Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:18])[C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH2:17])=N[CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([C:21]1[CH:26]=[CH:25][C:24]([C:27](=[CH:33]N(C)C)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:23][CH:22]=1)#[N:20].[CH2:37](O)C>C(Cl)Cl>[CH2:1]([NH:8][C:9]([C:10]1[CH:15]=[CH:14][C:13]([NH:16][NH:17][CH:33]=[C:27]([C:24]2[CH:25]=[CH:26][C:21]([C:19]#[N:20])=[CH:22][CH:23]=2)[C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:37][CH:11]=1)=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=CN(C)C)c1ccc(C#N)cc1
Reactant: NNc1ccc(C(=O)NCc2ccccc2)cn1
Reactant: CCO
Solvent: ClCCl
Product: CCOC(=O)C(=CNNc1ccc(C(=O)NCc2ccccc2)cc1)c1ccc(C#N)cc1
Yield: 39 %

Procedure:
Combined N-benzyl-6-hydrazinylnicotinamide (126 mg, 0.520 mmol) and ethyl 2-(4-cyanophenyl)-3-(dimethylamino)acrylate (127 mg, 0.520 mmol) in ethanol (10 mL) and stirred at room temperature overnight. The reaction mixture was evaporated to give a residue which was dissolved in DCM (100 ml), extracted with saturated aqueous sodium bicarbonate (50 ml), dried with Na2SO4, and concentrated to a residue which was purified by chromatography (12 g SiO2, DCM-MeOH 0 to 10%) to give the title compound (90 mg, 39%) as an oil. MS m/z [M+H]+ 442.4.
Reaction SMILES: O[C:2]1([C:8]2[O:12][C:11]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:10]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=[N:28][OH:29])[CH2:23][CH2:22]4)[CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[OH-].COC(NS([N+](CC)(CC)CC)(=O)=O)=O>C1COCC1.C(OCC)(=O)C.O>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:12][C:8]([C:2]3[CH2:7][CH2:6][NH:5][CH2:4][CH:3]=3)=[CH:9][C:10]=2[C:19]2[CH:20]=[C:21]3[C:25](=[CH:26][CH:27]=2)[C:24](=[N:28][OH:29])[CH2:23][CH2:22]3)=[CH:14][CH:15]=1
Reactant: ON=C1CCc2cc(-c3cc(C4(O)CCNCC4)oc3-c3ccncc3)ccc21
Agent: CC[N+](CC)(CC)S(=O)(=O)NC(=O)OC
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: ON=C1CCc2cc(-c3cc(C4=CCNCC4)oc3-c3ccncc3)ccc21
Yield: 60.6 %

Procedure:
A solution of the product of Example 29, Step 1 (1.06 g, 2.0 mmol) in THF (25 ml) at 0° C. was treated with (methoxycarbonylsulfamoyl)-triethylammonium hydroxide inner salt (Burgess reagent, 952 mg, 4 mmol). After 18 hours at room temperature the mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried and concentrated in vacuo. Purification of the residue by silica gel chromatography gave the title compound (450 mg, 46%); MS(ES+) m/e 486 [M+H]+.
Reaction SMILES: CN(C[CH:5]1[CH2:10]C[CH2:8][CH2:7][NH:6]1)C.[C:11](O)(=O)[C@H:12]([C@@H:14]([C:16](O)=O)O)O.[C:21]1([C@@H:27]([N:29]=C=O)C)C=CC=CC=1>C(O)C>[CH2:7]([N:6]([CH2:11][CH:12]1[CH2:14][CH2:16][CH2:21][CH2:27][NH:29]1)[CH2:5][CH3:10])[CH3:8]
Reactant: C[C@H](N=C=O)c1ccccc1
Reactant: CN(C)CC1CCCCN1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Solvent: CCO
Product: CCN(CC)CC1CCCCN1

Procedure:
The title compound is prepared analogously to Example 52(a) from racemic 2-[(dimethylamino)methyl]piperidine and D-(-)-tartaric acid. The ditartrate melted at 191°-192.5° C. The base, with a boiling point 17 mm Hg 88°-94° C., had a content of (+)-enantiomer determined by reaction with (S)-(-)-1-phenylethylisocyanate and subsequent HPLC investigation, of 98.5%. [α]D20 =+64° (ethanol).
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[CH2:3][CH2:4][OH:5].C(N(CC)CC)C.[N+:17]([C:20]1[CH:28]=[CH:27][C:23]([C:24](Cl)=[O:25])=[CH:22][CH:21]=1)([O-:19])=[O:18].O>ClCCl>[N+:17]([C:20]1[CH:21]=[CH:22][C:23]([C:24]([O:5][CH2:4][CH2:3][C:2]([CH3:9])([CH3:1])[CH2:6][CH:7]=[CH2:8])=[O:25])=[CH:27][CH:28]=1)([O-:19])=[O:18]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: C=CCC(C)(C)CCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCC(C)(C)CCOC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
In a 500-mL, two-necked round-bottom flask, 3,3-dimethylhex-5-en-1-ol (5.30 g, 0.041 mol) and triethylamine (16 mL, 0.057 mol) were dissolved in dichloromethane (110 mL), and then the mixture was cooled, under nitrogen atmosphere, in an ice bath to 5° C. A dichloromethane (10 mL) solution of 4-nitrobenzoyl chloride (9.1 g, 0.049 mol) was added dropwise in 20 minutes. After the mixture had been stirred at 5-10° C. for 1 hour, water was added. The organic layer was washed with acid, water, brine, dried over sodium sulfate, and filtered. After evaporation of the solvent, the crude product was purified by column chromatography (silica gel; ethyl acetate/hexanes 1/9 as eluant) to give the title compound as a yellow liquid.
Reaction SMILES: [C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14](Cl)[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[N+:19](CCC(C1C=CC=CC=1)=O)([O-:21])=[O:20].[Si](OS(C(F)(F)F)(=O)=O)(C(C)(C)C)(C)C.CCN(CC)CC>C(Cl)Cl>[C:1]([Si:5]([O:8]/[C:9](/[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:19]([O-:21])=[O:20])[CH:13]=1)=[CH:10]\[CH3:11])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(CC[N+](=O)[O-])c1ccccc1
Reactant: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc(Cl)c1
Agent: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C/C=C(\O[Si](C)(C)C(C)(C)C)c1cccc([N+](=O)[O-])c1
Yield: 98 %

Procedure:
Compound 9g was synthesized by a procedure similar to that described for 9a using commercially available 3-nitropropiophenone (8g, 5.0 g, 0.028 mol), TBDMSOTf (7.1 mL, 30.7 mmol), and Et3N (6.2 mL) in CH2Cl2 (50 mL). After purification on alumina, 8.0 g (98%) of 9g was isolated as colorless oil: 1H NMR (CDCl3) δ 8.34-8.30 (m, 1H), 8.12-8.06 (m, 1H), 7.80-7.75 (m, 1H), 7.52-7.42 (m, 1H), 5.40 (q, 1H, J=6.9 Hz), 1.78 (d, 3H, J=6.9 Hz), 1.02 (s, 9H), −0.02 (s, 6H); 13C NMR (CDCl3) δ 148.8, 141.6, 131.3, 129.0, 122.1, 120.5, 108.6, 106.8, 25.9, 18.4, 12.0, −3.8. C15H23NO3Si.
Reaction SMILES: C(O)=O.[NH2:4][CH2:5][CH2:6][C:7]1[CH:30]=[CH:29][C:10]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([NH:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)=[O:19])[CH2:14][CH2:13]2)=[CH:9][CH:8]=1.C([Si]([O:48][C:49]1[CH:54]=[CH:53][C:52]([O:55][CH2:56][CH:57]2[CH2:59][O:58]2)=[CH:51][CH:50]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][NH:20][C:18]([N:15]1[CH2:14][CH2:13][CH:12]([NH:11][C:10]2[CH:9]=[CH:8][C:7]([CH2:6][CH2:5][NH:4][CH2:59][C@H:57]([OH:58])[CH2:56][O:55][C:52]3[CH:53]=[CH:54][C:49]([OH:48])=[CH:50][CH:51]=3)=[CH:30][CH:29]=2)[CH2:17][CH2:16]1)=[O:19]
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: NCCc1ccc(NC2CCN(C(=O)NCc3cccc(F)c3)CC2)cc1
Solvent: O=CO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1cccc(F)c1)N1CCC(Nc2ccc(CCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 20.8 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-(3-fluorobenzyl)-1-piperidinecarboxamide formate (0.50 g, 1.20 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.436 g, 1.08 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.174 g, 0.225 mmol).
Reaction SMILES: [OH:1][C:2]1[N:6]([CH:7](O)[CH3:8])[N:5]=[C:4]([CH3:10])[CH:3]=1.[CH3:11][N:12]([CH3:23])[C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[CH:18][CH:19]=O)=[CH:15][CH:14]=1.CC([OH:28])CC>>[CH3:23][N:12]([CH3:11])[C:13]1[CH:22]=[CH:21][C:16]([CH:17]=[CH:18][CH:19]=[C:3]2[C:4]([CH3:10])=[N:5][N:6]([CH2:7][CH2:8][OH:28])[C:2]2=[O:1])=[CH:15][CH:14]=1
Reactant: CCC(C)O
Reactant: Cc1cc(O)n(C(C)O)n1
Reactant: CN(C)c1ccc(C=CC=O)cc1
Product: CC1=NN(CCO)C(=O)C1=CC=Cc1ccc(N(C)C)cc1

Procedure:
12.85 g of 5-hydroxy-1-hydroxyethyl-3-methyl-1H-pyrazole and 3.5 g of 4-dimethylaminocinnamaldehyde in 30 mL of 2-butanol were allowed to reflux 14 hours. Upon cooling, the dye crystallized.
Reaction SMILES: [CH2:1]([N:9]=[C:10](Cl)[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].ClS(O)(=O)=O.[CH3:24][N:25]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]1[CH2:31][C:32]([O:34][CH3:35])=[O:33].[Cl:36]([OH:40])(=[O:39])(=[O:38])=[O:37]>>[Cl:36]([OH:40])(=[O:39])(=[O:38])=[O:37].[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:10](=[N:9][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8])[C:29]2[N:25]([CH3:24])[C:26]([CH2:31][C:32]([O:34][CH3:35])=[O:33])=[CH:27][C:28]=2[CH3:30])=[CH:12][CH:13]=1
Reactant: CCCCCCCCN=C(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)Cc1cc(C)cn1C
Agent: O=S(=O)(O)Cl
Agent: [O-][Cl+3]([O-])([O-])O
Product: CCCCCCCCN=C(c1ccc(Cl)cc1)c1c(C)cc(CC(=O)OC)n1C

Procedure:
The title compound was prepared as in Example X from N-octyl 4-chlorobenzimidoyl chloride (1.44 g, 5 mmole), chlorosulfonic acid (0.58 g, 0.5 mmole), methyl 1,4-dimethyl-1H-pyrrole-2-acetate (0.84 g, 5 mmole), and 70% perchloric acid (0.79 g, 5.5 mmole) to yield 1.99 g (77%) of a red viscous oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][C:20](=[O:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][C:32](C)=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1.Cl[C:37]1C=C2C(C3N=C(NC4CCCC(=O)C4)C(F)=CN=3)=CN(S(C3C=CC=CC=3)(=O)=O)C2=NC=1.C[Mg]Br>C1COCC1.C(OCC)(=O)C.[NH4+].[Cl-]>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][CH:18]4[CH2:23][CH2:22][CH2:21][C:20]([CH3:37])([OH:24])[CH2:19]4)[C:14]([F:25])=[CH:13][N:12]=3)=[CH:9][N:8]([S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=1
Reactant: O=C1CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)ncc2F)C1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC4CCCC(=O)C4)n3)c3cc(Cl)cnc32)cc1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC1(O)CCCC(Nc2nc(-c3cn(S(=O)(=O)c4ccccc4)c4ncc(Cl)cc34)ncc2F)C1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a cold (0° C.) solution of 3-[[2-[5-chloro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-5-fluoro-pyrimidin-4-yl]amino]cyclohexanone, 28a, (0.47 g, 0.92 mmol) in THF (5 mL) was added methylmagnesium bromide (3.30 ml of 1.4M solution, 4.58 mmol). The reaction mixture was stirred at 0° C. for 1 h. The reaction mixture was diluted with ethyl acetate and aqueous saturated NH4Cl solution. The organic phase was separated, dried (MgSO4), filtered and concentrated in vacuo. The products were purified by silica chromatography with DCM and methanol, two products were eluded with 95% DCM and 5% methanol no separation. The two diastereomers were taken on as a mixture without further purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5])C.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:4]([C:6]1[C:7]2[S:14][CH:13]=[C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[F:31])[CH:18]=3)[C:8]=2[CH:9]=[N:10][CH:11]=1)=[O:5]
Reactant: CCOC(=O)c1cncc2c(COc3cccc(NC(=O)c4ccccc4F)c3)csc12
Reactant: NCCO
Product: O=C(Nc1cccc(OCc2csc3c(C(=O)NCCO)cncc23)c1)c1ccccc1F

Procedure:
3-[3-(2-Fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid (2-hydroxy-ethyl)-amide was prepared from 3-[3-(2-fluoro-benzoylamino)-phenoxymethyl]-thieno[3,2-c]pyridine-7-carboxylic acid ethyl ester (from Example 12 supra) and ethanolamine (Aldrich) following the procedure described in Example 16 as a white solid.
Reaction SMILES: [CH2:1]([C:8]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[S:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([OH:17])=O)[C:9]1=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.Cl.[CH2:48]([O:55][NH2:56])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[CH2:1]([C:8]1([S:19]([C:22]2[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=2)(=[O:20])=[O:21])[S:12][C:11](=[O:13])[N:10]([CH2:14][C:15]([NH:56][O:55][CH2:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)=[O:17])[C:9]1=[O:18])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NOCc1ccccc1
Reactant: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)O)C2=O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)C2(Cc3ccccc3)SC(=O)N(CC(=O)NOCc3ccccc3)C2=O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 56.3 %

Procedure:
To a solution of 2-[5-Benzyl-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-3-yl]-acetic acid (Example 27) (0.400 g, 0.92 mmol) in 13 mL of dichloromethane was added 1-hydroxybenzotriazole (0.126 g, 0.93 mmol), 4-methylmorpholine (0.506 g, 5.00 mmol), O-benzylhydroxylamine hydrochloride (0.440 g, 2.76 mmol), and 1-[3-(Dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.232 g, 1.21 mmol) and the mixture was stirred at room temperature for 24 hours under a nitrogen atmosphere. The mixture was diluted with 50 mL of dichloromethane and washed with 2×100 mL of water. The combined aqueous washings were back extracted with 100 mL of dichloromethane and the combined organic phases were washed with 100 mL of brine, dried over anhydrous Na2SO4 and concentrated in vacuo. Column chromatography provided 0.280 g of 2-[5-Benzyl-5-(4-methoxybenzenesulfonyl)-2,4-dioxothiazolidin-3-yl]-N-benzyloxyacetamide as a colorless foam. This material was dissolved in 25 mL of dioxane and stirred at room temperature under a hydrogen atmosphere with an excess of 10% Pd on carbon for 2 days. The mixture was filtered through a celite pad washing with dioxane, followed by ethyl acetate, then methanol. The combined filtrates were concentrated in vacuo and column chromatography provided 0.050 g of the title compound as a white powder. m.p. 81-85° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:13])=O>CCOC(C)=O.CN(C=O)C>[Cl:1][C:2]1[S:6][C:5]([C:7]([Cl:13])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(Cl)s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Cl)c1ccc(Cl)s1
Reaction time: 2 h

Procedure:
To a chilled solution of 5-chlorothiophene-2-carboxylic acid (0.16 g, 1.0 mmol) in EtOAc (3 mL) and DMF (1 drop) was added neat oxalyl chloride (92 μL, 1.05 mmol). The reaction mixture was stirred cold for 2 hr and concentrated in vacuo to give crude 5-chlorothiophene-2-carbonyl chloride.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[CH:13]=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:7]=[CH:8][C:9]=1[OH:10])([OH:3])=[O:2].[C:30](OC(=O)C)(=[O:32])[CH3:31].C1(C)C=CC(S(O)(=O)=O)=CC=1.[C:48](O)(=[O:50])[CH3:49]>>[C:30]([O:10][C:9]1[CH:8]=[CH:7][C:6]([N:11]2[C:19]3[CH2:18][CH2:17][C:16]4[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=4[C:14]=3[C:13]([C:48](=[O:50])[CH3:49])=[C:12]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]=1[C:1]([OH:3])=[O:2])(=[O:32])[CH3:31]
Reactant: CC(=O)O
Reactant: CC(=O)OC(C)=O
Reactant: O=C(O)c1cc(-n2c(-c3ccccc3)cc3c2CCc2ccccc2-3)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: CC(=O)Oc1ccc(-n2c3c(c(C(C)=O)c2-c2ccccc2)-c2ccccc2CC3)cc1C(=O)O
Yield: 16 %

Procedure:
A mixture of 1.25 g. (0.0033 mole) of 3-(3-carboxy-4-hydroxyphenyl)-4,5-dihydro-2-phenylbenz[e]indole, 1 ml. of acetic anhydride, 10 ml. of glacial acetic acid, and 0.1 g. of p-toluenesulfonic acid was stirred at room termperature under nitrogen for 6 days. The solid which separated was collected, washed with acetic acid and petroleum ether, dried and recrystallized from methanol to provide 0.23 g (16%) of 3-(4-acetoxy-3-carboxyphenyl)-1-acetyl-4,5-dihydro-2-phenylbenz[e]indole. Concentration of the mother liquor, followed by recrystallization of the residue from ethanol-water, gave 0.25 g. (18%) of crystals, m.p. 223°-226°.
Reaction SMILES: FC(F)(F)S([O:6][C:7]1C=CC=[C:11]2[C:16]=1[N:15]=[C:14]([C:17]1[N:21]3[CH:22]=[CH:23][C:24](OCCOC)=[CH:25][C:20]3=NN=1)[CH:13]=[CH:12]2)(=O)=O.N1CCC([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:46])([CH3:45])[CH3:44])CC1.N1(C(O[C:57](C)([CH3:59])[CH3:58])=O)CCNCC1>>[CH:7]([C:16]1[CH:11]=[CH:12][C:13]2[C:14](=[C:17]([N:21]3[CH2:20][CH2:25][CH:24]([CH2:39][NH:40][C:41](=[O:47])[O:42][C:43]([CH3:45])([CH3:44])[CH3:46])[CH2:23][CH2:22]3)[CH:58]=[CH:57][CH:59]=2)[N:15]=1)=[O:6]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CC(C)(C)OC(=O)NCC1CCNCC1
Reactant: COCCOc1ccn2c(-c3ccc4cccc(OS(=O)(=O)C(F)(F)F)c4n3)nnc2c1
Product: CC(C)(C)OC(=O)NCC1CCN(c2cccc3ccc(C=O)nc23)CC1

Procedure:
Prepared as described in Example 1, Step H, substituting 8-bromoquinoline-2-carbaldehyde for 2-(7-(2-methoxyethoxy)-[1,2,4]triazolo[4,3-a]pyridin-3-yl)quinolin-8-yl trifluoromethane sulfonate, and tert-butyl piperidin-4-ylmethylcarbamate for tert-butyl piperazine-1-carboxylate.
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].[NH+]1C=CC=CC=1.[F:17][C:18]([F:23])([F:22])[C:19]([CH3:21])=O.O>C1(C)C=CC=CC=1>[CH3:21][C:19]1([C:18]([F:23])([F:22])[F:17])[NH:1][CH:2]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:3][O:4]1
Reactant: CC(=O)C(F)(F)F
Reactant: NC(CO)c1ccccc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C(F)(F)F)NC(c2ccccc2)CO1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
45 g (328.0 mmol) of rac-2-amino-2-phenylethanol and 8.24 g (32.8 mmol) of pyridinium p-toluolsulphonate were added to 55.13 g (492.0 mmol) of 1,1,1-trifluoroacetone in toluene (1.35 l). The reaction mixture was boiled under reflux on a water separator for 16 h. The mixture was cooled to 0° C. and the solid formed was filtered off and dried under high vacuum. This gave 68.6 g (77% of theory, purity 85%) of the target compound.
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[C:23]12([C:33](Cl)=[O:34])[CH2:32][CH:27]3[CH2:28][CH:29]([CH2:31][CH:25]([CH2:26]3)[CH2:24]1)[CH2:30]2.N1C=CC=CC=1>C1(C)C=CC=CC=1>[C:23]12([C:33]([O:1][CH2:2][C@@:3]34[C@@H:20]5[C@H:11]([C@H:12]6[C@@:16]([CH2:18][CH2:19]5)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]6)[CH2:10][CH2:9][C:8]3=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]4)=[O:34])[CH2:30][CH:29]3[CH2:28][CH:27]([CH2:26][CH:25]([CH2:31]3)[CH2:24]1)[CH2:32]2
Reactant: O=C(Cl)C12CC3CC(CC(C3)C1)C2
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43COC(=O)C34CC5CC(CC(C5)C3)C4)[C@@H]1CCC2=O

Procedure:
A solution of 22 g of 19-hydroxyandrost-4-ene-3,17-dione, 18 g of 1-adamantanecarboxylic acid chloride, and 29 ml of pyridine in 2.2 liters of toluene is refluxed overnight. The reaction mixture is cooled, and the toluene layer is washed with water, dried over magnesium sulfate and filtered then the solvent is removed. The resulting residue is crystallized from methanol to give 19-(1-adamantanylcarbonyloxy)androst-4-ene-3,17-dione, M.P. 161°-163° C.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4][CH:3]1[CH2:13][C:14]([OH:16])=O.C(C(Cl)=O)C.[NH2:22][OH:23]>>[OH:23][NH:22][C:14](=[O:16])[CH2:13][CH:3]1[C:2](=[O:1])[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[CH2:5][CH2:4]1
Reactant: NO
Reactant: O=C(O)CC1CCc2ccccc2NC1=O
Agent: CCC(=O)Cl
Product: O=C(CC1CCc2ccccc2NC1=O)NO

Procedure:
The (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetic acid is treated with EtCOCl and freshly prepared NH2OH by following a similar procedure described in example 1 to provide the title compound N-hydroxy-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-acetamide which is purified by preparative LC/MS. 1H NMR (400 MHz, MeOD) δ 7.28 (m, 2H), 7.17(dt, 1H, J=1.2 Hz, J=8.0 Hz), 7.04 (dd, 1H, J=1.2 Hz, J 8.0 Hz), 2.90 (m, 2H), 2.72 (m, 1H), 2.55 (m, 1H), 2.28 (m, 1H), 2.15 (m, 1H), 1.97 (m, 1H). MS: (ES+): 235.3 [M+1].
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][CH2:6][CH2:7][CH2:8][N:9]1[C@@H:18]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[CH:20]=2)[C@@H:17]([C:27](O)=[O:28])[C:16]2[C:11](=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[CH:14][CH:15]=2)[C:10]1=[O:33].[Cl-].[Al+3].[Cl-].[Cl-]>C1C=CC=CC=1>[Br:5][CH2:6][CH2:7][CH2:8][N:9]1[C:18]2[C:19]3[CH:20]=[C:21]([O:25][CH3:26])[CH:22]=[CH:23][C:24]=3[C:27](=[O:28])[C:17]=2[C:16]2[C:11](=[CH:12][C:13]([N+:30]([O-:32])=[O:31])=[CH:14][CH:15]=2)[C:10]1=[O:33]
Reactant: COc1cccc([C@H]2[C@@H](C(=O)O)c3ccc([N+](=O)[O-])cc3C(=O)N2CCCBr)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)-c1c(c3ccc([N+](=O)[O-])cc3c(=O)n1CCCBr)C2=O
Temperature: 25 °C
Yield: 55.1 %

Procedure:
Thionyl chloride (10 mL) was slowly added to a solution of cis-4-carboxy-N-(3-chloropropyl)-3,4-dihydro-3-(4-methoxyphenyl)-7-nitro-1(2H)isoquinolone (48, 1.94 g, 4.18 mmol) in benzene (60 mL). The reaction mixture was heated at reflux for 30 min, allowed to cool to room temperature, and concentrated. The residue was diluted with nitrobenzene (80 mL), chilled in an ice bath, and aluminum chloride (3.00 g, 22.5 mmol) was added. The reaction mixture was removed from the bath and heated at 100° C. for 1 h. Water (200 mL) was added, and the solution was extracted with CHCl3 (3×70 mL). The combined organic layers were washed with sodium bicarbonate (3×75 mL) and brine (75 mL), and dried over sodium sulfate. The solution was concentrated, hexanes (250 mL) were added, and the liquid was decanted. The solid was washed with hexanes (100 mL) and the liquid was decanted again. The solid was purified by silica gel column chromatography, eluting with chloroform-methanol, 20:1, to provide a red-orange solid (1.02 g, 55%): mp 282-284° C. (dec). IR (Film) 1699, 1667, 1612, 1555, 1499, 1332, 1159, 1078, 840, 785, 688, 662 cm−1; 1H NMR (CDCl3, 300 MHz) δ 8.85 (d, J=2.5 Hz, 1H), 8.70 (d, J=8.9 Hz, 1H), 8.55 (d, J=8.9 Hz, 1H), 7.60 (d, J=8.5 Hz, 1H), 7.38 (s, 1H), 7.06 (d, J=8.3 Hz, 1H), 4.60 (t, J=7.3 Hz, 2H), 3.91 (s, 3H), 3.75 (t, J=6.4 Hz, 2H), 2.36 (t, J=7.0 Hz, 2H); EIMS m/z (rel intensity) 444 (M+, 100), 442 (M+, 100), 363 [(M-Br)+, 69]; HRESIMS calcd for C20H15BrN2O5 442.0164 (MH+). found 442.0158 (MH+); Anal. Calcd for C20H15BrN2O5.0.8H2O: C, 52.49; H, 3.66; N, 6.12; Br, 17.46. Found: C, 52.20; H, 3.54; N, 5.96; Br, 17.46.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[CH:4][C:3]=1[C:7]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)=[O:8].CN(C)[CH:16]=[CH:17][C:18]([C:20]1[CH:21]=[CH:22][C:23]([F:31])=[C:24]([N:26]([CH3:30])[C:27](=[O:29])[CH3:28])[CH:25]=1)=O>CC(O)C>[F:31][C:23]1[CH:22]=[CH:21][C:20]([C:18]2[N:6]3[N:5]=[CH:4][C:3]([C:7]([C:9]4[S:10][CH:11]=[CH:12][CH:13]=4)=[O:8])=[C:2]3[N:1]=[CH:16][CH:17]=2)=[CH:25][C:24]=1[N:26]([CH3:30])[C:27](=[O:29])[CH3:28]
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1F
Reactant: Nc1[nH]ncc1C(=O)c1cccs1
Solvent: CC(C)O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C(=O)c4cccs4)cnn23)ccc1F
Temperature: 5 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
A 300 L vessel was flushed with nitrogen. Acetic acid (40.0 L) was charged, and then 7.312 kg (37.84 moles) of (5-amino-1H-pyrazol-4-yl)-thiophen-2-yl-methanone and 10.000 kg (37.84 moles) of N-[5-(3-dimethylamino-acryloyl)-2-fluoro-phenyl]-N-methyl-acetamide were added consecutively. The mixture was heated to 120° C. (±5° C.) with stirring. The reaction was controlled by HPLC until completion (<1% of each starting material), which typically occurs in 4 hours. The reaction mass was cooled to 60-70° C. 2-Propanol (80.0 L) was charged to reaction mixture, cooled to 40-45° C. and aged for at least 1 hour. The mixture was cooled over approximately 2.5 hours to 0-5° C. and aged for at least 2 hours. Solids were filtered and washed twice with 10.0 L of chilled 2-propanol. The solid product was dried under vacuum at 50° C. (±5° C.) to remove residual solvents (<0.5% w/w of acetic acid and <0.5% w/w of 2-propanol). N-{2-fluoro-5-[3-(thiophene-2-carbonyl)-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide was obtained as a crystalline material (12.686 kg). Yield 85%. Purity ≧95%.