Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C=O)C.[NH2:6][C:7]1[C:8]2[C:36]([CH3:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:44])[NH:34][C:9]=2[N:10]=[C:11]([NH:13]/[N:14]=[C:15](\[C:26]2[CH:31]=[C:30]([Cl:32])[CH:29]=[CH:28][C:27]=2Br)/[CH2:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=2[F:25])[N:12]=1.CNCCNC>CCOC(C)=O.[Cu]I>[NH2:6][C:7]1[C:8]2[C:36]([CH3:43])([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:35](=[O:44])[NH:34][C:9]=2[N:10]=[C:11]([N:13]2[C:27]3[C:26](=[CH:31][C:30]([Cl:32])=[CH:29][CH:28]=3)[C:15]([CH2:16][C:17]3[C:22]([F:23])=[CH:21][CH:20]=[C:19]([F:24])[C:18]=3[F:25])=[N:14]2)[N:12]=1
Reactant: CC1(c2ccccc2)C(=O)Nc2nc(N/N=C(/Cc3c(F)ccc(F)c3F)c3cc(Cl)ccc3Br)nc(N)c21
Agent: [Cu]I
Agent: CNCCNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC1(c2ccccc2)C(=O)Nc2nc(-n3nc(Cc4c(F)ccc(F)c4F)c4cc(Cl)ccc43)nc(N)c21

Procedure:
A DMF (5 mL) solution of the crude intermediate from Step C (ca 0.24 mmol), copper (I) iodide (45.3 mg, 0.24 mmol) and N,N′-dimethylethylenediamine (25.2 mg, 0.29 mmol) was stirred at ambient temperature for 1 hour. The reaction mixture was diluted with EtOAc and washed with 10% aqueous NH4OH solution (2×), water (2×), 0.5 N HCl (1×), and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by preparative thin layer chromatography using 5% MeOH/CHCl3 as eluent. The isolated material was purified again by silica gel column chromatography using a hexanes/EtOAc gradient to give the indicated compound. 1H NMR (500 MHz, DMSO-d6): δ (ppm) 11.19 (1H, s), 8.86 (1H, d, J=9.0 Hz), 7.93 (1H, d, J=2.0 Hz), 7.55-7.43 (2H, m), 7.34-7.24 (5H, m), 7.20 (1H, t, J=9.7 Hz), 6.74 (2H, s), 4.46 (2H, s), 1.77 (3H, s). m/z=535.4 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[C:4](O)=[O:5].B.C1COCC1>C1COCC1>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[C:16]([CH3:17])=[C:15]([C:18]([F:19])([F:21])[F:20])[N:14]([CH3:22])[N:13]=2)=[CH:7][C:3]=1[CH2:4][OH:5]
Reactant: Cc1c(-c2cc(C(=O)O)c(Cl)cc2F)nn(C)c1C(F)(F)F
Agent: B
Solvent: C1CCOC1
Product: Cc1c(-c2cc(CO)c(Cl)cc2F)nn(C)c1C(F)(F)F
Temperature: 0 °C
Yield: 90.4 %

Procedure:
A solution of 1.5 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazol-3-yl]-4-fluorobenzoic acid (Ex. 2) in 30 mL of anhydrous THF was treated with 10 mL of 1.0M borane-THF solution and heated to reflux for 24 hr. The mixture was allowed to cool and added to ice water. A precipitate formed which was collected by filtration, washed with cold water and dried to give 1.3 g of 2-chloro-5-[1,4-dimethyl-5-(trifluoromethyl)-1H-pyrazole-3-yl]-4-fluorobenzenemethanol as a white solid: mp 58° C.; 1HNMR (CDCl3) δ2.09 (q, 3H), 4.00 (s, 3H), 4.75 (s, 2H), 7.20 (d, 1H), 7.57 (d, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)N)=[CH:5][CH:4]=1.O=[C:21]([CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=[O:27]>CO>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:12]3[C:17](=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)[C:30]([CH3:31])=[C:21]2[CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:5][CH:4]=1
Reactant: COc1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: CCC(=O)CCCCC(=O)OC
Agent: Cl
Solvent: CO
Product: COc1ccc2c(c1)c(C)c(CCCCC(=O)O)n2Cc1ccc(Cl)cc1

Procedure:
Following the procedure of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)-hydrazine hydrochloride and methyl 6-oxooctanoate as the starting materials and methanol as the solvent, the title compound was prepared.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[CH2:11](Cl)Cl>>[CH:7]1[C:4]([CH:5]=[O:6])=[CH:3][C:2]2[O:1][CH2:11][O:10][C:9]=2[CH:8]=1
Reactant: ClCCl
Reactant: O=Cc1ccc(O)c(O)c1
Product: O=Cc1ccc2c(c1)OCO2
Yield: 70 %

Procedure:
One process for preparing piperonal from 3,4-dihydroxybenzaldehyde comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride and alkali in a non-protic polar solvent such as dimethyl sulfoxide, and gives a 61% yield of piperonal (British Pat. No. 1,097,270). Another process comprises reacting 3,4-dihydroxybenzaldehyde with methylene chloride in aqueous alkali under the influence of an interphasic moving catalyst such as quaternary ammonium compound, and gives a 70-73% yield of piperonal. However, the catalyst used in this process is expensive and, by nature, easily soluble in both aqueous and organic phases. Accordingly, the recovery of the catalyst is too low to make this process practicable (Japanese Patent Application Disclosure Nos. 23,265/'76 and 113,967/'77). In any event, neither of these process can provide satisfactory yields based on the amount of the starting material. In addition, James H. Clark et al. have described still another process in which 3,4-dihydroxybenzaldehyde is reacted with dibromomethane in N,N-dimethylformamide under the influence of an excess of potassium fluoride or cesium fluoride to give a 90% yield of piperonal [Tetrahedron Letters, No. 38, pp. 3361-3364 (1976)]. This process is of advantage in that no strong base is used, the reaction time is relatively short, and a high yield can be obtained. However, an expensive fluoride must be used in large excess as a halogen trapping agent and cannot be recycled because its fluorine component is stoichiometrically replaced by the halogen atoms in the dihalomethane used. Accordingly, this process is not satisfactory for industrial applications. Moreover, when based on the amount of pyrocatechol used, the yield attainable with this process does not reach 70%.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[F-:15].[K+]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([F:15])(=[O:13])=[O:12]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: [F-]
Agent: [K+]
Product: O=S(=O)(F)c1ccc2ccccc2c1
Yield: 92 %

Procedure:
2-Naphthalenesulfonyl fluoride was prepared from 2-naphthalenesulfonyl chloride and potassium fluoride as described in Example 1. A product with mp 85°-86° C (literature 86°-88° C; W. Davies and J. H. Dick, J. Chem. Soc., 2104, 1931) was obtained in 92% yield. The chemical analysis NMR and IR spectra were in agreement with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][C:17]#[N:18])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(CCC#N)CC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1ccc(N2CCN(CCCN)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 83.7 %

Procedure:
A solution of 3-(4-(4-methoxyphenyl)piperazin-1-yl)propanenitrile (0.8 g, 3.26 mmol) in 15 mL ether was added to the suspension of LiAlH4 (0.19 g, 4.89 mmol) in 5 mL of ether. The mixture was stirred at room temperature for 16 hours, then quenched with 2N NaOH (1 mL). The ether phase was dried over MgSO4 and evaporated to dryness to give 0.68 g (84%) white solid, which was used directly without further purification. 1H NMR (400 MHz, CDCl3) δ 6.89 (d, J=9.1 Hz, 2H), 6.82 (d, J=9.1 Hz, 2H), 3.75 (s, 3H), 3.15-3.04 (m, 4H), 2.87 (s, br. 2H), 2.76 (t, J=6.8 Hz, 2H), 2.67-2.53 (m, 4H), 2.51-2.37 (m, 2H), 1.75-1.54 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 153.8, 145.7, 118.1, 114.4, 56.4, 55.5, 53.48, 50.6, 40.6, 30.1. Valenta, et al. (1990) Collect. Czech. Chem. Commun. 55:797-808.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15]Cl)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1.[I-].[K+].[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([CH2:15][N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]=[C:7]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:6]=2[CH:24]=1
Reactant: C1CCNC1
Reactant: ClCc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1Cl)=NC2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CN3CCCC3)n1-2

Procedure:
In the manner given in Preparation 48, 8-chloro-1-(chloromethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, potassium iodide, and pyrrolidine in tetrahydrofuran are reacted to give 8-chloro-1-(pyrrolidinomethyl)-6-(o-chlorophenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[C:36]([CH3:38])[N:35]=[C:34]([CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:15][N:14]([CH3:16])[C:12]1[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]2[NH:21][C:22](=[O:40])[CH2:23][C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]4[CH:33]=[C:34]([CH3:39])[N:35]=[C:36]([CH3:38])[CH:37]=4)[CH:27]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(C(F)(F)F)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(N(C)C)c(C(F)(F)F)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from (5-dimethylamino-2-{3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M304) (0.38 g, 0.67 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (203 mg, 67%).
Reaction SMILES: C([O: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][CH:13]=[C:14]2[C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)[CH2:6]1)(=O)C.[OH-].[Na+].Cl.C(=O)(O)[O-].[Na+]>CO.O>[N:26]1[CH:27]=[CH:28][CH:29]=[C:24]([C:14]2[C@:15]3([CH2:17][CH2:18][C@H:19]4[C@@H:10]([CH2:9][CH:8]=[C:7]5[C@:20]4([CH3:23])[CH2:21][CH2:22][C@H:5]([OH:4])[CH2:6]5)[C@@H:11]3[CH2:12][CH:13]=2)[CH3:16])[CH:25]=1
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@@H]3[C@@H]2CC[C@]2(C)C(c4cccnc4)=CC[C@@H]32)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(c3cccnc3)=CC[C@@H]12
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 79 %

Procedure:
To a solution of 3β-acetoxy-17-(3-pyridyl)androsta-5,16-diene (4.90g, 12.5 mmol) in methanol (50 ml) was added an aqueous solution of sodium hydroxide (10% w/v, 10 ml) and the mixture heated, with stirring, on an oil bath at 80° C. for 5 min., then allowed to cool. The mixture was poured into water, neutralised with hydrochloric acid (1M), rebasified with sainted sodium bicarbonate solution, and extracted with hot toluene (3×100 ml). The toluene extracts were combined, dried (Na2CO3), and concentrated. Chromatography, on elution with toluene-diethyl ether (2:1 ) afforded the title compound (3.45 g, 79%) which crystallised from toluene, mp 228°-229° C.; 1H-NMR (CDCl3 inter alia δ1.05(3H,s, 19-CH3), 1.07(3H,s,18-CH3), 3.54(1H,m,3α-H), 5.40(1H,dm,J 5.0 Hz, 6-H), 5.99(1H,m, 16-H), 7.22(1H,m,Py5-H), 7.65(1H,m,Py 4-H), 8.46(1H,m,Py 6H), 8.62(1H,m,Py 2-H), Anal. Calcd: C, 82.47; H, 8.94; N, 4.01. Found: C, 82.40; H, 8.91; N. 3.97%.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[S:11][C:12]=1[CH3:13])(=O)=O.[N-:22]=[N+:23]=[N-:24].[Na+]>>[N:22]([CH2:6][CH2:7][C:8]1[N:9]=[C:10]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH2:20][CH3:21])[CH:15]=2)[S:11][C:12]=1[CH3:13])=[N+:23]=[N-:24]
Reactant: CCc1cc(-c2nc(CCOS(C)(=O)=O)c(C)s2)ccn1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CCc1cc(-c2nc(CCN=[N+]=[N-])c(C)s2)ccn1

Procedure:
The product was obtained starting from 2-(2-(2-ethylpyridin-4-yl)-5-methylthiazol-4-yl)ethyl methanesulfonate (226 mg, 692 μmol) and sodium azide (63.0 mg, 969 μmol) according to the method described in example 46, step 2 as light yellow oil (138 mg, 505 μmol, 72.9%).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[NH:16][C:17](=[O:21])[CH2:18][C:19]#[CH:20])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([N:29]=[N+:30]=[N-:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>C(O)(C)(C)C.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[CH2:22]([N:29]1[CH:20]=[C:19]([C:18]2[C:17](=[O:21])[NH:16][C:10]3[C:9]([C:1]=2[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:14][C:13]([Cl:15])=[CH:12][CH:11]=3)[N:31]=[N:30]1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C#CCC(=O)Nc1ccc(Cl)cc1C(=O)c1ccccc1
Reactant: [N-]=[N+]=NCc1ccccc1
Agent: [Cu+2]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)([O-])[O-]
Solvent: CC(C)(C)O
Solvent: O
Product: O=c1[nH]c2ccc(Cl)cc2c(-c2ccccc2)c1-c1cn(Cc2ccccc2)nn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 82.5 %

Procedure:
To a solution of but-3-ynoic acid (2-benzoyl-4-chloro-phenyl)-amide (from Example 7) (0.056 g, 0.188 mmol) in 50% aq. tert-butanol (5 mL) was added benzyl azide (0.07 mL, 0.56 mmol), sodium ascorbate (0.012 g, 0.0564 mmol), and copper(II) sulfate pentahydrate (0.002 g, 5.64 μmol). After stirring at 70° C. for 15 hours, the reaction mixture was partitioned between ethyl acetate (15 mL) and water (15 mL). The aqueous layer was further extracted with ethyl acetate (2×15 mL) and the combined organic layers were dried (MgSO4) and concentrated. The residual yellow oil was purified by flash chromatography (silica gel) to afford 3-(1-benzyl-1H-[1,2,3]triazol-4-yl)-6-chloro-4-phenyl-1H-quinolin-2-one (0.064 g, 82% yield) as white solid. 1H NMR (300 MHz, CDCl3): δ 12.42 (s, 1H), 7.51 (s, 1H), 7.39-7.32 (m, 7.5H), 7.29 (s, 0.5H), 7.18-7.15 (m, 3H), 7.09-7.06 (m, 2H), 5.46 (s, 2H). MS: 413 (M+H).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[O:8][CH2:9][CH:10]=[C:11]2[CH2:16][CH2:15][CH:14]([C:17]#[N:18])[CH2:13][CH2:12]2)[N:3]=[CH:2]1.C([O-])([O-])=[O:24].[K+].[K+].OO>CS(C)=O>[NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][CH:20]=[CH:19][C:7]=2[O:8][CH2:9][CH:10]=[C:11]2[CH2:12][CH2:13][CH:14]([C:17]([NH2:18])=[O:24])[CH2:15][CH2:16]2)[N:3]=[CH:2]1
Reactant: N#CC1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Reactant: O=C([O-])[O-]
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: NC(=O)C1CCC(=CCOc2ccccc2-c2c[nH]cn2)CC1
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of 4-(2-(2-(1H-imidazol-4-yl)phenoxy)ethylidene)cyclohexanecarbonitrile (90 mg, 0.307 mmol) in DMSO (3 mL) at room temperature was added K2CO3 (42 mg, 0.307 mmol) followed by H2O2 (30%, 0.7 mL, 6.14 mmol). After stirring for 16 h, the reaction was concentrated and the crude product was purified by flash column chromatography (silica gel, 10% MeOH/DCM) to yield the desired amide as a white solid (40 mg, 0.129 mmol, 42%). 1H NMR (DMSO-d6): 1.41-1.51 (m, 4H), 1.71-1.82 (m, 4H), 2.17-2.20 (m, 1H), 4.05-4.11 (m, 2H), 6.66 (d, 1H, J=10.5 Hz), 6.93 (t, 1H, J=7.5 Hz), 7.02 (d, 1H, J=8.1 Hz), 7.11 (d, 1H, J=7.2 Hz), 7.15 (s, 2H), 7.51 (s, 1H), 7.68 (s, 1H), 8.08 (d, 1H, J=7.5 Hz), 12.05 (br s, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@H:35]([C:37](O)=[O:38])[CH3:36])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:12])[CH3:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:49]([S:56]([CH2:59][C@@H:60]([NH2:68])[CH2:61][C:62]1[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=1)(=[O:58])=[O:57])[C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1>>[C:1]([O:5][C:6]([N:8]([CH3:48])[C@H:9]([C:13]([NH:15][C@H:16]([C:20]([N:22]([C@@H:24]([C@@H:44]([CH3:47])[CH2:45][CH3:46])[C@H:25]([O:42][CH3:43])[CH2:26][C:27]([N:29]1[CH2:33][CH2:32][CH2:31][C@H:30]1[C@H:34]([O:40][CH3:41])[C@@H:35]([CH3:36])[C:37]([NH:68][C@@H:60]([CH2:61][C:62]1[CH:63]=[CH:64][CH:65]=[CH:66][CH:67]=1)[CH2:59][S:56]([CH2:49][C:50]1[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1)(=[O:58])=[O:57])=[O:38])=[O:28])[CH3:23])=[O:21])[CH:17]([CH3:19])[CH3:18])=[O:14])[CH:10]([CH3:11])[CH3:12])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)O)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C
Reactant: N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)CS(=O)(=O)Cc1ccccc1)OC)N(C)C(=O)[C@@H](NC(=O)[C@H](C(C)C)N(C)C(=O)OC(C)(C)C)C(C)C

Procedure:
N-(tert-Butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-3-{[(2S)-1-(benzylsulphonyl)-3-phenylpropan-2-yl]amino}-1-methoxy-2-methyl-3-oxopropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide was prepared in analogy to the synthesis of Intermediate 55, by reaction of 20 mg (29 μmol) of N-(tert-butoxycarbonyl)-N-methyl-L-valyl-N-[(3R,4S,5S)-1-{(2S)-2-[(1R,2R)-2-carboxy-1-methoxypropyl]pyrrolidin-1-yl}-3-methoxy-5-methyl-1-oxoheptan-4-yl]-N-methyl-L-valinamide with 9.3 mg (20 μmol) of (2S)-1-(benzylsulphonyl)-3-phenylpropan-2-amine
Reaction SMILES: [OH:1][C@@:2]12[CH2:19][C@@H:18]([O:20]C(=O)C(C)(C)C)[CH2:17][CH2:16][C@:15]1([CH3:27])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C:9](=[O:28])[C@H:8]1[CH2:29][C@@H:7]31)[CH:4]=[CH:3]2.[OH-].[K+]>C(O)(=O)C.O1CCCC1.[Zn]>[OH:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:27])[C@:2]([OH:1])([CH:3]=[CH:4][C@@H:5]3[C@@H:14]2[CH2:13][CH2:12][C@@:10]2([CH3:11])[C@H:6]3[C@@H:7]3[CH2:29][C@@H:8]3[C:9]2=[O:28])[CH2:19]1
Reactant: CC(C)(C)C(=O)O[C@H]1CC[C@]2(C)[C@H]3CC[C@]4(C)C(=O)[C@H]5C[C@H]5[C@H]4[C@@H]3C=C[C@]2(O)C1
Agent: [K+]
Agent: [OH-]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: C[C@]12CC[C@H]3[C@@H](C=C[C@]4(O)C[C@@H](O)CC[C@]34C)[C@@H]1[C@@H]1C[C@@H]1C2=O

Procedure:
The starting material of the process is 3β-hydroxy-15β,16β-methyleneandrost-5-en-17-one. The hydroxy in 7β position is introduced in a fermentation process using Botryodiplodia malorum, the resultant compound is acetylated in a regioselective manner with pivalic anhydride in the presence of 4-dimethylaminopyridine yielding the corresponding 3β-pivaloyloxy derivative. Said pivaloyloxy derivative was reacted with tert-butyl hydroperoxide in the presence of VO (acetonylacetonate)2 catalyst to give the 5β,6β-epoxy derivative which, in turn, was reacted with triphenylphosphine and carbon tetrachloride in dichloromethane to yield the 7α-chloro derivative. Said 7α-chloro derivative was reacted with zinc in a mixture of acetic acid and tetrahydrofuran yielding the 5β-hydroxy-15β,16β-methylene-3β-pivaloyloxyandrost-6-en-17-one which then was hydrolyzed with potassium hydroxide to give 3β,5β-dihydroxy-15β,16β-methyleneandrost-6-en-17-one.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:24]=[C:8]2[CH2:9][N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[C:11]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:7]2[N:6]=1)=O.[BH4-].[Na+]>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[N:10]1[C:11]2[N:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:7]2[N:6]=[C:5]([CH2:3][OH:2])[N:24]=[C:8]2[CH2:9]1
Reactant: COC(=O)c1nc2n(n1)-c1cccnc1N(c1ccccc1Cl)C2
Agent: [BH4-]
Agent: [Na+]
Product: OCc1nc2n(n1)-c1cccnc1N(c1ccccc1Cl)C2

Procedure:
using 15.00 g (0.044 mol) of 5-(2-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid methyl ester and 8.28 g (0.219 mol) of sodium borohydride there is obtained 5-(2-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-methanol having a melting point of 193°-196°;
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[CH3:21][NH:22][CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH3:21][N:22]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:2]1[CH:7]=[C:6]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=3)[N:11]=[C:10]([CH3:20])[CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Cc1cccc(-n2nc(C)cc2-c2ccnc(Cl)c2)c1
Reactant: CNCCc1ccccc1
Product: Cc1cccc(-n2nc(C)cc2-c2ccnc(N(C)CCc3ccccc3)c2)c1
Temperature: 200 °C
Yield: 67 %

Procedure:
A mixture of 2-chloro-4-[1-(3-methylphenyl)-3-methyl-1H-pyrazol-5-yl]pyridine (Example 45; 0.5 g, 0.0018 mol) and N-methylphenethylamine (15 mL) was heated at 200° C. for 24 hours. The excess amine was removed under vacuum and the residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated and the crude was purified by chromatography on silica gel (ethyl acetate/hexane, 2:8) to give 0.45 g (67% yield) of product as a yellow oil: Anal. Calc'd. for C25H26N4: C, 78.50; H, 6.85; N, 14.65. Found: C, 78.43; H, 6.87; N, 14.30.
Reaction SMILES: [O:1]=[C:2]1[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20](O)=[O:21].FC1C=CC(C2(C3C=CC(F)=CC=3)CCN(CC(O)=O)C2=O)=CC=1.[Cl:47][C:48]1[CH:58]=[CH:57][C:51](/[C:52](=[N:55]/[H])/[NH:53]O)=[CH:50][CH:49]=1.ON/C(=N\[H])/C1C=CC(C(F)(F)F)=CC=1>>[Cl:47][C:48]1[CH:58]=[CH:57][C:51]([C:52]2[N:55]=[C:20]([CH2:19][N:3]3[CH2:4][CH2:5][C:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)([C:13]4[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=4)[C:2]3=[O:1])[O:21][N:53]=2)=[CH:50][CH:49]=1
Reactant: [H]/N=C(\NO)c1ccc(Cl)cc1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Agent: O=C(O)CN1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Agent: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Product: O=C1N(Cc2nc(-c3ccc(Cl)cc3)no2)CCC1(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared using the procedure described in Example 190 substituting 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid from Example 1C for 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid and (Z)-4-chloro-N-hydroxybenzimidamide for (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide. 1H NMR (300 MHz, CDCl3) δ ppm 7.99-7.91 (m, 2H), 7.49-7.14 (m, 12H), 4.88 (s, 2H), 3.57 (t, J=6.5, 2H), 2.89 (t, J=6.5, 2H); MS (DCI) m/z 430.1 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][NH2:11])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[Br:12][C:13]1[S:17][C:16]2=[N:18][C:19]([C:21](O)=[O:22])=[CH:20][N:15]2[CH:14]=1>>[Br:12][C:13]1[S:17][C:16]2=[N:18][C:19]([C:21]([NH:11][CH2:10][C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=3)=[O:22])=[CH:20][N:15]2[CH:14]=1
Reactant: CC(C)c1ccc(CN)cc1
Reactant: O=C(O)c1cn2cc(Br)sc2n1
Product: CC(C)c1ccc(CNC(=O)c2cn3cc(Br)sc3n2)cc1

Procedure:
The title compound was prepared by essentially following the same procedures described for Intermediate XLIV, using (4-isopropylphenyl)methanamine and 2-bromoimidazo[2,1-b]thiazole-6-carboxylic acid as starting materials.
Reaction SMILES: FC1C=C(NC2N=C3NN=CC3=C([C:24]3[CH:25]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:27]=[CH:28][CH:29]=3)N=2)C=CC=1N1CCOCC1.ClC1N=C(Cl)N=C2NN=CC=12.O1C=CCCC1.Cl[C:53]1[N:58]=[C:57]([Cl:59])[N:56]=[C:55]2[N:60]([CH:63]3[CH2:68][CH2:67][CH2:66][CH2:65][O:64]3)[N:61]=[CH:62][C:54]=12.C(NC1C=C(B(O)O)C=CC=1)(=O)C=C>>[Cl:59][C:57]1[N:56]=[C:55]2[N:60]([CH:63]3[CH2:68][CH2:67][CH2:66][CH2:65][O:64]3)[N:61]=[CH:62][C:54]2=[C:53]([C:28]2[CH:27]=[C:26]([NH:30][C:31](=[O:34])[CH:32]=[CH2:33])[CH:25]=[CH:24][CH:29]=2)[N:58]=1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCOCC4)c(F)c3)nc3[nH]ncc23)c1
Reactant: Clc1nc(Cl)c2cnn(C3CCCCO3)c2n1
Agent: C1=COCCC1
Agent: C=CC(=O)Nc1cccc(B(O)O)c1
Agent: Clc1nc(Cl)c2cn[nH]c2n1
Product: C=CC(=O)Nc1cccc(-c2nc(Cl)nc3c2cnn3C2CCCCO2)c1

Procedure:
As an example, N-(3-(6-((3-fluoro-4-morpholinophenyl)amino)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide can be prepared according to Route II. Beginning with 4,6-dichloro-1H-pyrazolo[3,4-d]pyrimidine, protection can be accomplished by reaction with 3,4-dihydro-2H-pyran. The resulting 4,6-dichloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidine can then be coupled with (3-acrylamidophenyl)boronic acid under palladium catalyzed conditions to provide N-(3-(6-chloro-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide.