Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=1)=[C:8]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:7]([CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:6]2.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9]([O:13][C:14]1[CH:15]=[CH:16][C:17](/[CH:20]=[CH:21]/[C:22]([OH:24])=[O:23])=[CH:18][CH:19]=1)=[C:8]([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:7]([CH2:31][CH:32]([CH3:34])[CH3:33])=[CH:6]2
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(CC(C)C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CC(C)Cc1cc2cc(O)ccc2c(Oc2ccc(/C=C/C(=O)O)cc2)c1-c1ccccc1
Yield: 68.4 %

Procedure:
Methyl ether (108) (0.15 g, 0.33 mmol) was treated with BBr3 in CH2Cl2 to give the crude product as a yellow viscous oil, which was purified by reverse phase preparation HPLC on Agilent 1100 to afford 99 mg (68%) of the title compound (109) as pale yellow solid. mp 126-128° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.72 (d, J=6.6 Hz, 6H), 1.55-1.65 (m, 1H), 2.47 (d, J=7.1 Hz, 2H), 6.26 (d, J=15.9 Hz, 1H), 6.55 (d, J=8.8 Hz, 2H), 6.96 (dd, J1=9.1 Hz, J2=2.4 Hz, 1H), 7.10-7.16 (m, 3H), 7.17-7.27 (m, 3H), 7.34 (d, J=8.8 Hz, 2H), 7.47 (s, 1H), 7.51 (d, J=15.9 Hz, 1H), 7.60 (d, J=9.0 Hz, 1H). LCMS (ESI): m/z 439 (M+H)+, m/z 437 (M−H)−. Anal. Calc for C29H26O4.0.25H2O: C, 78.62; H, 6.03. Found: C, 78.45; H, 5.96.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.[C:13]([O:17][C:18](=[O:30])[CH2:19][O:20][NH:21][CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:30])[CH2:19][O:20][N:21]([C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1)[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)CONCc1ccc(F)cc1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Product: CC(C)(C)OC(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Yield: 85 %

Procedure:
Reaction of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride with [N-(4-fluorobenzyl)aminooxy]-acetic acid tert-butyl ester as described in the preparation of compound 1-A gave the title amide as white crystals (85% yield): mp 119–120° C. (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm): 1.48 (9H, s, t-Bu), 1.74 (6H, s, CH3), 4.30 (2H, s, CH2), 4.88 (2H, s, CH2), 6.48 (1H, s, CH), 7.0 (2H, m, aromatics), 7.38 (2H, m, aromatics). Anal. calcd for C20H24FNO7: C, 58.67; H, 5.91; N, 3.42. Found: C, 58.83; H, 5.92; N, 3.31.
Reaction SMILES: [C:1]([C:4]1[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([O:14]CC)=[O:13])[CH:5]=1)(O)=O.CCN=C=NCCCN(C)C.[CH2:28]([N:32]1[C:39]([NH2:40])=[C:38]([NH2:41])[C:36](=[O:37])[N:35]([CH2:42][CH:43]([CH3:45])[CH3:44])[C:33]1=[O:34])[CH:29]([CH3:31])[CH3:30]>CO>[CH2:42]([N:35]1[C:36](=[O:37])[C:38]2[NH:41][C:1]([C:4]3[N:8]([CH3:9])[N:7]=[C:6]([O:10][CH2:11][C:12]([OH:14])=[O:13])[CH:5]=3)=[N:40][C:39]=2[N:32]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:33]1=[O:34])[CH:43]([CH3:45])[CH3:44]
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(CC(C)C)c1=O
Reactant: CCOC(=O)COc1cc(C(=O)O)n(C)n1
Agent: CCN=C=NCCCN(C)C
Solvent: CO
Product: CC(C)Cn1c(=O)c2[nH]c(-c3cc(OCC(=O)O)nn3C)nc2n(CC(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl (5-carboxy-1-methylpyrazol-3-yl)oxyacetate (0.5 mmol) and EDCI (0.5 mmol) in methanol (20 mL) was added a solution of 1,3-diisobutyl-5,6-diaminouracil (0.5 mmol), dissolved in methanol (20 mL). The mixture was stirred at room temperature for two hours, the solvent was then removed in vacuo, water added, and the solid that formed was collected by filtration and washed with additional cold water. The intermediate amide was heated in 20 mL of 2.5 N NaOH at 70° C. for 30 minutes to afford the desired 2-[5-(1,3-diisobutyl-xanthin-8-yl)-1-methylpyrazol-3-yloxy]acetic acid.
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][O:7][CH2:6][CH2:5][N:4]1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([C@H:18]2[CH2:22][C@@H:21]([OH:23])[CH2:20][NH:19]2)=[O:17])=[CH:11][CH:10]=1.C(N(CC)CC)C.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1>ClCCl>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39]([N:19]2[CH2:20][C@H:21]([OH:23])[CH2:22][C@@H:18]2[C:16]([NH:15][C:12]2[CH:11]=[CH:10][C:9]([N:4]3[CH2:5][CH2:6][O:7][CH2:8][C:3]3=[O:2])=[CH:14][CH:13]=2)=[O:17])=[O:40])=[CH:34][CH:33]=1
Reactant: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1
Reactant: O=C=Nc1ccc(Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCOCC2=O)cc1)[C@H]1C[C@@H](O)CN1C(=O)Nc1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 86 %

Procedure:
7.3 12.64 g (36.98 mmol) of N-[4-(3-oxomorpholin-4-yl)phenyl]-(2R,4R)-4-hydroxypyrrolidine-2-carboxamide hydrochloride are suspended in 1200 ml of dichloromethane, and 5.4 ml of triethylamine are added with cooling in an ice bath. The solution of 5.96 g (38.83 mmol) of 4-chlorophenyl isocyanate in 100 ml of dichlormethane is subsequently added dropwise to the mixture at 2° C. over the course of 1.5 hours, and the reaction solution is then left to stir for a further 30 minutes with ice cooling. The dichloromethane solution is then washed successively with 100 ml of 1N hydrochloric acid and 100 ml of water and dried over sodium sulfate. After the drying agent has been filtered off and the methylene chloride solution has been evaporated to ⅓ of the original volume in a rotary evaporator, the precipitated product is filtered off, washed with 50 ml of petroleum ether and dried in a desiccator, giving 14.6 g (86%) of 1-N-[(4-chlorophenyl)]-2-N-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide (“A8”) as a white powder, ESI 459; m.p. 216°.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]([CH3:13])[C:4](=[O:14])[C:3]=1[C:15]#[N:16].[NH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>ClCCl>[CH3:13][N:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[C:2]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[C:3]([C:15]#[N:16])[C:4]1=[O:14]
Reactant: C1CNCCN1
Reactant: Cc1ccc2c(c1)c(Cl)c(C#N)c(=O)n2C
Solvent: ClCCl
Product: Cc1ccc2c(c1)c(N1CCNCC1)c(C#N)c(=O)n2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.1 %

Procedure:
A solution of Compound 23 (1 g, 4.3 mmol) in dichloromethane was added slowly to a stirred solution of piperazine (1.1 g, 12.9 mmol) in dichloromethane at room temperature. The solution was stirred overnight at room temperature. The solvent was removed under reduced pressure. The residue was taken in water, sonicated briefly, and filtered. The solids were dissolved in ethyl acetate and washed by water. The organic layer was dried over Na2SO4 and concentrated to yield 1.07 g (88%) yellow solids. M.P. 274° C. 1H NMR (DMSO-d6): δ 2.39 (s, 3H), 2.94 (m, 4H), 3.48 (m, 4H), 3.54 (s, 3H), 7.45 (d, J=8.6 Hz, 1H), 7.56 (dd, J=1.3, 8.6 Hz, 1H), 7.64 (s, 1H). EIMS m/z 283 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].[C:12]([O-:15])([O-])=O.[K+].[K+]>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:4][C:3]2[CH:6]=[CH:7][C:8]([O:15][CH3:12])=[CH:9][CH:2]=2)[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=C([O-])[O-]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(COc2cc(Cl)c(C=O)c(Cl)c2)cc1
Temperature: 45 °C
Reaction time: 3 h

Procedure:
To a mixture of 2,6-dichloro-4-hydroxybenzaldehyde (1.00 g, 5.24 mmol) and K2CO3 (1.45 g, 10.5 mmol) in THF (25 mL) under N2 was added dropwise1-bromomethyl-4-methoxybenzene (1.10 mL, 7.85 mmol). The reaction was heated at 65° C. for 3 h, at 45° C. overnight then at 65° C. for 3 hr. The reaction was allowed to cool to ambient temperature then was filtered and the filtrate concentrated under reduced pressure. The concentrate was diluted with EtOAc (150 mL) and extracted with water (30 mL). The organic phase was dried over Na2SO4 and evaporated. The residue was purified by silica gel chromatography using a gradient of 5-15% EtOAc/heptane as eluent to afford 2,6-dichloro-4-(4-methoxybenzyloxy)-benzaldehyde as a white solid. MS (m/z) 311.0 (M+1); 1H NMR (DMSO-d6, 400 MHz) δ 10.28 (s, 1H), 7.40 (d, J=8.59 Hz, 2H), 7.29 (s, 2H), 6.97 (d, J=8.72 Hz, 2H), 5.19 (s, 2H), 3.76 (s, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([CH:13]=[CH:14][C:15]([OH:17])=O)=[O:12])=[CH:3]1.[NH:18]1[CH2:25][CH2:24][CH2:23][C@H:19]1[C:20]([OH:22])=[O:21]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([CH:13]=[CH:14][C:15]([N:18]2[CH2:25][CH2:24][CH2:23][C@H:19]2[C:20]([OH:22])=[O:21])=[O:17])=[O:12])=[CH:3]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: Cn1cc(C(=O)C=CC(=O)O)c2ccccc21
Product: Cn1cc(C(=O)C=CC(=O)N2CCC[C@H]2C(=O)O)c2ccccc21

Procedure:
As for Example 29, 3-(1-methyl-3-indolylcarbonyl)acrylic acid is coupled to L-proline to give 1-[3-(1-methyl-3-indolylcarbonyl)acryloyl]-L-proline.
Reaction SMILES: ClC(Cl)C.[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Al+3].[Cl-].[Cl-].[Cl-].[CH2:16]1[O:18][CH2:17]1>CC([O-])C.CC([O-])C.CC([O-])C.CC([O-])C.[Ti+4]>[C:5]1([CH3:11])[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:17]([OH:18])[CH3:16]
Reactant: Cc1ccccc1
Reactant: C1CO1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: CC(Cl)Cl
Product: Cc1ccccc1C(C)O

Procedure:
400 g of dichloroethane and 110 g (1.2 mol) of toluene were introduced initially together with 63 g (0.47 mol) of AlCl3 in the presence of 3 g (10-2 mol) of titanium tetraisopropylate or in the absence of titanium alcoholate. 44 g (1 mol) of ethylene oxide were added in the course of 1.5 h at the temperature stated in Table 3. After hydrolysis the reaction mixture was concentrated and analyzed by gas chromatography. The yields of 2-tolylethanol, obtained as a mixture of isomers, based on converted toluene, are shown in the following table:
Reaction SMILES: [F:1][CH:2]([F:10])[C:3]1[C:4]([CH3:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Se]=[O:12]>O1CCOCC1>[F:1][CH:2]([F:10])[C:3]1[C:4]([CH:9]=[O:12])=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: Cc1ncccc1C(F)F
Reactant: O=[Se]
Solvent: C1COCCO1
Product: O=Cc1ncccc1C(F)F
Yield: 9.1 %

Procedure:
A mixture of 3-(difluoromethyl)-2-methylpyridine (110 mg, 0.768 mmol) and selenium oxide (102 mg, 0.922 mmol) in 1,4-dioxane (3 mL) was warmed at reflux for twelve hours. The reaction mixture was then concentrated and purified with flash chromatography (12+S Biotage, heptane/ethyl acetate=1:0 to 1:1), to give 3-(difluoromethyl)picolinaldehyde as an oil (11 mg). 1H NMR (400 MHz, CDCl3) δ 10.1 (s, 1H), 8.90 (d, 1H), 8.22 (d, 1H), 7.64 (m, 1H), 7.59 (t, 1H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:28][C:29]1[CH:38]=[CH:37][C:32]2[O:33][CH2:34][CH2:35][O:36][C:31]=2[CH:30]=1)[CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]2[C:25]3[C:20](=[C:21]([NH2:26])[CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][C:17]2=[O:27])[CH2:10][CH2:9]1)(C)(C)C.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[O:33]1[C:32]2[CH:37]=[CH:38][C:29]([CH2:28][NH:7][CH:8]3[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:16]4[C:25]5[C:20](=[C:21]([NH2:26])[CH:22]=[CH:23][CH:24]=5)[CH:19]=[CH:18][C:17]4=[O:27])[CH2:10][CH2:9]3)=[CH:30][C:31]=2[O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)ccc3c(N)cccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1cccc2c1ccc(=O)n2CCN1CCC(NCc2ccc3c(c2)OCCO3)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 80 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(5-amino-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate, 3 mL of 1,4-dioxane and 1 mL of 4.0 mol/L hydrogen chloride/1,4-dioxane were added, and stirred at room temperature overnight. The solvent was removed under reduced pressure, and the resulting solid was recrystallized in methanol-ethyl acetate to give 45 mg of 1-(2-(4-((2,3-dihydro-1,4-benzodioxin-6-ylmethyl)amino)piperidin-1-yl)ethyl)-5-aminoquinolin-2(1H)-one hydrochloride as a brown solid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].CS(O[CH2:14][CH2:15][CH2:16][CH2:17][O:18][CH3:19])(=O)=O.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[CH3:19][O:18][CH2:17][CH2:16][CH2:15][CH2:14][NH:7][C:2]1[C:1]([NH2:8])=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1N
Reactant: COCCCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COCCCCNc1ccccc1N
Yield: 56 %

Procedure:
To a solution of phenylenediamine (10.8 g) and 4-methoxybutyl methanesulfonate (9.11 g) in acetonitrile (100 ml) was added potassium carbonate (20.7 g), and the mixture was stirred heated under reflux for 15 hr. Water was added to the reaction mixture, and the mixture was extracted twice with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (35:65) was concentrated under reduced pressure to give the object product (5.44 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][CH:17]=1)[C:12](Cl)=[O:13])([O:7][CH3:8])=[O:6].[CH2:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH3:19]>ClCCl>[CH2:18]([C:20]1[CH:21]=[CH:22][C:23]([O:26][CH3:27])=[C:24]([CH:25]=1)[C:12]([C:11]1[CH:15]=[CH:16][CH:17]=[C:9]([C:5]([O:7][CH3:8])=[O:6])[CH:10]=1)=[O:13])[CH3:19]
Reactant: COC(=O)c1cccc(C(=O)Cl)c1
Reactant: CCc1ccc(OC)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1ccc(OC)c(C(=O)c2cccc(C(=O)OC)c2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Aluminium chloride (39.9 g, 0.3 mole) was stirred in dichloromethane (133 ml) and treated with 3-carbomethoxybenzoyl chloride (59.5 g, 0.3 mole) (ice-bath cooling), over 0.5 hours.4-Ethylanisole (40.8 g, 0.3 mole) in dichloromethane (70 ml) was added to the stirred, cooled mixture, which was then stirred at room temperature overnight. The reaction mixture was processed as in Example 15 to leave 5-ethyl-2-methoxy-3'-carbomethoxybenzophenone. The latter was heated in 55% aqueous hydrogen bromide (500 ml) at 110°-120° C. for 5 hours. The mixture was evaporated to dryness to leave 5-ethyl-2-hydroxy-3'-carboxybenzophenone, which was characterised by having the correct C, H and N microanalysis. The latter carboxylic acid was then refluxed overnight in methanol (500 ml) containing concentrated sulphuric acid (5 ml), poured into water (1 L) and extracted with ether. The combined ethereal extracts were washed with saturated NaHCO3 solution, dried (MgSO4), filtered and evaporated to leave the desired ester, which gave a satisfactory microanalysis.
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].S([CH2:21][N+:22]#[C-:23])(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].CCCCCCC>CO>[O:2]1[C:1]([C:3]2[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=2)=[CH:23][N:22]=[CH:21]1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCCCCCC
Product: N#Cc1ccc(-c2cnco2)cc1
Yield: 97 %

Procedure:
To a solution of 4-Formyl-benzonitrile (5 g, 38.17 mmol) and tosylmethyl isocyanide (TosMIC) (from Aldrich, 8.33 g, 42 mmol) in MeOH (200 mL) was added K2CO3 (6.85 g, 49.62 mmol) and the mixture was stirred at reflux for 1 h. The solvent was then evaporated and saturated aqueous NaHCO3 was added. The resultant suspension was extracted with dichloromethane (3×100 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous MgSO4 and concentrated to leave a yellow solid. Trituration with heptane afforded a solid that was collected by filtration and dried under vacuum to give the title compound (6.3 g, 97%). m.p.=140° C.
Reaction SMILES: [CH3:1][S:2]([CH3:4])=[O:3].C(OC(=O)C)(=O)C.[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[CH3:18]S(C)=O.[C:22](#[N:24])C>C(Cl)Cl>[CH:17]1([N:12]=[C:22]=[NH:24])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:18]1.[CH3:1][S:2]([CH3:4])=[O:3]
Reactant: CC#N
Reactant: c1ccncc1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CC(=O)OC(C)=O
Product: N=C=NC1CCCCC1

Procedure:
In words relative to the above diagram for the preparation of 1, the 4-(2-acetoxyvinyl)azetidine-2-one (3) is prepared by reacting chloro sulphonyl isocyanate and an acyloxybutadiene such as 1-acetoxybutadiene in a solvent such as anhydrous dimethyl ether at a temperature of from about -30° C. to 0° C. under a nitrogen atmosphere. The reaction intermediate 2 is converted to 3 by hydrolysis. The reduction of 3 to provide the 4-(2-acetoxyethyl)-2-azetidinone (4) is conducted by any convenient means such as hydrogenation in the presence of a catalyst such as platinum, palladium or oxides thereof under a hydrogen pressure of from 1 to 20 atmospheres in a solvent such as ethanol, ethylacetate, or the like at a temperature of from 0° to 25° C., for from 5 minutes to 1 hour. The 4-(2-hydroxyethyl)-2-azetidinone species, 5, is obtained from 4 by hydrolysis. The 8-oxo- 2,2-dimethyl-3-oxa-1-azabicyclo-[4.2.0]octane species, 6, is obtained on treatment of 5 with 2,2-dimethoxypropane in the presence of a catalyst such as boron trifluoride etherate in a solvent such as methylene chloride at a temperature of from 0° to 40° C. for from 1 to 40 minutes. Alternatively, 5 can be treated with borontrifluoride etherate and trimethylorthoformate to give 8-oxo-2-methoxy-3-oxa-1-azabicyclo[4.2.0]octane which can be mono- or dialkylated following the procedures for 6→7 or 8. Alkylation of 6 provides 7. Typically, 6 is treated with a strong base such as lithium diisopropyl amide, sodium hydride, phenyl lithium or butyl lithium and the like in a solvent such as tetrahydrofuran (THF), ether, dimethoxyethane and the like at a temperature of from -80° C. to 0° C., whereupon the alkylating agent of choice, R1X, is added (R1 is as described above and X is chloro or bromo; alternatively the alkylating agent may be R1 -tosylate, R1 -mesylate or an aldehyde or ketone such as acetaldehyde and the like) to provide mono- alkylated species 7. When desired dialkylated species 8 may be obtained from 7 by repeating the alkylating procedure, 6→7. Species 9 is obtained from 7 or 8 by acid hydrolysis. Oxidation of 9 with an oxidizing agent such as DMSO-acetic anhydride, pyridine.CrO3, cyclohexylcarbodiimide/DMSO, and the like in a solvent such as DMSO, pyridine, acetonitrile, methylene chloride, and the like at a temperature of from about 0° to 25° C. for from 0.5 to 12 hours provides 10 which upon treatment with the Grignard reagent R3MgX (R3 is as defined above and X is halogen) provides 11. Typically, the alkylation reaction 10→11 is conducted in a solvent such as ether, THF, benzene and the like at a temperature of from -78° to about 25° C. for from 0.5 to about 24 hours.
Reaction SMILES: [CH2:1]([NH:7][CH2:8][C:9]1[S:13][C:12](B(O)O)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].Br[C:18]1[CH:19]=[C:20]2[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=1)[NH:23][CH:22]=[C:21]2[CH:30]1[CH2:35][CH2:34][N:33]([S:36]([CH2:39][CH3:40])(=[O:38])=[O:37])[CH2:32][CH2:31]1.C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:39]([S:36]([N:33]1[CH2:32][CH2:31][CH:30]([C:21]2[C:20]3[C:24](=[C:25]([C:27]([NH2:29])=[O:28])[CH:26]=[C:18]([C:12]4[S:13][C:9]([CH2:8][NH:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])=[CH:10][CH:11]=4)[CH:19]=3)[NH:23][CH:22]=2)[CH2:35][CH2:34]1)(=[O:38])=[O:37])[CH3:40]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(Br)cc23)CC1
Reactant: CCCCCCNCc1ccc(B(O)O)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Yield: 16 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), hexylamine (33 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid. The crude {5-[(hexylamino)methyl]-2-thienyl}boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol). The crude product was purified once on an Agilent MDAP using the procedure shown in preparation of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide to give 13 mg of the title compound (16%).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.Cl[CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].O>C(Cl)Cl>[Br:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([N:1]2[CH2:21][CH2:22][CH2:23][S:24]2(=[O:26])=[O:25])[CH:11]=1
Reactant: COC(=O)c1ccc(Br)cc1N
Reactant: O=S(=O)(Cl)CCCCl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Br)cc1N1CCCS1(=O)=O
Temperature: 25 °C

Procedure:
Methyl 2-amino-4-bromobenzoate (5 g) and triethylamine (5.73 mL) were dissolved in methylene chloride (39 mL), 3-chloropropane-1-sulfonyl chloride (3.44 mL) was added under ice-cooling, and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent was evaporated. To the obtained residue were added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)(3.9 mL) and N,N-dimethylformamide (29 mL), and the mixture was stirred at room temperature. After completion of the reaction, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated brine, and the solvent was evaporated. To the obtained residue was added diisopropyl ether, and the precipitate was collected by filtration to give the title compound (5.05 g).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3][CH:2]=1.[CH3:13][C:14]1([CH3:21])[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[O:15]1.[OH-].[Na+].[Cl-].[Na+]>C(O)C>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=[CH:20][C:16]2[O:15][C:14]([CH3:21])([CH3:13])[C:18](=[O:19])[CH:17]=2)=[CH:3][CH:2]=1
Reactant: O=Cc1ccnc2ccccc12
Reactant: CC1=CC(=O)C(C)(C)O1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC1(C)OC(C=Cc2ccnc3ccccc23)=CC1=O
Reaction time: 4 h
Yield: 38 %

Procedure:
To a solution of 4-quinolinecarboxaldehyde (2.8 g, 17.8 mM) and 2,2,5-trimethyl-3(2H)-furanone (1.5 g, 11.9 mM) in ethanol (100 mL), was added 1N aqueous sodium hydroxide (1.2 mL, 1.2 mM). After the reaction solution was stirred for 4 hours, saturated aqueous sodium chloride (400 mL) was added. The aqueous layer was extracted with diethyl ether (3×100 mL). The combined ethereal extracts were washed with saturated aqueous sodium chloride (50 mL), dried over MgSO4, filtered and concentrated to give a brown oil. The crude product was purified by column chromatography (silica gel, pet. ether-ethyl acetate) to yield a yellow crystalline solid (1.2 g, 32% yield), m.p. 117°-118° C.