Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][N:11]3[C:7](=[N:8][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[CH:10]3)[C:6]=2[CH:23]=1.[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([SH:34])[CH2:30][CH2:29]1)([CH3:27])([CH3:26])[CH3:25].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([N:28]1[CH2:33][CH2:32][CH:31]([S:34][C:2]2[CH:3]=[CH:4][C:5]3[O:14][CH2:13][CH2:12][N:11]4[CH:10]=[C:9]([C:15]5[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=5)[N:8]=[C:7]4[C:6]=3[CH:23]=2)[CH2:30][CH2:29]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: CC(C)(C)N1CCC(S)CC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(Br)ccc1OCC2
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C)CC3)ccc1OCC2
Temperature: 120 °C

Procedure:
A mixture of 9-bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (100 mg, 0.27 mmol), 1-tert-butylpiperidine-4-thiol (120 mg, 0.69 mmol), Pd2(dba)3 (24 mg, 10 mol %), XantPhos (31 mg, 20 mol %) and DIPEA (186 μL, 1.07 mmol) in dioxane (3 mL) was purged with argon and heated at 120° C. for 40 min using microwave irradiation. The reaction mixture was diluted with DCM and purified by column chromatography (Si-PCC, gradient 0-20% MeOH in DCM then C18, gradient 20-50% MeOH in H2O). The resulting residue was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH and the product eluted with 2M NH3/MeOH. The residue was triturated with Et2O affording 139 as a white solid (16 mg, 51%). LCMS: RT 3.11 min [M+H]+ 467.4. 1H NMR (DMSO, 400 MHz): δ 8.54 (1H, d, J=2.35 Hz), 7.94 (1H, d, J=0.67 Hz), 7.77 (1H, s), 7.36 (1H, dd, J=8.49, 2.37 Hz), 7.02 (1H, d, J=8.48 Hz), 5.92-5.91 (1H, m), 4.55-4.49 (4H, m), 3.06-3.04 (3H, m), 2.30 (2H, t, J=11.23 Hz), 2.08-1.96 (2H, m), 1.65-1.64 (2H, m), 1.58 (6H, d, J=6.65 Hz), 1.08 (9H, s)
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH:20]([N:23]([CH:27]([CH3:29])[CH3:28])[CH2:24][CH2:25]Cl)([CH3:22])[CH3:21].[OH-].[K+].C(O)(C)C>O.C(OCC)(=O)C>[C:1]1([C:7]2[O:8][C:9]3[C:15]([C:16]([O:18][CH2:25][CH2:24][N:23]([CH:27]([CH3:29])[CH3:28])[CH:20]([CH3:22])[CH3:21])=[O:17])=[CH:14][CH:13]=[CH:12][C:10]=3[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)c1cccc2cc(-c3ccccc3)oc12
Reactant: CC(C)N(CCCl)C(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)N(CCOC(=O)c1cccc2cc(-c3ccccc3)oc12)C(C)C
Yield: 84.9 %

Procedure:
A mixture of 1.16 g of 2-phenylbenzofuran-7-carboxylic acid, 1.0 g of 2-(diisopropylamino)ethyl chloride hydrochloride, 0.66 g of potassium hydroxide and 20 ml of isopropanol is refluxed for 1 hour. After cooling, ethyl acetate and water are added to the reaction mixture. The organic layer is collected, washed with a saturated sodium chloride solution and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) to give 1.51 g 2-(diisopropylamino)ethyl 2-phenylbenzofuran-7-carboxylate as colorless oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][CH:10]2[CH:15]3[O:16][C:17]4[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=4[O:19][CH:14]3[CH2:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.[CH3:24][Br:25]>CC(C)=O>[Br-:25].[CH2:13]1[CH:14]2[CH:15]([O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[O:19]2)[CH:10]([O:9][CH2:8][CH2:7][N+:4]2([CH3:24])[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)[CH2:11][CH2:12]1
Reactant: CBr
Reactant: c1ccc2c(c1)OC1CCCC(OCCN3CCOCC3)C1O2
Solvent: CC(C)=O
Product: C[N+]1(CCOC2CCCC3Oc4ccccc4OC23)CCOCC1
Product: [Br-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
In an autoclave, 900 g (2.82 moles) of the amino ether of Example 3 were dissolved in 3 liters of acetone, and 535.6 g (5.64 moles) of methyl bromide were added. After crystallisation had started, the mixture was left with stirring for 2 hours at room temperature. After being filtered and rinsed with acetone, the solid formed was resuspended in petroleum ether, stirring, filtered, dried under vacuum and then recrystallised in a minimum quantity of the mixture diisopropyl ether/isopropanol (7:3). There were thus obtained 1000 g of the title-compound of melting point 155° C., having the elementary analysis:
Reaction SMILES: C([SiH2][O:6][C:7](C1C=CC=CC=1)(C1C=CC=CC=1)[C:8]1[CH:20]=[CH:19][C:11]2[C:12]([CH2:15][C:16]([NH2:18])=[O:17])=[CH:13][O:14][C:10]=2[CH:9]=1)(C)(C)C.C([O:35][C:36](=O)[C:37]([C:39]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([F:48])[CH:46]=2)[N:41]([CH3:49])[CH:40]=1)=O)C.CC(C)([O-])C.[K+]>C1COCC1>[F:48][C:45]1[CH:46]=[C:47]2[C:42](=[CH:43][CH:44]=1)[N:41]([CH3:49])[CH:40]=[C:39]2[C:37]1[C:36](=[O:35])[NH:18][C:16](=[O:17])[C:15]=1[C:12]1[C:11]2[CH:19]=[CH:20][C:8]([CH2:7][OH:6])=[CH:9][C:10]=2[O:14][CH:13]=1
Reactant: CCOC(=O)C(=O)c1cn(C)c2ccc(F)cc12
Reactant: CC(C)(C)[SiH2]OC(c1ccccc1)(c1ccccc1)c1ccc2c(CC(N)=O)coc2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cn1cc(C2=C(c3coc4cc(CO)ccc34)C(=O)NC2=O)c2cc(F)ccc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
To a solution of the 2-[6-(tert-butyl-diphenyl-silanyloxymethyl)-benzofuran-3-yl]-acetamide (0.36 g, 0.81 mmol) and (5-fluoro-1-methyl-1H-indol-3-yl)-oxo-acetic acid ethyl ester (0.20 g, 0.81 mmol) in dry THF (8 mL) was added a 1.0 M solution of potassium tert-butoxide in THF (6.49 mL) at 0° C. The reaction was stirred for 30 min, allowed to warm to room temperature and stirred for additional 30 min. The reaction was quenched with water, and diluted with EtOAc. The organic solution was washed with brine, then dried over Na2SO4 and concentrated. The residue was dissolved in THF and a 1.0 M solution of TBAF in THF (1.22 mL) was added at room temperature. The mixture was stirred for 2 h. The solution was quenched with NH4Cl and stirred for 5 min. The solvent was removed and the residue was dissolved in dichloromethane and washed twice with water and brine. The organic phase was dried over Na2SO4 and concentrated. The residue was purified by column chromatography (methanol:dichloromethane; 5:95 to 1:9) to give the 3-(5-fluoro-1-methyl-1H-indol-3-yl)-4-(6-hydroxymethyl-benzofuran-3-yl)-pyrrole-2,5-dione as an orange solid (0.23 g, 72%). 1H NMR (DMSO-d6, 400 MHz) 3.88 (s, 3H), 4.52 (d, J=5.7 Hz, 2H), 5.24 (t, J=5.7 Hz, 1H), 6.53 (dd, J=2.3, 10.3 Hz, 1H), 6.84 (d, J=8.1 Hz, 1H), 6.89 (d, J=8.2 Hz, 1H), 6.95 (dt, J=2.4, 9.1 Hz, 1H), 7.49 (dd, J=4.5, 9.5 Hz, 1H), 7.54 (s, 1H), 8.02 (s, 1H), 8.24 (s, 1H), 11.19 (s, 1H). 13C NMR (DMSO-d6, 100 MHz) 33.7, 63.1, 104.27, 104.31, 103.1, 106.3, 109.4, 110.5, 110.8, 111.7, 112.2, 112.3, 121.5, 121.9, 122.9, 124.5, 126.4, 126.5, 132.6, 133.9, 136.2, 140.6, 147.4, 154.9, 156.5, 172.2, 172.5.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH:9]1([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:23])[CH:14]=2)[CH2:12][CH2:11][CH2:10]1.CO>S(=O)(=O)(O)O>[CH:9]1([C:13]2[C:22]([I:1])=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([CH3:23])[CH:14]=2)[CH2:10][CH2:11][CH2:12]1
Reactant: COC(=O)c1ccc(C2CCC2)cc1C
Reactant: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1cc(I)c(C2CCC2)cc1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
N-Iodosuccinimide (3.52 g, 15.6 mmol) was added portionwise to a solution of methyl 4-cyclobutyl-2-methylbenzoate (compound 152.2, 3.2 g, 15.6 mmol) in concentrated sulfuric acid (25 ml) at 0° C. The mixture was stiffed at 0° C. for 30 min and at RT for 2 hours. The mixture turned very thick. The mixture was cooled to 0° C. again and MeOH (30 ml) was added. The mixture was heated at 60° C. for 2 hours. The methanol was removed under reduced pressure and the residue was poured into ice water (100 ml). The mixture was extracted with EtOAc (2×). The combined organic layers were washed with brine, then aq. 1N NaHCO3 (note-significant gas evolution), dried (Na2SO4) and concentrated. The residue was purified using column (silica gel) chromatography (hexanes:EtOAc 30:1 to 20:1). Yield: 4.17 g, light yellow oil, 81%. 1H NMR (400 MHz, Chloroform-d) δ 8.33 (s, 1H), 7.14 (s, 1H), 3.87 (s, 3H), 3.67-3.54 (m, 1H), 2.57 (s, 3H), 2.51-2.40 (m, 2H), 2.14-1.97 (m, 3H), 1.82-1.79 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH:14]=[CH2:15].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(C(C)C)CC)(C)C>C(#N)CC.CN(C=O)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[O:12]=[C:7]1[NH:8][C:9]2[N:10]=[CH:11][C:2](/[CH:15]=[CH:14]/[C:13]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][C:4]=2[CH2:5][CH2:6]1
Reactant: C=CC(=O)OCC
Reactant: O=C1CCc2cc(Br)cnc2N1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCC#N
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1cnc2c(c1)CCC(=O)N2
Yield: 55.6 %

Procedure:
A solution of 6-bromo-3,4-dihydro-1H-1,8-naphthyridin-2-one (5.0 g, 21.9 mmole), from Preparation 4, ethyl acrylate (3.3 g, 32.9 mmole), Pd(OAc)2 (1.1 g, 0.74 mmole), tri-ortho-tolylphosphine (1.3 g, 4.4 mmole), and diisopropylethylamine (11.4 mL, 65.7 mmole) in propionitrile (200 mL) and DMF (25 mL) was heated at reflux overnight. The dark mixture was filtered through celite®, and the filtrate was concentrated. Flash chromatography on silica gel (9:1 CHCl3/CH3OH containing 5% NH4OH) gave the title compound (3.0 g, 59%) as a light yellow solid: MS (ES) m/e 233 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:28]2[CH:33]([F:34])[CH2:32][CH2:31][CH2:30][C:29]=2[F:35])=[CH:8][C:9]=1[N:10]([C@H:20]1[CH2:25][CH2:24][C@H:23]([O:26][CH3:27])[CH2:22][CH2:21]1)[C:11]([C@H:13]1[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]1)=[O:12])=[O:4].C[O:37][C:38]([C:40]1[S:41][C:42]([C:63]2[CH2:68][CH2:67][CH2:66][CH:65]([F:69])[C:64]=2[F:70])=[CH:43][C:44]=1[N:45]([C@H:55]1[CH2:60][CH2:59][C@H:58]([O:61][CH3:62])[CH2:57][CH2:56]1)[C:46]([C@H:48]1[CH2:53][CH2:52][C@H:51]([CH3:54])[CH2:50][CH2:49]1)=[O:47])=[O:39].[Li+].[OH-].O>C1COCC1.O.CO>[F:35][C:29]1[CH2:30][CH2:31][CH2:32][CH:33]([F:34])[C:28]=1[C:7]1[S:6][C:5]([C:3]([OH:4])=[O:2])=[C:9]([N:10]([C@H:20]2[CH2:21][CH2:22][C@H:23]([O:26][CH3:27])[CH2:24][CH2:25]2)[C:11]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH3:19])[CH2:15][CH2:14]2)=[O:12])[CH:8]=1.[F:70][C:64]1[CH:65]([F:69])[CH2:66][CH2:67][CH2:68][C:63]=1[C:42]1[S:41][C:40]([C:38]([OH:39])=[O:37])=[C:44]([N:45]([C@H:55]2[CH2:56][CH2:57][C@H:58]([O:61][CH3:62])[CH2:59][CH2:60]2)[C:46]([C@H:48]2[CH2:53][CH2:52][C@H:51]([CH3:54])[CH2:50][CH2:49]2)=[O:47])[CH:43]=1
Reactant: COC(=O)c1sc(C2=C(F)C(F)CCC2)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Reactant: COC(=O)c1sc(C2=C(F)CCCC2F)cc1N(C(=O)[C@H]1CC[C@H](C)CC1)[C@H]1CC[C@H](OC)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CO[C@H]1CC[C@H](N(c2cc(C3=C(F)C(F)CCC3)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Product: CO[C@H]1CC[C@H](N(c2cc(C3=C(F)CCCC3F)sc2C(=O)O)C(=O)[C@H]2CC[C@H](C)CC2)CC1
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a solution of 5-(2,6-difluoro-cyclohex-1-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester and 5-(2,3-Difluoro-cyclohex-1-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid methyl ester (83 mg, 0.16 mmol) in THF: H2O: MeOH (3:1:2) (2 mL), was added LiOH in water (1N) (0.5 mL, 0.5 mmol). The reaction mixture was stirred at 70° C. for 5 h. The mixture was concentrated under reduced pressure on a rotary evaporator and the residue was treated with a solution of 0.1 N HCl and extracted in EtOAc. The EtOAc layer was dried over Na2SO4. Filtration and removal of the solvent under reduced pressure on a rotary evaporator followed by HPLC purification afforded 5-(2,6-difluoro-cyclohex-1-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (3 mg) and 5-(2,3-difluoro-cyclohex-1-enyl)-3-[(trans-4-methoxy-cyclohexyl)-(trans-4-methyl-cyclohexanecarbonyl)-amino]-thiophene-2-carboxylic acid (3 mg) in overall 8% isolated yield.
Reaction SMILES: [CH2:1]([C:8](=[CH2:12])[C:9]([OH:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:28](O)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>CCOCC.CN(C)C1C=CN=CC=1>[CH2:1]([C:8](=[CH2:12])[C:9]([O:11][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=C(Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Product: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 44 h

Procedure:
2-Benzylacrylic acid (2.20 g, 13.6 mmol) in dry ether (40 mL) was treated with dicyclohexylcarbodiimide (2.60 g, 12.6 mmol), benzyl alcohol (1.30 mL, 12.6 mmol) and 4-dimethylaminopyridine (0.310 g, 2.54 mmol). After stirring at room temperature for 44 h, the mixture was filtered and evaporated. Chromatography of the residue on silica with 5% oil: b.p. 150° C. (0.2 mm); TLC (20% ethyl acetate/80% hexane) Rf =0.31; 1H-NMR (CDCl3) 7.15-7.40 (m, 10H), 6.28 (m, 1H), 5.49 (m, 1H), 5.17 (2H,s), 3.67 (s, 2H).
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:30]=[CH:29][C:9]([O:10][CH2:11][C:12]2[N:13]=[C:14](/[CH:17]=[CH:18]/[C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)[O:15][CH:16]=2)=[CH:8][CH:7]=1.[NH:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[F:26][C:25]([F:28])([F:27])[C:22]1[CH:23]=[CH:24][C:19](/[CH:18]=[CH:17]/[C:14]2[O:15][CH:16]=[C:12]([CH2:11][O:10][C:9]3[CH:29]=[CH:30][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:31]4[CH:35]=[CH:34][N:33]=[C:32]4[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])=[CH:7][CH:8]=3)[N:13]=2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)c1ccc(/C=C/c2nc(COc3ccc(CCCCI)cc3)co2)cc1
Reactant: CCOC(=O)CCc1ncc[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(C(F)(F)F)cc3)n2)cc1
Temperature: 70 °C
Reaction time: 23 h
Yield: 57.1 %

Procedure:
A suspension of 4-[[4-(4-iodobutyl)phenoxy]methyl]-2-[(E)-2-[4-(trifluoromethyl)phenyl]ethenyl]-1,3-oxazole (6.00 g), ethyl 3-(1H-imidazol-2-yl)propionate (3.83 g) and potassium carbonate (1.58 g) in DMF (100 ml) was stirred at 70° C. for 23 hr. The reaction mixture was combined with water and extracted with ethyl acetate. The extract was successively washed with water and saturated brine and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate) and washed with diethyl ether-hexane to give the titled compound (3.69 g) as a colorless amorphous form.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]1([CH:18]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1.CCOCC>C(OCC)(=O)C>[Cl-:1].[N:11]1([CH:18]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:19]([O:21][C@@H:22]2[CH:27]3[CH2:28][CH2:29][N+:24]([CH2:2][C:3](=[O:4])[C:5]4[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=4)([CH2:25][CH2:26]3)[CH2:23]2)=[O:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(CCl)c1ccccc1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C(c1ccccc1)N1CCCCCC1
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C(c1ccccc1)N1CCCCCC1)C2)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
2-Chloro-1-phenylethanone (46.9 mg, 0.30 mmol) was added to a solution of (R)-quinuclidin-3-yl 2-(azepan-1-yl)-2-phenylacetate (104 mg, 0.30 mmol) in ethyl acetate (3 ml). The reaction was stirred at room temperature overnight then Et2O (2 mL) was added, the suspension was sonicated, filtered and dried under vacuum at 40° C. overnight to obtain the title compound (99 mg, 65.6% yield) as a white solid.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[Br:9]Br>CC(O)=O>[Br:9][CH:2]1[C:3](=[O:7])[CH2:4][CH2:5][CH2:6][C:1]1=[O:8]
Reactant: BrBr
Reactant: O=C1CCCC(=O)C1
Solvent: CC(=O)O
Product: O=C1CCCC(=O)C1Br
Reaction time: 2 h

Procedure:
To a stirred solution of cyclohexane-1,3-dione (1.12 g, 10 mmol) in AcOH (20 mL) at r.t. was added bromine (1.6 g, 0.51 mL, 10 mmol) dropwise. The reaction mixture was stirred for 2 h and then the product was isolated by filtration. The precipitate was washed twice with Et2O (100 mL) and then dried in vacuo to give the title compound in quantitative yield as a buff solid, which was used without further purification. LCMS (ES+) 190.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:6])([CH3:5])[C:3]#[N:4].[C:7]1([S:13][C:14](Cl)=[O:15])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[C:3]([C:2]([NH:1][C:14](=[O:15])[S:13][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH3:5])#[N:4]
Reactant: CC(C)(N)C#N
Reactant: O=C(Cl)Sc1ccccc1
Solvent: C1COCCO1
Product: CC(C)(C#N)NC(=O)Sc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
3.4 g. (0.04 mole) of 2-amino-2-methylpropanonitrile are dissolved in 10 ml. of dioxane and a solution of 3.2 ml. (0.2 mole) of (phenylthio)carbonyl chloride in 10 ml. of dioxane is added. After stirring for one hour at room temperature, the reaction mixture is filtered, the filtrate is concentrated, and the solid residue is recrystallized from a small amount of toluene to yield 2.7 g of (1-cyano1-methylethyl)carbamothioic acid, S-phenyl ester; m.p. 152°-155°.
Reaction SMILES: [CH:1]1[C:6](N)=[CH:5][CH:4]=[C:3](N)[CH:2]=1.OO.[OH2:11]>CC(O[Na])=O>[C:1]1([OH:11])[C:6]2[C:5](=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Nc1ccc(N)cc1
Reactant: O
Agent: CC(=O)O[Na]
Agent: OO
Product: Oc1cccc2ccccc12
Reaction time: 1 h

Procedure:
A 0.5 mg/ml solution of a first compound (p-phenylenediamine, "A") and a 0.5 mg/ml solution of a second compound (1-naphthol, "B") was prepared by dissolving the compound in the appropriate amount of 0.1 M CH3COONa, pH 5.5, buffer. A total volume of 100 ml was used in each LOM beaker. 100 ml "A" was added to one beaker and 50 ml "A" and 50 ml "B" were combined to form 100 ml in a second beaker. Swatches of the materials listed above were wetted in DI water and soaked in the precursor solutions. A Coprinus cinereus peroxidase ("CiP") with an activity of 180,000 POXU/ml was added to each beaker at a concentration of 0.05 POXU/ml. Either 200 or 500 μM hydrogen peroxide was added to each LOM beaker. The LOM beakers were sealed and mounted in the LOM. After 1 hour at 42 RPM and 30° C., the LOM was stopped. The spent liquor was poured off and the swatches were rinsed in cold tap water for about 15 minutes. The swatches were dried at room temperature and CIELAB values were measured for all of the swatches using the Macbeth ColorEye 7000. The results are given in Tables 38-41.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.Br[CH2:11][CH2:12][O:13][C:14]([CH3:17])([CH3:16])[CH3:15]>CN(C)C=O>[C:14]([O:13][CH2:12][CH2:11][N:7]1[CH2:8][CH2:9][CH:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)OCCBr
Reactant: OCCC1CCNCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OCCN1CCC(CCO)CC1
Yield: 68.3 %

Procedure:
4-(2-hydroxyethyl)piperidine (1.94 g, 15 mmol) in dimethylformamide (20 ml) was reacted with 2-(2-bromoethoxy)-2-methylpropane (3.13 g, 17.3 mmol) at 50° C. for 15 hours. The mixture was cooled and the solid removed by filtration. The solid was washed with ethyl acetate and the organics were washed with water, dried (magnesium sulphate) and concentrated to give 2-(1-(2-tert-butoxy ethyl)piperidin-4-yl)ethanol as a yellow oil (2.35 g, 100% yield):
Reaction SMILES: C(O[C:6]([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH2:19])[CH2:11]1)=[O:7])(C)(C)C.[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33](C(O)=O)=[C:32]([O:40][CH3:41])[CH:31]=1>>[NH2:29][C:30]1[C:38]([Cl:39])=[CH:37][C:33]([C:6]([NH:8][CH2:9][CH:10]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20](=[O:27])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:11]2)=[O:7])=[C:32]([O:40][CH3:41])[CH:31]=1
Reactant: CC(C)(C)OC(=O)NCC1CCN(CCCCN)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCCNC(=O)c2ccccc2)C1

Procedure:
4-(3-tert-Butoxycarbonylaminomethylpyrrolidin-1-yl)butylamine (1 g) as starting compound was reacted and treated in the same manner as in Example 1 using benzoyl chloride (0.43 ml) and 4-amino-5-chloro-2-methoxybenzoic acid (0.74 g) to give 4-amino-N-(1-(4-benzoylaminobutyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH:1]([O:4][C:5]([C:7]1[C:13]2[N:14]([CH3:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:24])([CH3:23])[CH2:10][NH:9][CH:8]=1)=[O:6])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][C:34]=1[F:35])[C:29](Cl)=[O:30]>>[CH:1]([O:4][C:5]([C:7]1[C:13]2[N:14]([CH3:22])[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:16][C:12]=2[C:11]([CH3:24])([CH3:23])[CH2:10][N:9]([C:29](=[O:30])[C:28]2[CH:32]=[CH:33][C:34]([F:35])=[C:26]([F:25])[CH:27]=2)[CH:8]=1)=[O:6])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2c(n1C)C(C(=O)OC(C)C)=CNCC2(C)C
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CCOC(=O)c1cc2c(n1C)C(C(=O)OC(C)C)=CN(C(=O)c1ccc(F)c(F)c1)CC2(C)C

Procedure:
The title compound was prepared in a manner similar to that described in Example 2 by using 1,4,4-trimethyl-1,4,5,6-tetrahydro-pyrrolo[2,3-d]azepine-2,8-dicarboxylic acid 2-ethyl ester 8-isopropyl ester and 3,4-difluoro-benzoyl chloride. 1H-NMR(CDCl3): δ 7.75 (1H, s), 7.43 (1H, m), 7.28 (2H, m), 6.86 (1H, d), 5.06 (1H, m), 4.28 (2H, q), 3.87 (2H, s), 3.66 (3H, s), 1.35 (3H, 3), 1.33 (6H, s), 1.21 (6H, d). MS (ES): 475 (MH+).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:11]=[C:12]([CH3:17])[CH:13]=[C:14]([CH3:16])[CH:15]=1.[CH3:18][NH:19][CH:20]=[O:21].CCCCCCCCCCCC>C(OCC)(=O)C.[Cu]I.C1(C)C=CC=CC=1>[CH3:16][C:14]1[CH:15]=[C:10]([N:19]([CH3:18])[CH:20]=[O:21])[CH:11]=[C:12]([CH3:17])[CH:13]=1
Reactant: CNC=O
Reactant: Cc1cc(C)cc(I)c1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(N(C)C=O)c1
Temperature: 110 °C
Reaction time: 24 h
Yield: 54 %

Procedure:
A Schlenk tube was charged with CuI (9.6 mg, 0.050 mmol, 5.0 mol %), 3,1′-dimethyl-4,5-dihydro-3H,1′H-[,2′]biimidazolyl-2-one (18 mg, 0.10 mmol, 10 mol %), K3PO4 (430 mg, 2.03 mmol), evacuated, backfilled with Ar. 5-Iodo-m-xylene (145 μL, 1.00 mmol), N-methylformamide (72 μL, 1.23 mmol), and toluene (1.0 mL) were added under Ar. The Schlenk tube was sealed with a Teflon valve and the reaction mixture was stirred at 110° C. for 24 h. The suspension was allowed to reach room temperature. Dodecane (internal GC standard, 230 μL) and ethyl acetate (2 mL) were added. A 0.1 mL sample of the supernatant solution was diluted with ethyl acetate (1 mL) and analyzed by GC to provide 54% yield of N-(3,5-dimethylphenyl)-N-methylformamide.