Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[N+:12]([C:15]1[CH:16]=[C:17]([C:27]2[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=2)[CH:18]=[CH:19][C:20]=1[N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1)([O-:14])=[O:13].C(N(CC)CC)C.O>ClCCCl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([N:24]2[CH2:25][CH2:26][N:21]([C:20]3[CH:19]=[CH:18][C:17]([C:27]4[CH:28]([CH3:34])[CH2:29][C:30](=[O:33])[NH:31][N:32]=4)=[CH:16][C:15]=3[N+:12]([O-:14])=[O:13])[CH2:22][CH2:23]2)=[O:8])=[CH:5][CH:4]=1
Reactant: CC1CC(=O)NN=C1c1ccc(N2CCNCC2)c([N+](=O)[O-])c1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: COc1ccc(C(=O)N2CCN(c3ccc(C4=NNC(=O)CC4C)cc3[N+](=O)[O-])CC2)cc1
Temperature: 25 °C

Procedure:
0.70 g (4.1 mmol) of 4-methoxybenzoyl chloride is added to a slurry of 1.0 g (3.15 mmol) of 6-[3-nitro-4-(1-piperazinyl)-phenyl]-5-methyl-4,5-dihydro-3(2H)-pyridazinone and 1.14 ml (8.2 mmol) of triethylamine in 40 ml of 1,2-dichloroethane and the reaction mixture is boiled under reflux for 0.5 h. It is then cooled to room temperature, 50 ml of water are added, and the organic phase is separated off.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:36][CH2:35][C:34](=[O:37])[CH2:33][CH2:32]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1.[CH3:38][Li]>C1COCC1>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[C:6]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[NH:20][CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[C:24]([NH:28][C:29]([N:31]4[CH2:32][CH2:33][C:34]([OH:37])([CH3:38])[CH2:35][CH2:36]4)=[O:30])[CH:23]=3)=[O:13])[CH:7]=[CH:8]2)=[N:3]1
Reactant: [Li]C
Reactant: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(=O)CC4)c3)cc2n1
Solvent: C1CCOC1
Product: Cn1cc2ccc(NC(=O)c3ccccc3NCc3ccnc(NC(=O)N4CCC(C)(O)CC4)c3)cc2n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 23.4 %

Procedure:
4-oxo-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (50 mg, 0.1 mmol) in dry THF under argon, at −78° C. was treated dropwise with methyllithium (1.5M in diethylether, 0.2 mL, 0.3 mmol). The reaction was stirred for 30 minutes at −78° C. before warming to rt. The reaction was stirred overnight before partitioning between EtOAc and saturated aqueous ammonium chloride solution. The organic phase was washed with brine, dried, filtered and concentrated in vacuo. The residue was purified by chromatography on Isolute® Flash silica gel (Separtis) (Gradient elution: 100% CH2Cl2 to CH2Cl2/EtOH 10:2) to give 4-hydroxy-4-methyl-piperidine-1-carboxylic acid (4-{[2-(2-methyl-2H-indazol-6-ylcarbamoyl)-phenylamino]-methyl}-pyridin-2-yl)-amide (12 mg, 23%) as a solid; 1H-NMR (300 MHz, d6-DMSO) 10.13 (1H, s), 9.02 (1H, s), 8.25 (1H, s), 8.13 (1H, d), 8.10 (1H, s), 7.94 (1H, t), 7.80 (1H, s), 7.72 (1H, d), 7.64 (1H, d), 7.23-7.32 (2H, m), 6.92 (1H, d), 6.66 (1H, t), 6.54 (1H, d), 4.43 (2H, d), 4.31 (1H, s), 4.13 (3H, s), 3.68-3.74 (2H, m), 3.16-3.25 (2H, m), 1.35-1.46 (4H, m), 1.12 (3H, s); m/z (ES+) 514 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13](/[CH:16]=[N:17]/[C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[O:27])[O:25][C:24]([CH3:29])([CH3:28])[O:23][C:22]=4[CH:30]=3)=[CH:12][CH:11]=2)=[CH:4][CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18]3[CH:19]=[CH:20][C:21]4[C:26](=[O:27])[O:25][C:24]([CH3:28])([CH3:29])[O:23][C:22]=4[CH:30]=3)=[CH:12][CH:11]=2)=[CH:6][CH:7]=1
Reactant: CC1(C)OC(=O)c2ccc(/N=C/c3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Solvent: O
Product: CC1(C)OC(=O)c2ccc(NCc3ccc(C#Cc4ccc(Cl)cc4)cc3)cc2O1
Temperature: 50 °C
Yield: 78.4 %

Procedure:
A mixture of 7-[((E)-{4-[(4-chlorophenyl)ethynyl]phenyl}methylidene)amino]-2,2-dimethyl-4H-1,3-benzodioxin-4-one (1.65 g, 3.97 mmol), sodium triacetoxyborohydride (2.52 g, 11.9 mmol) and acetic acid (0.34 mL, 5.95 mmol) in anhydrous DCE (100 mL) was heated at 50° C. for 3 h. Then the reaction mixture was diluted with H2O (100 mL) and a saturated aqueous solution of NaHCO3 (100 mL) and extracted with DCM (3×200 mL). The combined organic layers were dried over MgSO4 and the solvents were removed under reduced pressure. Precipitation by addition of pentane and filtration gave 1.30 g of the titled compound as a pale yellow powder (77%). M− (ESI): 415.9. HPLC, Rt: 5.05 min (Purity: 98.0%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([S:22]([NH2:25])(=[O:24])=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27].[C:41](O)(=[O:44])[CH2:42][CH3:43]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:10])([F:9])[F:11])=[CH:4][C:3]=1[NH:12][C:13]1[N:18]2[N:19]=[CH:20][C:21]([S:22]([NH:25][C:41](=[O:44])[CH2:42][CH3:43])(=[O:24])=[O:23])=[C:17]2[N:16]=[CH:15][C:14]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([C:34]2[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=2)[CH2:30][CH2:29]1)=[O:27]
Reactant: NS(=O)(=O)c1cnn2c(Nc3cc(C(F)(F)F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Reactant: CCC(=O)O
Product: CCC(=O)NS(=O)(=O)c1cnn2c(Nc3cc(C(F)(F)F)ccc3Cl)c(C(=O)N3CCC(c4ccc(F)cc4)CC3)cnc12
Yield: 87.5 %

Procedure:
Using 7-(2-chloro-5-trifluoromethylphenylamino)-6-[4-(4-fluorophenyl)piperidine-1-carbonyl]pyrazolo[1,5-a]pyrimidine-3-sulfonamide (0.050 g, 0.084 mmol) obtained in step 5 and propionic acid (0.031 mL, 0.419 mmol) instead of cyclopropanecarboxylic acid, and in the same manner as in Example 1 step 6, the title compound (0.048 g, 87%) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH2:11][OH:12])[C:3]=1[Cl:13].[C:14](Cl)(=[O:16])[CH3:15].O>N1C=CC=CC=1>[NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]([O:9][CH2:10][CH2:11][O:12][C:14](=[O:16])[CH3:15])[C:3]=1[Cl:13]
Reactant: CC(=O)Cl
Reactant: Nc1c(Cl)cnc(OCCO)c1Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OCCOc1ncc(Cl)c(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 22.3 grams (0.1 mole) of 4-amino-3,5-dichloro-2-(2-hydroxyethoxy)pyridine (prepared by the method of Example I) dissolved in 150 milliliters of pyridine was added dropwise, with agitation, 8.7 grams (0.11 mole) of acetylchloride. The mixture was brought to reflux (~100° C.) and held at this temperature for 1 hour. The mixture was cooled to room temperature and poured into water. The oil which separated was extracted with methylene chloride, washed with 200 milliliters of water and dried over potassium carbonate. The solvent was evaporated under reduced pressure and the 4-amino-3,5-dichloro-2-(2-acetoxyethoxy)pyridine product was recovered by recrystallization from hexane. The product was recovered in a yield of 13.7 grams which melts at 76°-77° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH2:13].ClC(Cl)(O[C:18](=[O:24])OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C.[NH2:33][C:34]1[CH:39]=[CH:38][C:37]([Br:40])=[CH:36][N:35]=1>O1CCCC1>[Br:40][C:37]1[CH:38]=[CH:39][C:34]([NH:33][C:18]([NH:13][C:4]2[CH:5]=[C:6]([C:9]([F:11])([F:10])[F:12])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:24])=[N:35][CH:36]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(C(F)(F)F)cc1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Br)cn1
Reaction time: 0.17 h
Yield: 139.4 %

Procedure:
3.32 g of 2-methoxy-5-trifluoromethylphenylamine in 30 mL of tetrahydrofuran are added dropwise to a solution of 1.8 g of triphosgene in 180 mL of tetrahydrofuran at 0° C. 4.95 mL of triethylamine are then added and the reaction is stirred at this temperature for 10 minutes. The temperature is allowed to rise to 20° C. and the mixture is stirred for 1 hour 15 minutes. A solution of 3 g of 2-amino-5-bromopyridine in 30 mL of THF is then added dropwise. After 16 hours, the suspension is filtered and the filtrate is then concentrated under reduced pressure. The residue is taken up in a mixture of ethyl acetate and water. An insoluble white precipitate is obtained, which is filtered off, washed with ethyl acetate and then dried under vacuum. 3.3 g of a white powder of 1-(5-bromopyrid-2-yl)-3-(2-methoxy-5-trifluoromethylphenyl)urea are obtained.
Reaction SMILES: [N:1]1([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:5][C@@H:4]([C:6]([O:8]C)=[O:7])[CH2:3][C@H:2]1[C:10]([O:12][CH3:13])=[O:11].[OH-].[Na+].Cl>C1COCC1>[C:17]([O:16][C:14]([N:1]1[C@H:2]([C:10]([O:12][CH3:13])=[O:11])[CH2:3][C@H:4]([C:6]([OH:8])=[O:7])[CH2:5]1)=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H]1C[C@@H](C(=O)OC)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: COC(=O)[C@@H]1C[C@H](C(=O)O)CN1C(=O)OC(C)(C)C
Yield: 70.1 %

Procedure:
To a solution of (2S,4S)-1-tert-butyl 2,4-dimethyl pyrrolidine-1,2,4-tricarboxylate (9.56 g, 33.3 mmol) in THF (70 mL) at 0° C. (external temperature, ice bath) was added NaOH (1N aqueous, 33 mL, 33.3 mmol) dropwise over 15 min. The solution was stirred at 0° C. for 5 h before acidification with HCl (1N). The solution was extracted with EtOAc (3×). The combined organic layers were dried over Na2SO4 and concentrated. The crude oil was purified by silica gel chromatography (2% to 5% to 10% MeOH/CH2Cl2) to provide (3S,5S)-1-(tert-butoxycarbonyl)-5-(methoxycarbonyl)pyrrolidine-3-carboxylic acid (6.38 g, 70%).
Reaction SMILES: [NH2:1][C:2]1[C:7](Br)=[N:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1.[CH2:11]([OH:14])[C:12]#[CH:13].C(N(CC)CC)C.O>O1CCOCC1.[Cu]I>[NH2:1][C:2]1[C:7]([C:13]#[C:12][CH2:11][OH:14])=[N:6][C:5]([S:9][CH3:10])=[CH:4][N:3]=1
Reactant: CSc1cnc(N)c(Br)n1
Reactant: C#CCO
Agent: [Cu]I
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O
Product: CSc1cnc(N)c(C#CCO)n1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88.9 %

Procedure:
To a solution of the compound obtained in Example 34 (2) (440 mg) in dioxane (10 ml), 2-propyn-1-ol (168 mg), bistriphenylphosphine palladium dichloride (72 mg), copper(I) iodide (38 mg) and triethylamine (304 mg) were added successively and the mixture was stirred in a sealed tube at 70° C. for 2 hours. After cooling, the reaction solution was poured into water, and the mixture was extracted with chloroform, dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting residue was separated using silica gel column chromatography (chloroform:methanol=10:1) to obtain 347 mg (88.9%) of the desired product as a brown oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C.CC#N>[N:5]1[CH:6]=[CH:7][C:2]([CH:10]=[CH:9][C:8]([O:12][CH3:13])=[O:11])=[CH:3][CH:4]=1
Reactant: Brc1ccncc1
Reactant: C=CC(=O)OC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COC(=O)C=Cc1ccncc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 93152.5 %

Procedure:
A mixture of 4-bromopyridine (40.6 g, 0.25 mmol), palladium acetate (1.16 g, 5.14 mmol), tri-(O-tolyl)phosphine (3.14 g, 10.3 mmol), CH3CN (129 mL), triethylamine (64.3 mL, 0.46 mmol) and methyl acrylate (46.8 mL, 0,514 mmol) was sealed in a bomb and placed in an oil bath at 120° C. for 4 hours. The mixture was cooled to 0° C., the bomb was vented, and the slurry thus obtained was partitioned between CH2Cl2 /water. The aqueous phase was separated, extracted with CH2Cl2 (2×200 mL) and the combined organic layers were dried over MgSO4. The solvent was removed in vacuo to afford 38 g of methyl 3-(4-pyridyl)propenoate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][OH:11])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>ClCCl.CCOCC.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[O:11])=[C:7]([CH3:12])[C:6]=2[C:13]=1[O:14][CH3:15]
Reactant: COc1c(Br)ccc2oc(CO)c(C)c12
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: CCOCC
Solvent: O
Product: COc1c(Br)ccc2oc(C=O)c(C)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.4 %

Procedure:
To a solution of 0.21 g (0.77 mmole) of 5-bromo-4-methoxy-3-methyl-1-benzofuran-2-yl) methanol (Example 136, Step 1) in 6 mL of dichloromethane, 0.36 g (0.85 mmole, 1.1 eq) of Dess Martin periodinane was added. The reaction was stirred at room temperature for 2 hours and then diluted with 15 mL of ether. To the reaction was added 5 mL of 1NaOH and the mixture was stirred for 30 minutes. The reaction was diluted with ether and water. The organic layer was washed with water and brine, dried over sodium sulfate, filtered and concentrated to provide 0.19 g of 5-bromo-4-methoxy-3-methyl-1-benzofuran-2-carbaldehyde. Yield 90.4%; m.p. 81-82° C.; MS: 268.9 (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[I:9]I.CO.S([O-])([O-])=O.[Na+].[Na+]>O>[F:1][C:2]1[N:7]=[C:6]([I:9])[C:5]([OH:8])=[CH:4][CH:3]=1
Reactant: II
Reactant: Oc1ccc(F)nc1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Oc1ccc(F)nc1I
Temperature: 25 °C
Reaction time: 120 h
Yield: 19 %

Procedure:
6-Fluoro-3-hydroxypyridine (870 mg) and iodine (9.76 g) were dissolved in a mixed solvent composed of methanol (20 ml) and water (10 ml) to prepare a solution which was then stirred at room temperature for 120 hr. Thereafter, sodium sulfite was added until the solution became transparent. Methanol in the reaction solution was removed under the reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The chloroform layer was washed with water and saturated brine and was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by column chromatography using acetone-chloroform to give 6-fluoro-2-iodo-pyridin-3-ol (350 mg, yield 19%).
Reaction SMILES: [F:1][C:2]([C:5]1[O:9][C:8]([CH2:10][N:11]2[CH:15]=[CH:14][C:13]([NH2:16])=[N:12]2)=[CH:7][CH:6]=1)([F:4])[CH3:3].[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:25]/[C:26](O)=[O:27])[CH:21]=[CH:22][CH:23]=1>>[Cl:17][C:18]1[CH:19]=[C:20](/[CH:24]=[CH:25]/[C:26]([NH:16][C:13]2[CH:14]=[CH:15][N:11]([CH2:10][C:8]3[O:9][C:5]([C:2]([F:1])([F:4])[CH3:3])=[CH:6][CH:7]=3)[N:12]=2)=[O:27])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(F)(F)c1ccc(Cn2ccc(N)n2)o1
Reactant: O=C(O)/C=C/c1cccc(Cl)c1
Product: CC(F)(F)c1ccc(Cn2ccc(NC(=O)/C=C/c3cccc(Cl)c3)n2)o1

Procedure:
Following general procedure B, starting from 1-[5-(1,1-difluoro-ethyl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(3-chloro-phenyl)-acrylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=392.14.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:41]=[CH:40][C:32]([C:33]([O:35]C(C)(C)C)=[O:34])=[CH:31][CH:30]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl.FC(F)(F)C(O)=O>[CH2:1]([C:5]1[N:6]([CH2:28][C:29]2[CH:41]=[CH:40][C:32]([C:33]([OH:35])=[O:34])=[CH:31][CH:30]=2)[C:7](/[CH:10]=[C:11]2\[N:12]([CH2:22][C:23]3[S:24][CH:25]=[CH:26][CH:27]=3)[C:13](=[O:21])[N:14]([CH2:17][CH2:18][CH2:19][CH3:20])[C:15]\2=[O:16])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2cccs2)n1Cc1ccc(C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCc1ncc(/C=C2/C(=O)N(CCCC)C(=O)N2Cc2cccs2)n1Cc1ccc(C(=O)O)cc1
Reaction time: 6 h

Procedure:
1,1-dimethylethyl Z-4-[[2-butyl-5-[[1-butyl-2,5-dioxo-3-(2-thienylmethyl)-4-imidazolidinylidene]methyl]-1H-imidazol-1-yl]methyl]-benzoate (1.28 g, 2.26 mmol) was disolved in methylene chloride (25 mL) and trifluoroacetic acid (3.3 mL). After stirring for 16 hours an additional amount of trifluoroacetic acid (3 mL) was added. Stirred for a further 6 hours and then the reaction mixture was evaporated in vacuo. pH 7 buffer was added and the mixture extracted with ethyl acetate. This extract was drived over MgSO4 and then evaporated in vacuo and crystallized from ethyl acetate/ether.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(OC1C=CC=C(NCCCC)C=1NCCCC)CCC>C(OC(=O)C)(=O)C>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: CCCCNc1cccc(OCCCC)c1NCCCC
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2ccccc21
Reaction time: 1 h
Yield: 416.6 %

Procedure:
A mixture of 7.7 g of 3-(2'-carboxybenzoyl)-1-ethyl-2-methylindole and 7.9 g of bis(n-butylamino)phenol n-butyl ether in 30 g of acetic anhydride is stirred for 1 hour at 80°-85° C. Working up as described in Example 1 gives 14 g of a phthalide of formula ##STR11##
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6](Cl)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15].CC1(C)C(C)(C)OB([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)O1.[F-].[K+].CC#N>C(Cl)Cl.O.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>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:24]2[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=2)[N:5]=[C:4]([C:10]([O:12][CH3:13])=[O:11])[C:3]=1[O:14][CH3:15]
Reactant: COC(=O)c1nc(Cl)c(F)c(N)c1OC
Reactant: CC1(C)OB(c2ccc(C=O)cc2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [F-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O
Product: COC(=O)c1nc(-c2ccc(C=O)cc2)c(F)c(N)c1OC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a 5-mL microwave safe vial was added methyl 4-amino-6-chloro-5-fluoro-3-methoxypicolinate (0.400 g, 1.705 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (0.435 g, 1.875 mmol), KF (0.297 g, 5.11 mmol), and PdCl2(PPh3)2 (0.120 g, 0.170 mmol). A mixture of H2O (1 mL) and CH3CN (2 mL) was added, and the reaction vial was capped and placed in a Biotage Initiator microwave reactor for 20 min at 115° C. with external IR-sensor temperature monitoring from the side of the vessel. Upon cooling to room temperature, the reaction mixture was diluted with CH2Cl2 (25 mL) and H2O (25 mL), and the organic layer was filtered through a cotton plug. An additional extraction using EtOAc (25 mL) was combined with the CH2Cl2 and dried over Na2SO4 (50 g). Following filtration of the combined organics through a cotton plug and concentration on a rotary evaporator, the residue was purified using a Teledyne ISCO purification system with a gradient eluent system of CH2Cl2 and EtOAc to yield the title compound as a tan solid (335 mg, 65%): 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 8.09 (dd, J=8.3, 1.5 Hz, 2H), 8.03-7.93 (m, 2H), 4.62 (s, 2H), 4.00 (s, 3H), 3.98 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −139.69; ESIMS m/z 305 ([M+H]+), 303 ([M−H]−).
Reaction SMILES: [CH3:1][CH2:2][N:3]([C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10](C)[CH:9]=1)=O)[CH2:4][CH3:5].C(#[N:22])C1C=CC=CC=1.[NH3:23]>[Zn]>[NH2:23][CH:2]([N:3]1[CH2:4][CH2:5][N:22]=[C:6]1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:1]
Reactant: CCN(CC)C(=O)c1cccc(C)c1
Reactant: N#Cc1ccccc1
Reactant: N
Agent: [Zn]
Product: CC(N)N1CCN=C1c1ccccc1
Temperature: 150 °C
Reaction time: 2.5 h

Procedure:
DETA (0.1 mole; 10.3 g), 0.1 mole (10.3 g) of benzonitrile and 0.2 g (2% by weight based on DETA) of sulfur were heated as in Example 2. In 2.5 hours, evolution of ammonia gas ceased, and the inside temperature finally reached 180° C. Then, 0.8 g (2 moles per mole of sulfur) of zinc dust was added to the reaction mixture, and the mixture was heated at an inside temperature of 150° C. for 2 hours. After the reaction mixture was allowed to cool, it was extracted with methanol. The extract was distilled under reduced pressure to give 0.078 mole (14.7 g; yield 78 mole %) of a crude 1-aminoethyl-2-phenylimidazoline fraction having a bp20 of 200°-204° C.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:66](=[O:67])[N:6]2[C:7]([C:53]([O:55]CC3C=CC([N+]([O-])=O)=CC=3)=[O:54])=[C:8]([S:11][C@@H:12]3[CH2:16][N:15](C(OCC4C=CC([N+]([O-])=O)=CC=4)=O)[C@H:14]([C:30]([N:32]4[CH2:35][CH:34]([N:36](C(OCC5C=CC([N+]([O-])=O)=CC=5)=O)[C:37](=[NH:39])[CH3:38])[CH2:33]4)=[O:31])[CH2:13]3)[C@H:9]([CH3:10])[C@H:5]12)[CH3:3].[H][H]>O1CCCC1.O.[Pd]>[C:37]([NH:36][CH:34]1[CH2:33][N:32]([C:30]([C@@H:14]2[CH2:13][C@H:12]([S:11][C:8]3[C@H:9]([CH3:10])[C@@H:5]4[C@@H:4]([C@H:2]([OH:1])[CH3:3])[C:66](=[O:67])[N:6]4[C:7]=3[C:53]([OH:55])=[O:54])[CH2:16][NH:15]2)=[O:31])[CH2:35]1)(=[NH:39])[CH3:38]
Reactant: CC(=N)N(C(=O)OCc1ccc([N+](=O)[O-])cc1)C1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)OCc4ccc([N+](=O)[O-])cc4)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: C1CCOC1
Product: CC(=N)NC1CN(C(=O)[C@@H]2C[C@H](SC3=C(C(=O)O)N4C(=O)[C@H]([C@@H](C)O)[C@H]4[C@H]3C)CN2)C1
Yield: 35.3 %

Procedure:
0.77 g of 4-nitrobenzyl (1R,5S,6S)-6-[(1R)-1-hydroxyethyl]-1-methyl-2-[(2S,4S)-2-{3-[N(4-nitrobenzyloxycarbonyl)-N-acetimidoylamino]azetidin-1-ylcarbonyl}-1-(4-nitrobenzyloxycarbonyl)pyrrolidin-4-ylthio]-1-carbapen-2-em-3-carboxylate [prepared as described in step (1) above] was dissolved in 15 ml of a 2:1 by volume mixture of tetrahydrofuran and water. 0.77 g of a 10% w/w palladium-on-carbon catalyst was then added to the resulting solution, after which the mixture was hydrogenated at room temperature for 2 hours in a hydrogen atmosphere. At the end of this time, the catalyst was removed by filtration, and the filtrate was washed with diethyl ether. The aqueous layer was then concentrated by evaporation under reduced pressure, and the resulting residue was subjected to reverse phase column chromatography (Cosmosil 75C18 -prep, manufactured by Nacalai Tesque, 100 ml). The fraction containing the title compound and obtained by elution with 4% by volume aqueous acetonitrile was concentrated by evaporation under reduced pressure and freeze-dried, to give 0.13 g of the title compound as a powder.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[S:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:29]=[CH:28][C:13]2[N:14]([C@@H:18]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:19][CH2:20][F:21])[C:15](=[O:17])[O:16][C:12]=2[CH:11]=1)(=[O:9])=[O:8].FC(F)(F)C(O)=O>ClCCl>[F:21][CH2:20][CH2:19][C@@H:18]([N:14]1[C:13]2[CH:28]=[CH:29][C:10]([S:7]([NH:6][C:30]3[S:34][N:33]=[CH:32][N:31]=3)(=[O:8])=[O:9])=[CH:11][C:12]=2[O:16][C:15]1=[O:17])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2ccc3c(c2)oc(=O)n3[C@H](CCF)c2ccccc2)c(OC)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1oc2cc(S(=O)(=O)Nc3ncns3)ccc2n1[C@H](CCF)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of the compound of Formula 37-3 was prepared by dissolving the compound of Formula 37-2 (crude from previous step) in dichloromethane (1 mL), and treating the resulting solution with trifluoroacetic acid (0.2 mL). After stirring for 30 minutes at RT, the solution was concentrated and purified by reverse phase HPLC (20-100% MeCN in water with 0.1% TFA, C18 column) to yield the compound of Formula 37-3 as the a white solid. 1H NMR δ (ppm)(Methanol-d): 8.20 (s, 1H); 7.74 (m, 1H); 7.51 (m, 2H); 7.42-7.42 (m, 3H); 7.12 (m, 1H); 5.60 (m, 1H); 4.65-4.37 (m, 2H); 3.01-2.65 (m, 2H). HRMS C18H15F2N404S2 [M+H] calc 453.0425, obs 453.0497.