Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]12(O)[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2.S(=O)(=O)(O)O>ClCCl>[OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cccc(O)c1
Reactant: OC12CC3CC(CC(C3)C1)C2
Agent: O=S(=O)(O)O
Solvent: ClCCl
Product: COC(=O)c1ccc(C23CC4CC(CC(C4)C2)C3)c(O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
12.16 g (80 mM) of methyl 3-hydroxybenzoate and 12.16 g (80 mM) of adamantanol in 160 ml of dichloromethane are treated with a dropwise addition of 4.37 ml of concentrated sulphuric acid. The reaction mixture is stirred at room temperature overnight. The solid residue is washed withwater and dried to lead to 18.3 g (79.9%) of the expected derivative, of melting point 244°-246° C.
Reaction SMILES: C(OC([N:6]1[C:10]2[S:11][C:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:13][C:9]=2[C:8]([NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])=[N:7]1)=O)C>CO>[C:17]([O:16][C:14]([C:12]1[S:11][C:10]2[NH:6][N:7]=[C:8]([NH:21][C:22](=[O:30])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[NH2:29])[C:9]=2[CH:13]=1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccccc2N)c2cc(C(=O)OC(C)(C)C)sc21
Solvent: CO
Product: CC(C)(C)OC(=O)c1cc2c(NC(=O)c3ccccc3N)n[nH]c2s1
Yield: 91.4 %

Procedure:
30 mg of 3-(2-Amino-benzoylamino)-thieno[2,3-c]pyrazole-1,5-dicarboxylic acid 5-tert-butyl ester 1-ethyl ester (0.058 mmol) were treated with a 10% solution of TEA and methanol (8 mL) at room temperature for 3 hours. The solvent was removed under vacuum and the residue was purified by flash chromatography (eluant dichloromethane/methanol 99/1) yielding 19 mg (91%) of the title compound.
Reaction SMILES: [O:1]=[O+][O-].[CH3:4][C:5]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:33])[CH:17]([NH:21][C:22](=[O:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:18][CH2:19][CH3:20])=[N:12][N:11]=1)([CH3:9])[CH2:6][CH:7]=C.N#N>C(Cl)Cl>[CH3:4][C:5]([C:10]1[S:14][C:13]([NH:15][C:16](=[O:33])[CH:17]([NH:21][C:22](=[O:32])[CH2:23][C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[CH2:18][CH2:19][CH3:20])=[N:12][N:11]=1)([CH3:9])[CH2:6][CH:7]=[O:1]
Reactant: O=[O+][O-]
Reactant: C=CCC(C)(C)c1nnc(NC(=O)C(CCC)NC(=O)Cc2cc(F)cc(F)c2)s1
Agent: N#N
Solvent: ClCCl
Product: CCCC(NC(=O)Cc1cc(F)cc(F)c1)C(=O)Nc1nnc(C(C)(C)CC=O)s1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A stream of ozone was generated and passed through a solution of 2-[2-(3,5-difluoro-phenyl)-acetylamino]-pentanoic acid [5-(1,1-dimethyl-but-3-enyl)-[1,3,4]thiadiazol-2-yl]-amide (631 mg, 1.445 mmol) in 40 ml of methylene chloride until the mixture turned to blue solution or until the disappearance of starting material at −78° C. The mixture was stirred at −78° C. for 10 min, then the excess ozone was replaced with N2 at −78° C. The mixture was quenched with excess of dimethylsulfide and stirred at r.t. overnight. The mixture was concentrated to dryness, purified by Shimadzu HPLC to give the title compound as a yellow solid, RT=2.3 min, M+1=439.5.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[CH:11]=[CH:12][C:13](O)=[O:14]>C(OCC)C>[Br:7][C:8]1[CH:9]=[C:10]([CH2:11][CH2:12][CH2:13][OH:14])[CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)C=Cc1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: OCCCc1cccc(Br)c1
Reaction time: 3 h

Procedure:
To suspension of LiAlH4 (0.5 g, 1.3 mmol) in diethyl ether (25 mL) was added 3-bromocinnamic acid (83, 1.0 g, 4 mmol), in portions, at RT. The resulting suspension was stirred for 3 hours. The reaction was quenched by the successive addition of 15% aq. NaOH solution (1 mL) and water. The resulting white suspension was filtered through a pad of Celite. The filter cake was washed with ether and then ethyl acetate. The filtrate was concentrated to afford crude 8 as yellow oil. Yield (0.7 g, 74%). 1H NMR (400 MHz, CDCl3) δ 7.10-7.35 (m, 4H), 3.65 (t, J=6.5 Hz, 2H), 2.68 (t, J=7.8 Hz, 2H), 1.82-1.91 (m, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[S:7](Cl)([C:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:15]([N:16]([CH3:18])[CH3:17])[C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]>C1(C)C=CC=CC=1>[S:7]([N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1)([C:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:15]([N:16]([CH3:18])[CH3:17])[C:14]=2[CH:13]=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: C1CNCCN1
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: Cc1ccccc1
Product: CN(C)c1cccc2c(S(=O)(=O)N3CCNCC3)cccc12
Yield: 168.9 %

Procedure:
Dansylpiperazine was prepared by refluxing a solution of 7.98 g piperazine (9.27 mmol) and 5.00 g dansyl chloride (18.5 mmol) in 100 mL toluene for 6 h. The product was isolated by washing the solution with 5% NaOH and then water and concentrating in vacuo to yield 5.0 g (84%) dansylpiperazine as yellow-green powder. 1H NMR (200 MHz, CDCl3) 2.7-2.9 (4H, multiplet), 2.9 (6H, singlet), 3.1-3.3 (4H, multiplet), 7.1-7.6 (3H, multiplet), 8.2-8.6 (3H, multiplet).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.C(N(CC)CC)C.OC1C2N=NNC=2C=CC=1.[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:42][CH2:41][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH2:47])[CH2:39][CH2:38]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:29])[CH3:28].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:27]([C:31]1[N:36]=[C:35]([N:37]2[CH2:38][CH2:39][N:40]([CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:1](=[O:9])[C:2]3[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=3)[CH2:41][CH2:42]2)[CH:34]=[C:33]([CH:48]2[CH2:51][CH2:50][CH2:49]2)[N:32]=1)([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCN)CC2)n1
Reactant: O=C(O)c1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1nc(C2CCC2)cc(N2CCN(CCCCNC(=O)c3cccnc3)CC2)n1
Reaction time: 16 h
Yield: 58.6 %

Procedure:
0.35 g of nicotinic acid (2.84 mmol) and 0.87 g of triethylamine (8.62 mmol) were dissolved in 30 ml of dimethylformamide. 0.45 g of hydroxybenzotriazole (HOBt, 3.33 mmol), 1.1 g of 4-[4-(2-tert-butyl-6-cyclobutyl-pyrimidin-4-yl)-piperazin-1-yl]-butylamine (3.18 mmol), and 0.6 g of N-ethyl-N′-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDCl, 3.13 mmol) were added at room temperature, and the reaction mixture was stirred for 16 h. The reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried over magnesium sulfate, filtered, and concentrated to dryness. The crude product was purified by chromatography on silica gel using dichloromethane-methanol (2-10%). The residue was treated with acetonitrile, filtered and dried to yield 0.75 g of the title compound as a white solid.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][OH:9])=[CH:5][CH:4]=1.[H][H]>[Ni].C(O)C>[OH:9][CH2:8][CH:6]1[O:7][CH:3]([CH2:2][OH:1])[CH2:4][CH2:5]1
Reactant: OCc1ccc(CO)o1
Reactant: [H][H]
Agent: [Ni]
Solvent: CCO
Product: OCC1CCC(CO)O1

Procedure:
Raney nickel [ethanol was added three times to 50% commercial aqueous Raney nickel suspension (5 mL) from Acros, and decanted] was added to a solution of (5-hydroxymethylfuran-2-yl)methanol (RK-325) (3.46 g, 27 mmol) in absolute ethanol (100 mL), and hydrogenated overnight at room temperature and at a pressure of 2 bar (hydrogen consumption 61 mmol). The reaction mixture was filtered and the filtrate was concentrated under vacuum.
Reaction SMILES: [C:1]([N:4](C(=O)C)[C:5]1[O:10][C:9]2[C:11]3[C:16]([CH:17]=[CH:18][C:8]=2[CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]=1[C:28]#[N:29])=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]>C(Cl)(Cl)Cl>[C:1]([NH:4][C:5]1[O:10][CH:9]2[C:11]3[C:16]([CH:17]=[CH:18][C:8]2=[C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([N+:25]([O-:27])=[O:26])[CH:20]=2)[C:6]=1[C:28]#[N:29])=[CH:15][CH:14]=[CH:13][CH:12]=3)(=[O:3])[CH3:2]
Reactant: CC(=O)N(C(C)=O)C1=C(C#N)C(c2cccc([N+](=O)[O-])c2)c2ccc3ccccc3c2O1
Solvent: ClC(Cl)Cl
Product: CC(=O)NC1=C(C#N)C(c2cccc([N+](=O)[O-])c2)=C2C=Cc3ccccc3C2O1
Reaction time: 24 h

Procedure:
2-Diacetylamino-4-(3-nitrophenyl)-4H-naphtho[1,2-b]pyran-3-carbonitrile (3.62 g) was dissolved in chloroform (200 ml) and mechanically stirred in the presence of Grade III alumina (36 g) for 24 hours at ambient temperature. The suspension was filtered, the alumina pad was washed through with 5% methanol in chloroform, the combined filtrates were evaporated and the residue was triturated with a little chloroform. The white solid was dissolved in dioxan (50 ml) and left to stand for 24 hours. An impurity precipitated out and this was filtered off. Water was added (200 ml) to the filtrate and the solid produced was filtered off, washed with water and dried. This solid was passed through a chloroform--`flash` silica column. The fractions containing product were bulked, evaporated to dryness and triturated with methanol to give yellow crystals of 2-acetamido-4-(3-nitrophenyl)-naphtho[1,2-b]pyran-3-carbonitrile, m.p. 234.5°-236° C.
Reaction SMILES: [CH3:1][C:2](C)([O-])[CH3:3].[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[NH:16][CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[N:19]=2)=[CH:11][CH:10]=1.C(I)(C)C>CN(C)C=O>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[N:16]([CH:2]([CH3:3])[CH3:1])[CH:17]=[C:18]([C:20]([F:23])([F:21])[F:22])[N:19]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc(-c2nc(C(F)(F)F)c[nH]2)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)I
Product: COc1ccc(-c2nc(C(F)(F)F)cn2C(C)C)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
At an internal temperature of 0°-50°, 10 g of potassium tert.-butoxide are added to a solution of 20 g of 2-(4-methoxyphenyl)-4-(trifluoromethyl)-1H-imidazole in 200 ml of dimethylformamide. After 20 minutes 10.7 ml of isopropyl iodide are added and the reaction mixture is subsequently stirred at room temperature. After 24 hours in each case, a further 10 g of potassium tert.-butoxide are added and then 10.7 ml of isopropyl iodide. In total, these measures are repeated three times. The total reaction period is 120 hours. Finally, the solvent is removed in a rotary evaporator, the residue is taken up in water and extracted several times with ethyl acetate. After evaporating off the organic phase, the residue is chromatographed on silica gel with ethyl acetate/hexane and 2-(4-methoxyphenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole is isolated from the main fractions in the form of a yellowish oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4](O)[C:5]2[N:10]([CH3:11])[CH:9]=[C:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=1.O=P(Cl)(Cl)[Cl:24]>>[Cl:24][C:4]1[C:5]2[N:10]([CH3:11])[CH:9]=[C:8]([C:12]3[C:17]([CH3:18])=[CH:16][C:15]([CH3:19])=[CH:14][C:13]=3[CH3:20])[C:6]=2[N:7]=[C:2]([CH3:1])[N:3]=1
Reactant: Cc1cc(C)c(-c2cn(C)c3c(O)nc(C)nc23)c(C)c1
Reactant: O=P(Cl)(Cl)Cl
Product: Cc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1

Procedure:
A mixture of 2,5-dimethyl-7-(2,4,6-trimethylphenyl)-5H-pyrrolo[3,2-d]pyrimidin-4-ol (1 mmol) in POCl3 (1.3 ml) was heated at reflux until all the starting material were consumed (about 1-3 hours). The mixture was concentrated to dryness. The residue was porued into ice-water and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16](I)=[CH:15][CH:14]=2)[CH:5]=1.[F:21][C:22]1[C:27]([F:28])=[CH:26][C:25](B(O)O)=[C:24]([O:32][CH3:33])[CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([C:25]3[CH:26]=[C:27]([F:28])[C:22]([F:21])=[CH:23][C:24]=3[O:32][CH3:33])=[CH:15][CH:14]=2)[CH:5]=1
Reactant: COC(=O)c1ccc(F)c(COc2ccc(I)cc2)c1
Reactant: COc1cc(F)c(F)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(F)c(COc2ccc(-c3cc(F)c(F)cc3OC)cc2)c1
Temperature: 45 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a mixture of 4-fluoro-3-(4-iodophenoxy)methylbenzoic acid methyl ester (1.1 g, 2.85 mmol) and 4,5-difluoro-2-methoxyphenylboronic acid (0.642 g, 3.4 mmol) in DMF (15 mL) and water (2.5 mL) was added Pd(dppf)Cl2 (220 mg, 0.27 mmol) and potassium carbonate (1.24 g, 9.0 mmol). The mixture was stirred at 45° C. overnight and solvents were evaporated. The residue was extracted with ethyl acetate and water. The organic layer was dried and concentrated. The residue was purified through flash column chromatography (120 g silica gel, 5% to 40% ethyl acetate in hexanes over 25 minutes) to give a white solid as 3-(4′,5′-difluoro-2′-methoxybiphenyl-4-yloxymethyl)-4-fluorobenzoic acid methyl ester (0.76 g, 67%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:20][CH:19]4[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:10]=2)=[N:6][CH:7]=1.[SH:37][CH2:38][C:39]([O:41][CH3:42])=[O:40]>>[CH3:42][O:41][C:39](=[O:40])[CH2:38][S:37][C:2]1[CH:3]=[C:4]([O:29][C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[C:5]([NH:8][C:9]2[S:13][N:12]=[C:11]([CH:14]3[CH2:20][CH:19]4[N:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH:16]([CH2:17][CH2:18]4)[CH2:15]3)[N:10]=2)=[N:6][CH:7]=1
Reactant: Cc1ncccc1Oc1cc(Br)cnc1Nc1nc(C2CC3CCC(C2)N3C(=O)OC(C)(C)C)ns1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(Nc2nc(C3CC4CCC(C3)N4C(=O)OC(C)(C)C)ns2)c(Oc2cccnc2C)c1
Yield: 84 %

Procedure:
Following the procedure in Example 52, tert-butyl 3-(5-(5-bromo-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (526 mg, 0.917 mmol) and methyl 2-mercaptoacetate (92.3 μL, 1.01 mmol) afforded tert-butyl 3-(5-(5-(2-methoxy-2-oxoethylthio)-3-(2-methylpyridin-3-yloxy)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)-8-azabicyclo[3.2.1]octane-8-carboxylate (461 mg, 0.770 mmol, 83.9% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:18][C:17]3[C:12](=[CH:13][C:14]([N+:19]([O-])=O)=[CH:15][CH:16]=3)[C:11](=[O:22])[N:10]2[CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:5][CH:4]=1)#[N:2].[H][H]>CO.[Pd]>[NH2:19][C:14]1[CH:13]=[C:12]2[C:17]([CH2:18][CH:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]([CH2:23][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[C:11]2=[O:22])=[CH:16][CH:15]=1
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc([N+](=O)[O-])ccc2CC1c1ccc(C#N)cc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCN1C(=O)c2cc(N)ccc2CC1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of Intermediate 1 (350 mg, 0.78 mmol) in 20 mL of MeOH was added 10% Pd/C (40 mg). A balloon filled with hydrogen gas was attached, and the reaction was stirred at 25° C. for 12 hrs. The mixture was filtered through Celite pad and the solvent was evaporated. The residue was purified by medium pressure liquid chromatography on silica gel using ethyl acetate:hexane (8:2) to yield Intermediate 13 as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1.C[O-].C([Sn+](CCCC)CCCC)CCC.C([O:29][C:30]([CH3:32])=[CH2:31])(=O)C.[F-].[K+]>C1(C)C=CC=CC=1.O.[Cl-].[Na+].O.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].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.CCOC(C)=O>[O:29]=[C:30]([CH3:32])[CH2:31][C:2]1[CH:3]=[C:4]([CH2:8][C:9]#[N:10])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCc1cccc(Br)c1
Reactant: C=C(C)OC(C)=O
Agent: [Pd]
Agent: CCCC[Sn+](CCCC)CCCC
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)Cc1cccc(CC#N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 69.1 %

Procedure:
A stirred solution of 3-bromophenylacetonitrile (10.0 g, 51.0 mmol), tributyltin methoxide (17.6 mL, 61.2 mmol), tris(dibenzylideneacetone)dipalladium(0) (500 mg, 0.5 mmol), isopropenyl acetate (6.74 mL, 61.2 mmol) and 2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl (800 mg, 2 mmol) in toluene (100 mL, degassed) was heated at 100° C. under nitrogen for 6 h. The reaction mixture was cooled to room temperature and EtOAc (30 mL) was added. A solution of potassium fluoride (10 g, 200 mmol) in water (52 mL) was then added and the resulting mixture was stirred overnight. Brine was added and the mixture was filtered through a pad of Celite. The layers were separated and the organic layer was dried over sodium sulfate, filtered (cotton plug) and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-30% EtOAc in hexanes) to give the title compound (6.1 g, 69% yield) as a brown oil.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]([CH3:14])[CH2:10][C:11]([OH:13])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].CS(O)(=O)=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>>[CH3:14][CH:9]1[CH2:10][C:11](=[O:13])[C:6]2[C:7](=[CH:15][CH:16]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[O:8]1
Reactant: CC(CC(=O)O)Oc1ccc([N+](=O)[O-])cc1
Agent: CS(=O)(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Product: CC1CC(=O)c2cc([N+](=O)[O-])ccc2O1
Temperature: 23 °C

Procedure:
A mixture of 31.2 g (139 mmol) 3-(4-nitrophenoxy)butyric acid, 139 ml methanesulfonic acid and 7 g phosphorus pentoxide was heated on the steam bath for 1.75 hours. The reaction was cooled to 23° C., poured onto 500 ml ice-water mixture and extracted with 2×200 ml diethyl ether. The combined organic extracts were washed with 2×150 ml 1N sodium hydroxide, clarified by filtration, washed with 2×50 ml water and 100 ml brine, dried over magnesium sulfate and concentrated in vacuo to give the crude product as a yellow solid, 2.9 g (10%). Recrystallization from methylene chloride and isopropyl ether gave 1.35 g (4.7%) golden platelets, m.p. 144°-145° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:13])=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].N1C=CC=CC=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C(Cl)Cl>[Cl:12][C:5]1[CH:4]=[C:3]([F:13])[C:2]([NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(N)c(F)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)c1cc(NS(C)(=O)=O)c(F)cc1Cl
Reaction time: 72 h
Yield: 45.4 %

Procedure:
To a solution of methyl 5-amino-2-chloro-4-fluorobenzoate (152 mg, 0.75 mmol) and pyridine (0.07 mL, 0.82 mmol) in 3 mL CH2Cl2 was added methanesulfonyl chloride (0.06 mL, 0.82 mmol). After 3 days at room temperature, the reaction mixture was washed with saturated aqueous NaHCO3 and filtered through a silica plug to provide methyl 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoate (96 mg, 44%) as a solid (ESI-MS 280 (M−H)), which was hydrolyzed using aqueous NaOH to provide 2-chloro-4-fluoro-5-[(methylsulfonyl)amino]benzoic acid (ESI-MS 266 (M−H)), which was used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:14]([O:16][C:17](=[O:21])[CH2:18][CH2:19][NH2:20])[CH3:15].ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>O.CN(C)C=O.C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([NH:20][CH2:19][CH2:18][C:17]([O:16][CH2:14][CH3:15])=[O:21])=[O:10])=[CH:11][CH:12]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)CCN
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOC(=O)CCNC(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
To a mixture of 4-nitrobenzoic acid (16.7 g), β-alanine ethyl ester hydrochloride (18.4 g), 1-hydroxybenzotriazol.monohydrate (18.4 g), triethylamine (16.7 mL) and N,N-dimethylformamide (200 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (23.0 g), and the mixture was stirred at room temperature for 8 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium hydrogen carbonate, dried over magnesium sulfate, and concentrated under reduced pressure to give a white solid. Recrystallization from ethyl acetate-hexane gave the title object compound (26.6 g, 100%) as white crystals.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[CH:11][N:12]3[C:17]([C:18]=2[CH3:19])=[C:16]([CH:20]2[CH2:22][CH2:21]2)[CH:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13]3=[O:28])[CH:6]=[CH:7][CH:8]=1.[CH3:29][NH2:30]>O1CCCC1>[CH:20]1([C:16]2[CH:15]=[C:14]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:13](=[O:28])[N:12]3[C:17]=2[C:18]([CH3:19])=[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:30][CH3:29])[CH:4]=2)[CH:10]=[CH:11]3)[CH2:21][CH2:22]1
Reactant: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(CBr)c3)ccn2c1=O
Reactant: CN
Solvent: C1CCOC1
Product: CCOC(=O)c1cc(C2CC2)c2c(C)c(-c3cccc(CNC)c3)ccn2c1=O
Reaction time: 10 h

Procedure:
31.2 mg of ethyl 8-(3-bromomethylphenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (Example 57) was dissolved in 2 ml of tetrahydrofuran. 0.1 ml of a solution of 2.0 M of methylamine in tetrahydrofuran was added to the obtained solution, and they were stirred for 10 hours. The reaction mixture was concentrated under reduced pressure. The obtained residue was purified by the silica gel column chromatography (eluent: chloroform/methanol=5/1) to obtain 18.1 mg of ethyl 1-cyclopropyl-9-methyl-8-(3-methylaminomethylphenyl)-4-oxo-4H-quinolizine-3-carboxylate.