Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.CN(C(SC1[N+]([O-])=CC=CC=1)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Cl:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[N:55]([NH2:59])[C:54]([CH3:60])=[CH:53]2>CN(C=O)C.O.CCOC(C)=O>[Cl:49][C:50]1[CH:51]=[C:52]2[C:56](=[CH:57][CH:58]=1)[N:55]([NH:59][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[C:54]([CH3:60])=[CH:53]2
Reactant: Cc1cc2cc(Cl)ccc2n1N
Reactant: Cc1nc(-c2cccc(F)c2)ncc1C(=O)O
Agent: CN(C)C(Sc1cccc[n+]1[O-])=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1nc(-c2cccc(F)c2)ncc1C(=O)Nn1c(C)cc2cc(Cl)ccc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (379 mg, 1.63 mmol), HOTT (662 mg, 1.78 mmol), and DIPEA (800 μL, 4.58 mmol) in DMF (10 mL) is stirred at rt under N2 for 10 min. 5-Chloro-2-methyl-indol-1-ylamine (274 mg, 1.52 mmol) is added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is triturated in ether to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-chloro-2-methyl-indol-1-yl)-amide (93 mg, 16%) as a solid. MS: 395 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.83 (s, 1H), 9.27 (s, 1H), 8.33 (d, 1H), 8.20-8.15 (m, 1H), 7.69-7.61 (m, 1H), 7.56 (d, 1H), 7.50-7.43 (m, 2H), 6.36 (s, 1H), 2.78 (s, 3H), 2.37 (s, 3H).
Reaction SMILES: [H-].[Na+].F[C:4]1[C:21]([CH3:22])=[C:20]([F:23])[C:19]([F:24])=[CH:18][C:5]=1[C:6]([C:8](=[CH:14][NH:15][CH2:16][CH3:17])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:7]>O1CCOCC1>[CH2:16]([N:15]1[C:4]2[C:5](=[CH:18][C:19]([F:24])=[C:20]([F:23])[C:21]=2[CH3:22])[C:6](=[O:7])[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:14]1)[CH3:17]
Reactant: CCNC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(C)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(CC)c2c(C)c(F)c(F)cc2c1=O
Temperature: 0 °C
Yield: 65.7 %

Procedure:
To the cooled mixture of 55% sodium hydride (0.47 g) in anhydrous dioxane (20 ml) was added ethyl 2-(2,4,5-trifluoro-3-methylbenzoyl)-3-ethylaminoacrylate (2.6 g) during 10 minutes with stirring. After stirring for 40 minutes at room temperature, the reacting mixture was poured into ice-water (50 ml), the resulting precipitate was collected by filtration, washed with chilled water and ether successively and recrystallized from dichloromethane-n-hexane to give the title compound (1.6 g) as colorless prisms, mp 177°-179.5° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13](I)[CH:14]=1)=[O:8])[CH3:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[S:42]1[C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=2[N:44]=[CH:43]1>CN(C=O)C.[Cu]I.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][CH2:3][CH:4]([NH:6][C:7]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=2)[CH:12]=[C:13]([C:43]2[S:42][C:46]3[CH:47]=[CH:48][CH:49]=[CH:50][C:45]=3[N:44]=2)[CH:14]=1)=[O:8])[CH3:5]
Reactant: COCC(C)NC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Reactant: c1ccc2scnc2c1
Agent: [Cu]I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-c2nc3ccccc3s2)c1
Temperature: 150 °C
Yield: 97.3 %

Procedure:
To a stirred solution of 5-iodo-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (150 mg, 0.37 mmol) in 1 ml dry DMF were added CuI (15.24 mg, 20% eq), Pd(OAc)2 (4.2 mg, 5% eq), PPh3 (19.5 mg, 20% eq) and benzothiazole (63.5 mg, 1.5 eq) at room temperature. The reaction mixture was heated to 150° C. by microwave irridiation for 45 minutes. The reaction mixture was cooled and extracted with EtOAc, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by preparative HPLC to give 5-benzothiazol-2-yl-4′-methyl-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (150 mg, 60%). MS (M+H)=417.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23](O)=[O:24])[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1.[CH3:29][O:30][C@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11]([N:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:23]([N:33]4[CH2:34][CH2:35][C@H:31]([O:30][CH3:29])[CH2:32]4)=[O:24])[CH:21]=3)[C:16]([S:26]([CH3:28])=[O:27])=[CH:15]2)=[N:12][CH:13]=1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Reactant: CO[C@H]1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: CO[C@H]1CCN(C(=O)c2ccc3c(S(C)=O)cn(-c4ncc(-c5ccccc5F)cn4)c3c2)C1

Procedure:
Amide coupling of 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid with (S)-3-methoxypyrrolidine utilizing HATU as coupling reagent. White solid. Yield: 100 mg (85% of theory)
Reaction SMILES: O=[C:2]1[NH:7][C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][C:4]2[NH:18][C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:20][C:3]1=2.C1(N(C)C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:38]>CC#N>[Cl:38][C:2]1[C:3]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:18][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1
Reactant: CCCCCCCC(=O)Nc1nc2[nH]c(CN3CCCC3)cc2c(=O)[nH]1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCCCCCCC(=O)Nc1nc(Cl)c2cc(CN3CCCC3)[nH]c2n1

Procedure:
A solution of octanoic acid (4-oxo-6-pyrrolidin-1-ylmethyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (0.36 g 1 mmol; J. Chem. Soc. Perkin Trans. 1 1998, 1637), BnNEt3Cl (0.70 g, 2 mmol), PhNMe2 (0.25 mL) and POCl3 (0.86 mL, 6 mmol) in CH3CN (5 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL×3), and evaporated to give octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide as a crude (0.33 g) which was used without purification. HPLC Rt: 6.737 min. 1H-NMR (CDCl3): δ 11.60 (br s, 1H), 10.20 (br s, 1H), 6.38 (s, 1H), 3.86 (s, 2H), 2.90 (m, 2H), 2.70 9s, 4H), 1.86 (s, 4H), 1.78 (t, 2H), 1.32–1.29 (m, 8H), 0.90 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=1.C(O)(=[O:28])C>>[F:1][C:2]([F:24])([F:25])[C:3]1[CH:4]=[C:5]([C:6](=[O:28])[C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[C:9]([CH3:16])[CH:8]=2)[CH:17]=[C:18]([C:20]([F:23])([F:22])[F:21])[CH:19]=1
Reactant: Cc1cc(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Reactant: CC(=O)O
Product: Cc1cc(C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Chromic oxide (IV) (0.41 g) was added to a solution of 4-(3,5-bis-trifluoromethyl-benzyl)-2-methylnitrobenzene (0.3 g) in acetic acid (10 ml) and stirred at room temperature for 1 hour. After the reaction, the reaction solution was extracted with ethyl acetate and washed with water, a saturated sodium bicarbonate solution and a saturated salt solution. After drying over anhydrous magnesium sulfate, the solvent was distilled off and the residue was purified by silica gel column chromatography to obtain 3′,5′-bis-trifluoromethyl-3-methyl-4-nitrobenzophenone (0.3 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH:20]([CH3:22])[CH3:21])[CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]>C(O)C.[Pd]>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=1)[CH:20]([CH3:21])[CH3:22])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N(CCOc1ccc([N+](=O)[O-])cc1)C(=O)OC(C)(C)C
Agent: [Pd]
Solvent: CCO
Product: CC(C)N(CCOc1ccc(N)cc1)C(=O)OC(C)(C)C
Yield: 99.1 %

Procedure:
A solution of isopropyl-[2-(4-nitro-penoxy)-ethyl]-carbamic acid tert-butyl ester (8.3 g, 25.58 mmol) (from step B above) and 600 mg of 10% palladium-on-carbon in ethanol (100 mL) was hydrogenated at 20 psi in a Parr shaker for 1 hour. The mixture was filtered through Celite™ and the solvent evaporated to give 7.46 g (99%) of [2-(4-amino-phenoxy)-ethyl]-isopropyl-carbamic acid tert-butyl ester.
Reaction SMILES: [NH2:1][C@@H:2]1[C:8](=[O:9])[N:7]([CH2:10][CH:11]2[CH2:13][CH2:12]2)[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[C:4]2[CH:18]=[CH:19][CH:20]=[CH:21][C:3]1=2.[CH3:22][C:23]([CH3:38])([C:27]([NH:29][CH2:30][C:31]([F:37])([F:36])[C:32]([F:35])([F:34])[F:33])=[O:28])[C:24](O)=[O:25]>>[CH:11]1([CH2:10][N:7]2[C:8](=[O:9])[C@@H:2]([NH:1][C:24](=[O:25])[C:23]([CH3:22])([CH3:38])[C:27]([NH:29][CH2:30][C:31]([F:36])([F:37])[C:32]([F:33])([F:34])[F:35])=[O:28])[C:3]3[CH:21]=[CH:20][CH:19]=[CH:18][C:4]=3[C:5]3[CH:17]=[CH:16][CH:15]=[CH:14][C:6]2=3)[CH2:13][CH2:12]1
Reactant: N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21
Reactant: CC(C)(C(=O)O)C(=O)NCC(F)(F)C(F)(F)F
Product: CC(C)(C(=O)NCC(F)(F)C(F)(F)F)C(=O)N[C@@H]1C(=O)N(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
(S)-7-amino-5-cyclopropylmethyl-5H,7H-dibenzo[b,d]azepin-6-one was coupled with 2,2-dimethyl-N-(2,2,3,3,3-pentafluoro-propyl)-malonamic acid in analogy to the description in example 73 to yield N-((S)-5-cyclopropylmethyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl)-2,2-dimethyl-N′-(2,2,3,3,3-pentafluoro-propyl)-malonamide as white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]=1[C:17]1[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:19][CH:18]=1.[Cl:32]N1C(=O)CCC1=O>CN(C=O)C>[Cl:32][C:11]1[C:10]2[NH:9][C:8](=[O:13])[C:7]3[S:14][CH:15]=[CH:16][C:6]=3[C:5]=2[C:4]([C:17]2[CH:31]=[CH:30][C:20]([CH2:21][NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[CH:19][CH:18]=2)=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COc1ccc2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: COc1cc(Cl)c2[nH]c(=O)c3sccc3c2c1-c1ccc(CNC(=O)OC(C)(C)C)cc1
Yield: 31.8 %

Procedure:
A solution of tert-butyl 4-(8-methoxy-4-oxo-4,5-dihydrothieno[2,3-c]quinolin-9-yl)benzylcarbamate (45 mg, 0.10 mmol) and N-chlorosuccinimide (17 mg, 0.13 mmol) in DMF (1 mL) was heated at 50° C. for 3 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by preparatory HPLC (water/acetonitrile w 0.05% TFA gradient) to afford the desired product (15 mg, 32%) as a brown solid: ESI MS m/z 471 [C24H23ClN2O4S+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH2:12][OH:13])[CH:5]=O.[NH2:14][C:15]1[CH:30]=[CH:29][CH:28]=[CH:27][C:16]=1[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Br:26])=[CH:22][CH:21]=1)=[O:18]>C(O)C>[Br:26][C:23]1[CH:24]=[CH:25][C:20]([N:19]2[C:17](=[O:18])[C:16]3[C:15](=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:14]=[C:5]2[C:4]2[CH:7]=[CH:8][C:9]([O:10][CH2:11][CH2:12][OH:13])=[C:2]([CH3:1])[CH:3]=2)=[CH:21][CH:22]=1
Reactant: Cc1cc(C=O)ccc1OCCO
Reactant: Nc1ccccc1C(=O)Nc1ccc(Br)cc1
Solvent: CCO
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(Br)cc2)ccc1OCCO
Temperature: 25 °C

Procedure:
To a solution of 3-methyl-4-hydroxyethoxy-benzaldehyde (0.38 g, 2.10 mmol) and 2-amino-N-(4-bromophenyl)benzamide (0.60 g, 2.10 mmol) in anhydrous ethanol (15 mL) was added anhydrous CuCl2 (0.85 g, 6.30 mmol). The reaction mixture was heated at reflux for 18 hours and then cooled to room temperature. Organic solvents were removed under reduced pressure, and the resulting residue was diluted with dichloromethane, washed with water, then brine, and dried over anhydrous magnesium sulfate. The solvent was removed under vacuum and the residual solid was purified by column chromatography (silica gel 230-400 mesh; 25-50% ethyl acetate in hexanes as eluent) to afford the title compound as a white solid. Yield: 0.21 g (22%). MP 92.0-93.0° C. 1H-NMR (400 MHz, CDCl3): δ 8.32 (d, J=8.4 Hz, 1H), 7.81 (dd, J=4.8 and 1.2 Hz, 2H), 7.45-7.54 (m, 3H), 7.23 (m, 1H), 7.00 (m, 3H), 6.63 (d, J=8.4 Hz and 1H), 4.05 (t, J=4.4 Hz, 2H), 3.97 (t, J=4.4 Hz, 2H), 2.15 (s, 3H). MS (ES+) m/z: 453.39, 451.37.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([OH:7])=[O:6].[CH3:12]O>>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[NH2:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: CO
Reactant: Nc1ccc(C(=O)O)cc1N
Product: COC(=O)c1ccc(N)c(N)c1

Procedure:
To the stirred suspension of commercial 3,4-diaminobenzoic acid (10.3 g) in methanol (150 ml) conc. sulphuric acid (5 ml) was added cautiously. The mixture was stirred under reflux for 3 h. About half of the solvent is removed by distillation and dichloromethane (150 ml) is added. The organic layer was poured in ice water (300 ml) and with vigorous stirring the pH was adjusted to 11 with 10M NaOH. The organic layer was separated and the aqueous layer extracted with dichloromethane (150 ml). The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified by fractional crystallisation from dichloromethane to give methyl 3,4-diaminobenzoate (7.05 g) as beige coloured solid.
Reaction SMILES: [CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH:20]([OH:22])[CH3:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:33]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:1]([C@@H:8]1[C@@H:16]([O:17][CH2:18][CH2:19][CH:20]([O:22][CH3:33])[CH3:21])[C@H:15]([CH3:23])[O:14][C:13](=[O:24])[C@@H:12]([NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])[CH2:11][O:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(O)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: ClCCl
Product: COC(C)CCO[C@@H]1[C@@H](Cc2ccccc2)COC[C@H](NC(=O)OC(C)(C)C)C(=O)O[C@H]1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-hydroxybutoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (82 mg, 0.18 mmol, 1.00 equiv) in CH2Cl2 (1.8 mL) were added proton sponge (156 mg, 0.726 mmol, 4.00 equiv) and trimethyloxonium tetrafluoroborate (54 mg, 0.36 mmol, 2.0 equiv). The resulting suspension was stirred at room temperature for 1 h, poured into ½ sat'd NaHCO3 solution (20 mL), and extracted with CH2Cl2 (3×20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated to provide a yellow oil. Purification by automated silica gel column chromatography (1-6% acetone in CH2Cl2) provided tert-butyl ((3S,7S,8R,9S)-7-benzyl-8-(3-methoxybutoxy)-9-methyl-2-oxo-1,5-dioxonan-3-yl)carbamate (71 mg, 84%) as a sticky oil: 1H NMR (400 MHz, CDCl3) δ 7.32-7.23 (m, 2H), 7.23-7.13 (m, 3H), 5.18 (d, J=6.9 Hz, 1H), 5.02-4.86 (m, 1H), 4.60 (q, J=7.2 Hz, 1H), 3.94-3.75 (m, 2H), 3.75-3.62 (m, 1H), 3.62-3.41 (m, 3H), 3.36 (dd, J=10.5, 6.5 Hz, 1H), 3.33-3.22 (m, 4H), 3.21-3.04 (m, 2H), 2.29 (t, J=12.5 Hz, 1H), 2.00-1.81 (m, 1H), 1.81-1.68 (m, 2H), 1.48 (s, 3H), 1.41 (s, 9H), 1.15 (d, J=6.1 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 172.21, 154.98, 139.93, 139.88, 129.13, 128.42, 126.10, 85.02, 80.03, 75.51, 75.45, 73.41, 73.39, 72.91, 72.58, 69.09, 68.84, 55.94, 55.89, 53.01, 47.27, 47.14, 37.41, 37.35, 35.14, 35.03, 28.27, 19.09, 18.73.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH:32]=O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][C@H:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][N:39]5[CH2:38][CH2:37][NH:36][C@@H:35]([CH3:34])[CH2:40]5)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][CH:12]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: C[C@H]1CNCCN1
Reactant: O=Cc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@H]1CN(Cc2ccc(-c3ccc(C(CC4CCOCC4)c4ccc(S(=O)(=O)C5CC5)cc4)[nH]3)nc2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 37.6 %

Procedure:
To a solution of 6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridine-3-carbaldehyde (250 mg) in tetrahydrofuran (10 mL) was added (2S)-2-methylpiperazine (270 mg), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added sodium triacetoxyborohydride (230 mg), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and saturated brine, dried (MgSO4) and concentrated. The residue was subjected to preparative HPLC to give the title compound (111 mg, yield 38%) as a colorless amorphous solid. MS: 549 (MH+).
Reaction SMILES: [F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH2:14])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:22]1([C:25](Cl)=[O:26])[CH2:24][CH2:23]1>ClCCl>[F:1][C:2]1[C:10]2[O:9][CH2:8][CH2:7][C:6]=2[C:5]([CH2:11][CH2:12][CH2:13][NH:14][C:25]([CH:22]2[CH2:24][CH2:23]2)=[O:26])=[CH:4][CH:3]=1
Reactant: O=C(Cl)C1CC1
Reactant: NCCCc1ccc(F)c2c1CCO2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCCc1ccc(F)c2c1CCO2)C1CC1
Reaction time: 0.33 h
Yield: 10.4 %

Procedure:
A mixture of 3-(7-fluoro-2,3-dihydro-benzofuran-4-yl)-propylamine (114 mg), triethylamine (0.089 ml), dichloromethane (5 ml) and cyclopropanecarbonyl chloride (67 mg) was stirred in ice for 20 minutes and stirring continued at room temperature overnight. The mixture was partitioned between 2N hydrochloric acid and dichloromethane and the organic phase washed with 8% sodium bicarbonate and evaporated. Purification of the residue by preparative hplc gave the title compound as a white solid (16 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH:15]([C:17]3[N:18]=[C:19]([Si](C(C)(C)C)(C)C)[N:20](S(=O)(=O)N(C)C)[CH:21]=3)O)=[CH:13][C:12]([CH3:35])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>CCO.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[C:14]([CH2:15][C:17]3[N:18]=[CH:19][NH:20][CH:21]=3)=[CH:13][C:12]([CH3:35])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2cc(C)cc(C(O)c3cn(S(=O)(=O)N(C)C)c([Si](C)(C)C(C)(C)C)n3)c2o1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1cc2cc(C)cc(Cc3c[nH]cn3)c2o1
Temperature: 25 °C
Yield: 3.9 %

Procedure:
A solution of rac-7-{[2-(tert-butyl-dimethyl-silanyl)-1-dimethylsulfamoyl-1H-imidazol-4-yl]-hydroxy-methyl}-5-methyl-benzofuran-2-carboxylic acid ethyl ester (470 mg; example 52.b) in EtOH (16 ml) was treated with 10% Pd/C (117 mg) and hydrogenated for 48 hrs at 100 bar and 100° C. The reaction mixture was cooled to r.t., filtrated and concentrated. The residue was dissolved in EtOH (5 ml) and treated with 3N HCl (5 ml). The solution was heated to 100° C. for 3 hrs, then concentrated. The residue was taken up in water. The solution was made basic by the addition of K2CO3 and extracted with CH2Cl2/MeOH 4:1. The organics were dried over MgSO4, filtrated and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2→CH2Cl2/MeOH 9:1) to give 7-(1H-imidazol-4-ylmethyl)-5-methyl-benzofuran-2-carboxylic acid ethyl ester (10 mg) as amorphous off-white solid. MS (ISP): 285.1 ((M+H)+.).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH:19][C:20]1[CH:21]=[C:22]([C:27]2[C:28](=[S:39])[NH:29][C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)=[N:31][CH:32]=2)[CH:23]=[CH:24][C:25]=1[OH:26].B(F)(F)F.CCOCC>ClCCl.S1(CCCC1)(=O)=O>[NH2:13][C@@H:10]1[C:11](=[O:12])[N:8]2[C@@H:9]1[S:14][CH2:15][C:6]([CH2:5][S:39][C:28]1[C:27]([C:22]3[CH:23]=[CH:24][C:25]([OH:26])=[C:20]([OH:19])[CH:21]=3)=[CH:32][N:31]=[C:30]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[N:29]=1)=[C:7]2[C:16]([OH:18])=[O:17]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Oc1ccc(-c2cnc(-c3ccccc3)[nH]c2=S)cc1O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Product: N[C@@H]1C(=O)N2C(C(=O)O)=C(CSc3nc(-c4ccccc4)ncc3-c3ccc(O)c(O)c3)CS[C@H]12
Yield: 81.9 %

Procedure:
7-Aminocephalosporanic acid (162 mg) (0.6 mmol) and 216 mg (0.66 mmol) of 5-(3,4-dihydroxyphenyl)-2-phenyl-4(3H)-pyrimidinethione are suspended in 7 ml of dichloromethane/sulpholane (1:1 v/v). 4 ml of boron trifluoride diethyl etherate are added thereto while stirring. After 16 hours the mixture is concentrated in a high vacuum at room temperature, the residue is washed with diethyl ether and dissolved in about 3 ml of water. Sodium hydrogen carbonate is added thereto until the pH is adjusted to 5. Then, 1 ml of diethyl ether and 0.5 ml of ethanol are added thereto. The precipitated product is filtered off under suction, washed in succession with water, ethanol and ether and dried in a high vacuum at room temperature. There are obtained 250 mg of (6R,7R)-7-amino-3-[[[5-(3,4-dihydroxyphenyl)-2-phenyl-4-pyrimidinyl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5](=[O:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH:21]([F:23])[F:22].N1C=CN=N1>>[F:22][CH:21]([F:23])[N:6]1[C:5](=[O:7])[N:4]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:3]=[C:2]1[CH3:1]
Reactant: FC(F)Cl
Reactant: Cc1nn(-c2ccccc2)c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]nn1
Product: Cc1nn(-c2ccccc2)c(=O)n1C(F)F
Yield: 89.3 %

Procedure:
This compound was prepared in the manner of Example 1, with 25.0 grams of 4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-1,2,4-triazole (0.110 mole--1.0 equiv.), 30.0 grams (0.217 mole--2.0 equiv.) of potassium carbonate, and 14.3 grams (0.165 mole--1.5 equiv.) of chlorodifluoromethane in 220 mL of polyglyme (% wt/vol. triazole to solvent--11%) as reagents. A yield of 28.7 grams of 91.5% pure 4-difluoromethyl-4,5-dihydro-3-methyl-5-oxo-1-phenyl-1H-1,2,4-triazole (87.8% yield) was obtained. GC analysis of the product indicated the presence of about 5.0% O-isomer by-product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:5](=[CH:7][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:9][CH:10]=1)[OH:6].[CH2:16](I)[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:14])[CH3:13])=[CH:7][C:5]=1[O:6][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: COC(=O)c1ccc(NC(C)=O)cc1O
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1cc(NC(C)=O)ccc1C(=O)OC
Temperature: 70 °C
Reaction time: 30 h
Yield: 69.9 %

Procedure:
A mixture of p-acetylaminosalicylic acid methyl ester (5.0 g), hexyl iodide (7.6 g), potassium carbonate (9.9 g), and dimethylformamide (20 ml) is stirred at 70° C. for 30 hours. The reaction mixture is poured into ice-water and extracted with diethyl ether. The organic layer is washed successively with aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over magnesium sulfate, and evaporated. The residue is chromatographed on silica gel with chloroform-methanol (20:1) to give 4-acetylamino-2-hexyloxybenzoic acid methyl ester (4.9 g) as an oil.