Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=O)[CH:3]=[CH:2]1.[NH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=1.CO>CC(N(C)C)=O>[C:4]1(=[O:6])[N:8]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)[C:1](=[O:7])[CH:2]=[CH:3]1
Reactant: O=C1C=CC(=O)O1
Reactant: CC(=O)c1ccc(N)cc1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: CC(=O)c1ccc(N2C(=O)C=CC2=O)cc1
Yield: 65 %

Procedure:
In dimethylacetamide, 98 g of maleic anhydride was reacted with 135 g of p-aminoacetophenone at 140° C. for 4 hours. After the reaction, methyl alcohol was added to the reaction solution to precipitate a solid. The precipitate was recovered by filtration and dried in vacuo to obtain 139 g (a yield of 65%) of p-maleimidoacetophenone.
Reaction SMILES: I.I[C:3]1[N:8]=[CH:7][N:6]=[C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[C:12]([CH3:24])[CH:11]=2)[C:4]=1[NH2:25].[CH2:26]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[C:27]#[CH:28]>C(#N)C.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[NH2:25][C:4]1[C:3]([C:28]#[C:27][CH2:26][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:8][CH:7]=[N:6][C:5]=1[NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:12]([CH3:24])[CH:11]=1
Reactant: C#CCNC(=O)OC(C)(C)C
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc(I)c3N)cc2C)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1ccc(Oc2ccc(Nc3ncnc(C#CCNC(=O)OC(C)(C)C)c3N)cc2C)cn1
Yield: 73.8 %

Procedure:
6-Iodo-N4-{3-methyl-4-[(6-methylpyridin-3-yl)oxy]phenyl}pyrimidine-4,5-diamine hydroiodide (500 mg) was dissolved in a mixed solvent of acetonitrile (14.8 mL)/triethylamine (11.0 mL), and tert-butyl 2-propynylcarbamate (166 mg), trans-dichlorobis(triphenylphosphine)palladium(II) (31.3 mg) and copper(I) iodide (10.2 mg) were sequentially added. The title compound (303 mg) was obtained as a powder by the reaction in the same manner as in Example 9 (iv).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][C@H:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[F:13][C:8]1[CH:7]=[C:6]2[C:11]([CH2:12][C:4]3[CH:3]=[CH:2][N:16]([CH2:17][C@H:18]([OH:20])[CH3:19])[C:5]=32)=[CH:10][CH:9]=1
Reactant: O=CCC1Cc2ccc(F)cc2C1=O
Reactant: C[C@@H](O)CN
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@@H](O)Cn1ccc2c1-c1cc(F)ccc1C2
Reaction time: 0.5 h
Yield: 74.9 %

Procedure:
A solution of 1.92 g of (RS)-2-(2-oxo-ethyl)-6-fluoro-1-indanone and 80 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 3.0 g of (R)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 30 minutes, during which the solvent was reduced to a volume of 20 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). 1.73 g (75%) of (R)-1-(7-fluoro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol were obtained as a brown oil which was used without further purification in the next reaction.
Reaction SMILES: [C:1](Cl)(=[O:5])[O:2][CH2:3][CH3:4].[CH2:7]([S:11][CH:12]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[C:13]([Cl:16])([Cl:15])[Cl:14])[CH2:8][CH2:9][CH3:10].CC(C)=O>C(N(CC)CC)C>[CH2:7]([S:11][CH:12]([NH:17][C:18](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][C:1]([O:2][CH2:3][CH3:4])=[O:5])[C:13]([Cl:15])([Cl:16])[Cl:14])[CH2:8][CH2:9][CH3:10]
Reactant: CCOC(=O)Cl
Reactant: CCCCSC(NC(=O)c1ccccc1O)C(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCSC(NC(=O)c1ccccc1OC(=O)OCC)C(Cl)(Cl)Cl
Yield: 78.3 %

Procedure:
13 g of ethyl chlorocarbonate was added to the mixture of 3.4 g of N-(1-n-butylthio-2,2,2-trichloroethyl)-2-hydroxybenzamide and 50 ml of acetone under stirring, and 1.0 g of triethylamine was added dropwise thereto at 0°-5° C. After effecting the reaction at room temperature for one hour, the solvent was distilled off under reduced pressure, 50 ml of water was added thereto and the solution was extracted with ethyl acetate. After washing the extract with water and drying, the solvent was distilled off to obtain 3.2 g of N-(1-n-butylthio-2,2,2-trichloroethyl)-2-ethoxycarbonyloxybenzamide as a brown oily substance. nD25 1.5350
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:3]=1[CH2:4][O:5][C:6]1[N:11]2[N:12]=[C:13]([CH3:18])[C:14]([C:15](O)=[O:16])=[C:10]2[CH:9]=[C:8]([O:19][CH3:20])[CH:7]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:57][CH2:58][C:59]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])([CH3:63])[CH2:60][CH2:61][CH3:62]>O1CCCC1>[C:67]([O:66][C:65](=[O:71])[NH:64][C:59]([CH3:63])([CH2:60][CH2:61][CH3:62])[CH2:58][NH:57][C:15]([C:14]1[C:13]([CH3:18])=[N:12][N:11]2[C:6]([O:5][CH2:4][C:3]3[C:21]([F:25])=[CH:22][CH:23]=[CH:24][C:2]=3[F:1])=[CH:7][C:8]([O:19][CH3:20])=[CH:9][C:10]=12)=[O:16])([CH3:70])([CH3:69])[CH3:68]
Reactant: CCCC(C)(CN)NC(=O)OC(C)(C)C
Reactant: COc1cc(OCc2c(F)cccc2F)n2nc(C)c(C(=O)O)c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCC(C)(CNC(=O)c1c(C)nn2c(OCc3c(F)cccc3F)cc(OC)cc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 44 %

Procedure:
A solution of 170 mg (0.366 mmol, 75% purity) of 7-[(2,6-difluorobenzyl)oxy]-5-methoxy-2-methylpyrazolo[1,5-a]pyridine-3-carboxylic acid (Example 163A) in 8 ml of tetrahydrofuran was admixed with 84 mg (0.44 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (CAS: 25952-53-8) and 60 mg (0.44 mmol) of 1-hydroxy-7-azabenzotriazole (CAS: 39968-33-7). The solution was stirred at room temperature for 20 minutes. The reaction mixture was admixed with 0.191 ml (1.01 mmol) of N,N-diisopropylethylamine and 158 mg (0.732 mmol) of rac-(1-amino-2-methylpentan-2-yl)carbamic acid tert-butyl ester (Example 152A). The mixture was stirred at room temperature for a further 18 hours, and the reaction mixture was then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water. The organic phase was removed, extracted with a saturated aqueous sodium hydrogencarbonate solution, water and aqueous sodium chloride solution, dried over sodium sulphate, filtered and concentrated under reduced pressure. The remaining residue was purified by flash chromatography using a prepacked silica gel cartridge (eluent:dichloromethane/methanol, gradient 0% to 10%), which gave 120 mg (44% yield, 73% purity) of product.
Reaction SMILES: [CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22](=O)[CH3:23])=[CH:18][CH:17]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.Cl.[NH2:26][OH:27]>>[CH3:1][O:2][C:3]1([C:9]2[S:13][C:12]([O:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19](/[C:22](=[N:26]/[OH:27])/[CH3:23])=[CH:18][CH:17]=3)=[N:11][CH:10]=2)[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1
Reactant: NO
Reactant: COC1(c2cnc(OCc3ccc(C(C)=O)cc3)s2)CCOCC1
Agent: Cl
Product: COC1(c2cnc(OCc3ccc(/C(C)=N/O)cc3)s2)CCOCC1
Yield: 57 %

Procedure:
Using an analogous procedure to that described in Example 15, 4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-yloxymethyl]acetophenone was reacted with hydroxylamine hydrochloride to give (E)-4'-[5-(4-methoxytetrahydropyran-4-yl)thiazol-2-yloxymethyl]acetophenone oxime in 57% yield, m.p. 107°-109° C.;
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][N:9]([CH2:12][CH2:13][CH2:14]N3C4C(=CC=CC=4)CC3=O)[CH2:8][CH2:7]2)[N:5]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:4][N:3]1[C@H:31]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:32]([O:34]C(C)(C)C)=[O:33].[O:45]1[CH2:50][CH2:49]OCC1>Cl>[O:1]=[C:2]1[C:6]2([CH2:7][CH2:8][N:9]([CH2:12][CH2:13][CH2:14][C:50](=[O:45])[C:49]3[CH:10]=[CH:11][CH:6]=[CH:7][CH:8]=3)[CH2:10][CH2:11]2)[N:5]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH2:4][N:3]1[C@@H:31]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:32]([OH:34])=[O:33]
Reactant: C1COCCO1
Reactant: CC(C)(C)OC(=O)[C@@H](c1ccccc1)N1CN(c2ccccc2)C2(CCN(CCCN3C(=O)Cc4ccccc43)CC2)C1=O
Agent: Cl
Product: O=C(CCCN1CCC2(CC1)C(=O)N([C@H](C(=O)O)c1ccccc1)CN2c1ccccc1)c1ccccc1
Yield: 28 %

Procedure:
A solution of (R)-tert-butyl 2-(4-oxo-8-(3-(2-oxoindolin-1-yl)propyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)-2-phenylacetate (257 mg, 0.453 mmol, 1 equiv) in 4M hydrogen chloride solution in dioxane was stirred at ambient temperature for 5 h. The mixture was concentrated in vacuo and purified using preparative thin layer chromatography in 10% methanol in dichloromethane. The pure extract was treated with 4M hydrogen chloride solution in dioxane to afford the hydrogen chloride salt of the title compound as a cream powder (100 mg, 28%); 1H NMR (400 MHz, DMSO-d6): δ 1.88 (m, 2H); 2.05-2.09 (m, 2H); 2.85 (m, 2H); 3.15-3.24 (m, 2H); 3.56-3.59 (m, 4H); 4.19 (d, 1H, J=4.4 Hz); 4.89 (d, 1H, J=4.8 Hz); 5.81 (s, 1H); 6.84 (m, 1H); 6.99 (d, 2H, J=8.4 Hz); 7.23 (t, 2H, J=7.6 and 8.4 Hz); 7.45-7.47 (m, 5H); 7.55 (t, 2H, J=7.6 and 8 Hz); 7.64-7.68 (m, 1H); 7.98-8.01 (m, 2H); 10.4 (bs, 1H); 13.5 (bs, 1H); MS for C31H33N3O4 m/z 512.4 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11](=O)[C:10](=[CH:13]N(C)C)[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1.[N+]([O-])(O)=O.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:33][C:34]([NH2:36])=[NH:35])[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:11]3[N:35]=[C:34]([NH:33][C:27]4[CH:28]=[C:29]([O:31][CH3:32])[CH:30]=[C:25]([O:24][CH3:23])[CH:26]=4)[N:36]=[CH:13][C:10]=3[CH2:9][C:8](=[O:17])[NH:7][C:6]=2[CH:18]=1
Reactant: CN(C)C=C1CC(=O)Nc2cc(Cl)ccc2C1=O
Reactant: COc1cc(NC(=N)N)cc(OC)c1
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)cc(OC)c1

Procedure:
In a manner similar to that described for method I, 8-chloro-4-dimethylaminomethylene-3,4-dihydro-1H-benzo[b]azepine-2,5-dione (v-j) and N-(3,5-dimethoxy-phenyl)-guanidine nitrate were converted to I-55 (62%): HRMS Calcd. for C20H17ClN4O3: 397.1067, Found 397.1056.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:13])[C:9]([F:12])([F:11])[F:10])=[CH:4][CH:3]=1.[C:14]1([CH3:23])[CH:19]=[CH:18][CH:17]=[C:16](B(O)O)[CH:15]=1.C([O-])([O-])=O.[K+].[K+].CCO>[Pd].O>[F:10][C:9]([F:12])([F:11])[CH:8]([C:5]1[CH:6]=[CH:7][CH:2]=[CH:3][C:4]=1[C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH3:23])[CH:15]=1)[OH:13]
Reactant: Cc1cccc(B(O)O)c1
Reactant: OC(c1ccc(Br)cc1)C(F)(F)F
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cccc(-c2ccccc2C(O)C(F)(F)F)c1
Temperature: 80 °C
Yield: 71.5 %

Procedure:
1-(4-Bromophenyl)-2,2,2-trifluoroethanol (0.13 g, 0.525 mmol), m-tolylboronic acid (0.1 g, 0.736 mmol), Fibercat (4.28% Pd, 47 mgs, 0.0157 mmol Pd), K2CO3 (0.22 g, 1.576 mmol), EtOH (3 mls), and H2O (0.5 mls) were combined and heated at 80° C. for 4 hours. The reaction was shown complete by TLC(CH2Cl2). The mixture was cooled, filtered, concentrated, slurried in CH2Cl2, and chromatographed over silica gel (CH2Cl2) to give 0.1 g of 2,2,2-trifluoro-1-(3′-methylbiphenyl-2-yl)ethanol. Yield: 72%.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH2:11][CH2:12][CH2:13][C:3]=12.[CH3:14][C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][NH:17][CH2:16]1.C(N(CC)CC)C>C(O)(C)C>[CH3:14][C:15]1([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][N:17]([C:2]2[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]3[CH2:11][CH2:12][CH2:13][C:3]=23)[CH2:16]1
Reactant: O=[N+]([O-])c1cnc2c(c1Cl)CCC2
Reactant: CC1(NC(=O)OC(C)(C)C)CCCNC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CC1(NC(=O)OC(C)(C)C)CCCN(c2c([N+](=O)[O-])cnc3c2CCC3)C1
Temperature: 100 °C
Reaction time: 0.33 h

Procedure:
A mixture of 4-chloro-3-nitro-6,7-dihydro-5H-cyclopenta[b]pyridine (200 mg, 1.01 mmol), tert-butyl (3-methylpiperidin-3-yl)carbamate (227 mg, 1.06 mmol) and triethylamine (281 μL, 2.01 mmol) in isopropyl alcohol (1.2 mL) was stirred at 100° C. for 20 min. After cooling, the sub-title compound precipitated out and was collected by vacuum filtration, followed by washing with cold ether to give the sub-title compound as light yellow powder. LCMS calc. for C19H29N4O4 (M+H)+: m/z=377.2. Found: 377.2.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH2:12][CH2:13]OS(C)(=O)=O)[CH2:8]1)=[O:6].I.[CH2:32]([O:34][CH2:35][CH2:36][N:37]1[C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=2[N:39]=[C:38]1[N:46]1[CH2:52][CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)[CH3:33]>ClCCl.CO>[CH3:1][O:2][C:3]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][C:4]=1[C:5]([N:7]1[CH2:11][CH2:10][C:9]([CH2:12][CH2:13][N:49]2[CH2:50][CH2:51][CH2:52][N:46]([C:38]3[N:37]([CH2:36][CH2:35][O:34][CH2:32][CH3:33])[C:41]4[CH:42]=[CH:43][CH:44]=[CH:45][C:40]=4[N:39]=3)[CH2:47][CH2:48]2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8]1)=[O:6]
Reactant: COc1ccc(OC)c(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)c1
Reactant: CCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: CO
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(OC)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 102.1.2 using 1-(2,5-dimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) (0.55 g, 1.27 mmol) and 4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt (0.71 g, 1.3 mmol) to give, after chromatography on silica gel eluting with dichloromethane/methanol/concentrated aqueous ammonia 95/5/0.05, the title compound: Rf=0.85 (silica gel, dichloromethane/methanol/concentrated aqueous ammonia 90/10/0.1).
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH3:9][C:8]1([CH2:7][O:6][C:5]2[CH:11]=[CH:12][C:2]([OH:1])=[CH:3][CH:4]=2)[O:15][CH2:14][CH2:13][O:10]1
Reactant: CC(=O)COc1ccc(O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(COc2ccc(O)cc2)OCCO1

Procedure:
A solution of 1-(4-hydroxyphenoxy)propan-2-one (3.2 g), 1,2-ethanediol (3.0 ml) and p-toluenesulphonic acid (50 mg) in toluene (100 ml) was stirred under reflux in a Dean and Stark apparatus for 3 1/2 hours in an atmosphere of argon. The reaction mixture was cooled, washed with 5% aqueous sodium bicarbonate (100 ml), washed with water (2×50 ml), washed with brine (50 ml) and dried. Toluene was removed under reduced pressure to give 4-[(2-methyl-1,3-dioxolan-2-yl)methoxy]phenol as an oil (3.4 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:14][C:15]1[C:16](=[O:22])[NH:17][N:18]=[CH:19][C:20]=1Cl.C([O-])([O-])=O.[K+].[K+].CCOCC>CN(C=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:19]=[N:18][NH:17][C:16](=[O:22])[C:15]=2[Cl:14])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=c1[nH]ncc(Cl)c1Cl
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=c1[nH]ncc(N2CCN(Cc3ccccc3)CC2)c1Cl
Temperature: 110 °C

Procedure:
A mixture of 7 g of 1-benzylpiperazine, 6.55 g of 4,5-dichloro-3(2H)-pyridazinone and 11 g of K2CO3 in 150 ml of DMF is heated at 110° C. for 4 hours and then concentrated under vacuum. The residue is chromatographed on silica gel, eluting with a DCM/MeOH (95/5; v/v) mixture. The product obtained is taken up in iso ether and triturated and the precipitate formed is isolated with suction. This gives 7 g of the expected product, which is recrystallized from iso ether; m.p.=173-175° C.
Reaction SMILES: [CH2:1]([CH:19]([N:38]=[N+:39]=[N-:40])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11]/[CH:12]=[CH:13]\[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:41][N:42]([CH3:46])[CH2:43][C:44]#[CH:45].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>O.C(O)(C)(C)C>[CH3:18][CH2:17][CH2:16][CH2:15][CH2:14]/[CH:13]=[CH:12]\[CH2:11]/[CH:10]=[CH:9]\[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][CH:19]([N:38]1[CH:45]=[C:44]([CH2:43][N:42]([CH3:46])[CH3:41])[N:40]=[N:39]1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]/[CH:28]=[CH:29]\[CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: C#CCN(C)C
Reactant: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)N=[N+]=[N-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: CCCCC/C=C\C/C=C\CCCCCCCCC(CCCCCCCC/C=C\C/C=C\CCCCC)n1cc(CN(C)C)nn1
Reaction time: 96 h
Yield: 91.4 %

Procedure:
A solution of dilinoleyl methyl azide (500 mg, 0.90 mmol) and 3-dimethylamino-1-propyne (75 mg, 0.90 mmol) in H2O and tert-butyl alcohol (1:1, 12 mL) was treated with sodium ascorbate (0.090 mmol, 17.94 taken from a 1M solution in water), followed by CuSO4.5H2O (2.3 mg, dissolved in 30 μL of water) and stirred (96 h). The solution was then diluted with H2O (50 mL) and extracted with CH2Cl2 (3×), dried (Na2SO4), filtered, concentrated and purified via column chromatography (2%→4% MeOH/CH2Cl2) to yield the title compound as a colorless oil (524 mg, 91%). 1H NMR (400 MHz, CDCl3, δH) 7.76 (br. s, 1H), 5.47-5.25 (m, 8H), 4.48 (p, 1H), 3.80 (br. s, 2H), 2.75 (app. t, 4H), 2.49 (s, 6H), 2.15-2.00 (m, 8H), 1.91-1.75 (m, 4H), 1.40-1.12 (m, 34H), 1.11-0.98 (m, 2H), 0.85 (t, 6H). FW 637.08, C42H76N4.
Reaction SMILES: [B-]C#N.[Na+].[CH3:5][C:6]1([CH3:19])[C:15]2[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=2)[CH2:9][NH:8][CH2:7]1.C(O)(=O)C.[CH:24]1([CH:30]=O)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(=O)(O)[O-].[Na+]>CO>[CH:24]1([CH2:30][N:8]2[CH2:7][C:6]([CH3:19])([CH3:5])[C:15]3[C:10](=[CH:11][C:12]([N+:16]([O-:18])=[O:17])=[CH:13][CH:14]=3)[CH2:9]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CC1(C)CNCc2cc([N+](=O)[O-])ccc21
Reactant: O=CC1CCCCC1
Agent: O=C([O-])O
Agent: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CC1(C)CN(CC2CCCCC2)Cc2cc([N+](=O)[O-])ccc21
Temperature: 35 °C
Reaction time: 16 h

Procedure:
Sodium cyanotrihydroborate (0.600 g, 9.55 mmol) was added to a solution of 4,4-dimethyl-7-nitro-1,2,3,4-tetrahydroisoquinoline (0.600 g, 2.91 mmol), acetic acid (0.210 mL, 3.66 mmol) and cyclohexanecarbaldehyde (0.4 g, 3.57 mmol) in methanol (40 mL). The reaction mixture was stirred at 35° C. for 16 hours. The reaction was neutralized with saturated sodium bicarbonate solution, and the mixture was concentrated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. The crude product was purified with silica gel column chromatography (3% ethyl acetate/petroleum ether) to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:13]([O-])=O)[C:5]1=[O:16])[CH3:3].O>CC(O)=O.[Fe]>[NH2:13][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH2:12][N:4]([CH:2]([CH3:3])[CH3:1])[C:5]2=[O:16]
Reactant: CC(C)N1Cc2c(cccc2[N+](=O)[O-])C1=O
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)N1Cc2c(N)cccc2C1=O
Reaction time: 2 h
Yield: 86 %

Procedure:
A stirred mixture of 5.0 grams (0.022 mole) of 2-(1-methylethyl)-4-nitroisoindolin-1-one and 10 mL of water in 100 mL of HOAc was warmed to 50 C., and 5.0 grams of iron dust was slowly added. Upon completion of addition, the reaction mixture was stirred at 25 C. for about two hours, then it was filtered through diatomaceous earth. The filtrate was diluted with water and extracted with EtOAc. The organic layer was separated and dried with magnesium sulfate. The mixture was filtered, and the filtrate was concentrated under reduced pressure to a residue. The residue was purified by column chromatography on silica gel using mixtures of EtOAc and methylene chloride as eluants. The fractions containing product were combined and concentrated under reduced pressure, yielding 3.6 grams of subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:26])[CH3:25]>>[C:24]([C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH3:19])[C:11]1[N:20]([CH3:23])[C:21](=[O:22])[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:9][C:10]2=1)(=[O:26])[CH3:25]
Reactant: CC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Product: CC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as in preparation 1.9B above, using 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one from Example 63A above and acetyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[CH:10]([CH3:12])[CH3:11])=[CH:4][CH:3]=1.C([Li])CCC.[B:24](OC(C)C)([O:29]C(C)C)[O:25]C(C)C>C1COCC1>[CH:10]([Si:9]([CH:16]([CH3:18])[CH3:17])([CH:13]([CH3:15])[CH3:14])[O:8][C:5]1[CH:6]=[CH:7][C:2]([B:24]([OH:29])[OH:25])=[CH:3][CH:4]=1)([CH3:12])[CH3:11]
Reactant: CC(C)[Si](Oc1ccc(Br)cc1)(C(C)C)C(C)C
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)[Si](Oc1ccc(B(O)O)cc1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
To a stirring solution of 4-(triisopropyl)silyloxy-1-bromobenzene (6) (540 mg, 1.64 mmol) in THF (15 ml) at −78° C. was added n-butyl lithium (0.9 ml, 2.18 M in hexanes, 1.96 mmol) dropwise. The reaction mixture was stirred for 30 minutes then triisopropyl borate (0.5 ml, 2.17 mmol) was added in one portion. The reaction was stirred at −78° C. for 1 hour, allowed to warm to ambient temperature over 4 hours, quenched with 3 N HCl (5 ml) and stirred for 30 minutes at 0° C. The aqueous layer was extracted with ethyl acetate (3×) and the combined organic layers were dried over MgSO4. Purification by flash SiO2 chromatography (loaded with DCM, eluted with hexanes/ethyl acetate (10:1) to (3:1) to (1:1)) gave 7 as a white solid (328 mg, 68% yield): 1H-NMR (400 MHz, chloroform-d) δ 8.10 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 1.30 (septet, J=7.6 Hz, 3H), 1.13 (d, J=7.6 Hz, 18H); 13C-NMR (100 MHz, chloroform-d) δ 160.1, 137.4, 119.6, 17.9, 12.7.
Reaction SMILES: [C:1]([C:3]1[CH2:20][CH2:19][C@@:18]2([CH3:21])[C:5](=[CH:6][CH2:7][C@@H:8]3[C@@H:17]2[CH2:16][CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:22](=[O:30])SC2C=CC=CN=2)[CH:4]=1)#[N:2].[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH2:41])([CH3:40])[CH3:39])=[CH:34][CH:33]=1>>[CH3:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([NH:41][C:22]([C@H:12]2[CH2:11][CH2:10][C@H:9]3[C@H:8]4[C@H:17]([CH2:16][CH2:15][C@:13]23[CH3:14])[C@:18]2([CH3:21])[C:5]([CH:4]=[C:3]([C:1]#[N:2])[CH2:20][CH2:19]2)=[CH:6][CH2:7]4)=[O:30])([CH3:39])[CH3:40])=[CH:34][CH:33]=1
Reactant: Cc1ccc(C(C)(C)N)cc1
Reactant: C[C@]12CC[C@H]3[C@@H](CC=C4C=C(C#N)CC[C@@]43C)[C@@H]1CC[C@@H]2C(=O)Sc1ccccn1
Product: Cc1ccc(C(C)(C)NC(=O)[C@H]2CC[C@H]3[C@@H]4CC=C5C=C(C#N)CC[C@]5(C)[C@H]4CC[C@]23C)cc1
Yield: 88 %

Procedure:
Following a procedure similar to that described in Example 3(b), but using S-2-pyridyl 3-cyanoandrosta-3,5-diene-17β-thiocarboxylate [prepared as described in Example 3(a)] and 1-(4-methylphenyl)-1-methylethylamine (prepared as described in Preparation 10h) as starting materials, in relative proportions similar to those used in that Example, the title compound was obtained in a yield of 88%.