Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.NC1C2C(=CC(CC(NC(=O)CNS(C3C(C)=C(C)C4OC(C)(C)CCC=4C=3C)(=O)=O)C(=O)N3CCCCC3)=CC=2)C=CN=1.[NH2:46][C:47]1[C:56]2[C:51](=[CH:52][C:53]([CH2:57][CH:58]([NH:67][C:68](=O)[O-:69])[C:59](=[O:66])[N:60]3[CH2:65][CH2:64][O:63][CH2:62][CH2:61]3)=[CH:54][CH:55]=2)[CH:50]=[CH:49][N:48]=1.[CH3:71][C:72]([O:75][C:76](=[O:97])[CH2:77][C@H:78]([NH:82][S:83]([C:86]1[C:91]([CH3:92])=[CH:90][C:89]([O:93][CH3:94])=[C:88]([CH3:95])[C:87]=1[CH3:96])(=[O:85])=[O:84])C(O)=O)([CH3:74])[CH3:73].N[C@H](C(O)=O)CC(=O)OC(C)(C)C.COC1C=C(C)C(S([Cl:123])(=O)=O)=C(C)C=1C>>[ClH:123].[CH3:74][C:72]([O:75][C:76](=[O:97])[CH2:77][C@H:78]([NH:82][S:83]([C:86]1[C:91]([CH3:92])=[CH:90][C:89]([O:93][CH3:94])=[C:88]([CH3:95])[C:87]=1[CH3:96])(=[O:85])=[O:84])[C:68]([NH:67][CH:58]([CH2:57][C:53]1[CH:52]=[C:51]2[C:56](=[CH:55][CH:54]=1)[C:47]([NH2:46])=[N:48][CH:49]=[CH:50]2)[C:59](=[O:66])[N:60]1[CH2:61][CH2:62][O:63][CH2:64][CH2:65]1)=[O:69])([CH3:71])[CH3:73]
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1C
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)O)c(C)c1C
Reactant: Nc1nccc2cc(CC(NC(=O)[O-])C(=O)N3CCOCC3)ccc12
Agent: CC(C)(C)OC(=O)C[C@H](N)C(=O)O
Agent: Cc1c(C)c(S(=O)(=O)NCC(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCCCC2)c(C)c2c1OC(C)(C)CC2
Agent: Cl
Product: COc1cc(C)c(S(=O)(=O)N[C@@H](CC(=O)OC(C)(C)C)C(=O)NC(Cc2ccc3c(N)nccc3c2)C(=O)N2CCOCC2)c(C)c1C

Procedure:
Protection of 0.23 g of amino acid 1i and subsequently coupling with morpholine according to the procedure described for 5a yielded 1,1-dimethylethyl [1-[(1-amino-6-isoquinolinyl)methyl]-2-oxo-2-(4-morpholinyl)ethylcarbamate. The procedure described for 5c was used for the deprotection of 90 mg of 1,1-dimethylethyl [1-[(1-amino-6-isoquinolinyl)methyl]-2-oxo-2-(4-morpholinyl)ethylcarbamate and coupling with 96 mg of (2S)-2-[[(4-methoxy-2,3,6-trimethylphenyl)sulfonyl]amino]butanedioic acid 4-(1,1-dimethylethyl)ester (prepared from Asp(OtBu)-OH and (4-methoxy-2,3,6-trimethylphenyl)sulfonylchloride using the procedure described for 5b) to yield the title compound (56 mg) as a mixture of diastereomers (1:1). 1H-NMR 400 MHz (CD3OD) δ: 1.29 and 1.33 (9H, 2x s), 2.12 and 2.13 (3H, 2x s), 2.19-2.47 (2H, m), 2.52 and 2.53 (3H, 2x s), 2.62 (3H, s), 2.95-3.65 (I OH, m), 3.81 and 3.86 (3H, 2x s), 3.95-4.08 (1H, m), 5.03-5.18 (1H, m), 6.73 and 6.75 (1H, 2x s), 7.18-7.23 (1H, m), 7,53-7.78 . (3H, m), 8.31-8.38 (1H,m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24]Cl)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1.[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH2:23][CH2:24][N:32]([CH3:33])[CH3:31])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:26]#[N:27])=[C:4]([F:28])[CH:3]=1
Reactant: CNC
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCCl
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc(Cl)cc3F)c(C#N)cnc2cc1OCCCN(C)C
Temperature: 125 °C

Procedure:
A mixture of 1 g (2.38 mmol) of 4-(4-Chloro-2-fluoro-phenylamino)-7-(3-chloro-propoxy)-6-methoxy-quinoline-3-carbonitrile and 0.07 g of sodium iodide in 17.85 ml of 2M dimethylamine in tetrahydrofuran was placed in a sealed tube and heated to 125° C. for 3.5 hr. The solvent was removed and the residue was mixed with warm ethyl acetate and saturated sodium bicarbonate solution. The organic layer was separated and dried over magnesium sulfate. Solvent was removed and ether was added. One standing, the crystals were deposited giving 0.93 g of the title compound as a white solid: mass spectrum (electrospray, m/e) M+H 428.9.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[NH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][CH:17]=1.C(N(CC)CC)C>CN(C)C=O>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:20][CH:21]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(O)Cc1ccc(Nc2c([N+](=O)[O-])cnc3ccccc23)cc1

Procedure:
Using the method of Example 1, 4-chloro-3-nitroquinoline was reacted with 4-aminophenylacetic acid in N,N-dimethylformamide in the presence of triethylamine to provide N-(3-nitro-4-quinolinyl)-4-aminophenylacetic acid. This acid was reduced using the method of Example 26 to provide N-(3-amino-4-quinolinyl)-4-aminophenylacetic acid. This diamine was then reacted with formic acid using the method of Example 137 to provide 1-(4-carboxymethylphenyl)-1H-imidazo[4,5-c]quinoline. Recrystallization from methanol provided solid of m.p. 236°-240° C. Analysis: Calculated for C18H13N3O2 : %C, 71.3; %H, 4.3; %N, 13.9; Found; %C, 70.8; %H, 4.3; %N, 13.7.
Reaction SMILES: CC[C:3]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[C:21]2[C:4]=1[CH2:5][N:6]1[C:11](=[O:12])[C:10]3[CH2:13][O:14][C:15]([C@:17]([OH:20])([CH2:18][CH3:19])[C:9]=3[CH:8]=[C:7]12)=[O:16].CS(C)=O.O.[C:34](O)(=O)[CH3:35].C(O)(=[O:40])C.IC1C=CC=CC=1>[Pt].C(O)(=O)C>[CH3:34][CH2:35][C:24]1[CH:25]=[CH:26][C:27](=[O:40])[C:28]2=[CH:3][C:4]3[CH2:5][N:6]4[C:7](=[CH:8][C:9]5[C@@:17]([OH:20])([CH2:18][CH3:19])[C:15](=[O:16])[O:14][CH2:13][C:10]=5[C:11]4=[O:12])[C:21]=3[NH:22][C:23]=12
Reactant: CC(=O)O
Reactant: CCc1c2c(nc3ccccc13)-c1cc3c(c(=O)n1C2)COC(=O)[C@]3(O)CC
Agent: [Pt]
Solvent: O
Solvent: Ic1ccccc1
Solvent: CS(C)=O
Product: CCc1ccc(=O)c2cc3c([nH]c1-2)-c1cc2c(c(=O)n1C3)COC(=O)[C@]2(O)CC
Temperature: 25 °C

Procedure:
In a 100 ml beaker, 0.5 g (1.239 mmol) of 7-ethylcamptothecin, 0.32 g of 5% hydrogenation catalyst Pt/C (containing 0.028 mmol of platinum) and 0.025 ml (0.352 mmol) of dimethyl sulfoxide are added to 70 ml of acetic acid. The obtained suspension is quantitatively transferred into a 100 ml autoclave. After closure, the autoclave is flushed three times with nitrogen at the pressure of 0.5 MPa and then three times with hydrogen at the pressure of 0.5 MPa. The temperature is adjusted to 65° C. and the mixture is stirred at 950 r.p.m. The hydrogen pressure is adjusted to 0.5 MPa. After 43.5 hours the consumption of hydrogen stops and the procedure is terminated. After cooling to 25° C., the stirring is stopped and the internal pressure is equilibrated with the ambient atmosphere. The autoclave is flushed three times with nitrogen, the hydrogenation catalyst is removed from the hydrogenation mixture by filtration under pressure of nitrogen and the catalyst cake is washed with 10 ml of acetic acid. The obtained solution (80 ml) of 7-ethyl-1,2,6,7-tetrahydrocamptothecin is immediately added under vigorous stirring into a 250 ml one-necked flask containing 22 ml (1.218 mol) of water and 0.77 g (2.343 mmol) of iodobenzene diacetate. The obtained solution is stirred for 15 minutes at 22° C. Then the solvent is evaporated and the residue is mixed with 10 ml of acetonitrile. The obtained suspension is homogenized by sonication. The solid 7-ethyl-10-hydroxycamptothecin is isolated by filtration, washed on the filter with 10 ml of acetonitrile and dried to the constant weight in a vacuum oven at 60° C. to 65° C. The yield of 7-ethyl-10-hydroxycamptothecin is 0.283 g (58.3%). Its relative purity, determined by high performance liquid chromatography, is 90.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:13][OH:14])=[CH:11]N=2)=[CH:4][CH:3]=1.[C:15]1(=O)[CH2:19][CH2:18][C:17](=[O:20])[CH2:16]1.[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]([CH2:13][O:14][C:15]3[CH2:19][CH2:18][C:17](=[O:20])[CH:16]=3)=[CH:11][CH:22]=2)=[CH:4][CH:3]=1
Reactant: OCc1cnc(-c2ccc(Cl)cc2)s1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CCC(=O)C1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Product: O=C1C=C(OCc2ccc(-c3ccc(Cl)cc3)s2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.9 %

Procedure:
To a solution of [2-(4-Chloro-phenyl)-thiazol-5-yl]-methanol (4.89 g, 21.75 mmol) in anhydrous THF (100 ml), at 0° C. under an atmosphere of nitrogen was added cyclopentane-1,3-dione (2.78 g, 28.27 mmol) followed by triphenylphosphine (7.41 g, 28.27 mmol). Diisopropylazodicarboxylate (5.48 ml, 28.27 mmol) was then added dropwise over a period of 5 minutes and the reaction allowed to warm to room temperature and stirred for 2 hours. The crude reaction mixture was dry loaded onto silica and purified by flash chromatography to give 3-[5-(4-Chloro-phenyl)-thiophen-2-ylmethoxy]-cyclopent-2-enone (5.1 g).
Reaction SMILES: [O:1]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.OP([O-])(O)=O.[K+].[CH3:19][CH2:20][C@@H:21]([C:23]([O:25][C@@H:26]1[C@@H:31]2[C@@H:32]([CH2:37][CH2:38][C@@H:39]([OH:47])[CH2:40][C@@H:41]([OH:46])[CH2:42][C:43]([OH:45])=[O:44])[C@@H:33]([CH3:36])[CH:34]=[CH:35][C:30]2=[CH:29][CH2:28][CH2:27]1)=[O:24])[CH3:22]>>[CH3:19][CH2:20][C@@H:21]([C:23]([O:25][C@@H:26]1[C@@H:31]2[C@@H:32]([CH2:37][CH2:38][C@@H:39]([OH:47])[CH2:40][C@@H:41]([OH:46])[CH2:42][C:43]([OH:45])=[O:44])[C@@H:33]([CH3:36])[CH:34]=[CH:35][C:30]2=[CH:29][C@@H:28]([OH:1])[CH2:27]1)=[O:24])[CH3:22]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC[C@H](C)C(=O)O[C@H]1CCC=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Agent: O=P([O-])(O)O
Agent: [K+]
Product: CC[C@H](C)C(=O)O[C@H]1C[C@H](O)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)O)[C@H]21
Reaction time: 36 h

Procedure:
1 ml of a spore suspension of YS-44442 (or YS-45494) stored in GL(10_glycerol—5_lactose) at −80_was opened in laminar flower and added into a 300 ml shake flask containing 20 ml of the seed medium (for every liter: glucose 10 g, peptone 2 g, soy protein 4 g and KH2PO4 1 g, pH 7.0÷0.2). The seed culture was incubated at 27_ for 24 to 48 hrs in a rotary shaker at 200 to 220 rpm (growth phase). Afterward, 1.5 to 2 ml of the seed culture was incubated into a 300 ml shake flask containing 20 ml of the fermentation medium (per liter: glucose 15 g, peptone 5 g, corn steep powder (C.S.P.) 5 g and soybean meal 4 g, KH2PO4 1 g, pH 7.0±0.2). The shake flask was incubated at 27±0.5_ for 18 to 24 hrs in a rotary shaker at 200 rpm (growth phase). The fermentation broth was added with compactin prepared as above into the fermentation broth at a final concentration of 1500 to 2000 mg/L and the incubation was continued for 16 to 24 hrs.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]=[CH:16][C:15]=1[N+:24]([O-:26])=[O:25].C(N(CC)CC)C.O>ClCCl>[N+:24]([C:15]1[CH:16]=[N:17][C:18]2[C:23]([C:14]=1[NH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])=[N:22][CH:21]=[CH:20][CH:19]=2)([O-:26])=[O:25]
Reactant: CC(C)(C)OC(=O)NCCCN
Reactant: O=[N+]([O-])c1cnc2cccnc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCCCNc1c([N+](=O)[O-])cnc2cccnc12
Reaction time: 2.5 h
Yield: 98.9 %

Procedure:
A solution of tert-butyl 3-aminopropylcarbamate (15.7 g, 90.2 mmol) in dichloromethane (50 mL) was added dropwise over 30 minutes to a solution of 4-chloro-3-nitro[1,5]naphthyridine (18.0 g, 85.9 mmol) and triethylamine (15.6 mL, 112 mmol) in dichloromethane (235 mL) at room temperature. The reaction mixture was stirred for 2.5 hours and then concentrated under reduced pressure to afford an orange solid. Water (300 mL) was added and the mixture was stirred for one hour. The solid was isolated by filtration, washed with water (3×50 mL), and dried under vacuum at 70° C. to afford 29.5 g of tert-butyl 3-[(3-nitro[1,5]naphthyridin-4-yl)amino]propylcarbamate as a yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([O:27]C(C3C=CC=CC=3)C3C=CC=CC=3)=[O:26])=[C:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8].C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>CCCCCCC>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([NH:9][CH:10]1[C:41](=[O:42])[N:12]2[C:13]([C:25]([OH:27])=[O:26])=[C:14]([C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:15][S:16][C@H:11]12)=[O:8]
Reactant: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C(=O)c3ccccc3)CS[C@H]12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCCC
Product: O=C(Cc1cccs1)NC1C(=O)N2C(C(=O)O)=C(C(=O)c3ccccc3)CS[C@H]12
Temperature: 5 °C

Procedure:
To a cooled (5° C.), stirred slurry of 0.227 g. of benzhydryl 7-(2-thienylacetamido)-3-benzoyl-3-cephem-4-carboxylate in 2 ml. of anisole was added 1 ml. of cold trifluoroacetic acid. After the reaction mixture was allowed to stir with cooling for 20 minutes, 20 ml. of n-heptane was added, and the resulting solution was evaporated in vacuo to a low volume to remove excess trifluoroacetic acid. An additional 20 ml. of n-heptane was added to the residue and the resulting solution was stirred with cooling for approximately 5 minutes. The white precipitate which formed was filtered from the solution and dissolved in acetone. The acetone solution was filtered and the filtrate evaporated in vacuo to a low volume. The residue was dissolved in cold ethyl acetate and transferred to a separatory funnel. The ethyl acetate solution was extracted twice with cold aqueous sodium bicarbonate solution. The aqueous extracts were combined, layered with cold ethyl acetate and acidified with cold 1N.HCl. The ethyl acetate layer was separated, washed twice with brine, and dried over anhydrous sodium sulfate. Evaporation in vacuo to dryness provided 0.157 g. (96 percent) of the title acid which crystallized from methylene chloride/hexane. The product exhibited activity against gram-positive and gram-negative organisms at 0.1 mg/ml in a standard disc assay.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][NH:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([F:28])[C:26]=1[F:27])[C:21](O)=[O:22].C(N(CC)C(C)C)(C)C.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:14][CH2:15][OH:16])[CH2:13][CH2:12][N:11]([C:21](=[O:22])[C:20]3[CH:24]=[C:25]([F:28])[C:26]([F:27])=[C:18]([F:17])[CH:19]=3)[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: O=C(O)c1cc(F)c(F)c(F)c1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1cc(F)c(F)c(F)c1)N1CCC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Reaction time: 18 h

Procedure:
Combine 3-(3,4-dichloro-phenyl)-3-(2-hydroxy-ethyl)-pyrrolidine (286 mg, 1.1 mmol), 3,4,5-trifluoro-benzoic acid (1 mmol), N,N-diisopropylethylamine (0.19 mL, 1.1 mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) (0.21 g, 1.1 mmol), and 1-hydroxybenzotriazole hydrate (HOBT) (0.15 g, 1.1 mmol) in dichloromethane (10 mL). After 18 hour, dilute with dichloromethane and extract with 1M hydrochloric acid solution, 5% sodium bicarbonate solution, and water. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give the title compound: Rf =0.45 (silica gel, 10% methanol/dichloromethane).
Reaction SMILES: [Cl:1][C:2]1[C:11]([CH:12]=O)=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:16]1[CH:21]=CC=C[CH:17]=1.O=C(C)C=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.[NH2:46][OH:47]>C(O)C.N1C=CC=CC=1>[Cl:1][C:2]1[C:11]([CH:12]=[CH:17][C:16](=[N:46][OH:47])[CH3:21])=[C:10]([O:14][CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: c1ccccc1
Reactant: NO
Reactant: COC(=O)c1ccc(OC)c(C=O)c1Cl
Agent: CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: COC(=O)c1ccc(OC)c(C=CC(C)=NO)c1Cl
Temperature: 0 °C

Procedure:
To methyl 2-chloro-3-formyl-4-methoxybenzoate in an amount of 3.08 g (0.0135 mole), were added 30 ml benzene and then 2-oxopropylidenetriphenylphosphorane in an amount of 4.52 g (0.0142 mole), and the resulting mixture was then stirred for an hour under reflux and heating. After cooling the reacted-mixture, insoluble materials therein were separated by filtration, and methyl 2-chloro-3-(3-oxo-1-butenyl)-4-methoxybenzoate obtained by condensing the solvent in the mixture under reduced pressure was dissolved in a mixed-solvent of 25 ml ethanol and 25 ml pyridine, and the resulting solution was stirred for an hour under reflux and heating following to the addition of hydroxylamine hydrochloride in an amount of 3.3 g (0.047 mole) into the solution. The reacted-mixture was poured into ice water and extracted with ethyl acetate, and the ethyl acetate layer obtained was washed with 1N-hydrochloric acid and saturated saline solution, respectively, and dried with anhydrous magnesium sulfate. The solvent remained in the layer was distillated out under reduced pressure to obtain methyl 2-chloro-3-(3-hydroxyimino-1-butenyl)-4-methoxybenzoate. The obtained product was then dissolved in 50 ml THF, whereto 40 ml aqueous solution of sodium hydrogenbicarbonate in an amount of 4.1 g (0.049 mole) was added, and the resulting mixture was then further added with both 35 ml aqueous solution of potassium iodide in an amount of 7.4 g (0.045 mole) and iodine in an amount of 3.4 g (0.014 mole) and then stirred for 3 hours under reflux and heating while blocking light. The reacted-mixture was poured into ice water and extracted with ethyl acetate following to the addition of sodium hydrogensulfite into the mixture. The organic layer obtained was washed with saturated saline solution and dried with anhydrous magnesium sulfate, then solvent remained in the layer was distillated out under reduced pressure. The residue obtained was purified by using a silica gel column chromatography to obtain methyl 2-chloro-4-methoxy-3-(3-methyl-1,2-isoxazol-5-yl)benzoate in an amount of 2.2 g. The yield was 53.5%.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@:6]32[C@H:10]2[C@H:19]([CH2:20][CH2:21][C@:4]13[CH3:5])[C@@H:18]1[C:13](=[CH:14][C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][C@H:11]2[CH3:23].[CH2:24](N(CC)CC)C.[C:31]1([SH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.[OH-].[K+]>C=O.C(O)C>[OH:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[CH2:9][C@@:6]32[C@H:10]2[C@H:19]([CH2:20][CH2:21][C@:4]13[CH3:5])[C@@H:18]1[C:13](=[C:14]([CH2:24][S:37][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:15](=[O:22])[CH2:16][CH2:17]1)[CH2:12][C@H:11]2[CH3:23]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)C[C@H]4C[C@]43[C@@H]21
Reactant: CCN(CC)CC
Reactant: Sc1ccccc1
Agent: C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: C[C@@H]1CC2=C(CSc3ccccc3)C(=O)CC[C@@H]2[C@H]2CC[C@]3(C)[C@H](CO)C[C@H]4C[C@]43[C@@H]21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
i)—A solution of (7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-14,15-methyleneestr-4-en-3-one (Example 1, 0.40 g) in a mixture of formaldehyde (37 wt. % solution in water, 0.24 ml), triethylamine (0.288 ml), thiophenol (0.276 ml) and ethanol (0.721 ml) was stirred at room temperature overnight. The reaction mixture was poured into a aqueous solution of potassium hydroxide (0.5 M) and the product was extracted into ethyl acetate. The combined organic phases were washed with a aqueous solution of potassium hydroxide (0.5 M) and brine, dried over sodium sulfate and concentrated under reduced pressure. Column chromatography afforded (7α,14β,15β,17α)-17-(hydroxymethyl)-7-methyl-4-[(phenylthio)methyl]-14,15-methyleneestr-4-en-3-one (0.13 g).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20][C:21]([Br:24])(Br)Br.C(N(CC)CC)C.[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:46][CH2:45][C@H:44]([CH:47]=O)[CH2:43][CH2:42]1)[CH3:39])([CH3:35])([CH3:34])[CH3:33]>C(Cl)Cl>[C:32]([O:36][C:37](=[O:49])[N:38]([CH2:40][C@H:41]1[CH2:42][CH2:43][C@H:44]([CH:47]=[C:21]([Br:24])[Br:20])[CH2:45][CH2:46]1)[CH3:39])([CH3:35])([CH3:33])[CH3:34]
Reactant: CN(C[C@H]1CC[C@H](C=O)CC1)C(=O)OC(C)(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C[C@H]1CC[C@H](C=C(Br)Br)CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of 257.6 g (982 mmol) triphenylphosphine in 1 l methylenechloride was treated with 162.8 g (491 mmol) tetrabromomethane (the reaction was heated up to reflux and was then cooled with an ice bath) and after 40 minutes at room temperature treated with 157.4 ml (1129 mmol) triethylamine (the reaction was heated up to reflux and became dark violet). After cooling (0° C.), 62.7 g (245.5 mmol) of trans-(4-formyl-cyclohexylmethyl)-methyl-carbamic acid tert-butyl ester (example 1.2) in 600 ml methylenechloride were added during 20 minutes. The solution was stirred for 20 hours at room temperature, evaporated and filtered through silica gel (deactivated with hexane/Et3N) with a 99:1 to 4:1 v/v mixture of hexane and ether as eluent to yield 61.5 g (61%) of trans-[4-(2,2-dibromo-vinyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester as brown oil, MS: 409 (M, 2Br).
Reaction SMILES: Cl.[CH:2]([NH:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:11]=[CH:10][C:9]=1[NH:19]C(=O)OC(C)(C)C)([CH3:4])[CH3:3]>O1CCOCC1.CO>[NH2:19][C:9]1[CH:10]=[CH:11][C:12]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)=[CH:13][C:8]=1[NH:7][C:6]([NH:5][CH:2]([CH3:4])[CH3:3])=[O:27]
Reactant: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CC(C)NC(=O)Nc1cc(-c2cccs2)ccc1N
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
A 4M solution of HCl in dioxane (2 mL) was added to a stirred solution of tert-butyl (2-(3-isopropylureido)-4-(thiophen-2-yl)phenyl)carbamate (0.15 g, 0.40 mmol, 1 equiv.) in methanol (4 mL) at 0° C. The reaction was warmed to room temperature and stirred for 2 h. The reaction was then concentrated under reduced pressure. A saturated aqueous solution of sodium bicarbonate was added. The obtained solid was filtered, washed with water and dried to yield 1-(2-amino-5-(thiophen-2-yl)phenyl)-3-isopropylurea (0.10 g, 91% yield). ESI+ MS: m/z 276 ([M+H]+), 1H NMR (500 MHz, d6-DMSO): δ 7.67 (d, J=2.0 Hz, 1H), 7.47 (s, 7.33 (d, J=5.0 Hz, 1H), 7.17 (d, J=3.0 Hz, 1H), 7.09 (dd, J=1.5, 8.0 Hz, 1H), 7.05-7.01 (m, 1H), 6.72 (d, J=8.0 Hz, 1H), 6.08 (d, J=8.0 Hz, 1H), 4.87 (s, 2H), 3.76 (sept, J=7.0 Hz, 1H), 1.10 (d, J=7.0 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[NH:9][C:10]1[C:18]2[C:13](=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=2)[N:12]([CH2:26][CH2:27][CH:28]=O)[N:11]=1.[CH3:30][NH:31][CH3:32].Cl.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(N(CC)CC)C>ClCCCl>[CH3:30][N:31]([CH3:32])[CH2:28][CH2:27][CH2:26][N:12]1[C:13]2=[N:14][C:15]([NH:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[N:16][CH:17]=[C:18]2[C:10]([NH:9][C:3]2[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])=[N:11]1
Reactant: CNC
Reactant: Cc1cccc(C)c1Nc1nn(CCC=O)c2nc(Nc3ccccc3)ncc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(C)c1Nc1nn(CCCN(C)C)c2nc(Nc3ccccc3)ncc12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 66 mg (0.2 mmol) of crude 3-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)propanal 36 (Example 4, Step A) and 28 mg (0.3 mmol) of dimethylamine•HCl in 7 mL of 1,2-dichloroethane was treated sequentially with 60 mg (95%, 0.3 mmol) of NaBH(OAc)3 and 75 μl (0.5 mmol) of triethylamine. The resulting brown slurry was stirred at room temperature for 17 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 44:6 grading to CH2Cl2:MeOH, 4:1) to give the title compound 38. 1H-NMR (CD3OD) δ 2.06-2.14 (m, 2H), 2.28 (s, 6H), 2.49 (s, 6H), 2.72 (t, J=7.3 Hz, 2H), 4.19 (t, J=6.3 Hz, 2H), 7.01 (t, J=7.4 Hz, 1H), 7.12-7.19 (m, 3H), 7.31 (t, J=8.0 Hz, 2H), 7.75 (dd, J=8.6 Hz, 0.9 Hz, 2H), 8.27 (s, 1H). Mass Spectrum (ESI) m/e=416.1 (M+1).