Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([CH3:9])[C:5]([F:10])=[CH:4][C:3]=1[CH3:11].[N+:12]([O-])([O-:14])=[O:13].[K+]>S(=O)(=O)(O)O>[F:8][C:7]1[C:2]([F:1])=[C:3]([CH3:11])[C:4]([N+:12]([O-:14])=[O:13])=[C:5]([F:10])[C:6]=1[CH3:9]
Reactant: Cc1cc(F)c(C)c(F)c1F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(F)c(F)c(C)c([N+](=O)[O-])c1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 78.1 %

Procedure:
To 2,3,5-trifluoro-4-methyltoluene (1.9 g) is added conc. sulfuric acid (19 ml) and the mixture is cooled to 0° C., to which a solution of potassium nitrate (1.71 g) in conc. sulfuric acid (4.6 ml) is added dropwise below 10° C. and the mixture is stirred for 15 minutes. The mixture is poured into ice-water, extracted with diethyl ether, and the extract is washed with water and dried. The solvent is distilled off under reduced pressure and the residue is purified by silica-gel column-chromatography (dichloromethane: n-hexane =1 : 6) to give 2,3,6-trifluoro-4-methyl-5-nitrotoluene (1.9 g).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15].[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[O:28][C:26]1=[O:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[Cl-].[NH4+]>C1COCC1.CCCCCC>[CH2:17]([O:24][C@@H:25]1[C@@H:31]([O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C@H:30]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C@@H:29]([CH2:48][O:49][CH2:50][C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)[O:28][C:26]1([C:7]1[CH:8]=[C:9]([CH3:16])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[OH:27])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOc1ccc(C)cc1Br
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOc1ccc(C)cc1C1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 0.25 h
Yield: 37.1 %

Procedure:
A 1.6 M hexane solution of n-butyl lithium (11 ml) was added dropwise to a solution of 3-bromo-4-ethoxytoluene (3.6 g) in THF (50 ml) at −78° C. and the mixture was stirred for 15 minutes. Then, a solution of 2,3,4,6-tetra-O-benzyl-D-(+)-glucono-1,5-lactone (7.6 g) in THF (10 ml) was added dropwise to the reaction mixture and the mixture was stirred for 2.5 hours. Saturated aqueous solution of ammonium chloride was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated. The resulting precipitates were collected by filtration to obtain 2,3,4,6-tetra-O-benzyl-1-C-(2-ethoxy-5-methylphenyl)-D-glucopyranose (3.53 g).
Reaction SMILES: CCN(CC)CC.[Si:8]([O:15]S(C(F)(F)F)(=O)=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9].[C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[C:31]2=[O:39])(=O)[CH3:24]>C(Cl)Cl>[Si:8]([O:15][C:23]([C:26]1[CH:27]=[CH:28][CH:29]=[C:30]2[C:35]=1[N:34]=[C:33]([S:36][CH3:37])[N:32]([CH3:38])[C:31]2=[O:39])=[CH2:24])([C:11]([CH3:12])([CH3:13])[CH3:14])([CH3:9])[CH3:10]
Reactant: CSc1nc2c(C(C)=O)cccc2c(=O)n1C
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=C(O[Si](C)(C)C(C)(C)C)c1cccc2c(=O)n(C)c(SC)nc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Et3N (0.094 mL, 0.674 mmol) and TBSOTf (0.131 mL, 0.570 mmol) were sequentially added to a yellow solution of 8-acetyl-3-methyl-2-(methylthio)quinazolin-4(3H)-one (128.7 mg, 0.518 mmol) in DCM (2.7 mL) at 0° C., and the resulting light-yellow solution was stirred at 0° C. for 30 min. The mixture was partitioned between DCM (50 mL) and saturated aq. NaHCO3 (20 mL). The organic layer was separated, and the aq. layer was extracted with DCM (30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(1-((tert-butyldimethylsilyl)oxy)vinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as a peach-colored solid. This material was combined with 8-(1-ethoxyvinyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one (35.5 mg, 0.128 mmol), and the resulting mixture was taken up in THF (2.70 mL). Water (0.149 mL, 8.29 mmol) and NBS (115 mg, 0.648 mmol) were sequentially added at 25° C., and the resulting solution was stirred at 25° C. for 30 min. The mixture was partitioned between Et2O (50 mL) and water (30 mL). The organic layer was separated, sequentially washed with saturated aq. NaHCO3 (20 mL), water (20 mL), and brine (20 mL), then dried over Na2SO4, filtered, and concentrated in vacuo to provide crude 8-(2-bromoacetyl)-3-methyl-2-(methylthio)quinazolin-4(3H)-one as an off-white solid. NH4OAc (200 mg, 2.59 mmol) and piperidine-2,4-dione (88 mg, 0.777 mmol) were added to this solid, and the resulting mixture was taken up in EtOH (2.70 mL) and heated under argon in a sealed flask at 40° C. for 16 h. The reaction suspension was vacuum filtered, and the collected solid was washed with MeOH (20 mL) and dried in vacuo. The residue was triturated with DMSO (2.0 mL), and the resulting suspension was vacuum filtered. The collected solid was sequentially washed with MeOH (5 mL) and DCM (5 mL) and dried in vacuo to provide 3-methyl-2-(methylthio)-8-(4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridin-2-yl)quinazolin-4(3H)-one (57.1 mg, 0.168 mmol, 26% yield) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.67 (1H, br. s.), 8.05 (1H, dd, J=7.6, 1.2 Hz), 7.95 (1H, dd, J=7.8, 1.0 Hz), 7.44 (1H, t, J=7.8 Hz), 7.03 (1H, d, J=2.3 Hz), 6.96 (1H, br. s.), 3.56 (3H, s), 3.41 (2H, td, J=6.8, 2.2 Hz), 2.85 (2H, t, J=6.9 Hz), 2.74 (3H, s). m/z (ESI, +ve) 341.1 (M+H)+.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.BrC1C=CC=CC=1.C(P)=CC=C.[C:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])#[N:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(#N)C>[C:20]([CH2:22][C:23]([O:25][CH2:26][CH2:27][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:24])#[N:21]
Reactant: Ic1ccccc1
Reactant: CCOC(=O)CC#N
Agent: C=CC=CP
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Brc1ccccc1
Solvent: CC#N
Product: N#CCC(=O)OCCc1ccccc1

Procedure:
The general procedure (acetonitrile, 82° C., 12 hours with iodobenzene; 30 hours in the case of bromobenzene) was followed using 9.52 mg (0.05 mmol) of copper iodide CuI, 31.4 mg (0.1 mmol) of (Z)-cinnamic butadienylphosphine of example A-1-1, 80 ml (0.75 mmol) of ethyl cyanoacetate, 318 mg (1.5 mmol) of potassium phosphate (K3PO4), 56 μl (0.5 mmol) of iodobenzene (53 μl of bromobenzene) and 500 μl of acetonitrile. The residue obtained after treatment (dichloromethane/water extraction) was purified by chromatography on a silica column (gradient: hexanes/CH2Cl2 100:0 to 75:25).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4](F)[CH:3]=1.[NH:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13].C(=O)([O-])[O-].[K+].[K+].Cl>C(O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([N:12]([CH2:14][C:15]([OH:17])=[O:16])[CH3:13])[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1F
Reactant: CNCC(=O)O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(CC(=O)O)c1cc(Br)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A mixture of 4-bromo-2-fluoro-1-nitro-benzene (9 g, 40 mmol), sarcosine (3.6g, 40 mmol), and potassium carbonate (5.5 g, 40 mmol) in ethanol (100 ml) and water (40 ml) was heated to reflux for 5 hours. After cooling to room temperature, the mixture was diluted with water and was adjusted to pH 6 with 1N aqueous HCl solution. The yellow precipitate was collected, washed with water and dried in vacuo to obtain crude [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid (10 g, 87%). A portion of the crude sample was recrystallized from EtOAc/hexane to afford the pure [(5-bromo-2-nitro-phenyl)-methyl-amino]-acetic acid: mp 152-155° C.; 1H-NMR (DMSO-d6) δ 2.81 (s, 3H), 4.00 (s, 2H), 7.06 (dd, 1H, J=8.79, 1.98 Hz), 7.22 (d, 1H, J=1.98 Hz), 7.69 (d, 1H, J=8.79 Hz), 12.8 (s, 1H); MS (+APCI) m/z 289/291 (M+H)+.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]=1.[Li]CCCC.C([O:23][B:24](OC(C)C)[O:25]C(C)C)(C)C.Cl>C1COCC1.C(OCC)(=O)C>[CH2:11]([C:4]1[CH:3]=[C:2]([B:24]([OH:25])[OH:23])[C:10]2[O:9][CH2:8][O:7][C:6]=2[CH:5]=1)[CH:12]([CH3:14])[CH3:13]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)Cc1cc(Br)c2c(c1)OCO2
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)Cc1cc2c(c(B(O)O)c1)OCO2
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 55 %

Procedure:
To a mixture of 4-bromo-6-isobutyl-benzo[1,3]dioxole (232 mg, 0.90 mmol) in THF (3 mL) cooled to −78° C. under an atmosphere of argon was added n-BuLi (0.72 mL, 2.5 M, 1.80 mmol) dropwise. The reaction mixture was stirred for 5 minutes and triisopropylborate (0.62 mL, 2.71 mmol) was added dropwise. The mixture was stirred at −50° C. for 2 hours then warmed up to room temperature and stirred overnight at room temperature. 2.0 N HCl was slowly added to the reaction mixture. After 30 minutes the mixture was diluted with ethyl acetate and the layers separated. The organic layer was further washed with water, brine, dried (MgSO4), filtered and evaporated. The residue was chromatographed on silica gel (30% ethyl acetate in hexane) to give 110 mg of 6-isobutyl-benzo[1,3]dioxole-4-boronic acid (55%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][CH2:23][CH3:24].[CH3:25][CH:26]([S-:28])[CH3:27].[Na+]>CN(C=O)C>[CH3:25][CH:26]([S:28][CH2:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[C:12]([NH2:21])[C:11]=2[N:10]=[C:9]1[CH2:22][CH2:23][CH3:24])[CH3:27]
Reactant: CC(C)[S-]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCCl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCSC(C)C
Temperature: 25 °C
Yield: 84 %

Procedure:
Nitrogen was bubbled through a solution of 1-[2-(3-chloropropoxy)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 7.21 mmol) in DMF (25 mL) for 5 minutes. Sodium 2-propanethiolate (0.85 g 8.65 mmol) was added and the reaction mixture was stirred under a nitrogen atmosphere at ambient temperature. After 16 hours analysis by HPLC indicated that 50% of the starting material had been consumed. Additional sodium 2-propanethiolate (0.6 g) was added followed by a second addition (0.25 g) 2.5 hours later. After a total of 21 hours the reaction mixture was poured into water (250 mL) with rapid stirring. The resulting tan precipitate was isolated by filtration to provide 2.34 g of 1-(2-{3-[(1-methylethyl)thio]propoxy}ethyl)-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [OH-].[Na+].CN(C)/[CH:5]=[CH:6]/[C:7]([C:9]1[S:13][C:12]([N:14]=CN(C)C)=[N:11][C:10]=1[CH3:19])=O.Cl.[F:22][C:23]([F:31])([F:30])[C:24]([CH3:29])([CH3:28])[C:25]([NH2:27])=[NH:26].O>COCCO>[CH3:19][C:10]1[N:11]=[C:12]([NH2:14])[S:13][C:9]=1[C:7]1[CH:6]=[CH:5][N:27]=[C:25]([C:24]([CH3:29])([CH3:28])[C:23]([F:31])([F:30])[F:22])[N:26]=1
Reactant: CC(C)(C(=N)N)C(F)(F)F
Reactant: Cc1nc(N=CN(C)C)sc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: COCCO
Product: Cc1nc(N)sc1-c1ccnc(C(C)(C)C(F)(F)F)n1
Temperature: 125 °C

Procedure:
Powdered sodium hydroxide (0.42 g) is added to a solution of N′-[5-((E)-3-dimethylamino-acryloyl)-4-methyl-thiazol-2-yl]-N,N-dimethyl-formamidine (0.93 g, prepared as described by S. Wang et al J. Med. Chem. 2004, 47, 1662-1675.) and 3,3,3-trifluoro-2,2-dimethyl-propionamidine hydrochloride (0.54 g) in 2-methoxyethanol (7 ml) and the mixture is heated at 125° C. for 1 hour with stirring. The reaction mixture is cooled, water is added, and the aqueous layer is extracted 4-times with 10% methanol in dichloromethane. The combined organic layers are purified by reversed phase chromatography and sodium bicarbonate is added to the fractions containing the title compound to give a white precipitate, which is collected by filtration. HPLC/MS: retention time 1.47 minutes, M+H 303.1.
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8](=[O:85])([O:17][C@H:18]1[C@:22]([F:24])([CH3:23])[C@H:21]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([NH:36]C(C2C=CC(OC)=CC=2)(C2C=CC(OC)=CC=2)C2C=CC=CC=2)=[N:29][C:30]=3[O:34][CH3:35])[O:20][C@@H:19]1[CH2:60][O:61]C(C1C=CC(OC)=CC=1)(C1C=CC(OC)=CC=1)C1C=CC=CC=1)[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:8](=[O:85])([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[O:17][C@H:18]1[C@:22]([F:24])([CH3:23])[C@H:21]([N:25]2[CH:33]=[N:32][C:31]3[C:26]2=[N:27][C:28]([NH2:36])=[N:29][C:30]=3[O:34][CH3:35])[O:20][C@@H:19]1[CH2:60][OH:61]
Reactant: COc1ccc(C(Nc2nc(OC)c3ncn([C@@H]4O[C@H](COC(c5ccccc5)(c5ccc(OC)cc5)c5ccc(OC)cc5)[C@@H](OC(=O)OCc5ccccc5)[C@@]4(C)F)c3n2)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1nc(N)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](OC(=O)OCc2ccccc2)[C@@]1(C)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.2 %

Procedure:
A 1 vol % of TFA solution in DCM (50 mL) was added to a flask loaded with 4 (2.69 g, 2.56 mmol). The mixture was stirred at room temperature for 2 h and it was complete. Sat. NaHCO3 (20 mL) was added and the mixture was partitioned in water and DCM. The organic layer was concentrated and solid residue was purified by column chromatography (silica gel, 0˜5% 2-PrOH in DCM) to afford 1.01 g of product, 5, as a white foam solid (yield 88%). 1H-NMR (CDCl3): δ 7.82 (s, 1H), 7.39-7.33 (m, 5H), 6.02 (d, 1H, J=19.2 Hz), 5.77 (dd, 1H, J=20.8, 8.8 Hz), 5.32-5.30 (m, 1H), 5.20 (s, 2H), 5.04 (s, 2H), 4.34 (d, 1H, J=8.8 Hz), 4.15 (m, 1H), 4.04 (s, 3H), 3.85-3.79 (m, 1H), 1.21 (d, 3H, J=22.8 Hz).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2.[CH2:8]=[CH:9][C:10](=[CH2:12])[CH3:11]>C1(C=CC=C(O)C=1O)O>[CH3:11][C:10]1[CH2:12][CH:3]2[CH:2]([CH:1]3[CH2:7][CH:4]2[CH2:5][CH2:6]3)[CH2:8][CH:9]=1
Reactant: C1=CC2CCC1C2
Reactant: C=CC(=C)C
Agent: Oc1cccc(O)c1O
Product: CC1=CCC2C3CCC(C3)C2C1
Yield: 37.9 %

Procedure:
A mixture of 715 g (7.6 M) of norbornene, 550 g (8.1 M) of isoprene and 2 g of pyrogallol was heated in a stainless steel autoclave at ca. 150° during 15 hours. An internal pressure of 20 atm. is thus reached. The reaction mixture was then distilled by means of a Vigreux column and yielded 467 g (yield 38%) of 5-methyl-tricyclo[6.2.1.02,7 ]undec-4-ene having b.p. 90°/10 Torr.
Reaction SMILES: [C:1]([NH:11][CH:12]([C:17](=[O:20])[CH2:18][CH3:19])[C:13]([O:15]C)=[O:14])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.P(Cl)(Cl)(Cl)=O>C1(C)C=CC=CC=1>[CH2:18]([C:17]1[O:20][C:1]([CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)=[N:11][C:12]=1[C:13]([OH:15])=[O:14])[CH3:19]
Reactant: CCC(=O)C(NC(=O)C=Cc1ccccc1)C(=O)OC
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: CCc1oc(C=Cc2ccccc2)nc1C(=O)O
Temperature: 90 °C
Reaction time: 0.67 h

Procedure:
A mixture of methyl 2-cinnamoylamino-3-oxovalerate (8.25 g), phosphorus oxychloride (5.6 ml) and toluene (80 ml) was refluxed with stirring for 40 minutes. The solvent was then distilled off and the residue was neutralized with aqueous sodium hydrogen carbonate and extracted with ethyl ether. The ethyl ether layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off and the oily residue was dissolved in ethanol (30 ml). To the solution was added 2N sodium hydroxide (30 ml) and the mixture was heated on a water bath at 90° C. for 5 minutes. After cooling, the reaction mixture was adjusted to pH 2 with 2N hydrochloric acid and diluted with water. The resulting crystalline precipitate was collected by filtration to give 5-ethyl-2-styryl-4oxazolecarboxylic acid; yield 7.12 g (97.7%). Recrystallization from ethanol gave colorless prisms melting at 143°-144° C.
Reaction SMILES: C[O:2][C:3](=[O:28])[C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:14][CH2:15][O:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[CH:12]=[O:13])=[CH:7][CH:6]=1.[OH-].[Na+]>CO.O1CCCC1>[CH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:25]=[CH:26][C:17]=1[O:16][CH2:15][CH2:14][N:11]([C:8]1[CH:7]=[CH:6][C:5]([C:4](=[O:27])[C:3]([OH:28])=[O:2])=[CH:10][CH:9]=1)[CH:12]=[O:13]
Reactant: COC(=O)C(=O)c1ccc(N(C=O)CCOc2ccc3ccccc3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=CN(CCOc1ccc2ccccc2c1)c1ccc(C(=O)C(=O)O)cc1
Yield: 66.5 %

Procedure:
A solution of 4-[N-[2-(2-naphthalenyloxy)ethyl]formamido]-alpha-oxobenzeneacetic acid methyl ester (0.5 g) in warm methanol (5 mL) and tetrahydrofuran (5 mL) was treated with 1N sodium hydroxide (2 mL) and the mixture was concentrated to remove the organic solvents. The residue was acidified with excess hydrochloric acid and extracted with dichloromethane. The organic layer was washed with water, dried (Na2SO4), filtered and evaporated. The residue was crystallized acetone-hexane to give 0.32 g of 4-[N-[2-(2-naphthalenyloxy)ethyl]formamido]-alpha-oxobenzeneacetic acid, mp 155°-156° C. as a yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:17]([OH:19])=O)=[N:4][O:5][C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.Cl.[NH2:45][C@@H:46]1[CH2:51][CH2:50][C@H:49]([OH:52])[CH2:48][CH2:47]1.C(N(CC)CC)C>C(#N)C>[Cl:1][C:2]1[C:3]([C:17]([NH:45][C@H:46]2[CH2:51][CH2:50][C@@H:49]([OH:52])[CH2:48][CH2:47]2)=[O:19])=[N:4][O:5][C:6]=1[C:7]1[CH:8]=[CH:9][C:10]([C:13]([F:14])([F:15])[F:16])=[CH:11][CH:12]=1
Reactant: O=C(O)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Reactant: N[C@H]1CC[C@@H](O)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C(N[C@H]1CC[C@@H](O)CC1)c1noc(-c2ccc(C(F)(F)F)cc2)c1Cl
Temperature: 150 °C
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4-chloro-5-(4-(trifluoromethyl)phenyl)isoxazole-3-carboxylic acid (50 mg, 0.17 mmol) in acetonitrile (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (85 mg, 0.22 mmol), followed by cis-4-aminocyclohexanol hydrochloride (26 mg, 0.17 mmol). Triethylamine (52 mg, 0.51 mmol) was added before heating in the microwave at 150° C. for 10 minutes. After 10 minutes, the solvent was removed in vacuo, and the residue was partitioned between water and dichloromethane. The aqueous layer was separated and extracted with dichloromethane (3×10 mL), the combined organic extracts were dried with MgSO4, filtered and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford the title compound: (26 mg, 0.067 mmol).
Reaction SMILES: O[CH:2]1[C:8]2=[C:9]([CH3:16])[C:10](=[O:15])[C:11]([CH3:14])=[C:12]([CH3:13])[C@:7]32[O:17][C@:4]([CH3:18])([CH2:5][O:6]3)[CH2:3]1.[H][H].S(=O)(=O)(O)O>Cl(O)(=O)(=O)=O.CO>[OH:15][C:10]1[C:9]([CH3:16])=[C:8]2[C:7](=[C:12]([CH3:13])[C:11]=1[CH3:14])[O:17][C@:4]([CH3:18])([CH2:5][OH:6])[CH2:3][CH2:2]2
Reactant: CC1=C(C)[C@]23OC[C@](C)(CC(O)C2=C(C)C1=O)O3
Reactant: [H][H]
Agent: O=S(=O)(O)O
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CO
Product: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CO)O2
Reaction time: 15 h
Yield: 111.3 %

Procedure:
A mixture of 0.59 g of (3S,9aR)-(-)-2,3,4,5,7,9a-hexahydro-5-hydroxy-3,6,8,9-tetramethyl-3,9a-epoxy-1-benzoxepin-7-one, 0.7 g of palladium-on-barium sulfate (5% by weight) and 3 drops of concentrated perchloric acid in 20 ml of methanol was hydrogenated with ca 120 ml of hydrogen under normal pressure. Subsequently, 2 ml of 2-N sulfuric acid were added and air was conducted into the mixture for 15 hours. The reaction mixture was again hydrogenated with ca 25 ml of hydrogen. After removal of the catalyst by filtration over Hyflo, the filtrate was treated with dilute sodium bicarbonate solution and extracted with ether. The combined organic phases were dried over magnesium sulfate. After distillation of the solvent on a rotary evaporator, there were obtained 0.62 g of brown crystals, which, for purification, was chromatographed on Kieselgel with acetic ester/toluene (1/1 parts by volume). The resulting (S)-(+)-6-hydroxy-hydroxy-2,5,7,8-tetramethylchroman-2-methanol crystallized from methylene chloride/hexane at a yield of 487 mg; melting point 126.5°- 128.5°.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=1)#[CH:2].[Br:9][C:10]1[CH:15]=[C:14]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])[C:13](I)=[CH:12][N:11]=1.C(N(CC)CC)C>CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:9][C:10]1[N:11]=[CH:12][C:13]2[CH:2]=[C:1]([C:3]3[CH:4]=[N:5][N:6]([CH3:8])[CH:7]=3)[N:16]([S:17]([CH3:20])(=[O:19])=[O:18])[C:14]=2[CH:15]=1
Reactant: CS(=O)(=O)Nc1cc(Br)ncc1I
Reactant: C#Cc1cnn(C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cc(-c2cc3cnc(Br)cc3n2S(C)(=O)=O)cn1
Temperature: 60 °C
Yield: 45.2 %

Procedure:
4-Ethynyl-1-methyl-1H-pyrazole (20) (4.11 g, 38.7 mmole) was dissolved in DMF (95 mL) and N-(2-bromo-5-iodopyridin-4-yl)methanesulfonamide 8 (12.18 g 32.3 mmole) was added. To the solution was added triethylamine (19.6 mL, 14.1 g 139 mmole) and copper(I) iodide (214 mg 1.12 mmole). The reaction was sealed and flushed with nitrogen. Bis(triphenylphosphine)palladium dichloride (797 mg 1.13 mmole) was added and the reaction was again flushed with nitrogen and heated at 60° C. for 105 minutes. Most of the DMF was evaporated and the residue taken up in ethyl acetate (350 ml). The solution was washed with water (3×100 mL) and brine. Each aqueous fraction was backwashed with the same 100 mL portion of ethyl acetate. The combined organics were dried and evaporated. The residue was flash chromatographed (silica) eluting with dichloromethane, 1:4 ethyl acetate:dichloromethane, 1:1 ethyl acetate:dichloromethane and ethyl acetate to give the title compound (5.19 g 45.9%). 1H-NMR (CDCl3, 500 MHz): δ 2.98 (s, 3H), 4.01 (s, 3H), 6.69 (d, J=0.95 Hz, 1H), 7.73 (s, 1H), 7.78 (s, 1H), 8.25 (t, J=0.95 Hz, 1H), 8.64 (d, J=0.95 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](Cl)=[O:25])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>C(O)C>[C:17]1([N:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24](=[O:25])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][CH:16]=2)[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(C(=O)Nc2ccccc2)c1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1)c1cccc(NC(=O)N(c2ccccc2)c2ccccc2)c1
Yield: 42.6 %

Procedure:
A mixture of 3-amino-N-phenylbenzamide (2.0 g, 9.4 mmol), diphenylcarbamoyl chloride (2.2 g, 9.4 mmol) and triethylamine (2.6 mL, 19 mmol) in ethanol (10 mL) was heated to reflux for 4.5 hours. The mixture was cooled and concentrated, water was added, the slurry was acidified with 1 N HCl and the solid was collected, washed with water, dried and recrystallized from acetone/hexanes, to give a colorless solid (1.63 g, 42%).
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[O:7])=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: O=C(Cl)c1ccc(I)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(c1ccc(I)cc1)N1CCOCC1
Reaction time: 2 h
Yield: 81.2 %

Procedure:
A mixture of 4-iodobenzoyl chloride (500 mg), morpholine (163 mg) and triethylamine (380 mg) in CH2Cl2 (20 ml) is stirred 2 h before washing with H2O (20 ml) and brine (20 ml). The organic layer is dried over MgSO4 and the solvent is evaporated to obtain 482 mg of (4-iodo-phenyl)-morpholin-4-yl-methanone, yellowish semisolid, MS (ESI) 318.0 (M+H)+.