Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28].[I-].[Na+].[CH3:31][NH:32][CH3:33]>O1CCCC1.C(OCC)(=O)C>[CH3:31][N:32]([CH3:33])[CH2:2][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[C:10]([C:15]#[N:16])[CH:11]=[N:12]2)=[CH:7][C:6]=1[O:27][CH3:28]
Reactant: CNC
Reactant: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCCl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Nc3ccc4cn[nH]c4c3)c(C#N)cnc2cc1OCCN(C)C
Temperature: 135 °C
Yield: 46 %

Procedure:
A mixture of 0.67 g (1 equivalent) of 7-(2-chloroethoxy)-4-(1H-indazol-6-ylamino)-6-methoxyquinoline-3-carbonitrile, 0.097 g (0.4 equivalent) of sodium iodide and 15 ml of 2M dimethylamine in tetrahydrofuran was heated at 135° C. for 14 hours in a sealed tube. The reaction mixture was diluted with ethyl acetate, washed with saturated sodium bicarbonate, the organic layer was dried over magnesium sulfate and concentrated to give 0.50 g. The crude product was purified by chromatography (Silica Gel: ethyl acetate, ethyl acetate/methyl alcohol/triethylamine 6:4:0.1) to give 0.312 g (46%) of pure product. MP 218-219° C. mass spectrum (electrospray m/e): M+H=402.9.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].Br[C:19]1[C:28]2[C:23](=[C:24]([C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1.CC([O-])(C)C.[Na+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[F:32][C:29]([F:30])([F:31])[C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:23]=1[N:22]=[CH:21][CH:20]=[C:19]2[N:8]1[CH2:7][CH2:6][C:5]2([CH2:1][N:2]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:3][CH2:4]2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1cccc2c(Br)ccnc12
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC2(CCN(c3ccnc4c(C(F)(F)F)cccc34)CC2)C1
Yield: 40 %

Procedure:
A mixture of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (2.5 mmol, 1.0 eq.) and 4-bromo-8-(trifluoromethyl)quinoline (2.5 mmol, 1.0 eq.) and tBuONa (7.5 mmol, 3.0 eq.) in toluene (12 ml) was degassed with argon for 10 min. BINAP (0.15 mmol, 0.06 eq.) and Pd(OAc)2 (0.05 mmol, 0.02 eq.) were added and the reaction mixture obtained was heated under reflux for 14 h. The reaction mixture was filtered over Celite and the filtrate was concentrated in vacuo in order to obtain the crude product, which was purified by column chromatography (silica gel, 22-25% ethyl acetate in hexane), in order to obtain the desired product. Yield: 40%
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([F:18])=[C:14]([Cl:17])[CH:15]=2)/[C:10](=[CH:19]/[C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=2[O:27][C:28]([CH2:35][CH3:36])([C:31]([O:33][CH3:34])=[O:32])[CH2:29][CH3:30])/[C:9]1=[O:37])=O)(C)(C)C.[F:38][C:39]1[CH:40]=[CH:41][C:42]([CH3:54])=[C:43]([CH:45]=[N:46][C:47]([O:49][Si](C)(C)C)=[CH2:48])[CH:44]=1>C1(C)C=CC=CC=1>[Cl:17][C:14]1[CH:15]=[C:16]2[NH:8][C:9](=[O:37])[C:10]3([CH:19]([C:20]4[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=4[O:27][C:28]([C:31]([O:33][CH3:34])=[O:32])([CH2:29][CH3:30])[CH2:35][CH3:36])[CH2:48][C:47](=[O:49])[NH:46][CH:45]3[C:43]3[CH:44]=[C:39]([F:38])[CH:40]=[CH:41][C:42]=3[CH3:54])[C:11]2=[CH:12][C:13]=1[F:18]
Reactant: C=C(N=Cc1cc(F)ccc1C)O[Si](C)(C)C
Reactant: CCC(CC)(Oc1ccc(Cl)cc1/C=C1\C(=O)N(C(=O)OC(C)(C)C)c2cc(Cl)c(F)cc21)C(=O)OC
Solvent: Cc1ccccc1
Product: CCC(CC)(Oc1ccc(Cl)cc1C1CC(=O)NC(c2cc(F)ccc2C)C12C(=O)Nc1cc(Cl)c(F)cc12)C(=O)OC
Yield: 19 %

Procedure:
In a manner similar to the method described in Example 10d, E/Z-6-chloro-3-[5-chloro-2-(1-ethyl-1-methoxycarbonyl-propoxy)-benzylidene]-5-fluoro-2-oxo-2,3-dihydro-indole-1-carboxylic acid tert-butyl ester (1.4 g, 2.5 mmol) was reacted with 1-(5-fluoro-2-methyl-phenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene (8 mmol) in toluene (8 mL) to give the title compound (300 mg).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH:36]1([NH2:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>C(Cl)(Cl)Cl.C(OCC)(=O)C>[CH3:1][C@@H:2]1[CH2:20][C@H:19]([CH3:21])[C@@H:18]([OH:22])[CH2:17][C:15](=[O:16])[O:14][C@H:13]([C@H:23]2[C@H:27]([C:28]([OH:30])=[O:29])[CH2:26][CH2:25][CH2:24]2)[CH2:12][CH:11]=[CH:10][CH:9]=[C:8]([C:31]#[N:32])[C@H:7]([OH:33])[C@@H:6]([CH3:34])[CH2:5][C@H:4]([CH3:35])[CH2:3]1.[CH:36]1([NH-:42])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: NC1CCCCC1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)C/C=C/C=C(/C#N)[C@H](O)[C@@H](C)C1
Agent: C[C@@H]1C[C@H](C)C[C@H](C)[C@@H](O)CC(=O)O[C@H]([C@@H]2CCC[C@H]2C(=O)O)CC=CC=C(C#N)[C@H](O)[C@@H](C)C1
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: [NH-]C1CCCCC1
Reaction time: 3 h

Procedure:
To a mixed anhydride solution prepared from 200 mg (0.41 mmol) of borrelidin according to Example 3 234 μl (2 mmol, 203 mg) of cyclohexylamine were added. After stirring for 3 hours, the starting borrelidin (Rf=0.52) disappeared and the product (Rf=0.68) appeared, which was proved by thin-layer chromatography (silica gel plate, eluent system: chloroform/ethyl acetate 3:7). The reaction mixture was evaporated to dryness. The dry residue was dissolved in 100 ml of chloroform, washed with 3×30 ml of water, dried over sodium sulfate and evaporated to dryness. The dry residue was chromatographed on a silica gel column with mixtures of chloroform and methanol of increasing methanol content. The fractions containing the product eluting with a 96:4 eluting mixture were combined and evaporated to dryness. The structure of the thus-obtained solidifying oily product (205 mg) was confirmed by spectroscopic (PMR, CMR, TS) data.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[S:6][N:5]=1
Reactant: [Zn+]C1CCCC1
Reactant: CSc1nsc(Cl)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCC2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
1.00 g of 5-chloro-3-methylthio-1,2,4-thiadiazole and 244 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were dissolved in 12 ml of tetrahydrofuran under nitrogen atmosphere, 13.2 ml of solution of cyclopentyl zinc bromide in tetrahydrofuran (0.5 mol/l) was added thereto under ice-cooling taking for about 15 minutes, and the reaction mixture was stirred for 13 hours at room temperature. Then, the reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 710 mg of 3-methylthio-5-cyclopentyl-1,2,4-thiadiazole.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([OH:16])=O)=[CH:11][CH:12]=2)[CH:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2].[NH2:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][O:35][CH2:36][CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[O:16])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:25])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2C(Nc2ccc(Cl)cc2)C[C@@H]1C
Reactant: CC(C)(C)OC(=O)CCOCCOCCOCCN
Product: CC(=O)N1c2ccc(C(=O)NCCOCCOCCOCCC(=O)OC(C)(C)C)cc2[C@H](Nc2ccc(Cl)cc2)C[C@@H]1C
Yield: 102.1 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 29 mg of (2S)-1-acetyl-4-[(4-chlorophenyl)amino]-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 44 mg of tert-butyl 12-amino-4,7,10-trioxadodecanoate. Thus, 51 mg (100%) of the title compound was obtained as a colorless oily substance.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24](B2OC(C)(C)C(C)(C)O2)[CH:23]=1)=[O:14])([CH3:11])([CH3:10])[CH3:9].CCO.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[C:8]([O:12][C:13]([N:15]1[CH2:20][CH2:19][O:18][CH2:17][C@H:16]1[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([C:2]2[N:7]=[CH:6][CH:5]=[CH:4][N:3]=2)[CH:27]=1)=[O:14])([CH3:11])([CH3:9])[CH3:10]
Reactant: CC(C)(C)OC(=O)N1CCOC[C@H]1Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: Brc1ncccn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCOC[C@H]1Cc1cccc(-c2ncccn2)c1
Temperature: 80 °C

Procedure:
2-Bromopyrimidine (43 mg, 0.27 mmol) was added in one portion to a RT solution of (R)-3-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-morpholine-4-carboxylic acid tert-butyl ester B-7 (100 mg, 0.25 mmol) in dioxane (0.76 mL) under argon. EtOH (0.38 mL) was then added followed by 2M aq. Na2CO3 (0.38 mL, 0.74 mmol) and argon was bubbled through the resulting suspension for 1 min. Pd(dppf)Cl2.DCM (12 mg, 6 mol %) was added in one portion and the resulting mixture was heated to 80° C. for 2 h. The reaction mixture was cooled to RT, quenched into water and filtered through a celite plug washing with TBME. The layers were separated and the aqueous phase was extracted with TBME (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered through a second celite plug and evaporated in vacuo to give the crude product that was purified by prep. HPLC (method E) to give the title compound as a yellow oil. LC-MS B: tR=0.79 min; [M+H]+=356.05.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([NH:11][C:12]2[CH:16]=[C:15]([CH3:17])[NH:14][N:13]=2)[C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[CH:7]=1.[SH:18][C:19]1[CH:24]=[CH:23][C:22]([NH:25][C:26]([CH:28]2[CH2:30][CH2:29]2)=[O:27])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:17][C:15]1[NH:14][N:13]=[C:12]([NH:11][C:4]2[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=[C:2]([S:18][C:19]3[CH:20]=[CH:21][C:22]([NH:25][C:26]([CH:28]4[CH2:29][CH2:30]4)=[O:27])=[CH:23][CH:24]=3)[N:3]=2)[CH:16]=1
Reactant: Cc1cc(Nc2nc(Br)cn3ccnc23)n[nH]1
Reactant: O=C(Nc1ccc(S)cc1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(Sc3ccc(NC(=O)C4CC4)cc3)cn3ccnc23)n[nH]1

Procedure:
(6-Bromo-imidazo[1,2-a]pyrazin-8-yl)-(5-methyl-1H-pyrazol-3-yl)-amine (21 mg, 0.072 mmol), N-(4-mercaptophenyl)cyclopropanecarboxamide (28 mg, 0.145 mmol) and potassium carbonate (20 mg) were mixed in DMF (1 ml). This mixture was reacted in a microwave reactor at 170° C. for 15 minutes. DMF was removed in vacuo and the residue was purified by HPLC to afford the title compound Example 8 as an off-white solid. (11.9 mg). 1H NMR (400 MHz, DMSO) δ 10.39 (s, 1H) 7.99 (d, J=0.8 Hz, 1H) 7.96 (s, 1H) 7.70 (s, 1H) 7.69 (d, J=8.4 Hz, 2H) 7.49 (d, J=8.4 Hz, 2H) 6.03 (s, 1H) 2.14 (s, 3H) 1.75-1.82 (m, 1H) 0.77-0.81 (m, 2H). [M+H] calc'd for C20H19N7OS, 406; found, 406.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH:10]2[C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:21][N:22]=[C:23]=[O:24].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:21][NH:22][C:23](=[O:24])[O:20][C:16]1[CH:17]=[CH:18][CH:19]=[C:14]([CH:10]2[CH2:11][CH2:12][CH2:13][N:9]2[CH2:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:15]=1
Reactant: CN=C=O
Reactant: Oc1cccc(C2CCCN2CCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2CCc2ccccc2)c1
Reaction time: 4 h
Yield: 84 %

Procedure:
To a solution of 3-[1-(2-phenylethyl)-2-pyrrolidinyl]phenol (0.83 g) in dry tetrahydrofuran (40 ml) was added methyl isocyanate (0.20 ml) followed by milled potassium carbonate (0.51 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 4 hrs, filtered through a pad of celite, and the solids were washed with ethyl acetate. The combined filtrates were concentrated, and the residue was purified by flash column chromatography (silica gel 30-75% ether/heptane). The appropriate fractions were collected and concentrated to afford 0.84 g (84%) of product. The analytical sample was prepared by flushing the compound through alumina with ether.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(I)C=CC=CC=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O:17][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)O
Reactant: c1ccccc1
Solvent: Ic1ccccc1
Product: CC(=O)Oc1ccccc1

Procedure:
The procedure of Example 1 is repeated except that 5 mmols of benzene are employed instead of the phenyl iodide of Example 1. Also, an additional 10 mls. of acetic acid solvent is employed. After the 4 hours of reaction at 75° C., no detectable phenyl acetate is formed. This again underscores the criticality of use of an aryl iodide of this invention as catalyst.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH:18]([O:22][CH2:23][CH3:24])[C:19]([OH:21])=[O:20])=[CH:13][CH:12]=2)[C:3]2[CH:25]=[CH:26][CH:27]=[CH:28][C:2]1=2.[OH-].[Mg+2:30].[OH-]>>[Mg+2:30].[CH2:23]([O:22][CH:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:28]=[CH:27][CH:26]=[CH:25][C:3]2=3)=[CH:16][CH:15]=1)[C:19]([O-:21])=[O:20])[CH3:24].[CH2:23]([O:22][CH:18]([CH2:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][CH2:9][CH2:8][CH2:7][N:4]2[CH2:5][CH2:6][O:1][C:2]3[CH:28]=[CH:27][CH:26]=[CH:25][C:3]2=3)=[CH:16][CH:15]=1)[C:19]([O-:21])=[O:20])[CH3:24]
Reactant: CCOC(Cc1ccc(NCCCN2CCOc3ccccc32)cc1)C(=O)O
Agent: [Mg+2]
Agent: [OH-]
Product: CCOC(Cc1ccc(NCCCN2CCOc3ccccc32)cc1)C(=O)[O-]
Temperature: 50 °C

Procedure:
A mixture of methanolic solution (2 ml) of 2-ethoxy-3-[4-{3-(3,4-dihydro-2H-benzo[b][1,4]oxazin-4-yl)propylamino}phenyl]propanoic acid (75 mg, 1 eq, 0.19 mmol) obtained in example 2 and magnesium hydroxide (5.6 mg, 0.5 eq, 0.095 mmol) was heated at 50° C. for 5 h. The resulting solution was condensed, azeotroped with benzene and then finally dried on high vacuum pump to obtain the title compound as freed flowing solid (100% yield, mp: 132-134° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH3:32])[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[O:25])[CH:22]=3)[C:17]([S:33][CH3:34])=[CH:16]2)=[N:13][CH:14]=1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[C:9]1[CH:10]=[N:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:24]([N:26]([CH3:32])[CH2:27][C:28]([NH:30][CH3:31])=[O:29])=[O:25])[CH:22]=3)[C:17]([S:33]([CH3:34])=[O:40])=[CH:16]2)=[N:13][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CNC(=O)CN(C)C(=O)c1ccc2c(SC)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1
Solvent: ClCCl
Product: CNC(=O)CN(C)C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4cc(C)ccc4F)cn3)c2c1

Procedure:
Oxidation of 304d) (0.1 g, 0.209 mmol) with m-chloroperoxybenzoic acid (77%, 0.038 g, 0.167 mmol) in dichloromethane (10 mL). White solid. Yield: 0.065 g (63% of theory)
Reaction SMILES: C([O:3][C:4](=O)[C:5](Br)=[C:6](Br)[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1)C.Cl.[NH2:21][OH:22].[OH-].[Na+]>>[OH:3][C:4]1[CH:5]=[C:6]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=2)[O:22][N:21]=1
Reactant: CCOC(=O)C(Br)=C(Br)c1ccc(C(F)(F)F)cc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Oc1cc(-c2ccc(C(F)(F)F)cc2)on1
Yield: 81.3 %

Procedure:
α,β-Dibromo-4-trifluoromethylcinnamic acid ethyl ester (17.9 g), hydroxylamine hydrochloride (3.8 g) and sodium hydroxide (9.1 g) were subjected to reaction and post-treatment in a similar manner to that described in Reference example 10(c) to obtain the title compound (8.3 g, 83%) as colorless crystals.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][CH:3]=1.C1C(=O)N([Cl:21])C(=O)C1>C1COCC1>[Cl:21][C:7]1[CH:6]=[C:5]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:4]=[CH:3][C:2]=1[OH:1]
Reactant: CCOC(=O)Cc1ccc(O)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Product: CCOC(=O)Cc1ccc(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 116.5 %

Procedure:
To a 0° C. solution of ethyl 2-(4-hydroxyphenyl)acetate (5.0 g, 0.02 mol) in THF (100 mL) was added NCS (4.45 g, 0.03 mol). The reaction mixture was then stirred at RT for 16 h and then extracted with EtOAc (2×200 mL). The combined organic layers were washed with water, dried over Na2SO4, and concentrated in vacuo to afford ethyl 2-(3-chloro-4-hydroxyphenyl)acetate (5 g, 84%) as a solid.
Reaction SMILES: C([O:8][C:9](=[O:33])[CH2:10][C@@H:11]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=3)=[CH:23][CH:22]=2)=[CH:17]1)[C:12]([NH:14][CH3:15])=[O:13])C1C=CC=CC=1>C(O)(=O)C>[CH3:15][NH:14][C:12](=[O:13])[C@H:11]([N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]3[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=3)=[CH:23][CH:22]=2)=[CH:17]1)[CH2:10][C:9]([OH:33])=[O:8]
Reactant: CNC(=O)[C@@H](CC(=O)OCc1ccccc1)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Solvent: CC(=O)O
Product: CNC(=O)[C@@H](CC(=O)O)n1ccc(-c2ccc(-c3ccncc3)cc2)c1
Yield: 90 %

Procedure:
According to the procedure described in Example 7(a), N-methyl-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid benzyl ester was hydrogenolyzed in acetic acid to yield in 90% yield N-methyl-3(R)-[3-[4-(pyridin-4-yl)phenyl]-1H-pyrrol-1-yl]succinamic acid as a yellow amorphous solid. 1HNMR (DMSO-d6): δ 8.58 (d, 2H, J=5.9 Hz), 7.75 (d, 2H, J=8.1 Hz), 7.71 (d, 2H, J=6.2 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.29 (s, 1H), 6.77 (t, 1H, J=2.2 Hz), 6.42 (t, 1H, J=2.2 Hz), 4.80 (d, 1H, J=10.7 Hz), 3.16 (dd, 1H, J=15.8, 11.0 Hz), 2.36 (s, 3H). Anal. Calculated for C20H19N3O3.1.0 H2O.0.33 AcOH: C, 64.08; H, 5.81; N, 10.85. Found: C, 64.23, 64.16; H, 5.66, 5.67; N, 10.83, 10.78.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.[CH2:22]([NH:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[CH3:23]>C(Cl)(Cl)(Cl)Cl.C(OCC)C.O>[CH2:22]([N:24]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])[C:13](=[O:15])[CH2:12][CH2:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH3:23]
Reactant: CCCCCCCNCC
Reactant: O=C(O)CCCc1ccc([N+](=O)[O-])cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Solvent: O
Product: CCCCCCCN(CC)C(=O)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 128 %

Procedure:
A 500 ml round bottom flask fitted with an addition funnel and a calcium sulfate drying tube was charged with 8.0 g (0.03 mol) of 4-(4-nitrophenyl)butyric acid in 180 ml of carbon tetrachloride. To this stirred solution was added 16.5 ml (0.19 mol) of oxalyl chloride dropwise. The addition funnel was removed and a condenser was fitted onto the flask. The reaction mixture was refluxed for 3 hours, cooled and the excess oxalyl chloride was evaporated under reduced pressure. Approximately 100 ml of dry diethyl ether was added to the solution which was subsequently cooled in ice. To this cooled solution was added 16.3 g (0.115 mol) of ethylheptylamine dissolved in approximately 60 ml of diethyl ether. The resulting reaction mixture was stirred at room temperature overnight and diluted with a mixture of water and diethyl ether. The aqueous phase was separated and further extracted three times with diethyl ether. The organic extracts were combined, washed with water, hydrochloric acid, water (2×), a 10% aqueous sodium carbonate solution and a saturated sodium chloride solution. The organic phase was separated, dried over anhydrous sodium sulfate and evaporated to dryness under reduced pressure to provide 12.847 g of N-ethyl-N-heptyl-4-nitrobenzenebutanamide as an oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:16][CH2:17][CH3:18])[CH2:5][CH2:6][CH2:7][NH:8]C(OC(C)(C)C)=O)[CH2:2][CH3:3].Cl.O1CCOCC1>CO>[CH2:16]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][NH2:8])[CH2:17][CH3:18]
Reactant: CCCN(CCC)CCCNC(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CCCN(CCC)CCCN
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 44.4 %

Procedure:
The compound (2.67 g) obtained in Example 22-2 was dissolved in anhydrous methanol (2.0 ml) and then added with a 4 mol/l hydrogen chloride/dioxane solution (20.0 ml), followed by stirring at room temperature for 1.5 hours. After completion of the reaction, the solvent was distilled off. Then, the residue was added with a 1 mol/l sodium hydroxide aqueous solution and extracted with dichloromethane. The extract was washed with distilled water and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. Subsequently, the solvent was distilled off, thereby obtaining the subject compound (726 mg) as a pale-yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:33](=O)[CH3:34].C(O)(=O)C.C([BH3-])#N.[Na+]>ClCCl.CO.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH2:22]/[CH:23]=[CH:24]/[C:25]3[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=3)[C:28]#[N:29])[CH2:33][CH3:34])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC/C=C/c3cccc(C#N)c3)cc2)CC1
Reactant: CC=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: CCN(C/C=C/c1cccc(C#N)c1)c1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)cc1
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 3-[3-[N-[4-(1-t-butoxycarbonylpiperidin-4-yloxy)phenyl]amino]-1-(E)-propenyl]benzonitrile (1000 mg) and acetaldehyde (0.52 ml) in a mixture of dichloromethane (10 ml) and methanol (20 ml) were added acetic acid (0.26 ml) and sodium cyanoborohydride (144 mg) in an ice bath. The mixture was stirred at the same temperature for 2 hours and then at room temperature overnight. To the reaction mixture was added water, and the mixture was then extracted with ethyl acetate. The extractant was washed with brine, dried over anhydrous magnesium sulfate and filtered, and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=4/1→2/1 as an eluant to give the desired compound (661 mg, yield 62%) as a yellow oil.