Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([CH:30]=O)=[CH:28][C:27]=1[CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.S([O-])(O)=O.[Na+]>CCOCC.O.CC(N(C)C)=O>[CH2:15]([O:22][CH2:23][CH2:24][O:25][C:26]1[C:33]([CH3:34])=[CH:32][C:29]([C:30]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)=[CH:28][C:27]=1[CH3:35])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1cc(C=O)cc(C)c1OCCOCc1ccccc1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: CCOCC
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(OCCOCc4ccccc4)c(C)c3)nc2c1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
To a 100 mL round bottom flask was added 2-amino-4,6-dimethoxy-benzamide (318 mg, 1.6 mmol), 4-(2-benzyloxy-ethoxy)-3,5-dimethyl-benzaldehyde (461 mg, 1.6 mmol), p-toluenesulfonic acid monohydrate (32 mg, 0.16 mmol), sodium hydrogensulfite (318 mg, 1.8 mmol) and dimethylacetamide (5 mL). The mixture was stirred in a 150° C. oil bath under nitrogen overnight. Water (40 mL) and ether (30 mL) were added. The precipitate was filtered off, washed with water then ether, and air-dried. The intermediate 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one was obtained as light brown/beige solid. Yield 474 mg (64%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-5,7-dimethoxy-3H-quinazolin-4-one (474 mg, 1.03 mmol) was stirred in phosphorus oxychloride (10 mL) at 100° C. for 4 h. Excess phosphorus oxychloride was removed under reduced pressure. Ice was added and the solid was collected. The solid was washed with water and ether, and air-dried. 2-[4-(2-benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline was obtained as a light brown solid (yield: 356 mg, 72%). 2-[4-(2-Benzyloxy-ethoxy)-3,5-dimethyl-phenyl]-4-chloro-5,7-dimethoxy-quinazoline (192 mg, 0.4 mmol) was dissolved in a small amount of THF and 10% Pd/C (dry) (66 mg) was added. Anhydrous methanol (20 mL) and ammonium formate (955 mg) were added. The mixture was stirred in a 80° C. oil bath for 5 h. The mixture was filtered through Celite, washed with MeOH/DCM, purified by column chromatography to give 2-(4-(5,7-dimethoxyquinazolin-2-yl)-2,6-dimethylphenoxy)ethanol (36 mg, 25%) as an off-white solid. Selected data: MS (ES) m/z: 355.04; mp 169-170° C.
Reaction SMILES: [C:1]([C:8]1[C:13]([NH2:14])=[C:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]([CH2:22][C:23]([OH:25])=[O:24])[CH3:21])=[O:19])[CH:11]=[CH:10][N:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].CN1CCOCC1.F[P-](F)(F)(F)(F)F.[N:40]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][C:43]=2N=N1>CC#N.CCOC(C)=O>[C:1]([C:8]1[C:13]([NH2:14])=[C:12]([CH2:15][CH2:16][CH2:17][C:18]([N:20]([CH2:22][C:23]([OH:25])=[O:24])[CH3:21])=[O:19])[CH:11]=[CH:10][N:9]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:4]([O:3][C:1](=[O:2])[CH2:8][C@@H:13]([CH2:12][CH2:15][C:16]1[C:43]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[NH:40][CH:17]=1)[NH2:14])[CH3:5]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CN(CC(=O)O)C(=O)CCCc1ccnc(C(=O)OC(C)(C)C)c1N
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C[C@H](N)CCc1c[nH]c2ccccc12
Reaction time: 8 h

Procedure:
Acid 4-3 (84 mg, 0.24 mmol), amine 4-4 (see Duggan et al., U.S. Pat. No. 5,264,420) (68 mg, 0.26 mmol), NMM (104 μL, 0.95 mmol) and BOP (127 mg, 0.29 mmol) were combined in 2.4 mL CH3CN. After stirring overnight the mixture was diluted with EtOAc, washed with water (4×), sat. NaHCO3, and brine, dried (MgSO4) and concentrated. Flash chromatography (silica, EtOAc) provided 4-5 as a colorless oil
Reaction SMILES: [C:1]([O:5][CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:4])[NH:2][NH2:3].C(OCC)(=O)NN.[C:17](Cl)([Cl:19])=[O:18]>C(OCC)C>[CH3:8][CH:7]([CH3:9])[CH2:6][O:5][C:1]([NH:2][NH:3][C:17]([Cl:19])=[O:18])=[O:4]
Reactant: O=C(Cl)Cl
Reactant: CC(C)COC(=O)NN
Agent: CCOC(=O)NN
Solvent: CCOCC
Product: CC(C)COC(=O)NNC(=O)Cl

Procedure:
Example 1 was repeated but substituting iso-butyl carbazate (24.75 g, 0.6 mole) for the ethyl carbazate and using phosgene (20 ml, 0.3 mole) in diethyl ether. 2-(2-methylpropyloxycarbonyl)hydrazinecarbonyl chloride was isolated as a viscous oil (31 g, 84%) whose ir spectrum was similar to that of 2-ethoxycarbonylhydrazinecarbonyl chloride.
Reaction SMILES: [F:1][C:2]1[C:3]([N:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:16][CH2:15]2)=[C:4]([C:7]([F:13])=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH2:5]O.C(N(S(F)(F)[F:31])CC)C.C(N(CC)CC)C>ClCCl>[F:13][C:7]1[C:4]([CH2:5][F:31])=[C:3]([N:14]2[CH2:15][CH2:16][N:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][CH2:19]2)[C:2]([F:1])=[CH:9][C:8]=1[N+:10]([O-:12])=[O:11]
Reactant: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CO)CC1
Reactant: CCN(CC)S(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCN(c2c(F)cc([N+](=O)[O-])c(F)c2CF)CC1
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
3,6-Difluoro-2-(4-ethoxycarbonyl-1-piperazinyl)-5-nitrobenzyl alcohol (1.5 g) is dissolved in dichloromethane (18 ml), and thereto is added dropwise a solution of diethylaminosulfur trifluoride (DAST) (0.7 ml) and triethylamine (0.78 ml) in dichloromethane (3 ml) over a period of 5 minutes while stirring at 0° C. in ice bath. The mixture is stirred at 0° C. for 1.2 hour, and thereto is further added DAST (0.3 ml). After 5 minutes, the reaction mixture is poured into ice water, and the organic layer is separated. The solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (solvent, ethyl acetate:n-hexane=1:10→1:5 v/v) to give 2,5-difluoro-3-fluoromethyl-4-(4-ethoxycarbonyl-1-piperazinyl)nitrobenzene (1.1 g).
Reaction SMILES: Cl.[F:2][CH:3]([F:31])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH:24]4[CH2:28][O:27]C(C)(C)[O:25]4)[CH:22]=3)[CH:12]=2)[N:5]=1.O.[OH-].[Na+]>CO>[F:31][CH:3]([F:2])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([NH:10][C:11]2[CH:12]=[C:13]([C:18]3[CH:19]=[N:20][N:21]([CH2:23][CH:24]([OH:25])[CH2:28][OH:27])[CH:22]=3)[CH:14]=[C:15]([CH3:17])[CH:16]=2)[N:5]=1
Reactant: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC3COC(C)(C)O3)c2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1cc(Nc2nccc(C(F)F)n2)cc(-c2cnn(CC(O)CO)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Hydrochloric acid (6N, 6.6 mL, 39.7 mmol) was added to 4-(difluoromethyl)-N-(3-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-5-methylphenyl)pyrimidin-2-amine (16.5 g, 39.7 mmol) in MeOH (150 mL). The mixture heated at reflux for 2 h then cooled to RT. Water (200 mL) was added and then the pH was adjusted to 7 with NaOH (6N). The solution was seeded with crystalline product (prepared via an earlier small scale) and crystallization occurred. Additional water (150 ml) was added and the mixture was stirred for 30 min, then filtered, washed with water (2×50 mL) and dried for 14 h under a nitrogen bag to afford 3-(4-(3-((4-(difluoromethyl)pyrimidin-2-yl)amino)-5-methylphenyl)-1H-pyrazol-1-yl)propane-1,2-diol an off white solid.
Reaction SMILES: [NH:1]1[CH:8]=[CH:7][C:5]([NH2:6])=[N:4][C:2]1=[S:3].Cl[CH2:10][C:11]#[C:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].CN(C=O)C.N12CCCCC1C=NCCC2>CCOC(C)=O.O>[NH2:6][C:5]1[CH:7]=[CH:8][N:1]=[C:2]([S:3][CH2:10][C:11]#[C:12][CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])[N:4]=1
Reactant: Nc1cc[nH]c(=S)n1
Reactant: O=C1c2ccccc2C(=O)N1CC#CCCl
Agent: C1=NCCCN2CCCCC12
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: Nc1ccnc(SCC#CCN2C(=O)c3ccccc3C2=O)n1
Reaction time: 2 h
Yield: 94.1 %

Procedure:
A mixture of thiocytosine (0.5 g.), N-(4-chlorobut-2-ynyl)phthalimide (1.03 g.), DMF (5 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (0.67 g.) was stirred for 2 hours. The solution was treated with water (20 ml.) and EtOAc (10 ml.) and the insoluble solid collected to give 4-amino-2-(4-phthalimidobut-2-ynylthio)pyrimidine (1.2 g.) m.p. 197°-202° (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)(O)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]([CH:13]3[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: O=C1Nc2cc(Cl)ccc2C1(O)C1CCCCC1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: O=C1Nc2cc(Cl)ccc2C1C1CCCCC1
Temperature: 90 °C
Reaction time: 1 h

Procedure:
A suspension of rac-6-chloro-3-cyclohexyl-3-hydroxy-1,3-dihydro-indol-2-one (0.14 g, 0.52 mmol) (from Example 19a supra) in a mixture of triethylsilane (0.25 mL, 1.58 mmol) (Aldrich) and trifluoroacetic acid (0.77 g, 7.6 mmol) (Aldrich) was heated in a 90° C. bath for 48 hours. After cooling to room temperature, mixture was diluted with ethyl acetate. Solid potassium carbonate was added and mixture stirred at room temperature for 1 hour. Mixture was filtered and concentrated. Residue was redissolved in ethyl acetate and washed with water and brine, dried (Na2SO4), filtered and concentrated. Residue was recrystallized from dichloromethane-hexanes to give rac-6-chloro-3-cyclohexyl-1,3-dihydro-indol-2-one as a grey solid. (Yield 0.11 g, 84%).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][NH:7][CH2:8][C@H:9]1[O:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1)(=[O:3])[CH3:2].[C:23](OC(=O)C)(=[O:25])[CH3:24].N1C=CC=CC=1>ClCCl.[Cl-].[Na+].O>[C:1]([O:4][CH2:5][CH2:6][N:7]([C:23](=[O:25])[CH3:24])[CH2:8][C@H:9]1[O:14][CH2:13][C@H:12]([NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][CH2:10]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCNC[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CC(=O)OCCN(C[C@@H]1CC[C@@H](NC(=O)OC(C)(C)C)CO1)C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
The compound (264 mg, 0.83 mmol) obtained in Step 4 above was dissolved in dichloromethane (8 ml), acetic anhydride (0.50 ml, 5.30 mmol) was added and the resulting mixture was stirred at room temperature for 1 hour. Then pyridine (0.10 ml, 1.24 mmol) was added and the resulting mixture was further stirred for 1 hour. Saturated brine (20 ml) was added to the reaction mixture and the resulting mixture was stirred for 1 hour, followed by extraction with dichloromethane. The organic layer was washed with saturated sodium bicarbonate solution and brine in that order and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue obtained was purified by silica gel column chromatography [chloroform:methanol=40:1 (v/v)] to give 244 mg (82%) of the title compound as a colorless amorphous solid.
Reaction SMILES: Cl.[CH3:2][C:3]12[CH2:10][CH:7]([CH2:8][CH2:9]1)[CH:6]([CH3:11])[C:5](=[O:12])[CH2:4]2.[CH3:13]OC(OC)OC.[CH2:20](O)[CH:21]=C>CS(O)(=O)=O.C(O)(=O)C.CO>[CH2:11]([C:6]1([CH3:13])[CH:7]2[CH2:10][C:3]([CH3:2])([CH2:9][CH2:8]2)[CH2:4][C:5]1=[O:12])[CH:20]=[CH2:21]
Reactant: COC(OC)OC
Reactant: CC1C(=O)CC2(C)CCC1C2
Reactant: C=CCO
Agent: CS(=O)(=O)O
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Product: C=CCC1(C)C(=O)CC2(C)CCC1C2
Reaction time: 3 h
Yield: 25.4 %

Procedure:
Hydrochloric acid (HCl, 6 g) was added to a solution of 1,4-dimethyl-bicyclo[3.2.1]octan-3-one (400 g, 2.6 mol, obtained as above in EXAMPLE III), trimethylorthoformate (HC(OCH3)3, 280 g, 2.6 mol), and methanol (CH3OH, 400 mL). The reaction mixture was aged for 3 hours and subsequently quenched with a NaOH solution. Allyl alcohol (CH2CHCH2OH, 300 g, 5.2 mol), acetic acid (CH3COOH, 50 g), and methanesulfonic acid (CH3SO2OH, MSA, 5 g) were added and aged at reflux. The volatile ingredients were distilled off with a Dean Stark trap. The resulting mixture was washed with a Na2CO3 solution. Fractional distillation of the organic layer provided 4-allyl-1,4-dimethyl-bicyclo[3.2.1]octan-3-one (127 g) having a boiling point of 64° C. at a pressure of 0.2 mmHg.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH2:15][CH3:16])[CH2:10][C@H:9]1[C:17]([OH:19])=O)=[O:7])(C)(C)C.C(Cl)(=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[Cl:29][C:30]1[CH:31]=[C:32]([N:37]2[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]2)[CH:33]=[CH:34][C:35]=1[Cl:36]>>[CH2:15]([O:14][N:13]=[C:11]1[CH2:10][C@@H:9]([C:17]([N:40]2[CH2:39][CH2:38][N:37]([C:32]3[CH:33]=[CH:34][C:35]([Cl:36])=[C:30]([Cl:29])[CH:31]=3)[CH2:42][CH2:41]2)=[O:19])[N:8]([C:6](=[O:7])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH2:12]1)[CH3:16]
Reactant: Clc1ccc(N2CCNCC2)cc1Cl
Reactant: O=C(Cl)c1ccccc1
Reactant: CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CCON=C1C[C@@H](C(=O)N2CCN(c3ccc(Cl)c(Cl)c3)CC2)N(C(=O)c2ccccc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(ethoxyimino)-2-pyrrolidinecarboxylic acid, benzoyl chloride, and 1-(3,4-dichlorophenyl)piperazine the title compound was obtained in 51% purity by LC/MS. MS(ESI+): m/z=489.6.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[F:19][C:20]([F:35])([CH:32]([F:34])[F:33])[CH2:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([C:29](O)=[O:30])=[N:27][CH:28]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:29]([C:26]3[CH:25]=[CH:24][C:23]([O:22][CH2:21][C:20]([F:35])([F:19])[CH:32]([F:34])[F:33])=[CH:28][N:27]=3)=[O:30])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1ccc(OCC(F)(F)C(F)F)cn1
Product: C[C@]1(c2cc(NC(=O)c3ccc(OCC(F)(F)C(F)F)cn3)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 5-(2,2,3,3-tetrafluoro-propoxy)-pyridine-2-carboxylic acid [example 30a), b)] following procedure I yielded the title compound as a white solid. MS (ISP): m/z=495.2 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[NH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.[I-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: C1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CN2CCCCC2)cc1
Yield: 90 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-(piperidin-1-ylmethyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.070 g; 0.202 mmol), piperidine (0.090 mL; 0.907 mmol) and sodium iodide (0.153 g; 1.01 mmol) in THF (3 mL), microwave irradiation at 150° C. for 10 minutes. Flash chromatography on silica gel (eluent 3 to 20% ethanol in dichloromethane) furnished 0.072 g (90%) of the title compound as a white solid.
Reaction SMILES: C(OC(N[CH:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[N:12]2[C:18](=[O:20])[CH2:19][C@H:11]2[S:10]1)=O)(C)(C)C.[CH3:21][CH2:22][N:23]([CH2:26]C)CC.[BH3-]C#[N:30].[Na+].C(=O)C>CO>[NH2:30][CH:19]1[C:18](=[O:20])[N:12]2[C:13]([C:15]([OH:17])=[O:16])=[C:14]([CH2:26][NH:23][CH2:22][CH3:21])[CH2:9][S:10][C@H:11]12
Reactant: [BH3-]C#N
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)NC1C=C(C(=O)O)N2C(=O)C[C@H]2S1
Agent: CC=O
Agent: [Na+]
Solvent: CO
Product: CCNCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Reaction time: 0.5 h

Procedure:
3-Aminomethyl-7-(t-butoxycarbonylaminoceph-3-em-4-carboxylic acid (987 mg at approximately 71% purity, equivalent to 700 mgs pure material) was added to a rapidly stirred solution of Et3N (215 mg, 0.294 ml) at ambient temperature: it did not dissolve completely. The mixture was stirred for 30 minutes, then NaCNBH3 (132 mg) was added, followed by acetaldehyde (0.119 ml, 93.7 mg) as a solution in methanol, over 40 minutes by infusion pump. The mixture was stirred for 1 hour at ambient temperature after which HPLC showed much starting material still remaining. A further 0.018 ml of acetaldehyde was added in one portion over about 20 seconds. HPLC after a further 30 minutes showed less starting material present. The mixture was evaporated to a foam, then dissolved in 50 ml water adjusted to pH 2-3 with acetic acid, and purified by medium pressure chromatography on HP-20 ss column using gradient elution with water up to 25% v/v acetonitrile. The product eluted at 13-15% acetonitrile.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=1.[H-].[Na+].[F:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:27][CH2:26][CH2:25][F:24])=[O:19])[N:9]=1
Reactant: FCCCBr
Reactant: CNC(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCF)C(=O)c1cc2ccccc2c(-c2ccccc2I)n1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 22.3 %

Procedure:
To a solution of 1-(2-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (22 mg, 0.06 mmol) in DMF (2 mL) was added 60% NaH (12 mg, 0.30 mmol) in one portion. The mixture was stirred under Ar at room temperature for 40 min. Then, 3-fluoropropyl bromide (22 ul, 0.30 mmol) was added. After stirring under Ar at room temperature for 24 h, the mixture was quenched by adding H2O (7 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane, 0.035% Et3N), thereby affording a semisolid (6 mg, 23%), and starting material (17.7 mg). 1H NMR (CDCl3) d 1.96-2.22 (m, 2 H, CH2), 3.16, 3.20 (two s, total 3 H, N-methyl), 3.59-3.85 (m, 2 H, N--CH2), 4.47 (qt, J=79.8, 47.1, 6 Hz, 2 H, CH2F), 7.21 (dt, J=7.5, 0.9 Hz, 1 H, aromatic), 7.36 (dd, J=7.5, 1.5 Hz, 1 H, aromatic), 7.51 (t, J=7.2 Hz, 1 H, aromatic), 7.56 (d, J=3.9 Hz, 2 H, aromatic), 7.69-7.81 (m, 1 H, aromatic), 7.99 (t, J=7.8 Hz, 1 H, aromatic), 8.11, 8.18 (two s, total 1 H, aromatic). HRMS calcd. for C20H18FIN2O: 448.0448. Found: 448.0456.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9](Br)[CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1.[CH3:15][Si:16]([C:19]#[CH:20])([CH3:18])[CH3:17]>C(N(CC)CC)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:1][C:2]1([CH3:14])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:20]#[C:19][Si:16]([CH3:18])([CH3:17])[CH3:15])[CH:10]=2)[S:5][C:4](=[O:13])[CH2:3]1
Reactant: CC1(C)CC(=O)Sc2ccc(Br)cc21
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)Sc2ccc(C#C[Si](C)(C)C)cc21
Temperature: 55 °C
Reaction time: 24 h

Procedure:
A solution of 1.0 g (3.7 mmol) of 4,4-dimethyl-6-bromo-2-oxo-thiochroman in 1 ml of triethylamine was placed in a heavy-walled tube and degassed and then treated under argon with 2.0 g (2.75 ml, 20.0 mmol) of trimethylsilylacetylene and a powdered mixture of 0.038 g of cuprous iodide and 0.084 g of bis(triphenylphosphine) palladium (II) chloride. The reaction mixture was degassed again, then placed under argon and the tube was sealed. The mixture was heated at 55 degrees C. for 24 hours, allowed to cool to room temperature and taken up with methylene chloride and silica. Solvent was removed in-vacuo and the resulting residual material on silica was purified using flash chromatography (SiO2 ; 2% ethyl acetate in hexanes) to give the title compound as a yellow oil.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH2:25])=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1>>[CH3:15][C:16]1[O:17][C:18]2[C:24]([NH:25][C:8]3[CH:7]=[CH:6][C:5]4[C:4]([NH:1][CH2:32][C:28]5[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=5)=[CH:13][CH:12]=[CH:11][C:10]=4[N:9]=3)=[CH:23][CH:22]=[CH:21][C:19]=2[CH:20]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1cccnc1
Reactant: Cc1cc2cccc(N)c2o1
Product: Cc1cc2cccc(Nc3ccc4c(NCc5cccnc5)cccc4n3)c2o1

Procedure:
The title compound, MS: m/e=381.0 (M+H+), was prepared from 5-nitro-2-chloroquinoline, (2-methyl-1-benzofuran-7-yl)amine and pyridine-3-carbaldehyde as described in example 26.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][N:5]=1)[CH3:2]>CO.[Pd]>[NH2:10][C:7]1[CH:8]=[CH:9][C:4]([N:3]([CH2:13][CH3:14])[CH2:1][CH3:2])=[N:5][CH:6]=1
Reactant: CCN(CC)c1ccc([N+](=O)[O-])cn1
Agent: [Pd]
Solvent: CO
Product: CCN(CC)c1ccc(N)cn1
Yield: 94.5 %

Procedure:
40 g of the 2-diethylamino-5-nitropyridine was subjected to catalytic reduction in one liter of methanol through the use of 2 g of 10% Pd-C. The catalyst was removed by filtration, and the filtrate was concentrated to give 32 g of 5-amino-2-diethylaminopyridine (yield: 95% oleaginous form).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:15]Br)[CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25](B2OC(C)(C)C(C)(C)O2)[C:22]=1[C:23]#[N:24].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.CCO.C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18])[CH2:15][C:25]1[CH:26]=[CH:27][CH:28]=[C:21]([CH3:20])[C:22]=1[C:23]#[N:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1OCc1ccccc1
Reactant: Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1C#N
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+]
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCO
Product: Cc1cccc(Cc2ccc([N+](=O)[O-])c(OCc3ccccc3)c2)c1C#N
Temperature: 60 °C

Procedure:
A mixture of 2-benzyloxy-4-bromomethyl-1-nitrobenzene (2.99 g, 9.27 mmol) and Pd(PPh3)4 (536 mg, 0.464 mmol) in DME (10 mL) is heated to 60° C. for 2 min. in a microwave. 2-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile (5.96 g of crude, ˜13.9 mmol) in DME (10 mL) and EtOH (2 mL) is added along with Na2CO3 (2 M, 3.3 mL). The reaction mixture is heated to 110° C. for 30 min. by microwave. Then the reaction is heated to 120° C. for an additional 15 min. by microwave. The reaction mixture is diluted with DCM (150 mL) and extracted with water (50 mL). The aqueous layer is extracted with DCM (30 mL) and the combined organics is dried over Na2SO4. Evaporation yields a brown oil, and it is then purified by flash column to yield a tan solid as the title compound: MS (M−H)−=357.2.
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH:5]([OH:10])[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:3].C(N(CC)CC)C.[CH3:18][S:19](Cl)(=[O:21])=[O:20]>C(Cl)(Cl)Cl>[CH3:18][S:19]([O:10][CH:5]([CH2:6][CH:7]([CH3:9])[CH3:8])[CH2:4][CH:2]([CH3:3])[CH3:1])(=[O:21])=[O:20]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)CC(O)CC(C)C
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(C)CC(CC(C)C)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
In a one liter three-neck flask was mixed 100 g (0.69 moles) of 2,6-dimethyl-4-heptanol and 580 g chloroform. Triethylamine (77.1 g; 6 moles) was added and the reaction mixture cooled to 0° C. Methanesulfonyl chloride (83.4 g; 0.73 moles) was added dropwise, keeping the reaction temperature about 0° C. After holding at about 0° C. for one hour, gas chromatograph (GC) showed less than 5% residual alcohol.