Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=3)[N:13]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:37][C:38]1[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=1>C(Cl)Cl.CCOC(C)=O.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]([CH3:34])[C:12]2[N:17]=[C:16]([N:18]3[CH2:19][CH2:20][N:21]([CH2:37][C:38]4[CH:39]=[N:40][CH:41]=[CH:42][CH:43]=4)[CH2:22][CH2:23]3)[N:15]=[C:14]([NH:24][CH2:25][CH2:26][C:27]3[CH:28]=[CH:29][C:30]([OH:33])=[CH:31][CH:32]=3)[N:13]=2)=[CH:4][CH:3]=1
Reactant: ClCc1cccnc1
Reactant: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCNCC2)n1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CN(CCCc1ccc(Cl)cc1)c1nc(NCCc2ccc(O)cc2)nc(N2CCN(Cc3cccnc3)CC2)n1
Yield: 48 %

Procedure:
The title compound was prepared in 48% yield via the procedure outlined for Example 5 using 4-(2-{[4-[[3-(4-chlorophenyl)propyl](methyl)amino]-6-(1-piperazinyl)-1,3,5-triazin-2-yl]amino}ethyl)phenol and 3-chloromethyl pyridine hydrochloride to give an off-white glass: 1H NMR (CDCl3, 400 MHz) δ 8.49-8.44 (m, 2H), 7.63 (d, 1H, J=7.6), 7.22 (t, 1H, J=4.8), 7.19-7.13 (m, 2H), 7.12-7.01 (m, 2H), 6.94 (d, 2H, J=8.0), 6.63 (d, 2H, J=8.0), 3.85-3.60 (m, 4H), 3.60-3.45 (m, 6H), 2.98 (s, 3H), 2.70 (t, 2H, J=6.4), 0.51 (m, 2H), 2.35 (m, 4H), 1.79(m, 2H); low resolution MS (ES+) m/e 574 (MH+); TLC (CH2Cl2/EtOAc/MeOH (5:5:1): Rf=0.43; Anal. calcd. for C31H37N8OCl: C, 64.96; H, 6.51; N, 19.55. Found: C, 64.72; H, 6.58; N, 19.46.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[CH3:8].Cl.O=[C:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH:13]1[C:18](OC)=[O:19]>>[CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]2[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[C:18](=[O:19])[O:9][C:4]=2[CH:3]=1
Reactant: Cc1ccc(O)cc1C
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Product: Cc1cc2oc(=O)c3c(c2cc1C)CCNC3
Yield: 84.2 %

Procedure:
Prepared by the method described in Example 1 from 3,4-dimethylphenol (10.0 g, 0.082 moles) and methyl 4-oxo-3-piperdinecarboxylate hydrochloride (11.3 g, 0.058 moles). Recrystallization from 2-methoxyethanol yielded the product (11.2 g), mp 172°-l74° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1O[CH:6]=[CH:7][C:8](=[O:18])[C:9]=1[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O.[CH2:20]([NH2:22])[CH3:21].[OH-].[Na+]>C(O)C>[CH2:20]([N:22]1[CH:6]=[CH:7][C:8](=[O:18])[C:9]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[C:4]1[CH2:3][O:2][CH3:1])[CH3:21]
Reactant: CCN
Reactant: COCc1occc(=O)c1OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCn1ccc(=O)c(OCc2ccccc2)c1COC
Temperature: 70 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of 2-methoxymethyl-3-benzyloxy-pyran-4(1H)-one (2.46 g, 10 mmol, 1 eq.) in ethanol (10 ml)/water (10 ml) was added 1.93 g (30 mmol, 3 eq.) of 70% aqueous ethylamine followed by 2N sodium hydroxide solution until pH 13 was obtained. The reaction mixture was sealed in a thick-walled glass tube and stirred at 70° C. overnight. After adjustment to pH 1 with concentrated hydrochloric acid, the solvent was removed by rotary evaporation prior to addition of water (50 ml) and washing with diethyl ether (3×50 ml). Subsequent adjustment of the aqueous fraction to pH 7 with 10N sodium hydroxide solution was followed by extraction into dichloromethane (4×50 ml), the combined organic layers then being dried over anhydrous sodium sulphate, filtered and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (eluant: 15% CH3OH/85% CHCl3) to afford the title compound (2.05 g, 75.1%) as a yellow oil.
Reaction SMILES: C([CH:3]([C:7]1([CH3:20])[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[N+:16]([O-])=O)[NH:9][C:8]1=S)[C:4]([O-:6])=[O:5])C.[BH4-].[Na+].[CH2:23]1COC[CH2:24]1>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[NH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[C:7]([CH2:3][C:4]([O:6][CH2:23][CH3:24])=[O:5])([CH3:20])[CH2:8][NH:9]2
Reactant: CCC(C(=O)[O-])C1(C)C(=S)Nc2cccc([N+](=O)[O-])c21
Reactant: C1CCOC1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCOC(=O)CC1(C)CNc2cccc(N)c21
Reaction time: 0.17 h

Procedure:
To a solution of (±)-ethyl (3-methyl-4-nitro-2-thioxo-2,3-dihydro-1H-indol-3-yl)acetate from Step A (3.65 g, 12.4 mmol) and nickel (II) chloride hexahydrate (23.6 g, 99.2 mmol) in MeOH (30 mL) and THF (30 mL), at 0° C., was added NaBH4 (11.3 g, 298 mmol) in portions over 1 h. The resulting mixture was stirred for 10 min, then filtered through a pad of Celite, washing with MeOH, and the filtrate was concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with CH2Cl2:MeOH—90:10, to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]#[CH:9])[CH:5]=[C:4]([Cl:10])[CH:3]=1.[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/I)[CH3:12].O>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>[CH2:11]([O:13][C:14](=[O:18])/[CH:15]=[CH:16]/[C:9]#[C:8][C:6]1[CH:7]=[C:2]([Cl:1])[CH:3]=[C:4]([Cl:10])[CH:5]=1)[CH3:12]
Reactant: C#Cc1cc(Cl)cc(Cl)c1
Reactant: CCOC(=O)/C=C/I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)/C=C/C#Cc1cc(Cl)cc(Cl)c1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
To a solution of 1,3-dichloro-5-ethynyl-benzene (1.52 g, 8.9 mmol) in triethylamine (32.4 mL) was added PdCl2(PPh3)2 (57.15 mg, 0.08 mmol), (E)-3-iodo-prop-2-enoic-acid ethyl ester (1.84 g, 8.1 mmol) and copper(I)iodide (7.7 mg, 0.04 mmol). The reaction mixture was stirred for 2 h at 50° C., whereafter the reaction mixture was cooled to room temperature, water (30 mL) added and the mixture extracted with diethyl ether (3×20 mL). The combined and dried organic phases were evaporated to give crude (E)-5-(3,5-dichlorophenyl)-pent-2-en-4-ynoic acid ethyl ester in 1.1 g yield.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:31][CH2:30][NH:29][CH2:28][CH:27]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)cc4s3)CC2)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.9 %

Procedure:
To a solution of tert-butyl 4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridine-1(2H)-carboxylate (166 mg, 0.310 mmol) in CH2Cl2 (3 mL) was added TFA (0.358 mL, 4.65 mmol). Upon completion of addition, the reaction mixture was stirred at rt for 3 hrs. After this time, the reaction mixture was diluted with CH2Cl2 (10 mL) and washed with aq NaOH (1 N, 5 mL) and brine (5 mL) and then dried (Na2SO4). The resulting mixture was filtered and concentrated under reduced pressure to afford Compound 1E as a light yellow solid (124 mg, 0.285 mmol, 92% yield). 1H NMR (400 MHz, chloroform-d) δ ppm 8.17 (2H, s), 7.59-7.68 (2H, m), 7.42 (1H, dd, J=8.5, 1.9 Hz), 6.11-6.21 (1H, m), 5.39-5.55 (1H, m), 4.23 (2H, ddd, J=13.3, 6.8, 3.9 Hz), 3.62-3.77 (2H, m), 3.56 (2H, q, J=2.6 Hz), 3.14 (2H, t, J=5.7 Hz), 2.46-2.55 (2H, m), 2.41 (2H, t, J=7.6 Hz), 2.13-2.24 (2H, m), 1.88-2.00 (2H, m), 1.52-1.61 (3H, m), 0.95 (3H, t, J=7.5 Hz).
Reaction SMILES: [F:1][C:2]([F:47])([F:46])[C:3]1[CH:4]=[C:5]([C:13]([CH3:45])([CH3:44])[C:14]([N:16]([CH3:43])[C:17]2[C:18]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[CH3:42])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29]OS(C)(=O)=O)[CH2:25][CH2:24]3)=[N:21][CH:22]=2)=[O:15])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:48][S-:49].[Na+].[OH-].[Na+]>CN(C=O)C>[F:11][C:9]([F:12])([F:10])[C:7]1[CH:6]=[C:5]([C:13]([CH3:45])([CH3:44])[C:14]([N:16]([C:17]2[C:18]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][C:36]=3[CH3:42])=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH:26]([CH2:29][S:49][CH3:48])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH3:43])=[O:15])[CH:4]=[C:3]([C:2]([F:1])([F:47])[F:46])[CH:8]=1
Reactant: Cc1cc(F)ccc1-c1cc(N2CCC(COS(C)(=O)=O)CC2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: C[S-]
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSCC1CCN(c2cc(-c3ccc(F)cc3C)c(N(C)C(=O)C(C)(C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)cn2)CC1
Temperature: 25 °C
Yield: 92.8 %

Procedure:
A solution of 0.29 g (0.42 mmol) methanesulfonic acid 5′-{[2-(3,5-bis-trifluoromethyl-phenyl)-2-methyl-propionyl]-methyl-amino}-4′-(4-fluoro-2-methyl-phenyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-ylmethyl ester and 44 mg (0.63 mmol) sodium methanethiolate in 8 ml DMF was heated at 80° C. for 30 min. After cooling to room temperature the reaction mixture was treated with a 1 N aqueous sodium hydroxide solution and extracted with three portions of tert-butyl methyl ether. The combined organic extracts were dried over sodium sulphate and concentrated. Flash column chromatography gave 0.25 g (92%) of the title compound as a white solid.
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([C:11]([F:14])([F:13])[F:12])[CH:5]=1)([CH3:3])[CH3:2].C(N(CC)CC)C.[Br:22][CH2:23][C:24](Br)=[O:25]>ClCCl>[Br:22][CH2:23][C:24]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][C:6]=1[C:11]([F:12])([F:13])[F:14])=[O:25]
Reactant: O=C(Br)CBr
Reactant: CC(C)c1ccc(N)c(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)c1ccc(NC(=O)CBr)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
50 g (246.06 mmol) of 4-isopropyl-2-(trifluoromethyl)aniline and 27.39 g (270.66 mmol) of triethylamine are initially charged in 1000 ml of dichloromethane. At 0°-5° C., 54.63 g (270.66 mmol) of bromoacetyl bromide, dissolved in 200 ml of dichloromethane, are added dropwise. The mixture is stirred at room temperature for 20 hours. The reaction mixture is then extracted successively with water, 1 N hydrochloric acid, water, saturated sodium bicarbonate solution and water. The organic phase is dried over sodium sulphate and the solvent is removed under reduced pressure. The residue is purified chromatographically. The product is recrystallized from cyclohexane/n-pentane, filtered off with suction and dried under reduced pressure at 40° C. for 20 hours. This gives 32.45 g (41% of theory) of the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[C:4]([CH3:7])([CH3:6])[CH3:5].[NH2:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.P(Cl)(Cl)(Cl)=O.[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32]>C1C=CC=CC=1.CO>[C:28]([OH:35])(=[O:34])/[CH:29]=[CH:30]/[C:31]([OH:33])=[O:32].[CH3:1][NH:2][C:3](=[N:9][C:10]1[CH:22]=[CH:21][CH:20]=[CH:19][C:11]=1[CH2:12][N:13]1[CH2:14][CH2:15][O:16][CH2:17][CH2:18]1)[C:4]([CH3:7])([CH3:6])[CH3:5]
Reactant: Nc1ccccc1CN1CCOCC1
Reactant: CNC(=O)C(C)(C)C
Agent: O=C(O)/C=C/C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CO
Solvent: c1ccccc1
Product: CNC(=Nc1ccccc1CN1CCOCC1)C(C)(C)C

Procedure:
A mixture of N-methylpivalamide (6.2 g) in benzene (50 ml), 4-(2-aminobenzyl)morpholine (9 g) in benzene (40 ml) and phosphorus oxychloride (5 ml) was heated at 80°-85° C. for 12 hours to yield a solid which was dissolved in methanol (25 ml) and treated with fumaric acid (1.4 g) to give N-methyl-N'-(2-morpholinomethylphenyl)pivalamidine monofumarate (m.p. 167°-168° C.) which was recrystallised from propan-2-ol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8]C)[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21]C)[CH:17]=2)[CH:12]=1.B(Br)(Br)Br>>[F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:10])=[CH:4][C:3]=1[C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[CH:17]=[C:16]([OH:21])[CH:15]=[CH:14]2
Reactant: COc1ccc2cc(-c3cc(F)c(OC)cc3F)ccc2c1
Agent: BrB(Br)Br
Product: Oc1ccc2cc(-c3cc(F)c(O)cc3F)ccc2c1

Procedure:
The title compound was prepared by 2-(2,5-difluoro-4-methoxyphenyl)-6-methoxynaphthalene (1.5 g, 5.0 mmol) with boron tribromide (25 mL of 1.0 M solution in CH2Cl2, 25 mmol) according to method D to yield 1.28 g (94%) of a yellowish solid: mp 217–219° C.; 1H NMR (DMSO-d6) δ 6.90 (1H, dd, J=11.87 Hz, J=7.51 Hz), 7.10–7.15 (2H, m), 7.45 (1H, dd, J=11.87, J=7.61 Hz), 7.53–7.55 (1H, m), 7.74 (1H, d, J=8.65 Hz), 7.92 (1H, s), 9.85 (1H, s), 10.50 (1H, s); MS (ESI) m/z 271 (M−H)−.
Reaction SMILES: [F-:1].[K+].[F:3][C:4]([F:15])([C:11]([F:14])([F:13])[F:12])[C:5]([F:10])([F:9])[C:6]([F:8])=[O:7].S(F)(F)(F)F.S(F)(O[C:25]([F:32])([F:31])[C:26]([F:30])=[C:27]([F:29])[F:28])(=O)=O>COCCOCCOC>[F:28][C:27]([F:29])=[C:26]([F:30])[C:25]([F:32])([F:31])[O:7][C:6]([F:1])([F:8])[C:5]([F:10])([F:9])[C:4]([F:15])([F:3])[C:11]([F:12])([F:13])[F:14]
Reactant: O=S(=O)(F)OC(F)(F)C(F)=C(F)F
Reactant: [F-]
Reactant: O=C(F)C(F)(F)C(F)(F)C(F)(F)F
Agent: FS(F)(F)F
Agent: [K+]
Solvent: COCCOCCOC
Product: FC(F)=C(F)C(F)(F)OC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
A mixture of dry potassium fluoride (7.50 g, 0.13 mol), diglyme (100 ml) and heptafluorobutyroyl fluoride (prepared from the acid by treatment with sulfur tetrafluoride) (28.1 g, 0.13 mol) was stirred at 5° C. for 30 min. Perfluoroallyl fluorosulfate was added dropwise at 5° C., the mixture was stirred at this temperature for 1 hour, then at 25° C. for 3 hours. The volatile components were transferred by distillation at 40° C. (8 mm Hg), washed with water (100 ml), and distilled from a small amount of concentrated sulfuric acid to give perfluoro-3-(butoxy)propene (30.3 g, 0.083 mol, 64%) bp 80°-84° C. whose structure was confirmed by:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C@@H:11]([NH2:13])[CH3:12])=[CH:3][CH:2]=1.C([O:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[C:27]1[CH:32]=[CH:31][C:30]([CH2:33][N:34]2[C:42]3[C:37](=[CH:38][C:39]([C:43](O)=[O:44])=[CH:40][CH:41]=3)[C:36]([CH3:46])=[C:35]2[CH3:47])=[CH:29][CH:28]=1)=[O:20])(C)(C)C>>[CH3:47][C:35]1[N:34]([CH2:33][C:30]2[CH:31]=[CH:32][C:27]([C:22]3[C:21]([C:19]([OH:20])=[O:18])=[CH:26][CH:25]=[CH:24][CH:23]=3)=[CH:28][CH:29]=2)[C:42]2[C:37]([C:36]=1[CH3:46])=[CH:38][C:39]([C:43](=[O:44])[NH:13][C@H:11]([C:4]1[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=1)[CH3:12])=[CH:40][CH:41]=2
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)c1ccnc2ccccc12
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)c3ccnc4ccccc34)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (S)-1-(quinolin-4-yl)ethanamine and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 554 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N+:10]([O-])=O.[C:13]([OH:18])(=[O:17])[C:14]([CH3:16])=O>CO.[Pd]>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][CH:14]([CH3:16])[C:13]([OH:18])=[O:17]
Reactant: CC(=O)C(=O)O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1F
Agent: [Pd]
Solvent: CO
Product: CC(Nc1ccc(F)c(F)c1F)C(=O)O
Temperature: 40 °C
Reaction time: 5 h
Yield: 96 %

Procedure:
2,3,4-Trifluoronitrobenzene (1.01 g) and pyruvic acid (0.75 g) were dissolved in methanol (8 ml). After adding 5% Pd—C (0.11 g), the mixture was stirred at 40° C. under a hydrogen gas pressure of 4.9 MPa (converted from 50 kgf/cm2) for 5 hours. After filtering off Pd—C, the obtained filtrate was concentrated under reduced pressure. Thus the title compound (1.20 g) was obtained as colorless crystals. Various spectral data of this product was identical with those of a specimen synthesized separately.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([O:18][CH3:19])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][C:3]=1C(O)=O.N1C2C(=CC=CC=2)C=CC=1.Cl>[Cu].C(Cl)(Cl)Cl>[CH3:1][C:2]1[C:6]2[C:7]([O:18][CH3:19])=[CH:8][CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2cccs2)c2oc(C(=O)O)c(C)c12
Agent: [Cu]
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccc2ncccc2c1
Product: COc1ccc(C(=O)c2cccs2)c2occ(C)c12
Temperature: 210 °C
Reaction time: 0.08 h

Procedure:
An intimate mixture of compound 2 (3.50 g, 11.0 mmol), quinoline (7 mL), and copper powder (0.70 g, 11.0 mol) was carefully heated to 210° C. and maintained at that temperature until gas evolution ceased (about 10 minutes). The resulting mixture was cooled to 80° C. and poured into 1N HCl (120 mL). Chloroform (50 mL) was added and the mixture stirred for 5 minutes and filtered through a pad of celite. The pad was washed with an additional portion of chloroform (25 mL). The organic layer was separated and the aqueous layer extracted with additional portions of chloroform (2×50 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The crude product was purified by preparative HPLC using 15% ethyl acetate in hexane as eluant to afford 3-methyl-4-methoxy-7-(2-thienoyl)benzofuran. mp 131°-134° C.; 1H NMR d 2.40 (3H, d, J=1 Hz), 4.02 (3H, s), 6.71 (1H, d, J=8 Hz), 7.17 (1H, m), 7.38 (1H, d, J=1 Hz), 7.70 (3H, m).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH3:20][Li]>O1CCCC1>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]([OH:11])[CH3:20])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: [Li]C
Solvent: C1CCOC1
Product: CCCCc1ncc(C(C)O)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazole-5-carboxaldehyde (1.1 g, 3.97 mmol) was dissolved in dry tetrahydrofuran (15 mL), cooled to -78° C. under argon, and a solution of methyl lithium (3.64 mL of 1.2M in diethyl ether, 4.57 mmol) was added dropwise. The mixture was stirred for 1.5 hours, quenched with ammonium chloride solution, warmed to ambient temperature and extracted with ethyl acetate. The washed, dried, concentrated product was flash chromatographed over silica gel with ethyl acetate to provide 1.07 g (92%) of 2-n-butyl-1-(2-chlorophenyl)methyl-5-(a-hydroxy)ethyl-1H-imidazole.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][CH:10]=[CH:9][C:3]=1[NH:4][C:5]([O:7][CH3:8])=[O:6].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17](Br)[CH:18]([CH3:20])[CH3:19]>C(Cl)Cl>[C:18]([C:11]1[CH:10]=[CH:9][C:3]([NH:4][C:5]([O:7][CH3:8])=[O:6])=[C:2]([F:1])[CH:12]=1)([CH3:20])([CH3:19])[CH3:17]
Reactant: COC(=O)Nc1ccccc1F
Reactant: CC(C)CBr
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COC(=O)Nc1ccc(C(C)(C)C)cc1F
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 111.2 %

Procedure:
2-Fluoro-N-methoxycarbonylaniline (500 mg, 3.11 mmol) was dissolved in methylene chloride (20 mL) to prepare a solution. Anhydrous aluminum chloride (986 mg, 7.77 mmol) was added to the solution, and the mixture was stirred at 40° C. for 20 min. Thereafter, the reaction solution was cooled to room temperature. A solution of isobutyl bromide (1.60 mL, 15.5 mmol) in a methylene chloride solution (6 mL) was added dropwise to the cooled reaction mixture while bubbling argon gas over a period of 10 min. The mixture was stirred for one hr. Water was added thereto, followed by separation of an organic layer. The organic layer was washed with water and was dried over anhydrous magnesium sulfate. The solvent was then removed from the dried organic layer by distillation to give 779 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline as a crude product. The crude product was further subjected to separation and purification by column chromatography on silica gel to give 433 mg of 4-t-butyl-2-fluoro-N-methoxycarbonylaniline (yield 64.0%, 4-t-butyl form: 5-t-butyl form=88:12).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:5]2[C:6]3[S:7][CH:8]=[CH:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.[Cu](C#N)[C:17]#[N:18]>CN(C=O)C.CCOC(C)=O>[S:7]1[C:6]2[C:5]3[CH:14]=[CH:15][C:2]([C:17]#[N:18])=[CH:3][C:4]=3[O:13][CH2:12][CH2:11][C:10]=2[CH:9]=[CH:8]1
Reactant: Brc1ccc2c(c1)OCCc1ccsc1-2
Reactant: N#C[Cu]C#N
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1ccc2c(c1)OCCc1ccsc1-2
Yield: 124.3 %

Procedure:
A solution of 8-bromo-4,5-dihydro-6-oxa-1-thia-benzo[e]azulene (0.500 grams, 1.77 mmol) and copper cyanide (0.48 grams, 5.30 mmol) in 10 ml of DMF was flash heated on Biotage microwave. The reaction mixture was diluted with a large volume of EtOAc and this solution was filtered through celite by vacuum filtration. The filtrate was plated onto a 1/1 mixture on silica/celite and dry load purified by MPLC on a 14 gram silica column eluting with 10 to 80% EtOAc/heptanes to give 500 mg (123%) of 4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carbonitrile as determined by LC/MS.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15](O)=[O:16])=[CH:10][CH:9]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:28])=CC=1>C1(C)C=CC=CC=1>[O:1]=[C:2]1[CH2:6][S:5][CH2:4][CH:3]1[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:16])=[S:28])=[CH:10][CH:9]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C(=O)O)c1ccc(CC2CSCC2=O)cc1
Solvent: Cc1ccccc1
Product: CC(C(O)=S)c1ccc(CC2CSCC2=O)cc1
Yield: 52.2 %

Procedure:
2-[4-(4-Oxothiolan-3-ylmethyl)phenyl]propionic acid (300 mg) obtained in Example 8 was dissolved in toluene (3.0 ml), and to the solution was added the Lawesson's reagent (729 mg), and then the reaction mixture was refluxed by heating for 4 hours. After completion of the reaction, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/1) to give the title compound (166 mg, 52.4%).
Reaction SMILES: [NH2:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[Cl:11][CH2:12][C:13](Cl)=[O:14].Cl>C1(C)C=CC=CC=1>[Cl:11][CH2:12][C:13]([NH:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8])=[O:14]
Reactant: O=C(Cl)CCl
Reactant: Cc1oc(N)c(C#N)c1C
Agent: Cl
Solvent: Cc1ccccc1
Product: Cc1oc(NC(=O)CCl)c(C#N)c1C
Yield: 122.3 %

Procedure:
20.4 g (0.1 mole) of 2-amino-3-cyano-4,5-dimethylfurane and 17.5 g (0.155 mole) of chloroacetyl chloride were boiled in 200 ml of toluene until the evolution of hydrogen chloride had subsided. Thereafter, the solvent was evaporated off under reduced pressure and the residue was recrystallized from ethyl acetate. 26 g of 2-chloroacetylamino-3-cyano-4,5-dimethylfurane of melting point 114° C. were obtained in this manner.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]#N.Cl[Si](C)(C)C.C(=O)([O-])[O-:20].[K+].[K+].O.[CH2:26]([OH:28])[CH3:27]>C(OCC)(=O)C>[F:1][CH:2]([F:13])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([O:28][CH2:26][CH3:27])=[O:20]
Reactant: N#CCc1ccccc1OC(F)F
Reactant: O=C([O-])[O-]
Reactant: CCO
Agent: C[Si](C)(C)Cl
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccccc1OC(F)F
Temperature: 50 °C
Reaction time: 5 h

Procedure:
(2-Difluoromethoxyphenyl)acetonitrile (1.45 g) was added dropwise to a solution of chlorotrimethylsilane (2.23 mL) in ethanol (2.0 mL), and the reaction solution was stirred at 50° C. for five hours. The reaction solution was left to cool to room temperature. Then, potassium carbonate, water and ethyl acetate were added and the organic layer was separated. The resulting organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate system) to obtain 620 mg of the title compound. The property values of the compound are as follows.