Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][C:7]2[C:8]([CH3:20])=[C:9]([CH3:19])[C:10]([CH:17]=O)=[C:11]([CH:16]=2)[C:12](OC)=[O:13])=[CH:4][CH:3]=1.[NH2:23][C@@H:24]1[C@@H:29]([OH:30])[CH2:28][CH2:27][O:26][CH2:25]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][C:7]2[CH:16]=[C:11]3[C:10]([CH2:17][N:23]([C@@H:24]4[C@@H:29]([OH:30])[CH2:28][CH2:27][O:26][CH2:25]4)[C:12]3=[O:13])=[C:9]([CH3:19])[C:8]=2[CH3:20])=[CH:21][CH:22]=1
Reactant: N[C@H]1COCC[C@@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(Cl)cc2)c(C)c(C)c1C=O
Solvent: C1CCOC1
Product: Cc1c(Cc2ccc(Cl)cc2)cc2c(c1C)CN([C@H]1COCC[C@@H]1O)C2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 23 %

Procedure:
To a solution of methyl 5-(4-chlorobenzyl)-2-formyl-3,4-dimethylbenzoate (0.02 g) in THF (1.00 mL) was added (3S,4S)-3-aminotetrahydro-2H-pyran-4-ol (8.14 mg), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated, and the residue was diluted with methanol (1.00 mL). Sodium triacetoxyborohydride (0.02 g) was added thereto under argon atmosphere, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by reverse-phase HPLC. The fractions were combined, saturated aqueous sodium hydrogencarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (5.60 mg).
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1B(O)O.[F-].[K+]>C1COCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[CH3:10])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(Cl)cc1
Reactant: Cc1ccccc1B(O)O
Agent: [F-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccccc1-c1ccc(C#N)cc1
Yield: 93.1 %

Procedure:
4-Chlorobenzonitrile (55 mg, 0.40 mmol) reacted with 2-methylphenylboronic acid (82 mg, 0.60 mmol) using 1 mol % of Pd(dba)2/Ph5FcP(t-Bu)2 and KF (70 mg, 1.21 mmol) in THF at 45° C. to give the title compound (72 mg, 94%) as a white solid: 1H-NMR (300 MHz, CDCl3): δ 7.73 (d, 2H, J=8.1 Hz), 7.46 (d, 2H, J=8.4 Hz), 7.27-7.34 (m, 3H), 7.21, (d, 1H, J=6.9 Hz), 2.80 (s, 3H). 13C{1H}-NMR (100 MHz, CDCl3): δ 146.76, 139.97, 135.00, 131.94, 130.64, 129.97, 129.39, 128.26, 126.07, 118.93, 110.70, 20.28. GC/MS (EI): m/z 193 (M+), 165.
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][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][C:19]#[N:20]>>[CH3:13][O:14][C:15]1[CH:16]=[C:17](/[C:18](=[CH:11]/[C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=[CH:2][CH:3]=2)/[C:19]#[N:20])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: O=Cc1ccnc2ccccc12
Product: COc1ccc(/C(C#N)=C/c2ccnc3ccccc23)cc1OC
Yield: 51.9 %

Procedure:
4-Quinolinecarboxaldehyde (500 mg) was condensed with 3,4-dimethoxybenzyl cyanide (564 mg) through Method A (production step 2), to thereby yield the target product (yield: 522 mg, 52%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7]([NH2:9])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:19])=CC=1>C1COCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][C:7](=[S:19])[NH2:9]
Reactant: COCCOCC(N)=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: C1CCOC1
Product: COCCOCC(N)=S
Temperature: 25 °C
Yield: 134.9 %

Procedure:
A solution of 2-(2-methoxyethoxyl)acetamide (Example 6A, 3.39 g, 25.5 mmol) in THF (40 mL) was treated with Lawesson's reagent (6.55 g, 16.19 mmol) and the reaction was refluxed for 18 hours. The reaction was then allowed to cool down to RT and was concentrated under vacuum, diluted with ethyl acetate, washed with sat. NaHCO3 (1×) and brine (1×). The aqueous phases were extracted with ethyl acetate (2×200 mL) and the organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (3.5×11 cm, 30% AcOEt/CH2Cl2) to give the title material (3.26 g, 86%) as a yellow oil. 1H NMR (CDCl3, 400 MHz) δ ppm: 8.58 (very broad s, 1H), 7.50 (very broad s, 1H), 4.36 (s, 2H), 3.66-3.69 (m, 2H), 3.53-3.56 (m, 2H), 3.39 (s, 3H).
Reaction SMILES: C[C:2]1(C)[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])O1.[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1C(Cl)=O.CO.S(=O)(=O)(O)O>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:13]=1[C:4]([CH2:6][C:7]([O:9][CH3:2])=[O:8])=[O:5]
Reactant: O=C(Cl)c1c(F)cccc1F
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CN(C)c1ccncc1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)CC(=O)c1c(F)cccc1F

Procedure:
To 3.6 g (25 mmole, 1 eq) of Meldrum's acid and 6.1 g of 4-dimethylamino-pyridine in 60 ml of methylenechloride was added with stirring, 4.4 g (25 mmole) of 2,6-difluorobenzoylchloride. The temperature was maintained at 0° throughout the addition period and for three additional hours of stirring under argon atmosphere. Most of the methylene chloride was then removed by distillation at 25° or less using a water aspirator to maintain reduced pressure. There was then added 60 ml of anhydrous methanol containing 25 mmole of conc. sulfuric acid.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1([C:16]([F:19])([F:18])[F:17])[O:7][C:6]([F:11])([CH2:8][CH2:9]I)[C:5]([F:15])([CH2:12][CH2:13]I)[O:4]1.[OH-].[K+]>>[F:19][C:16]([F:17])([F:18])[C:3]1([C:2]([F:1])([F:20])[F:21])[O:4][C:5]([F:15])([CH:12]=[CH2:13])[C:6]([F:11])([CH:8]=[CH2:9])[O:7]1
Reactant: FC(F)(F)C1(C(F)(F)F)OC(F)(CCI)C(F)(CCI)O1
Agent: [K+]
Agent: [OH-]
Product: C=CC1(F)OC(C(F)(F)F)(C(F)(F)F)OC1(F)C=C
Temperature: 25 °C
Reaction time: 4 h
Yield: 49.3 %

Procedure:
In a flask was charged above compound 9 (95 g, 0.17 mole), 10M KOH (189 ml, 1.89 mole) and phase transfer catalyst (Note) (24.6 g as 60% w/w aqueous solution, 0.034 mole). The reaction mixture was vigorously stirred at ambient temperature for 4 hrs. The bottom organic layer was separated and was further purified by distillation giving 25.0 g (49.3% yield) of the desired Product was obtained as a clear, colorless liquid, bp. 90° C./200 mm.
Reaction SMILES: Cl.[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([Cl:18])=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:21][S:22]([C:25]1[CH:35]=[CH:34][C:28]2[CH2:29][CH2:30][NH:31][CH2:32][CH2:33][C:27]=2[CH:26]=1)(=[O:24])=[O:23]>>[ClH:18].[N:2]1([CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([N:31]3[CH2:30][CH2:29][C:28]4[CH:34]=[CH:35][C:25]([S:22]([CH3:21])(=[O:24])=[O:23])=[CH:26][C:27]=4[CH2:33][CH2:32]3)=[O:17])=[CH:14][CH:13]=2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)c1ccc(OCCCN2CCCCC2)cc1
Reactant: CS(=O)(=O)c1ccc2c(c1)CCNCC2
Agent: Cl
Product: CS(=O)(=O)c1ccc2c(c1)CCN(C(=O)c1ccc(OCCCN3CCCCC3)cc1)CC2

Procedure:
The title compound was prepared from 4-(3-piperidin-1-ylpropoxy)benzoyl chloride hydrochloride (D3) (0.20 g) and 7-methanesulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine (WO00/21951) (0.17 g) using the procedure described for Example 1 and isolated as a white solid (0.24 g). MS electrospray (+ion) 471 (MH+). 1H NMR δ (DMSO-d6): 9.83 (1H, s), 7.71 (2H, m), 7.44 (1H, s), 7.35 (2H, d, J=8.5 Hz ), 7.01 (2H, d, J=8.6 Hz), 4.11 (2H, t, J=5.9 Hz), 3.71-3.45 (6H, m), 3.18 (6H, m), 3.05 (3H, s) 2.87 (2H, m), 2.20 (2H, m), 1.83-1.37 (6H, m).
Reaction SMILES: [CH:1]([CH:3]=[CH2:4])=[O:2].[CH2:5]([O:8][CH2:9][CH:10]=[CH2:11])[CH:6]=[CH2:7]>>[CH2:1]([O:2][CH2:11][CH2:10][CH2:9][O:8][CH2:5][CH:6]=[CH2:7])[CH:3]=[CH2:4]
Reactant: C=CCOCC=C
Reactant: C=CC=O
Product: C=CCOCCCOCC=C

Procedure:
GC revealed that peaks assigned to carbonyl compounds such as acrolein, 3-allyloxy-1-propionaldehyde and 3-hydroxy-1-propionaldehyde were not detected (these carbonyl compounds showed GC detection limit of 10 ppm or less in this example), but diallyl ether and 1,3-diallyloxypropane were produced.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][C:4]#[CH:5].Br[C:8]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([OH:26])[C:14]([N:18]3[S:22](=[O:24])(=[O:23])[NH:21][C:20](=[O:25])[CH2:19]3)=[CH:15]2)=[CH:10][CH:9]=1>>[OH:26][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[N:18]1[CH2:19][C:20](=[O:25])[NH:21][S:22]1(=[O:24])=[O:23])[CH:17]=[C:8](/[CH:5]=[CH:4]/[CH2:3][CH2:2][C:1]#[N:6])[CH:9]=[CH:10]2
Reactant: O=C1CN(c2cc3cc(Br)ccc3cc2O)S(=O)(=O)N1
Reactant: C#CCCC#N
Product: N#CCC/C=C/c1ccc2cc(O)c(N3CC(=O)NS3(=O)=O)cc2c1

Procedure:
The title compound is prepared analogously to Example 8, step A, beginning with pent-4-ynenitrile and 5-(7-bromo-3-hydroxynaphthalen-2-yl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (Example 3, step E): Retention time=0.91 min (Method A); (M−H)−=356.
Reaction SMILES: [C:1]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].II.O=[C:19]([CH:21]=[C:22]([CH3:24])[CH3:23])[CH3:20]>>[C:4]([O:3][C:1]([NH:8][C:9]1[CH:10]=[C:11]2[C:12](=[CH:13][CH:14]=1)[NH:15][C:22]([CH3:24])([CH3:23])[CH:21]=[C:19]2[CH3:20])=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(=O)C=C(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(N)cc1
Agent: II
Product: CC1=CC(C)(C)Nc2ccc(NC(=O)OC(C)(C)C)cc21
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A mixture of N-Boc-1,4-phenylenediamine (5.0 g) and iodine (1.3 g) in mesityl oxide (25 ml) was stirred at 100° C. for 2 h. The reaction mixture was concentrated in vacuo and the residue was chromatographed on Al2O3 (Alumina B, act. III) in heptane/dichloromethane=8/2 as eluent.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=1.[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][C:22]=1[CH3:30]>>[F:9][C:5]1[CH:4]=[C:3]([C:10]2[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[C:2]([C:24]2[CH:25]=[CH:26][C:21]([F:20])=[C:22]([CH3:30])[CH:23]=2)=[CH:7][C:6]=1[F:8]
Reactant: CS(=O)(=O)c1ccc(-c2cc(F)c(F)cc2Br)cc1
Reactant: Cc1cc(B(O)O)ccc1F
Product: Cc1cc(-c2cc(F)c(F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1F

Procedure:
Following the general procedure outlined in Synthetic Scheme VI, 1-bromo-4,5-difluoro-2-[4-(methylsulfonyl)phenyl]benzene (Example 18, Step 2) was reacted with 4-fluoro-3-methylphenylboronic acid (Step 1) to give 1,2-difluoro-4-(4-fluoro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]benzene as a colorless solid: mp 167.2-167.5° C.; NMR (CDCl3) δ 2.19 (d, J=2 Hz, 3H), 3.04 (s, 3H), 6.71-6.78 (m, 1H), 6.84 (t, J=9 Hz, 1H), 6.92 (dd, J=2, 8 Hz, 1H), 7.18-7.32 (m, 4H), 7.81 (d, J=8 Hz, 2H); MS (FAB) m/z 383 (M+Li)+; HRMS calc'd for M+ 376.0745, found 376.0752. Anal. Calc'd for C20H15F3O2S: C, 63.82; H, 4.02; F, 15.14. Found: C, 64.00; H, 3.95; F, 14.96.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17](F)[CH:18]=1)[C:14]#[N:15].C(=O)([O-])[O-].[K+].[K+]>CN1C(=O)CCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:16]=[C:17]([O:1][C:2]2[CH:7]=[C:6]([CH3:8])[NH:5][C:4](=[O:9])[CH:3]=2)[CH:18]=1)[C:14]#[N:15]
Reactant: N#Cc1cc(F)cc(Cl)c1
Reactant: Cc1cc(O)cc(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(Oc2cc(Cl)cc(C#N)c2)cc(=O)[nH]1
Temperature: 120 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine (3-2; 20.1 g; 161 mmol) in NMP (1.6 L) was added 3-chloro-5-fluorobenzonitrile (3-1; 25 g; 161 mmol) and potassium carbonate (44.4 g; 321 mmol). The resulting solution stirred at 120° C. overnight. The reaction mixture was cooled to ambient temperature and diluted with 4 L of ice-water. The aqueous layer was acidified to pH 5 to precipitate out the product. The precipitate was collected via filtration, washed with water, and air dried. The crude solid product was triturated in 5% methanol/dichloromethane and filtered to give a solid. The solid was triturated with 1:1 ethyl acetate:hexane, stirred, and filtered to afford the title product as a tan solid. MS M+1=261.0.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]23[CH2:20][CH:19]([OH:21])[C:16]([CH2:22][CH2:23][CH3:24])([CH2:17][O:18]2)[CH2:15][O:14]3)=[CH:9][CH:8]=1.O>N1C=CC=CC=1>[CH3:1][S:2]([O:21][CH:19]1[C:16]2([CH2:22][CH2:23][CH3:24])[CH2:15][O:14][C:13]([C:10]3[CH:9]=[CH:8][C:7]([Cl:6])=[CH:12][CH:11]=3)([O:18][CH2:17]2)[CH2:20]1)(=[O:4])=[O:3]
Reactant: CCCC12COC(c3ccc(Cl)cc3)(CC1O)OC2
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CCCC12COC(c3ccc(Cl)cc3)(CC1OS(C)(=O)=O)OC2
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Methanesulphonyl chloride (164 μl) was added to a stirred solution of 1-(4-chlorophenyl)-8-hydroxy-4-n-propyl-2,6-dioxabicyclo[2,2,2]octane (500 mg.) in dry pyridine (2.0 ml.). The mixture was stirred at room temperature for 6 hours. The mixture was poured into water and the aqueous mixture was extracted with diethyl ether. The ethereal extracts were washed with 1N hydrochloric acid solution. The ethereal extracts were then washed with saturated aqueous sodium hydrogen carbonate solution. The ethereal extracts were washed with water, dried over anhydrous magnesium sulphate and evaporated in vacuo.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH:11]=1)=[O:5].[CH2:19]1[CH2:23]O[CH2:21][CH2:20]1>>[C:19]1([C:23]2[CH:8]=[CH:7][CH:6]=[CH:11][CH:10]=2)[CH:16]=[CH:15][C:14]([C:4]([C:6]2[CH2:7][CH2:8][N:9]([C:12]3[N:13]=[CH:14][CH:15]=[CH:16][N:17]=3)[CH2:10][CH:11]=2)=[O:5])=[CH:21][CH:20]=1
Reactant: C1CCOC1
Reactant: CON(C)C(=O)C1=CCN(c2ncccn2)CC1
Product: O=C(C1=CCN(c2ncccn2)CC1)c1ccc(-c2ccccc2)cc1
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 1-pyrimidin-2-yl-1,2,3,6-tetrahydro-pyridin-4-carboxylic acid methoxy-methyl amide (48 mg, 0.196 mmol) in THF (1 ml), was added 1-biphenyl-4-yl magnesium bromide (0.5 M in THF) at 0° C. The mixture was stirred at this temperature for 1 hour and quenched with addition of water (5 ml) and EtOAc (20 ml). The aqueous phase was further extracted with EtOAc (2×8 ml). The combined organic layers were washed with brine (5 ml), dried (MgSO4), filtered, and concentrated under reduced pressure to furnish the crude product. This material was purified by column chromatography (4% MeOH/CH2Cl2) to give the title compound (20 mg, 30%) as an off-white solid: 1H NMR (CDCl3, 400 MHz) δ 8.38 (d, J=6.4 Hz, 2H), 7.82-7.42 (m, 9H), 6.70 (m, 1H), 6.58 (t, J=6.4 Hz, 1H), 4.51 (m, 2H), 4.13 (t, J=5.6 Hz, 2H), 2.72 (m, 2H); MS calc'd for C22H20N3O [M+H]+: 342; Found: 342.
Reaction SMILES: [C:1]1([C:7]2[N:16]=[C:15](Cl)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH:20]1[CH2:25][CH2:24][CH2:23][NH:22][CH2:21]1>C(O)(C)C>[C:1]1([C:7]2[N:16]=[C:15]([N:22]3[CH2:23][CH2:24][CH2:25][CH:20]([CH2:19][OH:18])[CH2:21]3)[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCC1CCCNC1
Reactant: Clc1nc(-c2ccccc2)nc2ccccc12
Solvent: CC(C)O
Product: OCC1CCCN(c2nc(-c3ccccc3)nc3ccccc23)C1
Yield: 50.1 %

Procedure:
A mixture containing 12.3 g (0.05 mole) of 2-phenyl-4-chloroquinazoline, 5.75 g (0.05 mole) 3-(hydroxymethyl) piperidine and 200 ml isopropanol was refluxed for 11/2 hrs. The resulting reaction mixture was filtered after standing at room temperature for 11/2 hrs. The white crystalline solid obtained from the filtration was recrystallized with methanol and water to give 8.0 g of the title compound, m.p. 116°-118° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4](=[O:18])[C:5](=[CH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15](=[O:17])[CH3:16])=[CH:10][CH:9]=2)[N:6]=1.CC(C)=[O:21]>O>[C:15]([O:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]=[C:5]([NH:6][C:2](=[O:21])[CH3:1])[C:4]([OH:3])=[O:18])=[CH:9][CH:10]=1)(=[O:17])[CH3:16]
Reactant: CC(=O)Oc1ccc(C=C2N=C(C)OC2=O)cc1
Reactant: CC(C)=O
Solvent: O
Product: CC(=O)NC(=Cc1ccc(OC(C)=O)cc1)C(=O)O

Procedure:
75.8 g (0.3 mol) of 2-methyl-4-(p-acetoxy-benzylidene)-5(4H)-oxazolone are dissolved in a mixture of 725 ml of acetone and 281 ml of water and thereafter the solution is heated to the boil, under a reflux condenser, for 15 hours. Hereupon, a yellowish precipitate separates out. The reaction mixture is cooled and then filtered. The resulting crystals are recrystallised from acetone-water. p-Acetoxy-α-acetylaminocinnamic acid of melting point 236°-237°C is obtained.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=[C:6]([C:15]([O:17]CC)=[O:16])[C:5]=1[C:20]1[C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][C:23]([O:31][CH3:32])=[C:22]2[O:33][CH2:34][O:35][C:21]=12)[CH3:2].[OH-].[K+].Cl>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:9]([O:10][CH2:11][CH3:12])=[C:8]([O:13][CH3:14])[CH:7]=[C:6]([C:15]([OH:17])=[O:16])[C:5]=1[C:20]1[C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]([O:31][CH3:32])=[C:22]2[O:33][CH2:34][O:35][C:21]=12)[CH3:2]
Reactant: CCOC(=O)c1cc(OC)c(OCC)c(OCC)c1-c1c(C(=O)OCC)cc(OC)c2c1OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1c(OC)cc(C(=O)O)c(-c2c(C(=O)O)cc(OC)c3c2OCO3)c1OCC
Temperature: 70 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
In 4 ml of dioxane was dissolved 49 mg of diethyl 2,3-diethoxy-4,4'-dimethoxy-2',3'-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylate obtained in Example 6, and ml of a 5% aqueous solution of potassium hydroxide was added to the solution. The mixture was heated at 70° C. and stirred overnight. The pH value was adjusted to 1 to 2 by 3N hydrochloric acid, the reaction mixture was extracted with chloroform, and the solvent was removed from the extract to obtain 38 mg of 2,3-diethoxy-4,4'-dimethoxy-2',3'-methylenedioxy-1,1'-biphenyl-6,6'-dicarboxylic acid having the following physical properties (the yield was 88%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[N:11]1[C:20]2[C:15](=[CH:16][C:17]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1.C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:36])(=O)=O)=CC=1>C1COCC1>[F:36][CH:21]([C:17]1[CH:16]=[C:15]2[C:20](=[CH:19][CH:18]=1)[N:11]=[CH:12][CH:13]=[CH:14]2)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1ccc2ncccc2c1
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C(F)c1ccc2ncccc2c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a 250 ml round-bottomed flask was added lithium bis(trimethylsilyl)amide (2.0 g, 12 mmol) and tetrahydrofuran (75 ml). The mixture was cooled to −78° C. and methyl 2-(quinolin-6-yl)acetate (2.0 g, 9.9 mmol) was added as a solution in 1 ml THF. After stirring at −78° C. for 30 min, n-fluorobenzenesulfonimide (3.8 g, 12 mmol) was added as a 1M solution in THF. This was stirred for 30 min at −78° C. and then allowed to warm to rt. The mixture was quenched with sat NH4Cl (50 mL) and diluted with water (200 mL). The mixture was concentrated in vacuo to remove the THF and then was extracted with EtOAc (2×100 ml). The combined extracts were washed with brine (100 ml), dried (Na2SO4) and concentrated onto silica. Purification by silica gel chromatography (20 to 60% EtOAc/hexane) afforded the title compound as a tan solid. MS (ESI, pos. ion) m/z: 220 (M+1).
Reaction SMILES: [CH:1]([CH:3]1[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5][N:4]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:2].CC(=CC)C.[O-:22]Cl=O.[Na+]>CC(C)=O.O>[C:13]([O:12][C:10]([N:4]1[CH:3]([C:1]([OH:22])=[O:2])[CH2:9][CH:8]2[CH:6]([CH2:7]2)[CH2:5]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CC2CC2CC1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)N1CC2CC2CC1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 75.9 %

Procedure:
To a mixture of tert-butyl 4-formyl-3-azabicyclo[4.1.0]heptane-3-carboxylate (D16) (615 mg, 2.73 mmol) in acetone/water (30/20 ml) NaH2PO4.2H2O (426 mg, 2.73 mmol), 2-methyl-2-butene (1.3 ml, 12.28 mmol) and NaClO2 (864 mg, 9.55 mmol) were added and the reaction mixture was stirred at RT overnight. Solvents were evaporated in vacuo and the remaining residue was taken up into EtOAc (10 ml) and water (10 ml). Phases were separated and the aqueous layer was extracted with EtOAc (2×10 ml). The combined organic extracts after solvent evaporation afforded the title compound (D17) (0.5 g).
Reaction SMILES: [CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=O)[CH2:4][C:3]1([CH3:12])[CH3:11].Cl.[NH2:14][OH:15]>>[CH3:1][N:2]1[C:7]([CH3:9])([CH3:8])[CH2:6][C:5](=[N:14][OH:15])[CH2:4][C:3]1([CH3:12])[CH3:11]
Reactant: NO
Reactant: CN1C(C)(C)CC(=O)CC1(C)C
Agent: Cl
Product: CN1C(C)(C)CC(=NO)CC1(C)C

Procedure:
1,2,2,6,6-Pentamethyl-piperidin-4-one oxime was prepared from 1,2,2,6,6-pentamethyl-piperidin-4-one and hydroxylamine hydrochloride using conditions of General Method 1. 1H NMR (250 MHz, CHLOROFORM-d) δ 2.52 (2H, s), 2.28 (3H, s), 2.21 (2H, s), 1.12 (6H, s), 1.11 (6H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:24])[CH3:23])=[N:7][C:8]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)=[N:9][C:10]=1[N:11]([CH3:13])[CH3:12].[F:26][C:27]([F:38])([F:37])[C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3](=[O:25])[CH2:4][C:5]1[C:6]([N:22]([CH3:23])[CH3:24])=[N:7][C:8]([CH2:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:32](=[O:33])[C:31]3[CH:35]=[CH:36][C:28]([C:27]([F:26])([F:37])[F:38])=[CH:29][CH:30]=3)=[CH:19][CH:20]=2)=[N:9][C:10]=1[N:11]([CH3:12])[CH3:13]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(N)cc2)nc1N(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Cc1c(N(C)C)nc(Cc2ccc(NC(=O)c3ccc(C(F)(F)F)cc3)cc2)nc1N(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
A solution of methyl[2-(4-aminobenzyl)-4,6-bis(dimethylamino)pyrimidin-5-yl]acetate (4.00 g, 11.65 mmol) in dichloromethane (120 mL) was treated with 4-trifluoromethylbenzoyl chloride (2.92 g, 13.98 mmol) and triethylamine (3.54 g, 34.94 mmol). After stirring for 1 hour at room temperature, the reaction mixture was partitioned between water and chloroform and the aqueous layer was extracted with chloroform. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the crude product as a yellow colored solid which was recrystallized from methanol to give methyl[4,6-bis(dimethylamino)-2-(4-{[4-(trifluoromethyl)benzoyl]amino}benzyl)pyrimidin-5-yl]acetate (4.34 g, 73%) as a white solid.
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[CH:8]=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[S:6]1(=[O:20])=[O:19])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(O)C.[Pd]>[C:1]([N:5]1[C:9](=[O:10])[CH2:8][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=2[F:18])[S:6]1(=[O:19])=[O:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(C2=CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc(C2CC(=O)N(C(C)(C)C)S2(=O)=O)c(F)c1
Yield: 79.5 %

Procedure:
2-tert-Butyl-5-(2-fluoro-4-methylphenyl)isothiazol-3(2H)-one 1,1-dioxide (4.5 g) in ethanol (120 mL) was treated with palladium (900 mg, 8.46 mmol) (10% palladium on carbon) and placed on a par hydrogenator under a 50 psi atmosphere of hydrogen for 24 h. The reaction was filtered though celite. After concentration, the crude material was purified by silica gel chromatography (3–10% ethyl acetate:hexanes) to afford product as a white solid (3.6 g, 79%). 1H NMR (400 MHz, CDCl3): δ7.21–7.17 (m, 1H), 7.02–6.96 (m, 2H), 5.04 (dd, J=9.0, 7.0 Hz, 1H), 3.26 (dd, J=17.2, 9.0 Hz, 1H), 3.08 (dd, J=17.2, 7.0 Hz, 1H), 2.37 (s, 3H), 1.66 (s, 9H).