Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH:6]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:8]([S@:12]([NH-:14])=[O:13])([CH3:11])([CH3:10])[CH3:9]>[O-]S([O-])(=O)=O.[Cu+2]>[CH:1]1(/[CH:6]=[N:14]/[S@@:12]([C:8]([CH3:11])([CH3:10])[CH3:9])=[O:13])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=CC1CCCC1
Reactant: CC(C)(C)[S@]([NH-])=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Product: CC(C)(C)[S@@](=O)/N=C/C1CCCC1
Temperature: 25 °C
Reaction time: 71 h

Procedure:
The title compound was synthesized according to General Method H utilizing cyclopentanecarboxaldehyde (15.0 g, 152.8 mmol, 1.0 eq.), (R)-t-butylsulfinylamide (24.1 g, 198.7 mmol, 1.3 eq.), and flame-dried CuSO4 (73.2 g, 458.5 mmol, 3.0 eq.). The resulting mixture was stirred at rt for 71 h. The reaction mixture was filtered through a pad of Celite and the pad was rinsed with CH2Cl2 (5×100 mL). The combined organic extracts were concentrated under reduced pressure yielding a clear yellow oil (37.2 g). Purification by flash chromatography (SiO2, h=6 cm, Ø=10 cm) using 1:9 EtOAc-cyclohexane as eluent gave the product (23.8 g, 78% isolated yield) as a clear pale yellow oil. 1H NMR (300 MHz, CDCl3) δ ppm 7.99 (d, J=5.5 Hz, 1H), 3.02-2.87 (m, 1H), 1.97-1.78 (m, 2H), 1.78-1.55 (m, 6H), 1.18 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:19]([OH:21])=O)[CH:11]=[N:12][C:13]=2[O:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)=[CH:4][CH:3]=1.[CH2:22]([C:24]1[S:25][CH:26]=[C:27]([CH2:29][NH2:30])[N:28]=1)[CH3:23]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([O:14][CH2:15][CH:16]3[CH2:17][CH2:18]3)=[N:12][CH:11]=[C:10]([CH:9]=2)[C:19]([NH:30][CH2:29][C:27]2[N:28]=[C:24]([CH2:22][CH3:23])[S:25][CH:26]=2)=[O:21])=[CH:6][CH:7]=1
Reactant: CCc1nc(CN)cs1
Reactant: O=C(O)c1cnc(OCC2CC2)c(-c2ccc(Cl)cc2)c1
Product: CCc1nc(CNC(=O)c2cnc(OCC3CC3)c(-c3ccc(Cl)cc3)c2)cs1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chlorophenyl)-6-(cyclopropylmethoxy)-3-pyridinecarboxylic acid (CAS Registry No. 1018782-76-7) and 2-ethyl-4-thiazolemethanamine as starting materials, LC-MS (UV peak area/ESI) 99%, 428.119 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]2[CH2:21][O:20]2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:26][NH:27][CH3:28]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]2[CH:25]=[CH:24][CH:23]=[CH:22][C:16]=2[O:17][CH2:18][CH:19]([OH:20])[CH2:21][N:27]([CH3:28])[CH3:26])[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(CCCCc2ccccc2OCC2CO2)cc(OC)c1
Reactant: CNC
Solvent: C1CCOC1
Product: COc1cc(CCCCc2ccccc2OCC(O)CN(C)C)cc(OC)c1
Yield: 62 %

Procedure:
Following a procedure similar to that described in Example 1(b), a solution of 0.42 g of 2-{2-[4-(3,5-dimethoxyphenyl)butyl]phenoxymethyl}oxirane [prepared as described in step (a) above] in 10 ml of tetrahydrofuran was treated with 2 ml of 50% by volume aqueous dimethylamine. After purification, 0.29 g (yield 62%) of the title compound was obtained as a colorless oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[O:22])=[CH:16][CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([N:7]2[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]2)=[O:22])=[CH:16][CH:15]=1
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Reactant: O=C=Nc1ccc(Cl)cc1
Product: CC1(C)CC(=O)N(C(=O)Nc2ccc(Cl)cc2)CC(C)(C)N1

Procedure:
Using conditions similar to Example 4, 17 parts of 2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one and 17 parts of p-chlorophenylisocyanate afforded 20 parts of 4-p-chlorophenylcarbamoyl-2,2,7,7-tetramethyl-1,4-diazacycloheptan-5-one as a colourless solid of melting point 119° -121°C. This material had the following elemental analysis by weight:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([OH:24])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C([O-])([O-])=O.[K+].[K+].[C:36]([O:39][CH2:40]Br)(=[O:38])[CH3:37]>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:27]/[O:28][CH3:29])/[C:8]([NH:10][CH:11]2[C:25](=[O:26])[N:13]3[C:14]([C:22]([O:24][CH2:40][O:39][C:36](=[O:38])[CH3:37])=[O:23])=[C:15](/[CH:18]=[CH:19]\[CH2:20][CH3:21])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CC(=O)OCBr
Reactant: CC/C=C\C1=C(C(=O)O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OCOC(C)=O)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 27.5 %

Procedure:
To a mixture of 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-1-butenyl]-3-cephem-4-carboxylic acid (300 mg, 0.69 m mole) and K2CO3 (95 mg, 0.69 m mole) in dry DMF (3 ml) was added dropwise at 0° C. a solution of bromomethyl acetate (105 mg, 0.69 m mole) in dry DMF (0.25 ml) and the mixture was stirred at 0° C. for 15 minutes. To the mixture was added again a solution of bromomethyl acetate (105 mg, 0.69 m mole) in dry DMF (0.25 ml). The reaction mixture was stirred for another 30 minutes and diluted with ethyl acetate (20 ml). The dilute was washed with water and a saturated NaCl solution, dried over anhydrous Na2SO4 and evaporated to dryness. The residue was dissolved in methanol and passed through a column of the packing (40 ml) of a PrepPAK cartridge (Waters), which was washed with water and then eluted with 50% methanol. The eluate was monitored by HPLC. The desired fractions were collected and evaporated to give 96 mg (27%) of the title compound. Estimated purity 90% (by HPLC). M.p. 149°-152° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:6][C:7]([F:21])([F:20])[C:8]1[N:12]2[CH2:13][CH2:14][NH:15][CH2:16][C:11]2=[C:10]([C:17]([O-])=[O:18])[N:9]=1>O>[N:1]1([C:17]([C:10]2[N:9]=[C:8]([C:7]([F:20])([F:6])[F:21])[N:12]3[CH2:13][CH2:14][NH:15][CH2:16][C:11]=23)=[O:18])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: O=C([O-])c1nc(C(F)(F)F)n2c1CNCC2
Solvent: O
Product: O=C(c1nc(C(F)(F)F)n2c1CNCC2)N1CCCC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 99.7 %

Procedure:
Pyrrolidine (560 mg, 8 mmol), methyl 3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazine-1-carboxylate 3b (400 mg, 1.60 mmol) and 0.4 mL of H2O were mixed in a sealed tube. After stirring at 50° C. for 4 hours, the reaction mixture was concentrated under reduced pressure to obtain crude pyrrolidin-1-yl-[3-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-1-yl]methanone 18a (460 mg) as a light yellow solid. The product was used directly in the next reaction without purification.
Reaction SMILES: [Br:1][C@H:2]1[C@H:7]([OH:8])[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15].C(Cl)CCl.[N+:21]([C:24]1[CH:25]=[C:26]([CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=1)[C:27]([S:29][CH2:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33])=[O:28])([O-:23])=[O:22]>N1C=CC=CC=1>[Br:1][C@H:2]1[C@H:7]([O:8][C:32](=[O:33])[C@H:31]([CH3:35])[CH2:30][S:29][C:27](=[O:28])[C:26]2[CH:36]=[C:37]([N+:39]([O-:41])=[O:40])[CH:38]=[C:24]([N+:21]([O-:23])=[O:22])[CH:25]=2)[C:6]2[CH:9]=[C:10]([C:13]#[N:14])[CH:11]=[CH:12][C:5]=2[O:4][C:3]1([CH3:16])[CH3:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](O)[C@@H]1Br
Reactant: C[C@@H](CSC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)Cl
Solvent: ClCCCl
Solvent: c1ccncc1
Product: C[C@H](CSC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1)C(=O)O[C@@H]1c2cc(C#N)ccc2OC(C)(C)[C@H]1Br
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93.1 %

Procedure:
To a mixture of 14.5 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-hydroxy-2H-1-benzopyran, 60 ml of ethylene chloride and 1.6 ml of pyridine was added 5.5 g of (S)-(-)-3-(3,5-dinitrobenzoylthio)-2-methylpropionyl chloride under ice-cooling and was stirred for 1.5 hours under room temperature. The reaction mixture was washed with diluted hydrochloric acid once and 10% aqueous sodium chloride solution twice. The organic layer was separated, dried over magnesium sulfate and concentrated under reduced pressure to give 8.9 g of (±)-trans-3-bromo-6-cyano-3,4-dihydro-2,2-dimethyl-4-[(S)-(-)-3-(3,5-dinitrobenzoylthio)-2-methylpropionyloxy]-2H-1-benzopyran as light yellow semicrystals.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1.[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)(=O)C.O>[C:12]([NH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:11])[CH:3]=1)(=[O:14])[CH3:13]
Reactant: Nc1ccc(C(=O)O)c(F)c1
Reactant: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: CC(=O)Nc1ccc(C(=O)O)c(F)c1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A mixture of 4-amino-2-fluoro-benzoic acid (5.61 g, 36.2 mmol) and acetic anhydride (5.13 mL, 54.3 mmol) in 60 mL acetic acid was stirred at 60° C. overnight. The mixture was taken up in 250 mL water and stirred for 30 min. The precipitate was filtered and washed with water. The filtrate was washed with ethyl acetate. The organic phase was neutralized with sat. K2CO3 (aq) and concentrated i.vac. A small volume was left, the precipitate was filtered and combined with the first isolated precipitate.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([CH2:6][C:7]2[CH:8]=[C:9]([CH:11]=[CH:12][CH:13]=2)[NH2:10])=[CH:2]1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26](O)=[O:27])=[C:17]([C:30]([O:32]C)=[O:31])[CH:16]=1>>[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:29])[CH2:23][O:24][CH2:25][C:26]([NH:10][C:9]2[CH:11]=[CH:12][CH:13]=[C:7]([CH2:6][C:3]3[CH:4]=[CH:5][O:1][CH:2]=3)[CH:8]=2)=[O:27])=[C:17]([CH:16]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: Nc1cccc(Cc2ccoc2)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)Nc1cccc(Cc2ccoc2)c1

Procedure:
Using the same method as in Example 15-(i), 3-(furan-3-ylmethyl)aniline was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 5-chloro-2-([(2-([3-(furan-3-ylmethyl)phenyl]amino)-2-oxoethoxy)acetyl]amino)benzoic acid.methyl ester (yield: 34%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]2[S:17][C:18]([CH:21]=O)=[CH:19][CH:20]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[S:24]1[CH2:28][C:27](=[O:29])[NH:26][C:25]1=[O:30].C([O-])(=O)C.[NH2+]1CCCCC1>C1(C)C=CC=CC=1>[O:30]=[C:25]1[NH:26][C:27](=[O:29])[C:28](=[CH:21][C:18]2[S:17][C:16]([C:12]3[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=3)[CH2:9][CH2:8][NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:20][CH:19]=2)[S:24]1
Reactant: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C=O)s2)c1
Reactant: O=C1CSC(=O)N1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCc1cccc(-c2ccc(C=C3SC(=O)NC3=O)s2)c1
Yield: 74.2 %

Procedure:
A solution of 2.4 g (7.2 mmol) of tert-butyl[3-(5-formylthiophen-2-yl)benzyl]methylcarbamate, 0.85 g (7.2 mmol) of 2,4-thiazolidinedione and 0.2 g (1.4 mmol) of piperidinium acetate in 50 ml of toluene is refluxed for 4 hours in Dean-Stark apparatus. After cooling, the product precipitates. The precipitate is filtered off and washed with ethyl ether. 2.3 g (76%) of tert-butyl {3-[5-(2,4-dioxothiazolidin-5-ylidenemethyl)thiophen-2-yl]benzyl}methylcarbamate are obtained.
Reaction SMILES: [F:1][CH:2]([F:25])[N:3]1[C:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([I:18])=[CH:13][C:12]=4[C:6]=2[N:5]=[C:4]1[C:20]([O:22]CC)=O)[CH2:9]3.[NH3:26]>>[F:25][CH:2]([F:1])[N:3]1[C:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([I:18])=[CH:13][C:12]=4[C:6]=2[N:5]=[C:4]1[C:20]([NH2:26])=[O:22])[CH2:9]3
Reactant: N
Reactant: CCOC(=O)c1nc2c(n1C(F)F)C1CC(C1)c1cc(F)c(I)cc1-2
Product: NC(=O)c1nc2c(n1C(F)F)C1CC(C1)c1cc(F)c(I)cc1-2
Temperature: 44 °C
Yield: 80 %

Procedure:
A pressure tube containing a solution of ethyl 3-(difluoromethyl)-8-fluoro-9-iodo-3,4,5,6-tetrahydro-4,6-methanobenzo[3,4]cyclohepta[1,2-d]imidazole-2-carboxylate (11 mg, at 52% purity LCMS-UV215) in methanolic ammonia (5 mL of 7.0M ammonia in methanol) was warmed to 44° C. for 36 hr. Evaporation of the reaction mixture furnished the title compound (12 mg at 80% purity LCMS-UV215) as a colorless solid which was carried through to the next synthetic step without purification: 1H NMR (500 MHz, CDCl3) δ 1.70-1.16 (m, 2H), 2.95-3.02 (m, 2H), 3.59 (td, J=8.2, 3.5 Hz, 1H), 3.86-3.91 (m, 1H), 5.58 (br. s, 1H), 6.86 (d, J=8.6 Hz, 1H), 7.40 (br. s, 1H), 8.71 (d, J=6.6 Hz, 1H), 8.75 (t, J=58.6 Hz, 1H); M+H=434.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+].[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15]C=1C.S(=O)(=O)(O)O.[C:26]([OH:29])(=[O:28])[CH3:27]>>[F:12][C:13]1[CH:18]=[C:17]([I:19])[CH:16]=[CH:15][C:27]=1[C:26]([OH:29])=[O:28]
Reactant: Cc1ccc(I)cc1F
Reactant: CC(=O)O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1ccc(I)cc1F
Temperature: 90 °C

Procedure:
A round bottom (RB) flask containing a solution of 8.0 g (27.0 mmol) of sodium dichromate in 44 mL of glacial acetic acid was placed in an external water bath (21° C.) and left exposed to air. To the resultant orange slurry was added 3.2 g (13.6 mmol) of 2-fluoro-4-iodotoluene followed by the dropwise addition of 22 mL of c. sulfuric acid via syringe (caution: if added too quickly there is a tendency for the mixture to erupt). After the addition of approximately 8 mL of sulfuric acid, a green solid precipitated and the water bath temperature had risen (25° C.). The green reaction mixture was heated in an oil bath (90° C.) for one hour, allowed to cool to ambient temperature, diluted with 1 N NaOH solution (aq.) and ethyl acetate (500 mL) and then quenched with sat. NaHCO3 (aq.) solution. The organic phase was separated and washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo to an orange oil. Residual acetic acid was removed by further extraction between ethyl acetate and sat. NaHCO3 (aq.) solution and washing of the organic phase with water and brine. The organic phase was dried over MgSO4, filtered and concentrated in vacuo to give the title compound as an orange solid. PMR (DMSO—d6): δ 7.61 (1 H, t, J=8.0 Hz, J (C—F)=8.0 Hz), 7.67 (1 H, dd, J=1.5, 8.2 Hz), 7.78 (1 H, dd, J=1.5 Hz, J (C—F)=8.9 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=O)[CH2:6][CH2:5]2.[Cl-].[OH:13][NH3+:14].C([O-])(=O)C.[Na+]>CO.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[N:14][OH:13])[CH2:6][CH2:5]2
Reactant: O=C1CCc2cc(Br)ccc21
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: ON=C1CCc2cc(Br)ccc21
Reaction time: 8 h
Yield: 95.2 %

Procedure:
5-Bromoindan-1-one (5.0 g) was dissolved in methanol. Hydroxylammonium chloride (2.5 g) and sodium acetate (2.9 g) were added to the solution at room temperature, and then stirred overnight. The reaction solution was diluted with water and extracted twice with ethyl acetate. The organic layers were combined, washed with water, and dried over anhydrous magnesium sulfate. The desiccant was filtered and separated, and then the solvent was evaporated off under reduced pressure to obtain 5-bromo-N-hydroxyindan-1-imine (5.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18](I)=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[CH3:30][CH:31]([N:35]1[C:43](=[O:44])[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:36]1=[O:45])[CH2:32][C:33]#[CH:34]>C1COCC1.[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>[CH2:1]([O:8][C:9](=[O:22])[NH:10][CH2:11][CH2:12][C:13]#[C:14][C:15]1[CH:20]=[CH:19][C:18]([C:34]#[C:33][CH2:32][CH:31]([N:35]2[C:36](=[O:45])[C:37]3[C:42](=[CH:41][CH:40]=[CH:39][CH:38]=3)[C:43]2=[O:44])[CH3:30])=[CH:17][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(NCCC#Cc1ccc(I)cc1)OCc1ccccc1
Reactant: C#CCC(C)N1C(=O)c2ccccc2C1=O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC#Cc1ccc(C#CCCNC(=O)OCc2ccccc2)cc1)N1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 92.2 %

Procedure:
A 100 mL, round-bottom flask containing a mixture of [4-(4-iodophenyl)but-3-ynyl]carbamic acid benzyl ester 23 (2.33 g, 5.75 mmol), CuI (0.22 g, 1.15 mmol), Et3N (10 mL) and THF (anhydrous, 15 mL) was vacuumed and refilled with nitrogen. The procedure was repeated three more time. To the suspension was added Pd(PPh3)2Cl2 (0.40 g, 0.58 mmol) in one portion, followed by a solution of compound 22 (1.35 g, 6.32 mmol) dissolved in THF (anhydrous, 10 mL), which was added dropwise over 2 h. The stirring was continued overnight. The reaction mixture was concentrated under vacuum. The residue was subjected to column chromatography eluting with a mixture of ethyl acetate (0-25%) and hexanes to afford the desired product 24 (2.60 g, 92%) as an off-yellow solid. 1H NMR (500 MHz, CDCl3) δ 1.71 (d, 3H), 2.61 (t, 2H), 2.92 (m, 1H), 3.14 (m, 1H), 3.43 (t, 2H), 4.67 (m, 1H), 5.07 (br, 1H), 5.11 (s, 2H), 7.12-7.33 (m, 9H), 7.71 (dd, 2H), 7.92 (dd, 1H); m/z (ESI) 491 [C31H26N2O4+H]+.
Reaction SMILES: [F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4](I)[CH:3]=1.[CH3:34][N:35]1[C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[Na+].[Na+]>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>[F:1][C:2]1[CH:32]=[CH:31][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[N:17]([C:18](=[O:28])[C:19]=2[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:16][CH2:15][O:14][C:13]3([CH3:30])[CH3:29])=[O:9])=[C:4]([C:39]2[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=2)[CH:3]=1
Reactant: Cn1nccc1B1OC(C)(C)C(C)(C)O1
Reactant: CC1(C)OCCn2c1nc(C(=O)NCc1ccc(F)cc1I)c(OCc1ccccc1)c2=O
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: [Na+]
Product: Cn1nccc1-c1cc(F)ccc1CNC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CCOC2(C)C
Yield: 66.7 %

Procedure:
N-(4-Fluoro-2-iodobenzyl)-3-(benzyloxy)-9,9-dimethyl-4-oxo-4,6,7,9-tetrahydropyrimido[2,1-c][1,4]oxazine-2-carboxamide (0.250 g, 0.44 mmol) was reacted with 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.183 g, 0.88 mmol), sodium carbonate (0.150 g, 1.41 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.10 g) to give 0.152 g (65% yield) of the title material as a white solid after chromatography on silica gel. 1H NMR 400 MHz (CDCl3) δ (ppm): 1.63 (6H, s, 2×CH3), 3.69 (3H, s, NCH3), 4.0–4.1 (4H, m, 2×CH2), 4.34 (2H, d, J=6.6 Hz, NCH2), 5.29 (2H, s, OCH2), 6.26 (1H, d, J=2.0 Hz, CH), 6.98 (1H, dd, J=2.5 Hz and J=8.6 Hz, aromatic), 7.13 (1H, m, aromatic), 7.3–7.35 (3H, m, aromatics), 7.47–7.55 (4H, m, aromatics and NH), 7.57 (1H, d, J=2.0 Hz, CH). MS (ESI+) m/z 518 [M+H+].
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][O:10][C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][CH:12]=1>CN(C)C=O>[Br:8][C:12]1[CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[S:15][C:11]=1[O:10][CH3:9]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC)s1
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)c(OC)s1
Reaction time: 1 h
Yield: 75.4 %

Procedure:
NBS (903 mg, 5.07 mmol) was added in portions to a 5 mL sealed tube reactor containing methyl 5-(methyloxy)-2-thiophenecarboxylate (0.73 g, 4.23 mmol) in N,N-Dimethylformamide (DMF) (20 mL) at room temperature and the reaction stirred for 1 hour. Additional NBS (249 mg) was added and after 1 h at room temperature the product was partitioned between CHCl3 and H2O. The organic layer was dried with Na2SO4, adsorbed onto silica and purified via column chromatography (0-25% EtOAc/Hexanes) affording the title compound (825 mg, 3.19 mmol, 75%): LC-MS (ES) m/z=252 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1)(=[O:30])=[O:29])[CH:22]=[CH:21]2.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[Br:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][CH:27]=1)[CH:24]=[C:23]([S:28]([N:31]1[CH2:32][CH2:33][N:34]([C:12](=[O:14])[C:11]3[CH:10]=[CH:9][C:8]([C:6]4[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=4)=[CH:16][CH:15]=3)[CH2:35][CH2:36]1)(=[O:29])=[O:30])[CH:22]=[CH:21]2
Reactant: Cc1cc(-c2ccc(C(=O)O)cc2)ccn1
Reactant: O=S(=O)(c1ccc2cc(Br)ccc2c1)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cc(-c2ccc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Br)ccc5c4)CC3)cc2)ccn1
Yield: 68 %

Procedure:
4-(2-Methyl-4-pyridyl)benzoic acid (62 mg), 1-(6-bromonaphth-2-ylsulphonyl) piperazine (94 mg) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (61 mg) were dissolved in DMF (2.5 ml) and the resultant solution stirred at ambient temperature for 16 hours. Excess DMF was removed in vacuo, water (10 ml) was added and the precipitate that formed was filtered, washed thoroughly with cold water and dried over P2O5. The solid thus obtained was purified by flash chromatography at 3 psi on silica (Merck ART 9385) eluting with 2.5% v/v methanol in dichloromethane. There was thus obtained the 1-(6-bromonaphth-2-ylsulphonyl)-4-[4-(2-methyl-4-pyridyl)benzoyl]piperazine (99 mg); mp 204-205° C.; 1H NMR (300 MHz, DMSO-d6) δ=2.48 (s,3H), 3.03 (s,4H), 3.57 (broad s, 4H), 7.46 (t,3H), 7.56 (s,1H), 7.77(d,2H), 7.83(d,2H), 8.17(q,2H), 8.42 (s,1H), 8.48 (d,2H) ppm; MS: m/z 550/552 (M+H)+ (1 Br pattern).
Reaction SMILES: II.[CH3:3][N:4]([CH3:17])[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1S(Cl)(=O)=O)=[O:6].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[S:37]([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[SH:37][C:9]1[CH:8]=[C:7]([CH:12]=[CH:11][CH:10]=1)[C:5]([N:4]([CH3:17])[CH3:3])=[O:6]
Reactant: CN(C)C(=O)c1ccccc1S(=O)(=O)Cl
Reactant: O=S([O-])[O-]
Agent: II
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CN(C)C(=O)c1cccc(S)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Iodine (1 g) was added to a stirred solution of 3-[(dimethylamino)carbonylbenzenesulfonyl chloride (2 g) (Borthwick et al, J. Med. Chem 2002, 45(1), 1-18) and triphenylphosphine (8.4 g) in 1,4-dioxane at 0° C. The mixture was stirred for 0.5 h at ambient temperature. The mixture was poured into a sodium sulphite solution (50 ml), extracted into ethyl acetate (2×30 ml) and washed with 2N sodium hydroxide solution (2×40 ml). The alkaline extracts were acidified and re-extracted into dichloromethane (3×50 ml). The extracts were washed with water (100 ml), dried (Na2SO4) and evaporated to give the title compound as a colourless solid (1.1 g).