the title hydroxamic acid 51 as a yellow foam (92%); NMR (CDCl3) δ 1.50 (d, 3H, J=7Hz, C3 --CH3); MS, m/e 399 (M+).