Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:26][CH3:27])[C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:7][CH:6]=1)[CH3:2].[CH2:28]=O.[BH4-].[Na+]>CO.O>[CH2:26]([N:3]([CH2:1][CH3:2])[C:4](=[O:25])[C:5]1[CH:6]=[CH:7][C:8]([N:11]([CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:12]2[CH2:17][CH2:16][N:15]([CH3:28])[CH2:14][CH2:13]2)=[CH:9][CH:10]=1)[CH3:27]
Reactant: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCNCC2)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCN(CC)C(=O)c1ccc(N(Cc2ccccc2)C2CCN(C)CC2)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of N,N-diethyl-4-[benzyl(piperidin-4-yl)amino]benzamide (Compound 8) (0.67 g, 0.207 mmole) in 10 mL of methanol was added 37% formalin solution (1 mL), and the resulting mixture was cooled in an ice bath under Argon. To this mixture was added sodium borohydride (0.69 g, 18.2 mmol) in small portions. The reaction mixture was allowed to warm to ambient temperature and was stirred for three days. The reaction mixture was diluted with water (25 mL), and the resulting solution was extracted three times with chloroform (25 mL). The organic extracts were combined, dried (Na2SO4), and concentrated to provide a pale yellow oil. This material was purified on a flash silica gel column (10% methanol-chloroform to 15% methanol-chloroform) to provide 0.54 g of N,N-diethyl-4-[benzyl(1-methylpiperidin-4-yl)amino]benzamide as a pale yellow semisolid. This material was dissolved in acetonitrile, and oxalic acid (0.13 g) was added. Upon addition of diethyl ether, a cream-colored precipitate came out of solution. Recrystallization from acetonitrile and diethyl ether afforded 0.18 g (18% yield) of a cream-colored solid, mp 101-105° C. MS (ES), m/z 380 (MH+). 300 MHz 1H NMR (DMSO-d6) δ0.85-1.15 (br m, 6H), 1.75-2.02 (br m, 2H), 2.72 (s, 3H), 2.95-3.15 (br m, 2H), 3.16-3.45 (m, 6H), 4.12-4.30 (br m, 1H), 4.49 (br s, 2H), 6.63-6.82 (br m, 2H), 7.10-7.40 (m, 7H). Elemental analysis: Calculated for C24H33N3O.C2H2O4.0.6H2O: C, 65.01; H, 7.60; N, 8.75; H2O, 2.25. Found C, 64.77; H, 7.25; N, 8.59; Karl Fischer H2O, 1.55.
Reaction SMILES: I[CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5].[F:7][C:8]1([F:52])[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[CH:22]([OH:24])[CH2:21][C:20]([CH3:26])([CH3:25])[CH2:19][C:18]=3[N:17]=[C:16]([CH:27]3[CH2:32][CH2:31][N:30]([C:33]4[N:38]=[CH:37][C:36]([OH:39])=[CH:35][N:34]=4)[CH2:29][CH2:28]3)[C:15]=2[CH:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:10][CH2:9]1>>[F:52][C:8]1([F:7])[CH2:9][CH2:10][CH:11]([C:14]2[C:23]3[CH:22]([OH:24])[CH2:21][C:20]([CH3:25])([CH3:26])[CH2:19][C:18]=3[N:17]=[C:16]([CH:27]3[CH2:28][CH2:29][N:30]([C:33]4[N:38]=[CH:37][C:36]([O:39][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5])=[CH:35][N:34]=4)[CH2:31][CH2:32]3)[C:15]=2[CH:40]([F:51])[C:41]2[CH:42]=[CH:43][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:45][CH:46]=2)[CH2:12][CH2:13]1
Reactant: CC(C)CCI
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Product: CC(C)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 21 were performed except for using 62 (0.47 mmol) of 1-iodo-3-methylbutane instead of 1-iodo-2-methylpropane, and from 55 mg (0.085 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 40 mg of the title compound was obtained as a white solid (yield: 65%).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[Cl:11].[C:12]([NH:16][C:17](=[O:31])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:19]=1)([CH3:15])([CH3:14])[CH3:13].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:28]2[CH2:27][CH2:26][N:25]([CH2:24][C:20]3[CH:19]=[C:18]([CH:23]=[CH:22][CH:21]=3)[C:17]([NH:16][C:12]([CH3:14])([CH3:15])[CH3:13])=[O:31])[CH2:30][CH2:29]2)=[O:8])=[CH:4][C:3]=1[Cl:11]
Reactant: Nc1ccc(C(=O)O)cc1Cl
Reactant: CC(C)(C)NC(=O)c1cccc(CN2CCNCC2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)c1cccc(CN2CCN(C(=O)c3ccc(N)c(Cl)c3)CC2)c1
Yield: 94.1 %

Procedure:
4-Amino-3-chlorobenzoic acid (1.04 g, 6.06 mmol), N-tert-butyl-3-(piperazin-1-ylmethyl)-benzamide (888 mg, 3.22 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydro-chloride (1.742 g, 9.09 mmol) and triethylamine (1.23 g, 1.69 mL, 12.12 mmol) were combined and stirred in acetonitrile (20 mL) at room temperature overnight (under nitrogen). The reaction was concentrated under reduced pressure and the residue was diluted with dichloromethane (30 mL) and water. The organic layer was separated, dried over sodium sulfate and concentrated under vacuum. The resulting residue was purified by silica chromatography (eluting with a solvent gradient from dichloromethane to 4% methanol/dichloromethane) to afford the title compound (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1.[CH2:14]([Sn](CCCC)(CCCC)C=C)[CH2:15]CC>ClC(Cl)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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([CH:14]=[CH2:15])[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[CH:3]=1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: COC(=O)c1cc(N)c(F)c(Cl)n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(Cl)Cl
Product: C=Cc1nc(C(=O)OC)cc(N)c1F
Temperature: 140 °C
Yield: 49.4 %

Procedure:
Methyl 4-amino-6-chloro-5-fluoropicolinate (1.9 g, 9.29 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.326 g, 0.464 mmol) were combined in dichloroethane (30 ml) and tributyl(vinyl)stannane (3.26 ml, 11.14 mmol) was added. The reaction mixture was heated in a microwave reactor at 140° C. for 2 hrs. The cooled reaction mixture was purified by flash chromatography (SiO2, 0-40% THF:Hex gradient) to provide the title compound as a white solid (0.9 g, 4.59 mmol, 49.4% yield): 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 5.57 (dd, J=10.9, 2.2 Hz, 1H), 6.28 (dd, J=17.3, 2.2 Hz, 1H), 6.54 (s, 2H), 6.84-6.97 (m, 1H), 7.37 (d, J=6.7 Hz, 1H); 19F NMR (376 MHz, DMSO-d6) δ −148.25; ESIMS m/z 197 ([M+H]+), 195 ([M−H]−).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:7][NH:6][CH2:5][C@@H:4]([CH3:8])[NH:3]1.Cl[CH2:10][C:11]1[CH:45]=[CH:44][C:14]([C:15]([NH:17][C:18]2[C:19]3[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)=[O:34])[S:30][C:20]=3[N:21](C(OC(C)(C)C)=O)[N:22]=2)=[O:16])=[CH:13][CH:12]=1.ClCC1C=CC(C(NC2C3C=C(C(NN(C4C=CC(Cl)=CC=4)C)=O)SC=3N(C(OC(C)(C)C)=O)N=2)=O)=CC=1.C(OCC)(=O)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.CO.CCCCCCC>[CH3:8][CH:4]1[NH:3][CH:2]([CH3:1])[CH2:7][N:6]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([NH:17][C:18]3[C:19]4[CH:32]=[C:31]([C:33]([NH:35][N:36]([CH3:43])[C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)=[O:34])[S:30][C:20]=4[NH:21][N:22]=3)=[O:16])=[CH:44][CH:45]=2)[CH2:5]1
Reactant: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccccc1
Reactant: C[C@@H]1CNC[C@H](C)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CN(NC(=O)c1cc2c(NC(=O)c3ccc(CCl)cc3)nn(C(=O)OC(C)(C)C)c2s1)c1ccc(Cl)cc1
Agent: [I-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Solvent: CO
Product: CC1CN(Cc2ccc(C(=O)Nc3n[nH]c4sc(C(=O)NN(C)c5ccccc5)cc34)cc2)CC(C)N1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 mg (108 μmol) of tetrabutylammonium iodide, followed by 184 mg (1.61 mmol) of cis-2,6-dimethylpiperazine, are added to a solution of 290 mg (0.54 mmol) of an approximately 70:30 mixture of tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-methyl-N′-phenylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate and tert-butyl 3-(4-chloromethylbenzoylamino)-5-(N′-(4-chlorophenyl)-N′-methylhydrazinocarbonyl)thieno[2,3-c]pyrazole-1-carboxylate in 6 mL of dimethylformamide under argon. The reaction mixture is stirred at a temperature in the region of 25° C. for 3 hours, and then poured into a mixture of ice, ethyl acetate and n-heptane. The mixture is filtered on a sinter funnel, suction-filtered and air-dried. The solid obtained is dissolved in 5 mL of methanol and the solution is introduced into a microwave oven tube. The tube is stoppered and the reaction mixture is irradiated at a temperature in the region of 100° C. for three times 10 minutes. The reaction mixture is then concentrated to dryness under vacuum (2 kPa) at a temperature in the region of 40° C. The residue is purified by preparative LC/MS (condition B′). 130 mg of 4-(3,5-dimethylpiperazin-1-ylmethyl)-N-[5-(N′-methyl-N′-phenylhydrazinocarbonyl)-1H-thieno[2,3-c]pyrazol-3-yl]benzamide are thus obtained in the form of a yellow powder melting between 192 and 202° C. LC-MS-DAD-ELSD: 518(+)=(M+H)(+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.C(Cl)(=O)C(Cl)=O.[OH-].[Na+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:25][CH2:26][NH2:27]>C1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([NH:27][CH2:26][CH2:25][C:24]2[CH:28]=[CH:29][C:30]([O:31][CH3:32])=[C:22]([O:21][CH3:20])[CH:23]=2)=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(CCN)cc1OC
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1ccc(CCNC(=O)Cc2cccc(Br)c2)cc1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Bromo-phenyl)-N-[2-(3,4-dimethoxy-phenyl)-ethyl]-acetamide (41) was prepared as follows: A solution of 3-bromo-phenylacetic acid (2.0 g, 9.3 mmol) and oxalyl chloride (36.4 g, 0.287 mol) in 80 mL of benzene was refluxed for 6 h. The solution was evaporated with benzene 3 times and dried in vacuum. A solution of 3-bromo-phenylacetic acid (1.1 eq.) in CH2Cl2 was added to mixture of 100 mL of 1N NaOH and solution of 3,4-di-methoxy-phenethylamine (1.31 g, 7.22 mmol) in 100 mL of CH2Cl2. The reaction mixture was stirred overnight at r.t. Another portion of acid chloride (0.1 eq.) in 10 mL of CH2Cl2 was added and stirred for 1 h. Organic phase was separated, washed with 1N HCl, 1N NaOH, water, dried over Na2SO4, filtered and evaporated. A residue was crystallized from EtOAc-hexanes mixtures. Yield is 2.59 g (95%).
Reaction SMILES: [C:1]([N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][CH2:13][OH:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C(#N)C.O.I(O)(=O)(=O)=[O:26]>O.[Ru](Cl)(Cl)Cl.C(Cl)Cl>[C:1]([N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:12][C:13]([OH:26])=[O:14])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: O=C(OCc1ccccc1)N(CCO)c1ccccc1
Agent: Cl[Ru](Cl)Cl
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: O=C(O)CN(C(=O)OCc1ccccc1)c1ccccc1
Temperature: 0 °C
Yield: 84.1 %

Procedure:
In a 100 mL round bottom flask equipped with a magnetic stirrer, N-Cbz phenyl glycinol (1.3 g, 5.0 mmol) was disssolved in CC14 (100 mL)and acetonitrile (100 mL). To this above solution was added water (15 mL) and periodic acid (4.7 g, 20.1 mmol, 4.1 eq). The reaction mixture was stirred until both phases became clear, then Ruthenium trichoride hydrate (0.025 g, 2.2 mol %). The reaction mixture was stirred at room temperature for 20 min and cooled to 0° C. then methylene cloride (30 mL) was added. The two phases were separated, the aqueous phase was extracted with chloroform (3×20 mL). The combined organic extracts were dried over (Na2SO4) and concentrated to afford the crud product. Flash chromatograpy (SiO2, 5×25 cm, 2-5% CH3OH—CHCl3 gradient elution) afforded pure pure N-Cbz phenyl glycine (1.2 g, 85%). Same Oxidation procedure was followed for compounds 1 and 2. No epimerization was observed during oxidation procedure.
Reaction SMILES: C1(N[C:8]2[C:9]3[S:33][CH2:32][CH2:31][C:10]=3[N:11]=[C:12]([N:14]3[CH2:19][CH2:18][N:17](C4C=CC(C(OCC)=O)=CC=4)[CH2:16][CH2:15]3)[N:13]=2)CCCCC1.[C:34]1([N:40]=C=O)C=CC=[CH:36][CH:35]=1>O1CCCC1>[N:14]1([C:12]2[N:13]=[C:8]([CH2:36][CH2:35][CH2:34][NH2:40])[C:9]3[S:33][CH2:32][CH2:31][C:10]=3[N:11]=2)[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3nc4c(c(NC5CCCCC5)n3)SCC4)CC2)cc1
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: NCCCc1nc(N2CCNCC2)nc2c1SCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
0.330 g (1.0 mmol) of cyclohexyl-(2-piperazin-1-yl-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amine (VI) and 0.115 mL (1.0 mmol) of phenyl isocyanate are placed in 12.5 mL of tetrahydrofuran, then stirred for 1 hour at ambient temperature. Then the reaction mixture is concentrated by evaporation. The residue is stirred with water, suction filtered, washed with water and petroleum ether, then dried. The crude product is purified by chromatography through a 25 g silica gel cartridge with a solvent mixture of petroleum ether/ethyl acetate 1/1. 0.240 g of product VII (53%) is obtained as a powder (m.p. 207-210° C.). 1H NMR (400 MHz, DMSO): 8.51 (1H, s); 7.47 (2H, d); 7.23 (2H, t); 6.92 (1H, t); 6.11 (1H, d); 3.91-3.78 (1H, m); 3.69-3.59 (4H, m); 3.53-3.44 (4H, m); 3.22 (2H, t); 2.98 (2H, t); 1.92-1.78 (2H, m); 1.79-1.67 (2H, m); 1.65-1.56 (1H, m); 1.37-1.21 (4H, m); 1.18-1.04 (1H, m).
Reaction SMILES: C(O[C:9](=[O:38])[NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[O:21][CH3:22])[N:17]=[CH:16][CH:15]=[C:14]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH:34]2[CH2:36][CH2:35]2)=[O:32])=[C:26]([F:37])[CH:25]=1)C1C=CC=CC=1.F[C:40](F)(F)C(O)=O>C1(SC)C=CC=CC=1>[CH:34]1([NH:33][C:31](=[O:32])[NH:30][C:27]2[CH:28]=[CH:29][C:24]([O:23][C:14]3[C:13]4[C:18](=[CH:19][C:20]([O:21][CH3:22])=[C:11]([NH:10][C:9](=[O:38])[CH3:40])[CH:12]=4)[N:17]=[CH:16][CH:15]=3)=[CH:25][C:26]=2[F:37])[CH2:35][CH2:36]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(=O)OCc1ccccc1
Solvent: CSc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC4CC4)c(F)c3)c2cc1NC(C)=O

Procedure:
{4-[4-(cyclopropylureido)-3-fluorophenoxy]-7-methoxyquinolin-6-yl]carbamic acid benzyl ester (11 mg) was heated and stirred in a mixture of trifluoroacetic acid (3 ml) and thioanisole (0.5 ml) at 60° C., in the same manner as Example 264, for debenzylation. The resulting amino compound was acetylated in the same manner as Example 265 to obtain the title compound (2 mg) as a solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([OH:36])=O)([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[CH:10]=[CH:9][C:8]3[O:39][CH2:40][O:41][C:7]=3[C:6]=2[N:5]=1)[CH3:2].C(OC1C=C(OC2CC3C(C(=O)N(C)CCCCC=CC4C(C([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=O)(NC3=O)C4)C2)C2C(=C(C)C(OC)=CC=2)N=1)C>>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]([O:14][CH:15]2[CH2:32][CH:31]3[CH:17]([C:18](=[O:38])[N:19]([CH3:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH:24]=[CH:25][CH:26]4[C:28]([C:34]([NH:77][S:78]([CH:81]5[CH2:83][CH2:82]5)(=[O:80])=[O:79])=[O:36])([NH:29][C:30]3=[O:33])[CH2:27]4)[CH2:16]2)[C:11]2[CH:10]=[CH:9][C:8]3[O:39][CH2:40][O:41][C:7]=3[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)O)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3
Reactant: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc(OC)c(C)c2n1
Product: CCOc1cc(OC2CC3C(=O)NC4(C(=O)NS(=O)(=O)C5CC5)CC4C=CCCCCN(C)C(=O)C3C2)c2ccc3c(c2n1)OCO3

Procedure:
The title compound (15) was prepared from 17-[8-ethoxy[1,3]dioxolo[4,5-h]quinolin-6-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (14) following the procedure reported for synthesis of N-[17-[2-ethoxy-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (3): m/z=669 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[C:6](B2OC(C)(C)C(C)(C)O2)=[CH:5][CH:4]=[N:3]1.[CH2:16]([O:23][C:24]1[CH:29]=[C:28](Br)[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>CC#N.O.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH2:16]([O:23][C:24]1[CH:29]=[C:28]([C:6]2[N:2]([CH3:1])[N:3]=[CH:4][CH:5]=2)[CH:27]=[CH:26][C:25]=1[F:31])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Fc1ccc(Br)cc1OCc1ccccc1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: Cn1nccc1-c1ccc(F)c(OCc2ccccc2)c1
Temperature: 100 °C
Yield: 74.8 %

Procedure:
To a solution of 1-methyl-1H-pyrazole-5-boronic acid pinacol ester (1058.42 mg, 5.09 mmol) in MeCN (40 mL) and water (10 mL) was added 2-benzyloxy-4-bromo-1-fluoro-benzene [CAS: 1036724-54-5](1300 mg, 4.62 mmol), sodium carbonate (1470.8 mg, 13.88 mmol) and bis(triphenylphosphine)palladium (II) dichloride (164.24 mg, 0.2300 mmol). The reaction was then heated at 100° C. for 4 hours. The cooled reaction mixture was poured into EtOAc (70 mL) and water (100 mL). The organics were separated, and washed with brine (75 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was then purified over silica (25 g, SNAP cartridge), eluting with EtOAc in isohexane from 0% to 40%. Fractions containing desired product were combined and concentrated in vacuo to give 5-(3-benzyloxy-4-fluoro-phenyl)-1-methyl-pyrazole (D82) (1026.5 mg, 3.4543 mmol, 74.7% yield) as a colourless oil;
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4](=O)[CH:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1.[C:16]([NH2:19])(=[S:18])[CH3:17]>>[CH3:1][O:2][C:3]([C:4]1[N:19]=[C:16]([CH3:17])[S:18][C:5]=1[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Cl:12])[CH:7]=1)=[O:15]
Reactant: COC(=O)C(=O)C(Cl)c1cccc(Cl)c1
Reactant: CC(N)=S
Product: COC(=O)c1nc(C)sc1-c1cccc(Cl)c1

Procedure:
prepared by reaction of 3-chloro-3-(3-chloro-phenyl)-2-oxo-propionic acid methyl ester with thioacetamide. LC-MS: tR=0.95 min; [M+H]+=268.0.
Reaction SMILES: [CH3:1][C:2]1([CH3:23])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[N:14]=[C:7]3[C:8](=[O:13])[CH2:9]2)[CH:4]=[N:3]1.Br[CH2:25][CH2:26][CH2:27][Cl:28]>>[CH3:1][C:2]1([CH3:23])[C:11](=[O:12])[CH:10]2[C:5](=[C:6]3[N:16]=[C:15]([CH:17]4[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]4)[N:14]=[C:7]3[C:8](=[O:13])[CH:9]2[CH2:25][CH2:26][CH2:27][Cl:28])[CH:4]=[N:3]1
Reactant: ClCCCBr
Reactant: CC1(C)N=CC2=C3N=C(C4CCCCC4)N=C3C(=O)CC2C1=O
Product: CC1(C)N=CC2=C3N=C(C4CCCCC4)N=C3C(=O)C(CCCCl)C2C1=O

Procedure:
Prepared analogous to Example 26a from 3.1 gm of 7,7-dimethyl-2-cyclohexyl-5H,7H-imidazo[4,5-h]isoquinoline-4,6-dione and 1.9 gm of 1-bromo-3-chloro-propane. The crude product was directly further processed.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=1[O:4][C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=2)[N:8]=[CH:7][CH:6]=1.C([Li])CCC.CCCCCC.[CH:35]1([C:40](Cl)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1.O>O1CCCC1>[CH:35]1([C:40]([C:2]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:3]=2[O:4][C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:17][CH3:18])=[C:12]([O:15][CH3:16])[CH:13]=3)[N:8]=[CH:7][CH:6]=2)=[O:41])[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: O=C(Cl)C1CCCC1
Reactant: COc1cc2nccc(Oc3ccc(C)cc3Br)c2cc1OC
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1cc2nccc(Oc3ccc(C)cc3C(=O)C3CCCC3)c2cc1OC
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 13 %

Procedure:
4-(2-Bromo-4-methylphenoxy)-6,7-dimethoxyquinoline (100 mg) was dissolved in tetrahydrofuran (6 ml) to prepare a solution which was then cooled to −78° C. A 1.59 M n-butyllithium/hexane solution (0.35 ml) was added to the cooled solution, and the mixture was stirred at −78° C. for 20 min. Cyclopentanecarbonyl chloride (0.2 ml) was added to the reaction solution, and the mixture was stirred at room temperature for 7 hr. Further, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using acetone-chloroform to give the title compound (14 mg, yield 13%).
Reaction SMILES: [CH3:1][C:2]([C@:4]1(OC(C)=O)[C@@:8]2([CH3:24])[CH2:9][CH2:10][C@@H:11]3[C@:21]4([CH3:22])[C:15](=[CH:16][C:17]([CH:19]=[CH:20]4)=[O:18])[C:14]([Cl:23])=[CH:13][C@H:12]3[C@@H:7]2[CH2:6][CH2:5]1)=[O:3].[CH3:29]OC1C=CC2C(C3C=CC(OCCN4CCCC4)=CC=3)=C(C3C=CC=CC=3)CCC=2C=1.COC1C=CC(/C(/C2C=CC(OCCN3CCCC3)=CC=2)=C(/[N+]([O-])=O)\C2C=CC=CC=2)=CC=1.C(C(O)(C(O)=O)CC(O)=O)C(O)=O.C1C(C2SC3C=C(O)C=CC=3C=2C(C2C=CC(OCCN3CCCCC3)=CC=2)=O)=CC=C(O)C=1.CC/C(/C1C=CC=CC=1)=C(/C1C=CC(OCCN(C)C)=CC=1)\C1C=CC=CC=1.C(C(O)(C(O)=O)CC(O)=O)C(O)=O.CN(CCOC1C=CC(/C(/C2C=CC=CC=2)=C(\C2C=CC=CC=2)/CCCl)=CC=1)C.C(C(O)(C(O)=O)CC(O)=O)C(O)=O.COC1C=CC(C2CCC3C=CC=CC=3C=2C(C2C=CC(OCCN3CCCC3)=CC=2)=O)=CC=1>>[CH3:29][C@H:5]1[C@H:4]([C:2]([CH3:1])=[O:3])[C@:8]2([CH3:24])[C@H:7]([C@H:12]3[C@H:11]([CH2:10][CH2:9]2)[C@:21]2([CH3:22])[C:15](=[CH:16][C:17]([CH2:19][CH2:20]2)=[O:18])[C@@H:14]([Cl:23])[CH2:13]3)[CH2:6]1
Reactant: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(OCCN2CCCC2)cc1
Reactant: CC(=O)O[C@]1(C(C)=O)CC[C@H]2[C@@H]3C=C(Cl)C4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@@]21C
Agent: CC/C(=C(\c1ccccc1)c1ccc(OCCN(C)C)cc1)c1ccccc1
Agent: CN(C)CCOc1ccc(/C(=C(/CCCl)c2ccccc2)c2ccccc2)cc1
Agent: COc1ccc(/C(=C(\c2ccccc2)[N+](=O)[O-])c2ccc(OCCN3CCCC3)cc2)cc1
Product: CC(=O)[C@H]1[C@H](C)C[C@H]2[C@@H]3C[C@H](Cl)C4=CC(=O)CC[C@]4(C)[C@H]3CC[C@@]21C

Procedure:
delmadinone acetate; nafoxidine; nitromifene citrate; raloxifene; tamoxifen citrate; toremifene citrate; trioxifene mesilate.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]([O:11]CC)=[O:10])[O:6][N:5]=1)([CH3:3])[CH3:2].O[NH:15]/[C:16](=N/[H])/[C:17]1C=CC=NC=1.[OH-].[Na+]>>[N:15]1[CH:16]=[CH:17][CH:2]=[C:1]([C:4]2[N:8]=[C:7]([C:9]([OH:11])=[O:10])[O:6][N:5]=2)[CH:3]=1
Reactant: [H]/N=C(/NO)c1cccnc1
Reactant: CCOC(=O)c1nc(C(C)C)no1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)c1nc(-c2cccnc2)no1

Procedure:
Following the procedure described in U.S. Pat. No. 5,578,550 for the preparation of ethyl 3-isopropyl-1,2,4-oxadiazole-5-carboxylate, the title product was prepared from (E)—N-hydroxynicotinimidamide (2.727 g, 19.88 mmol) and ethyl oxalyl chloride (2.89 mL, 25.9 mmol) followed by subsequent ester hydrolysis with sodium hydroxide solution according to Example 225(b). Yield 1.32 g. 1H NMR (400 MHz; d6-DMSO): δ 7.63 (m, HA), 8.32 (m, 1H), 8.86 (dd, 1H), 9.03 (dd, 1H).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][CH3:16])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:22](=[O:41])[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([C:32]2[CH:37]=[CH:36][N:35]=[C:34]([CH:38]([CH3:40])[CH3:39])[CH:33]=2)[CH:27]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:38]([C:34]1[CH:33]=[C:32]([C:28]2[CH:27]=[C:26]([C:24]3[CH2:23][C:22](=[O:41])[NH:21][C:9]4[CH:10]=[C:11]([C:17]([F:19])([F:20])[F:18])[C:12]([O:14][CH2:15][CH3:16])=[CH:13][C:8]=4[N:7]=3)[CH:31]=[CH:30][CH:29]=2)[CH:37]=[CH:36][N:35]=1)([CH3:39])[CH3:40]
Reactant: CCOc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C(C)C)c3)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3ccnc(C(C)C)c3)c1)=N2

Procedure:
The title compound was prepared from [2-{3-[3-(2-isopropyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-5-ethoxy-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M254) (0.32 g, 0.55 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as an off-white solid (200 mg, 78%).