Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][NH2:19])=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1.[H-].[Na+].[I:23][C:24]1[C:32]2[C:27](=[N:28][CH:29]=[N:30][C:31]=2N)[NH:26][N:25]=1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]([CH2:18][N:19]2[C:31]3=[N:30][CH:29]=[N:28][C:27]([NH2:26])=[C:32]3[C:24]([I:23])=[N:25]2)=[CH:16][C:15]2[C:10](=[C:11]([CH3:20])[CH:12]=[CH:13][CH:14]=2)[N:9]=1
Reactant: Cc1cccc2cc(CN)c(-c3ccccc3F)nc12
Reactant: Nc1ncnc2[nH]nc(I)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2cc(Cn3nc(I)c4c(N)ncnc43)c(-c3ccccc3F)nc12

Procedure:
Prepared according to Procedure I using (2-(2-fluorophenyl)-8-methylquinolin-3-yl)methanamine (0.200 g, 0.7 mmol), NaH (0.031 g, 60% in oil, 0.77 mmol, 1.1 eq) and 3-iodo-1H-pyrazolo{3,4-d}pyrimidin-4-amine (0.201 g, 0.77 mmol, 1.1 eq) in DMF. 1-((2-(2-fluorophenyl)-8-methylquinolin-3-yl)methyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine [PI3Kδ IC50=4 nM] was obtained after purification as a white solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 8.09 (1 H, s), 8.00 (1 H, s), 7.96 (1 H, s), 7.80 (1 H, d, J=7.9 Hz), 7.63 (1 H, d, J=7.3 Hz), 7.46-7.53 (1 H, m), 7.30 (1 H, dt), 7.08 (1 H, dd, J=7.6, 1.5 Hz), 7.02 (1 H, d, J=7.9 Hz), 6.91 (1 H, t, J=7.3 Hz), 5.46-5.54 (2 H, m), 2.90 (3 H, s) Mass Spectrum (ESI) m/e=511.0 (M+1)
Reaction SMILES: [C:1]1([C:7](=[N:14][C:15]2[CH:16]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[NH:25][CH:24]=3)=[O:22])[CH:18]=[N:19][CH:20]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[Cs+].[Cs+].FC(F)(F)S(O[CH:44]([CH2:54][O:55][Si:56]([CH3:62])([CH3:61])[C:57]([CH3:60])([CH3:59])[CH3:58])[CH2:45][O:46][Si:47]([CH3:53])([CH3:52])[C:48]([CH3:51])([CH3:50])[CH3:49])(=O)=O>CN(C=O)C>[C:1]1([C:7](=[N:14][C:15]2[CH:16]=[C:17]([C:21]([C:23]3[C:31]4[CH:30]=[N:29][CH:28]=[N:27][C:26]=4[N:25]([CH:44]([CH2:45][O:46][Si:47]([CH3:53])([CH3:52])[C:48]([CH3:51])([CH3:50])[CH3:49])[CH2:54][O:55][Si:56]([CH3:62])([CH3:61])[C:57]([CH3:60])([CH3:58])[CH3:59])[CH:24]=3)=[O:22])[CH:18]=[N:19][CH:20]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)OS(=O)(=O)C(F)(F)F
Reactant: O=C(c1cncc(N=C(c2ccccc2)c2ccccc2)c1)c1c[nH]c2ncncc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cncnc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (5-((Diphenylmethylene)amino)pyridin-3-yl)(7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone (Preparation 195, 1120 mg, 2.77 mmol) and Cs2CO3 (2710 mg, 8.31 mmol) in DMF (10 mL) was stirred at room temperature for 30 min. A solution of crude 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl trifluoromethanesulfonate (Preparation 108) in DMF (3.8 mL) was then added to the reaction and the resulting mixture stirred at room temperature for 16 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (100 mL) and the mixture extracted with EtOAc (100 mL×3). The combined organic layers were washed with water (200 mL), dried over sodium sulfate and concentrated in vacuo. The resulting material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 50:50) to provide (5-((diphenylmethylene)amino)pyridin-3-yl)(7-(2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)methanone.
Reaction SMILES: N1C=CC=CC=1[C:7]#[C:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:19][S:20]([O:11][CH2:10][CH2:9][C:8]#[CH:7])(=[O:22])=[O:21]
Reactant: OCCC#Cc1ccccn1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCOS(C)(=O)=O
Temperature: 4 °C
Reaction time: 8 h
Yield: 83 %

Procedure:
To a stirred solution of 4-(pyridin-2-yl)but-3-yn-1-ol (3.60 g, 24 mmol) in dry methylene chloride (30 mL) was added triethylamine (4.40 mL, 32 mmol). The mixture was cooled at 4° C. and methanesulfonyl chloride (2.50 mL, 32 mmol) was added and the reaction was stirred at room temperature overnight. The reaction mixture was then poured over ice/water (100 mL) and stirred for 5 min. To this mixture was added saturated aqueous sodium bicarbonate solution (50 mL) chilled to 4° C., and the mixture was stirred for 30 min, then extracted with DCM. The combined organic fractions were dried over MgSO4, filtered and concentrated under pressure to afford 4.60 g of 4-pyridin-2-yl)but-3-ynyl methanesulfonate (Yield: 83%) as a brown oil which can be used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([S:18]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)(=[O:20])=[O:19])=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].C1(P(C2C=CC=CC=2)C2C=CC=CN=2)C=CC=CC=1.O[CH:49]1[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]1.CC(OC(/N=N/C(OC(C)(C)C)=O)=O)(C)C>O1CCCC1>[CH2:21]([S:18]([C:13]1[N:12]=[C:11]2[N:10]([CH:49]3[CH2:54][CH2:53][N:52]([CH3:55])[CH2:51][CH2:50]3)[C:9](=[O:28])[N:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:17][C:16]2=[CH:15][N:14]=1)(=[O:20])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Reactant: CN1CCC(O)CC1
Agent: CC(C)(C)OC(=O)/N=N/C(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccn2)cc1
Solvent: C1CCOC1
Product: CN1CCC(N2C(=O)N(c3ccccc3Cl)Cc3cnc(S(=O)(=O)Cc4ccccc4)nc32)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.8 %

Procedure:
A mixture of sulfone 9.1 (1.0 g, 2.4 mmol), diphenyl-2-pyridylphosphine (1.9 g, 7.23 mmol) and 4-hydroxy-1-methylpiperidine (0.555 g, 4.8 mmol) was dissolved in anhydrous tetrahydrofuran under an atmosphere of nitrogen. To this solution was added di-tert-butylazodicarboxylate (1.67 g, 7.23 mmol) and the resulting mixture was stirred at room temperature for 2 hours, then concentrated in vacuo. The residue was purified by column chromatography on silica gel using 9:1 dichloromethane/methanol as eluant. The column fractions containing product were combined and concentrated in vacuo to give 354 mg of 7-benzylsulfonyl-3-(2-chlorophenyl)-1-(1-methylpiperidin-4-yl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH:11][CH:12]=[O:13])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([NH:10][NH:11][CH:12]=[O:13])=[CH:8][CH:9]=1
Reactant: O=CNNc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(NNC=O)cc1
Yield: 81.9 %

Procedure:
In 1,600 ml of ethanol, 30 g of 2-(4-nitrophenyl)-1-formylhydrazine was catalytically reduced at room temperature, using palladium-carbon as a catalyst. The reaction mixture was filtered and the filtrate was evaporated to dryness, whereby 20.5 g of white solid 2-(4-aminophenyl)-1-formylhydrazine was obtained. Melting point: 123° to 125° C.
Reaction SMILES: CO[C:3](=[O:27])[C:4]([C:6]1[C:14]2[C:9](=[C:10]([CH2:15][O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])[CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)=O.[C:28]1([CH2:40][C:41]([NH2:43])=[O:42])[C:38]2=[C:39]3[C:34](=[CH:35][CH:36]=[CH:37]2)[CH2:33][CH2:32][CH2:31][N:30]3[CH:29]=1>>[CH:24]([Si:17]([CH:18]([CH3:20])[CH3:19])([CH:21]([CH3:23])[CH3:22])[O:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:9]=1[NH:8][CH:7]=[C:6]2[C:4]1[C:3](=[O:27])[NH:43][C:41](=[O:42])[C:40]=1[C:28]1[C:38]2=[C:39]3[C:34](=[CH:35][CH:36]=[CH:37]2)[CH2:33][CH2:32][CH2:31][N:30]3[CH:29]=1)([CH3:26])[CH3:25]
Reactant: COC(=O)C(=O)c1c[nH]c2c(CO[Si](C(C)C)(C(C)C)C(C)C)cccc12
Reactant: NC(=O)Cc1cn2c3c(cccc13)CCC2
Product: CC(C)[Si](OCc1cccc2c(C3=C(c4cn5c6c(cccc46)CCC5)C(=O)NC3=O)c[nH]c12)(C(C)C)C(C)C

Procedure:
Beginning with 7-((triisopropylsilyloxy)methyl)indole-3-glyoxylic acid methyl ester and 2-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1-yl)acetamide, the title compound was prepared essentially as described in Example 1.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([N:6]1[CH2:12][CH2:11][C:10]2[N:13]=[C:14]([C:16]3[S:17][C:18]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=4[N:20]=3)[NH:15][C:9]=2[CH2:8][CH2:7]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OC(=O)C)C.O>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][N:6]1[CH2:7][CH2:8][C:9]2[N:15]=[C:14]([C:16]3[S:17][C:18]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[CH:23][CH:22]=[C:21]([O:31][CH3:32])[C:19]=4[N:20]=3)[NH:13][C:10]=2[CH2:11][CH2:12]1
Reactant: COCC(=O)N1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COCCN1CCc2nc(-c3nc4c(OC)ccc(N5CCOCC5)c4s3)[nH]c2CC1
Yield: 53.9 %

Procedure:
0.09 g 2-Methoxy-1-[2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4,5,7,8-tetrahydro-1H-imidazo[4,5-d]azepin-6-yl]-ethanone in 5 ml tetrahydrofurane were reacted with 0.2 ml lithiumaluminium hydride solution (1 M in tetrahydrofurane) over night at room temperature. 5 ml ethylacetate was added followed by 5 ml water at 0–5° C. Extraction with ethylacetate and chromatography on silicagel with dichloromethane/methanol 96:4 yielded 0.047 g (53%) 6-(2-methoxy-ethyl)-2-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-1,4,5,6,7,8-hexahydro-imidazo[4,5-d]azepine as yellow solid; MS (ISP): m/e=444 (M+H+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)=[C:6]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:3]=1.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>C(#N)C>[F:24][C:21]1[CH:22]=[CH:23][C:18]([C:6]2[C:7]([C:8]3[CH:9]=[C:10]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=3)=[C:2]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)[N:3]=[C:4]([C:25]([F:28])([F:27])[F:26])[N:5]=2)=[CH:19][CH:20]=1
Reactant: C1CNCCN1
Reactant: NS(=O)(=O)c1cccc(-c2c(Cl)nc(C(F)(F)F)nc2-c2ccc(F)cc2)c1
Solvent: CC#N
Product: NS(=O)(=O)c1cccc(-c2c(-c3ccc(F)cc3)nc(C(F)(F)F)nc2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The solution of 3-[4-chloro-6-(4-fluorophenyl)-2-(trifluoromethyl)pyrimidin-5-yl]benzenesulfonamide (0.1 g, 0.24 mmol, prepared according to the procedure described above in preparation 4, Step 2a), in acetonitrile (2 ml) was treated with piperazine (0.104 g, 1.203 mmol) and the reaction mixture was stirred overnight at room temperature. Subsequently the reaction mixture was poured into ice-cold water and was extracted with ethylacetate (25 ml). The organic layer was washed with water, brine solution and then evaporated to obtain the title compound. 1H-NMR (DMSO-d6) δ: 2.58 (s, 4H), 3.19 (s, 4H), 7.03-7.14 (m, 4H), 7.32 (d, 1H), 7.41 (brs, D2O exchangeable, 2H), 7.46-7.50 (t, 1H), 7.72 (s, 1H), 7.73 (d, 1H). MS m/z: 482.1 (M++1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][CH3:29])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:27]([C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1)[CH2:28][CH3:29]
Reactant: CCCc1ccc(OB([O-])[O-])cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.3 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (0.80 g), 4-propylphenyl borate (0.435 g) and potassium carbonate (0.67 g) in toluene/ethanol/water (25/2.5/2.5 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.14 g), and the mixture was refluxed for 18 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. Precipitated crystals were collected by filtration and the crystals were washed with ethyl acetate, diisopropylether and hexane to give colorless crystals of methyl 7-(4-propylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (557.2 mg).
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:29])[CH2:27][F:28])([C@@:6]1([CH3:30])[CH2:5][C@@H:4]2[OH:31])[CH2:24][NH:23][CH2:22]3.[F:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:29])[CH2:27][F:28])([C@@:6]1([CH3:30])[CH2:5][C@@H:4]2[OH:31])[CH2:24][N:23]([CH2:37][C:36]1[CH:39]=[CH:40][C:33]([F:32])=[CH:34][CH:35]=1)[CH2:22]3
Reactant: Fc1ccc(CBr)cc1
Reactant: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CNC[C@@]4(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3C[C@H]4CN(Cc5ccc(F)cc5)C[C@@]4(C(=O)CF)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.2 %

Procedure:
A mixture of compound 166 (145 mg, 0.315 mmol), 4-fluorobenzylbromide (0.059 ml, 0.473 mmol) and TEA (0.132 ml, 0.946 mmol) in DCM (10 ml) is stirred at RT overnight. The mixture is diluted with DCM and treated with 5% NaHCO3. The organic phase is then washed with brine, dried over Na2SO4 and filtered. The solvent is evaporated and the crude is purified by silica gel flash chromatography (eluent DCM(AcOEt 7/3 to 1/1) to yield a solid that is triturated in Et2O. Title compound (54 mg, 32.2% yield) is recovered by filtration.
Reaction SMILES: [CH3:1][CH:2]([CH3:29])[CH2:3][CH2:4][NH:5][C@@H:6]1[CH2:23][C@@:21]2([CH3:22])[C@@H:17]([CH2:18][CH2:19][C@@H:20]2[C:24]([O:26][CH3:27])=[O:25])[C@H:16]2[C@H:7]1[C@:8]1([CH3:28])[C@@H:13]([CH2:14][CH2:15]2)[CH2:12][CH:11]=[CH:10][CH2:9]1.BrCC(N)=[O:33].Cl(O)(=O)(=O)=O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>O1CCCC1.O.Cl.CO>[O:33]1[C@@H:11]2[CH2:12][C@H:13]3[C@:8]([CH3:28])([CH2:9][C@H:10]12)[C@@H:7]1[C@H:16]([C@H:17]2[C@@:21]([CH2:23][C@H:6]1[NH:5][CH2:4][CH2:3][CH:2]([CH3:29])[CH3:1])([CH3:22])[C@@H:20]([C:24]([O:26][CH3:27])=[O:25])[CH2:19][CH2:18]2)[CH2:15][CH2:14]3
Reactant: NC(=O)CBr
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC=CC[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Agent: Cl
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H]5O[C@H]5C[C@]4(C)[C@H]3[C@H](NCCC(C)C)C[C@]12C
Reaction time: 0.5 h
Yield: 44.1 %

Procedure:
Methyl 11α-(3-methylbutylamino)-5α-androst-2-ene-17β-carboxylate (403 mg) in tetrahydrofuran (15 ml), water (7 ml) and 2M hydrochloric acid (0.5 ml) was treated with N bromoacetamide (193 mg) and 60% perchloric acid (0.15 ml) and stirred for 30 min. 5% sodium metabisulphite (30 ml) was added and the resulting solution diluted with water and brought to pH 11 with 2M sodium hydroxide solution. This was extracted with ether and the ether extracts were washed with water, dried and evaporated to give an oil. This was dissolved in methanol (50 ml), treated with 2M sodium hydroxide (10 ml) and stirred for 30 min. The solution was concentrated by evaporation, diluted with water (100 ml) and extracted with ethyl acetate (3×). The extracts were washed with water, dried and evaporated to give an oil. This was purified by preparative t.l.c. in ethyl acetate to give the title compound (185 mg), [α]D +33.6°.
Reaction SMILES: [CH2:1]([C:3]1[NH:13][C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2].[OH-].[Li+].[I-].[CH:17]1[C:27]2[CH2:26][CH2:25][C:24]3[CH:28]=[CH:29][CH:30]=[CH:31][C:23]=3[NH:22][C:21]=2[CH:20]=[CH:19][C:18]=1[CH2:32][N+]1(C)CCCCC1.O>CN(C=O)C>[CH2:1]([C:3]1[N:13]([CH2:32][C:18]2[CH:19]=[CH:20][C:21]3[NH:22][C:23]4[CH:31]=[CH:30][CH:29]=[CH:28][C:24]=4[CH2:25][CH2:26][C:27]=3[CH:17]=2)[C:6]2=[N:7][C:8]([CH3:12])=[CH:9][C:10]([CH3:11])=[C:5]2[N:4]=1)[CH3:2]
Reactant: CCc1nc2c(C)cc(C)nc2[nH]1
Reactant: C[N+]1(Cc2ccc3c(c2)CCc2ccccc2N3)CCCCC1
Agent: [I-]
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CCc1nc2c(C)cc(C)nc2n1Cc1ccc2c(c1)CCc1ccccc1N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 46 %

Procedure:
[step 1] 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 36.55 g, 209 mmol) was dissolved in DMF (365.5 mL), and the solution was added with lithium hydroxide (5.62 g, 235 mmol), followed by stirring at room temperature for 15 min. 1-(10,11-Dihydro-5H-dibenzo[b,f]azepin-2-ylmethyl)-1-methylpiperidinium iodide (JP-A-7-61983; 95.0 g, 219 mmol) and DMF (73.1 mL) were added thereto, and the mixture was stirred at 40° C. for 8 hr. After cooling to room temperature, water (175.4 mL) was added dropwise, and the mixture was stirred under ice-cooling for 2 hr. The precipitate was collected by filtration, and dissolved in chloroform (520 mL) with heating. Activated carbon (5.2 g) was added, and the mixture was stirred for 30 min with heating, and the hot solution was filtered. Ethyl acetate (1041 mL) was added to the filtrate, and the precipitate was collected by filtration to give 2-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-10,11-dihydro-5H-dibenzo[b,f]azepine (36.7 g, 46%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])#[N:2].Cl.C(O)(=[O:21])C>>[C:1]([C:3]1[CH:4]=[C:5]2[N:11]([CH:12]=1)[CH2:10][CH2:9][C:8]1[CH:13]=[CH:14][CH:15]=[CH:16][C:7]=1[C:6]2=[O:17])(=[O:21])[NH2:2]
Reactant: N#Cc1cc2n(c1)CCc1ccccc1C2=O
Reactant: CC(=O)O
Agent: Cl
Product: NC(=O)c1cc2n(c1)CCc1ccccc1C2=O
Temperature: 25 °C
Yield: 83 %

Procedure:
2-Cyano-6,11-dihydro-5H-pyrrolo[2,1-b][3]benzazepin-11-one (30 g., 0.135 mole) in 100 ml. of concentrated hydrochloric acid and 100 ml. of acetic acid was refluxed for 2 hours. It was then poured onto 500 ml. of water and continuously extracted with methylene chloride. The solution, from which crystals deposited during the extraction, was left to cool to room temperature and filtered to afford 2-carbamoyl-6,11-dihydro-11-oxo-5H-pyrrolo[2,1-b][3]benzazepine (27 g. 83%), m.p. 228° C.
Reaction SMILES: [C:1](=[N:14][NH:15]C1C=CC(S(NCCN2CCOCC2)(=O)=O)=C(C)C=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:36]1[CH:37]=[C:38]([S:42]([NH:45][CH2:46][CH2:47][O:48][CH3:49])(=[O:44])=[O:43])[CH:39]=[CH:40][CH:41]=1>>[C:1](=[N:14][NH:15][C:36]1[CH:37]=[C:38]([S:42]([NH:45][CH2:46][CH2:47][O:48][CH3:49])(=[O:43])=[O:44])[CH:39]=[CH:40][CH:41]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(NN=C(c2ccccc2)c2ccccc2)ccc1S(=O)(=O)NCCN1CCOCC1
Reactant: COCCNS(=O)(=O)c1cccc(Br)c1
Product: COCCNS(=O)(=O)c1cccc(NN=C(c2ccccc2)c2ccccc2)c1

Procedure:
The compound was prepared in the same manner as described for 4-(N′-benzhydrylidenehydrazino)-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide, replacing 4-bromo-2-methyl-N-(2-morpholin-4-yl-ethyl)benzene sulfonamide with 3-bromo-N-(2-methoxyethyl)benzene sulfonamide. 1H-NMR (DMSO-d6) δ 9.32 (s, 1H), 7.67 (t, J=2.1 Hz, 1H), 7.63 to 7.48 (m, 4H), 7.46 to 7.41 (m, 3H), 7.39 to 7.26 (m, 6H), 7.15 to 7.12 (m, 1H), 3.29 (t, 5.7 Hz, 2H), 3.15 (s, 3H), 2.87 (q, J=5.7 Hz, 2H); MS LC-MS [M+H]+=410, RT=3.50 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].[Cl:23][C:24]1[CH:28]=[CH:27][S:26][C:25]=1[C:29]1[O:34]C(C)(C)[O:32][C:31](=O)[CH:30]=1>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[CH3:20])=[CH:10][C:9]=1[NH:21][C:31](=[O:32])[CH2:30][C:29]([C:25]1[S:26][CH:27]=[CH:28][C:24]=1[Cl:23])=[O:34])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC1(C)OC(=O)C=C(c2sccc2Cl)O1
Reactant: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(N)c1
Product: Cc1ccccc1-c1ccc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2sccc2Cl)c1

Procedure:
Prepared from (3-amino-2′-methyl-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G23) and 6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2) according to the general procedure K. Obtained as a viscous brown oil (154 mg).
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH3:13])=[O:4].[CH3:22][C:23]1[CH:24]=[C:25]([N:29]=[C:30]=[O:31])[CH:26]=[CH:27][CH:28]=1>>[CH3:13][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[N:5]([CH2:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:3](=[O:4])[CH2:2][NH:1][C:30]([NH:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:23]([CH3:22])[CH:24]=1)=[O:31]
Reactant: Cc1cccc(N=C=O)c1
Reactant: COc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CN
Product: COc1ccccc1N(CC(=O)OC(C)(C)C)C(=O)CNC(=O)Nc1cccc(C)c1
Yield: 49.2 %

Procedure:
Using a procedure similar to that described in Example 11, but starting with tert-butyl 2-[2-amino-N-(2-methoxyphenyl)acetamido]acetate (4.2 g) and 3-methylphenyl isocyanate (1.9 g), and after recrystallisation in ethyl acetate, tert-butyl 2-{N-(2-methoxyphenyl)-2-[3-(3-methylphenyl)ureido]acetamido}acetate (3 g), m.p. 171° C., is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([CH3:11])=[CH:6][C:5]=1[OH:12])([O-:3])=[O:2].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+].[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33]OS(C)(=O)=O)=[C:29]([CH3:39])[CH:28]=1>O>[CH3:24][O:25][C:26](=[O:40])[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][O:12][C:5]2[CH:6]=[C:7]([CH3:11])[C:8]([CH3:10])=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])=[C:29]([CH3:39])[CH:28]=1
Reactant: COC(=O)c1ccc(COS(C)(=O)=O)c(C)c1
Reactant: Cc1cc(O)c([N+](=O)[O-])cc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(COc2cc(C)c(C)cc2[N+](=O)[O-])c(C)c1
Temperature: 60 °C
Reaction time: 0.25 h
Yield: 91.6 %

Procedure:
Under atmosphere of argon, a mixture of 2-nitro-4,5-dimethylphenol (4 g), DMF (100 ml), potassium carbonate (6.6 g) and 4-mesyloxymethyl-3-methylbenzoic acid methyl ester (6.8 g) were stirred for 15 minutes at 60° C. After the termination of reaction, the mixture was cooled and poured into iced water. The mixture was extracted with ethyl acetate-hexane. The organic layer was washed, dried, concentrated under reduced pressure to give the title compound (7.22 g) having the following physical data.