Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:27]([O:29]CC)=[CH2:28])CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:29])[CH3:28]
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (12.78 mg, 0.02 mmol) was added to a stirred mixture of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (215 mg, 0.61 mmol) and tributyl(1-ethoxyvinyl)stannane (0.226 mL, 0.67 mmol) in 1,4-dioxane (5 mL) and the mixture was purged with nitrogen. The resulting mixture was stirred at 100° C. for 3 hrs. HC12N (0.5 mL) was added and the reaction mixture was stirred at 50° C. for 25 minutes then allowed to cool to room temperature and concentrated under vacuum. The product was diluted with diethyl ether and pentane to afford a solid, which was collected by filtration and washed with ether/pentane to give 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 104%) as a beige solid. Mass Spectrum: M+H+ 318.
Reaction SMILES: [CH2:1]([O:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:17][CH2:18][OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[OH-].[Na+].S([O-])(O[CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH3:52])(=O)=O>>[CH2:52]([O:19][CH2:18][CH2:17][N:16]([CH2:20][CH2:21][O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:14][O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[CH2:51][CH2:50][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][CH3:41]
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: CCCCCCCCCCCCOCCN(CCO)CCOCCCCCCCCCCCC
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCOCCN(CCOCCCCCCCCCCCC)CCOCCCCCCCCCCCC
Yield: 116.5 %

Procedure:
20 grams (0.042 mole) of di-(lauryloxyethyl)-hydroxyethyl amine (the second fraction recovered in Example 12) were reacted with 2.0 grams (0.05 mole) of sodium hydroxide and 12.1 grams (0.042 mole) of lauryl sulfate, Na salt using the procedure of Example 12. Purification of the product again using the procedure of Example 12, gave 32 grams of a yellow oily product having an amine number of 85.6.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22](=[O:44])[NH:23][C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:28][CH:29]=1.[CH:45]1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCC[CH2:46]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C(B(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C=O)C>[CH2:45]([C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:21]=[CH:20][C:14]3[O:15][C:16]([F:19])([F:18])[O:17][C:13]=3[CH:12]=2)=[O:10])=[CH:4][C:3]=1[C:22](=[O:44])[NH:23][C:24]1[CH:25]=[N:26][C:27]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[CH:33][CH:32]=2)=[N:28][CH:29]=1)[CH3:46]
Reactant: CN1CCN(c2ccc(Nc3ncc(NC(=O)c4cc(NC(=O)c5ccc6c(c5)OC(F)(F)O6)ccc4Cl)cn3)cc2)CC1
Reactant: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCB(CC)CC
Solvent: CN(C)C=O
Product: CCc1ccc(NC(=O)c2ccc3c(c2)OC(F)(F)O3)cc1C(=O)Nc1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A resealable tube was charged with N-(4-chloro-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenyl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide 38 (0.050 g, 0.080 mmol), palladium(II) acetate (0.0018 g, 0.0080 mmol), 2-(dicyclohexylphosphino)-2′,6′-dimethoxy-1,1′-biphenyl (0.0066 g, 0.016 mmol), potassium phosphate (0.068 g, 0.32 mmol), and DMF (2.0 mL). A solution of triethylborane (0.12 mL, 0.12 mmol) (1M in THF) was added. The reaction tube was evacuated and purged with argon, and then sealed. The mixture stirred at 100° C. for 6 h. The reaction mixture was filtered through a pad of Celite and concentrated to afford a yellow green solid. This material was purified via preparative thin layer chromatography (eluting three times with 95:5:0.5, dichloromethane/methanol/ammonium hydroxide) to afford N-(4-ethyl-3-((2-(4-(4-methylpiperazin-1-yl)phenylamino)pyrimidin-5-yl)carbamoyl)phenyl)-2,2-difluorobenzo[d][1,3]dioxole-5-carboxamide 39 as an off-white solid. MS m/z found 616.2 [MH+]; calc. for C32H31F2N7O4=615.63.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1Br)=[O:5])[CH3:2].[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19].N(C(C)C)C(C)C>C1COCC1.C(OCC)(=O)C.[Cu]I.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>[CH2:1]([O:3][C:4]([C:6]1[C:11]([Cl:12])=[C:10]([CH3:13])[C:9](=[O:14])[N:8]([CH3:15])[C:7]=1[C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1Br
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)c1c(Cl)c(C)c(=O)n(C)c1C#C[Si](C)(C)C
Temperature: 25 °C

Procedure:
To a mixture of 2-bromo-4-chloro-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1.00 equivalent), trimethylsilylacetylene (1.20 equivalents) and iPr2NH (2.00 equivalents) in THF is added CuI (0.10 equivalents) followed by Pd(PPh3)2Cl2 (0.10 equivalents). After stirring the reaction mixture at reflux for 16 hours, it is cooled to room temperature and diluted with ethyl acetate. The organic layer is washed with saturated NH4Cl solution and brine, dried (MgSO4) and concentrated under reduced pressure. The desired product is obtained by flash column chromatography as necessary.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](F)[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH2:12])=O.[F:13][C:14]([F:27])([F:26])[O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([NH2:25])=[O:24])=[CH:18][CH:17]=1>>[C:9]1([C@H:17]2[C@H:22]([C:19]3[CH:18]=[CH:17][C:16]([O:15][C:14]([F:26])([F:27])[F:13])=[CH:21][CH:20]=3)[C:23](=[O:24])[NH:25][C:16]2=[O:15])[C:3]2=[C:4]3[C:5](=[CH:6][CH:7]=[CH:2]2)[CH2:20][CH2:19][CH2:18][N:12]3[CH:10]=1
Reactant: NC(=O)Cc1ccc(F)cc1Cl
Reactant: NC(=O)Cc1ccc(OC(F)(F)F)cc1
Product: O=C1NC(=O)[C@@H](c2cn3c4c(cccc24)CCC3)[C@@H]1c1ccc(OC(F)(F)F)cc1

Procedure:
(±)-Trans-3-(5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolin-1yl)-4-(4-trifluoromethoxyphenyl)pyrrolidine-2,5-dione was prepared according to Example 40 replacing 2-chloro-4-fluorophenylacetamide with 4-trifluoromethoxyphenylacetamide. Yield 67.8 mg, 16.4%. 1H NMR (DMSO-d6) 400 MHz δ: 11.56 (s, 1H), 7.52 (d, 2H, J=8.4 Hz), 7.35 (s, 1H), 7.33 (d, 2H, J=8.0 Hz), 7.15 (d, 1H, J=7.2 Hz), 6.86 (m, 2H), 4.58 (d, 1H, J=8.0 Hz), 4.45 (d, 1H, J=8.0 Hz), 4.10 (t, 2H, J=6.0 Hz), 2.90 (t, 2H, J=6.0), 2.10 (t, 2H, J=5.6).
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3]1.[OH-].[K+].[C:14]1(C)[CH:19]=CC=C[CH:15]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[O:1]=[C:2]1[N:6]([CH2:19][C:14]#[CH:15])[CH:5]=[C:4]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3]1
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1c[nH]c(=O)s1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Product: C#CCn1cc(C(=O)OCC)sc1=O
Reaction time: 3 h

Procedure:
A mixture of 8.65 g of the product of Step A in 130 ml of toluene, 2.8 g of potassium hydroxide, 4.5 ml of 3-bromo-1-propane and 1.66 g of tetrabutyl ammonium bromide was heated to 95 C and stirred for 3 hours. The mixture was decanted, washed with N sodium hydroxide, with N hydrochloric acid and with water saturated with sodium chloride, dried and brought to dryness. The residue was chromatographed and elution with a hexane-chloroform-acetone mixture (70-15-15) yielded 4.74 g of the expected product melting at 70° to 71° C.
Reaction SMILES: [OH:1][CH2:2][C:3]#[C:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.N1C2C(=CC=CC=2)C=CC=1>CCOC(C)=O.[Pd].CC([O-])=O.CC([O-])=O.[Pb+2]>[OH:1][CH2:2]/[CH:3]=[CH:4]\[CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCO)CC1
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(/C=C\CO)CC1
Reaction time: 0.67 h

Procedure:
The alkyne from step B (6.5 g, 27.2 mmol) and quinoline (0.55 mL, 4.62 mmol) were dissolved in EtOAc (120 mL). Lindlar's catalyst (740 mg) was added and the reaction was stirred under hydrogen atmosphere (1 atm) for 40 minutes. The reaction was filtered and concentrated to yield a crude residue which was purified by silica gel chromatography (gradient elution, 0% to 100% EtOAc in hexanes) to yield the desired allylic alcohol. 1H NMR (500 MHz, CDCl3) δ 5.58 (m, 1H), 5.37 (dd, J 10.8 & 9.6 Hz, 1H), 4.22 (d, 2H), 4.16-3.99 (m, 2H), 2.80-2.78 (m, 2H), 2.52-2.40 (m, 1H), 1.61-1.56 (m, 2H), 1.45 (s, 9H), 1.36-1.22 (m, 2H).
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C(N[C@@H]2[C@@H]3C[C@@H](C=C3)[C@@H]2C(N)=O)=C2N=C(C3C=CC(CN4CCOCC4)=CC=3)NC2=NC=1.[NH2:42][C:43]1[C:48]([NH2:49])=[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])[C:46]([Cl:61])=[CH:45][N:44]=1.[CH3:62][N:63]([CH3:74])[C:64]1[CH:71]=[CH:70][C:67]([CH:68]=O)=[C:66]([O:72][CH3:73])[CH:65]=1>>[Cl:61][C:46]1[C:47]([NH:50][C@@H:51]2[C@@H:56]3[CH2:57][C@@H:53]([CH:54]=[CH:55]3)[C@@H:52]2[C:58]([NH2:60])=[O:59])=[C:48]2[N:49]=[C:68]([C:67]3[CH:70]=[CH:71][C:64]([N:63]([CH3:74])[CH3:62])=[CH:65][C:66]=3[O:72][CH3:73])[NH:42][C:43]2=[N:44][CH:45]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cc(N(C)C)ccc1C=O
Agent: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)[C@H]2C=C[C@@H]1C2
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N(C)C)ccc1-c1nc2c(N[C@H]3[C@@H](C(N)=O)[C@@H]4C=C[C@H]3C4)c(Cl)cnc2[nH]1
Yield: 52 %

Procedure:
In the same fashion as for Compound III, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide and 4-Dimethylamino-2-methoxy-benzaldehyde were reacted to produce the title compound (52%). 1H NMR (d-chloroform): 13.60 (br s, 1H), 8.16 (d, J=9 Hz, 1H), 7.79 (s, 1H), 7.44 (br s, 1H), 6.35-6.50 (m, 3H), 6.24 (d, J=2 Hz, 1H), 5.94 (s, 1H), 5.43 (t, J=8 Hz, 1H), 5.31 (br s, 1H), 4.16 (s, 3H), 3.27 (s, 1H), 3.10 (s, 6H), 3.02 (s, 1H), 2.72 (d, J=8 Hz, 1H), 2.35 (d, J=9 Hz, 1H), 1.70 (d, J=10 Hz, 1H). MS: 454.07 (M+H). HPLC retention time: 2.61 minutes (G Method).
Reaction SMILES: C[O:2][C:3](=[O:32])[CH2:4][S:5][C:6]1[S:10][C:9]([NH:11][C:12]([N:14]([CH:25]2[CH2:30][CH2:29][CH:28]([CH3:31])[CH2:27][CH2:26]2)[CH2:15][C:16]([CH3:24])([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH3:17])=[O:13])=[N:8][CH:7]=1.O[Li].O>C1COCC1.O>[CH3:31][C@H:28]1[CH2:29][CH2:30][C@H:25]([N:14]([CH2:15][C:16]([CH3:24])([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH3:17])[C:12](=[O:13])[NH:11][C:9]2[S:10][C:6]([S:5][CH2:4][C:3]([OH:32])=[O:2])=[CH:7][N:8]=2)[CH2:26][CH2:27]1
Reactant: COC(=O)CSc1cnc(NC(=O)N(CC(C)(C)c2ccccc2)C2CCC(C)CC2)s1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CN(C(=O)Nc1ncc(SCC(=O)O)s1)[C@H]1CC[C@H](C)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of {2-[3-(4-methyl-cyclohexyl)-3-(2-methyl-2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid methyl ester (350 mg, 0.737 mmol) in THF(50 mL) was added LiOH.H2O (186 mg, 4.42 mmol) in water (3 mL) at RT. The mixture was stirred at RT for 16 h. Water was added and the mixture was extracted with dichloromethane. The organic layer was collected, dried over anhydrous sodium sulfate. The solvent was removed at reduced pressure and the residue was purified by preparative HPLC to give {2-[3-(trans-4-Methyl-cyclohexyl)-3-(2-methyl-2-phenyl-propyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid.
Reaction SMILES: C([C@H:5]1[C@H:10]2[C@H:11]3[C:20]([CH2:21][CH2:22][C@:8]2([CH3:9])[C:7](=[O:24])[CH2:6]1)=[C:19]1[C:14](=[CH:15][C:16](=[O:23])[CH2:17][CH2:18]1)[CH2:13][CH2:12]3)CCC.C1(SCl)C=CC=CC=1>C(Cl)Cl.C(N(CC)CC)C>[CH3:9][C@:8]12[CH2:22][CH2:21][C:20]3[C@@H:11]([CH2:12][CH2:13][C:14]4[C:19]=3[CH2:18][CH2:17][C:16](=[O:23])[CH:15]=4)[C:10]1=[CH:5][CH2:6][C:7]2=[O:24]
Reactant: CCCC[C@@H]1CC(=O)[C@@]2(C)CCC3=C4CCC(=O)C=C4CC[C@H]3[C@H]12
Agent: ClSc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3C1=CCC2=O
Reaction time: 0.17 h
Yield: 100.6 %

Procedure:
A solution of 1.5 g of 15 α-hydroxy-4,9-estradiene-3,17-dione in 20 ml of methylene chloride and 1.2 ml of triethylamine is mixed with a solution of 0.83 g of phenylsulfenyl chloride in 5 ml of methylene chloride drop by drop at -20° C. After addition, stirring is performed for 10 minutes at -20° C., the reaction solution is then diluted with 100 ml of methylene chloride, washed, one after the other, with saturated sodium hydrogen carbonate solution and saturated ammonium chloride solution, dried with sodium sulfate and concentrated. Crystallization of the crude product from ethyl acetate/diisopropyl ether yields 1.24 g (88.2% of theory) of 4,9,14-estratriene-3,17-dione with a melting point of 143° to 144° C.
Reaction SMILES: [NH2:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][O:14][CH3:15])[CH:7]=1)[C:3]([OH:5])=[O:4].Cl[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].[OH-].[Na+]>O>[CH2:20]([O:19][C:17]([NH:1][CH:2]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([CH2:13][O:14][CH3:15])[CH:7]=1)[C:3]([OH:5])=[O:4])=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COCc1cc(C(N)C(=O)O)ccc1O
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COCc1cc(C(NC(=O)OCc2ccccc2)C(=O)O)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
α-Amino-4-hydroxy-3-(methoxymethyl)benzeneacetic acid (0.1 mole), is dissolved in water, the pH of which is about 8. This solution is cooled to 0° C. and benzyl chloroformate (0.1 mole) is added dropwise along with 1N sodium hydroxide so as to maintain the pH at 8 to 9. After the addition, the solution is stirred at 0° C. for 30 minutes and 30 minutes at room temperature. The solution is washed with ethyl ether and then acidified with hydrochloric acid. The title compound is then recovered from the aqueous solution.
Reaction SMILES: C[N+]([CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[NH:8][CH:7]=1)(C)C.[I-].[Cl:16][C:17]([Cl:22])([Cl:21])[C:18]([NH2:20])=[NH:19]>C(O)C>[NH:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]([CH2:5][NH:19][C:18](=[NH:20])[C:17]([Cl:22])([Cl:21])[Cl:16])=[CH:7]1
Reactant: N=C(N)C(Cl)(Cl)Cl
Reactant: C[N+](C)(C)Cc1c[nH]c2ccccc12
Agent: [I-]
Solvent: CCO
Product: N=C(NCc1c[nH]c2ccccc12)C(Cl)(Cl)Cl

Procedure:
A solution of gramine methiodide (31.6 g., 0.1 mole) in 250 ml. of ethanol is treated dropwise over a period of 30 minutes with a solution of trichloroacetamidine (16.1 g., 0.1 mole) in 50 ml. of ethanol. The solution is refluxed for 15 minutes, cooled and the solvent removed in vacuo to give a crystalline residue. The residue is partitioned between 150 ml. portions of chloroform and water and the water layer back-extracted with chloroform. The combined chloroform extracts are washed with water, dried over magnesium sulfate, filtered and concentrated in vacuo affording N-(3-indolylmethyl)-trichloroacetamidine m.p. 135.5 to 138.5 after recrystallization from benzene/hexane.
Reaction SMILES: Cl[CH2:2][C:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1.[O-:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Na+]>CS(C)=O.O>[O:11]([CH2:2][C:3]1([CH3:10])[CH2:7][O:6][C:5]([CH3:9])([CH3:8])[O:4]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: [O-]c1ccccc1
Reactant: CC1(CCl)COC(C)(C)O1
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(COc2ccccc2)COC(C)(C)O1

Procedure:
4-Chloromethyl-2,2,4-trimethyl-1,3-dioxolane (5.0g) and sodium phenoxide (3.7g, prepared from phenol and sodium hydride) in dimethyl sulphoxide (90 ml) were heated together at 140° C for 4 hours. The reaction mixture was diluted with water and the aqueous solution extracted with ether. The ether extracts were dried and the solvent was removed under reduced pressure to yield a liquid which, on distillation, gave the desired product having a b.p. 83.5° C at 0.3 mm Hg.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[C:11]([O:15][C:16](=[O:27])[C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:19]([C:20](O)=[O:21])[CH:18]=1)([CH3:14])([CH3:13])[CH3:12].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C1COCC1>[C:11]([O:15][C:16](=[O:27])[C:17]1[CH:25]=[CH:24][C:23]([CH3:26])=[C:19]([C:20]([NH:10][C:8]2[CH:9]=[C:4]3[CH:3]=[CH:2][NH:1][C:5]3=[N:6][CH:7]=2)=[O:21])[CH:18]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)O
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)OC(C)(C)C)cc1C(=O)Nc1cnc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1H-pyrrolo[2,3-b]pyridin-5-ylamine (example c), 0.5 mmol) and 4-methyl-isophthalic acid 1-tert-butyl ester from example 1-1 (0.5 mmol) in THF (5 ml) were added TBTU (0.5 mmol), HOBT (0.5 mmol) and Hunig's base (0.6 mmol) and stirred at RT for overnight. Solvent was concentrated, residue was diluted with EtOAc ( ), washed with 1(N) NaOH. Organics was concentrated to get 2.8 g of the crude title product. LC-MS: (m/z 352)
Reaction SMILES: C1=CCCC=CCC1.[CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]=1.[CH2:15]([O:17][C:18](=[O:22])[CH:19](Cl)[Cl:20])[CH3:16].CC([O-])(C)C.[K+].C([O-])(=O)C.[Na+].OO.[Na+].[Cl-]>C(O)(C)(C)C.C1COCC1>[Cl:20][CH:19]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)[C:18]([O:17][CH2:15][CH3:16])=[O:22]
Reactant: C1=CCCCC1
Reactant: CCOC(=O)C(Cl)Cl
Agent: C1=CCC/C=C\CC1
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: C1=CCCC=CCC1
Product: CCOC(=O)C(Cl)C1CCCCC1
Temperature: 45 °C
Reaction time: 2 h
Yield: 37.1 %

Procedure:
100 mL of 1M BH3-THF complex (100 mmol) were added to 170 mL of dry THF under a blanket of nitrogen at room temperature. 12.3 mL of cis-1,5-cyclooctadiene (100 mmol) were added dropwise to this mixture within a period of 5 minutes, and the temperature rose to 45° C. The reaction mixture was heated under reflux over a period of 1.5 h, again cooled to 45° C., and 10.1 mL of cyclohexene (100 mmol) were added and stirring was continued for a further 2 h at 45° C. After the reaction mixture had been cooled in an ice bath, 12.2 mL of ethyldichloroacetate (100 mmol) in 50 mL of tert-butanol were added, stirring was continued for a further 15 minutes and 1M potassium tert-butylate (100 mmol, 100 mL) was added dropwise within a further 15 minutes. The reaction mixture was then stirred over a period of 15 minutes, 33 mL of 3M sodium acetate solution (100 mmol) were added and 22.5 mL of 30% strength aq. H2O2 solution (750 mmol) were added dropwise. The mixture was stirred at room temperature over a period of 30 minutes, then salted out with NaCl, the organic phase dried over MgSO4 and the solvent removed under reduced pressure. Following washing of the residual solid matter with tert-butylmethyl ether, cyclohexane/tert-butylmethyl ether (9:1), tert-butylmethyl ether, and EA, there were obtained 7.6 g (37.4%) of product.
Reaction SMILES: Br[CH2:2][C:3]1[O:7][C:6]([CH3:8])=[N:5][CH:4]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[NH:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:8][C:6]1[O:7][C:3]([CH2:2][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[NH:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:4][N:5]=1
Reactant: CCOC(=O)N1CCC(Nc2nc3ccccc3[nH]2)CC1
Reactant: Cc1ncc(CBr)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)N1CCC(Nc2nc3ccccc3n2Cc2cnc(C)o2)CC1
Temperature: 80 °C
Reaction time: 18 h
Yield: 11.2 %

Procedure:
A mixture of 23 parts of 5-(bromomethyl)-2-methyloxazole, 57.6 parts of ethyl 4-[(1H-benzimidazol-2-yl)amino]-1-piperidinecarboxylate, 26.5 parts of sodium carbonate and 470 parts of N,N-dimethylformamide was stirred for 18 hours at 80° C. The reaction mixture was poured into water and the whole was extracted with 4-methyl-2-pentanone. The extract was washed with water, dried, filtered and evaporated. The residue was stirred in acetonitrile. The precipitate was filtered off and the filtrate was evaporated. The residue was purified by column chromatography (silica gel; CH2Cl2 /CH3OH 90:10). The eluent of the desired fraction was evaporated, yielding 6 parts (11.2%) of ethyl 4-[[1-[(2-methyl-5-oxazolyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinecarboxylate (comp. 2).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[C:24]([N:32]1[C:36]([CH3:38])([CH3:37])[CH2:35][NH:34][C:33]1=[O:39])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:24]([N:32]1[C:36]([CH3:37])([CH3:38])[CH2:35][N:34]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([C:16]4[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=4)[CH2:12][CH2:11]3)=[O:9])=[CH:4][CH:3]=2)[C:33]1=[O:39])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: CC1(C)CNC(=O)N1C(=O)c1ccccc1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(C)(C)N(C(=O)c5ccccc5)C4=O)cc3)CC2)c(C)c1
Yield: 56.1 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-benzoyl-5,5-dimethylimidazolidin-2-one (105 mg) described in Preparation Example 58 and by the reaction and treatment in the same manner as in Example 1, the title compound (115 mg) was obtained.
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([C:16]2(O)[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH:10]=1.C(=O)(O)[O-].[Na+]>>[F:8][C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]([C:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH:17]=2)[CH:10]=1
Reactant: Cc1ccc(F)cc1C1(O)CCC(=O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1C1=CCC(=O)CC1
Reaction time: 0.17 h

Procedure:
To 25 ml. of well stirred trifluoroacetic acid, 5.35 g. of 4-(p-fluoro-o-tolyl)-4-hydroxycyclohexanone (obtained as in Example 47) is added. After about 10 minutes, the mixture is poured into an excess of aqueous sodium bicarbonate solution and the material that precipitates is extracted with ether. The extract is washed with aqueous sodium bicarbonate solution, water and brine and then evaporated to dryness to give 4(p-fluoro-o-tolyl)-3-cyclohexen-1-one.