Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH:8]1([C:11](Cl)=[O:12])[CH2:10][CH2:9]1>N1C=CC=CC=1.ClCCl>[N:3]1[CH:4]=[CH:5][N:6]=[CH:7][C:2]=1[NH:1][C:11]([CH:8]1[CH2:10][CH2:9]1)=[O:12]
Reactant: Nc1cnccn1
Reactant: O=C(Cl)C1CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1cnccn1)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 10 g (105 mmol) of 2-aminopyrazine in 100 mL of pyridine was added dropwise a solution of 10.99 g (9.56 mL, 105 mmol) of cyclopropanecarbonyl chloride in 100 mL of dichloromethane. The resultant yellow solution was stirred at ambient temperature for 2 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and a small amount of water and washed sequentially with 1 M aqueous cuprous sulfate solution and water. The water layer was extracted with three portions of ethyl acetate. The combined organic phases were washed with brine, dried over magnesium sulfate, and concentrated. Purification by flash chromatography (silica gel, eluting sequentially with 50%, 80% and 100% ethyl acetate/hexane) gave the title compound.
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:25][S:24][C@@H:9]2[C@H:10]([NH:13][C:14]([CH2:16][S:17][C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:15])[C:11](=[O:12])[N:8]2[C:7]=1[C:26]([OH:28])=[O:27])=O.[CH3:29][N:30]1[C:34]([SH:35])=[N:33][N:32]=[N:31]1>>[CH3:29][N:30]1[C:34]([S:35][CH2:5][C:6]2[CH2:25][S:24][C@@H:9]3[CH:10]([NH:13][C:14](=[O:15])[CH2:16][S:17][C:18]4[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=4)[C:11](=[O:12])[N:8]3[C:7]=2[C:26]([OH:28])=[O:27])=[N:33][N:32]=[N:31]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)CSc3ccncc3)[C@H]2SC1
Reactant: Cn1nnnc1S
Product: Cn1nnnc1SCC1=C(C(=O)O)N2C(=O)C(NC(=O)CSc3ccncc3)[C@H]2SC1

Procedure:
7-(2-(4-pyridylthio)acetamido)cephalosporanic acid is reacted with 1-methyl-1H-tetrazole-5-thiol, yielding 3-(((1-methyl-1H-tetrazol-5-yl)thio)methyl)-7-(2-(4-pyridylthio)acetamido)-3-cephem-4-carboxylic acid.
Reaction SMILES: [CH3:1][C:2]([Si:5](Cl)([CH3:7])[CH3:6])([CH3:4])[CH3:3].N1C=CN=C1.[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]([CH2:24][C:25]([C:40]3[S:44][C:43]([CH2:45][O:46][CH2:47][CH2:48][OH:49])=[N:42][CH:41]=3)=[C:26]2[C:37]([OH:39])=[O:38])[CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.CO>[C:14]([O:18][C:19]([N:21]1[CH2:28][CH:27]2[N:29]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH:23]([CH2:24][C:25]([C:40]3[S:44][C:43]([CH2:45][O:46][CH2:47][CH2:48][O:49][Si:5]([C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:7])[CH3:6])=[N:42][CH:41]=3)=[C:26]2[C:37]([OH:39])=[O:38])[CH2:22]1)=[O:20])([CH3:15])([CH3:16])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC2CC(c3cnc(COCCO[Si](C)(C)C(C)(C)C)s3)=C(C(=O)O)C(C1)N2C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 108.9 %

Procedure:
TBDMS-Cl (184 mg, 1.22 mmol), and imidazole (131 mg, 1.95 mmol) were added to a stirred solution of the compound D7 (256 mg, 0.488 mmol) in THF (2.5 mL). The reaction mixture was stirred at rt for 15 h. The crude mixture was partitioned between Et2O and aq. sat. NH4Cl. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. The crude oil was dissolved in THF (4.5 mL), MeOH (0.7 mL), and water (0.7 mL), and K2CO3 (34 mg, 0.024 mmol) was added. The mixture was stirred at rt for 3 h. The mixture was partitioned between Et2O and aq. sat. NH4Cl, and the aq. layer was extracted once more with Et2O. The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed in vacuo to yield the title compound (0.34 g, quantitative yield) as a yellow oil that was not further purified. LC-MS: tR=1.10 min, ES+: 640.50.
Reaction SMILES: C(OC([N:8]1[CH:13]([C:14]2[NH:15][C:16]([C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[C:24]([C:29]5[CH:34]=[CH:33][C:32]([C:35]6[NH:36][C:37]([CH:40]7[CH2:46][C:43]8([CH2:45][CH2:44]8)[CH2:42][N:41]7[C:47](=[O:57])[CH:48]([NH:52][C:53]([O:55][CH3:56])=[O:54])[CH:49]([CH3:51])[CH3:50])=[N:38][CH:39]=6)=[CH:31][CH:30]=5)[CH:25]=4)[CH:20]=3)=[CH:17][N:18]=2)[CH:12]2[CH2:58][CH:9]1[CH2:10][CH2:11]2)=O)(C)(C)C.Cl.[CH:60]1([CH:63]([NH:67][C:68]([O:70][CH3:71])=[O:69])[C:64]([OH:66])=O)[CH2:62][CH2:61]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CO.C(Cl)Cl>[CH3:56][O:55][C:53](=[O:54])[NH:52][CH:48]([C:47]([N:41]1[CH:40]([C:37]2[NH:36][C:35]([C:32]3[CH:33]=[CH:34][C:29]([C:24]4[CH:23]=[CH:22][C:21]5[C:26](=[CH:27][CH:28]=[C:19]([C:16]6[NH:15][C:14]([CH:13]7[CH:12]8[CH2:58][CH:9]([CH2:10][CH2:11]8)[N:8]7[C:64](=[O:66])[CH:63]([CH:60]7[CH2:61][CH2:62]7)[NH:67][C:68]([O:70][CH3:71])=[O:69])=[N:18][CH:17]=6)[CH:20]=5)[CH:25]=4)=[CH:30][CH:31]=3)=[CH:39][N:38]=2)[CH2:46][C:43]2([CH2:45][CH2:44]2)[CH2:42]1)=[O:57])[CH:49]([CH3:51])[CH3:50]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)OC(C)(C)C)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)O)C1CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CO
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6C7CCC(C7)N6C(=O)C(NC(=O)OC)C6CC6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a slurry of 3-{5-[6-(4-{2-[5-(2-Methoxycarbonylamino-3-methyl-butyryl)-5-aza-spiro[2.4]hept-6-yl]-3H-imidazol-4-yl}-phenyl)-naphthalen-2-yl]-1H-imidazol-2-yl}-2-aza-bicyclo [2.2.1]heptane-2-carboxylic acid tert-butyl ester (0.05 g, 0.06 mmol) in MeOH (0.1 mL) was added HCl in dioxanes (4 M, 0.6 mL). The resulting solution was stirred at room temperature for 1 hour and the concentrated to dryness. Cyclopropyl-methoxycarbonylamino-acetic acid (0.02 g, 0.09 mmol, 1.5 equiv.) and CH2Cl2 (0.6 mL) were then added, followed by HATU (0.03 g, 0.08 mmol, 1.25 equiv.) and NMM (0.05 mL, 0.45 mmol, 5 equiv.). The resulting solution was stirred at room temperature for 18 hours. The reaction mixture was concentrated and purified by preparative HPLC (Gemini, 15→40% MeCN in H2O (0.1% formic acid)) and lyophilized to provide [1-(6-{5-[4-(6-{2-[2-(2-Cyclopropyl-2-methoxycarbonylamino-acetyl)-2-aza-bicyclo[2.2.1]hept-3-yl]-3H-imidazol-4-yl}-naphthalen-2-yl)-phenyl]-1H-imidazol-2-yl}-5-aza-spiro[2.4]heptane-5-carbonyl)-2-methyl-propyl]-carbamic acid methyl ester (0.03 g, 49%) as a white powder. LCMS-ESI+: calc'd for C48H54N8O6: 838.4 (M+). Found: 839.9 (M+H+). 1H-NMR: 400 MHz, (CDCl3) δ: (mixture of rotomers) 8.22 (s, 2H), 7.81-7.96 (m, 10H), 7.63 (d, 1H), 7.29 (d, 1H), 5.18 (t, 1H), 4.56 (d, 1H), 3.96 (t, 1H), 3.74 (m, 1H), 3.51 (s, 6H), 3.12 (t, 1H), 2.48 (s, 1H), 1.93-2.29 (m, 6H), 1.58-1.77 (m, 5H), 0.85 (d, 3H), 0.80 (d, 3H), 0.58 (m, 4H), 0.34 (m, 1H), 0.26 (m, 1H), 0.03 (m, 1H), −0.12 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=O)[C:10]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=O)=[CH:5][CH:4]=1.[NH2:21][C:22]1[CH:23]=[C:24]([S:29]([OH:32])(=[O:31])=[O:30])[CH:25]=[CH:26][C:27]=1[NH2:28]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[N:21][C:22]3[C:27](=[CH:26][CH:25]=[C:24]([S:29]([OH:32])(=[O:30])=[O:31])[CH:23]=3)[N:28]=2)=[CH:5][CH:4]=1
Reactant: Nc1ccc(S(=O)(=O)O)cc1N
Reactant: COc1ccc(C(=O)C(=O)c2ccc(OC)cc2)cc1
Solvent: CCO
Solvent: O
Product: COc1ccc(-c2nc3ccc(S(=O)(=O)O)cc3nc2-c2ccc(OC)cc2)cc1
Yield: 80 %

Procedure:
A solution of 1,2-bis(4-methoxyphenyl)ethane-1,2-dione (400 mg, 1.48 mmol, 1.00 equiv) and 3,4-diaminobenzenesulfonic acid (278 mg, 1.48 mmol, 1.00 equiv) in ethanol/water (10/10 mL) was stirred overnight at reflux in an oil bath. The resulting mixture was concentrated under vacuum, yielding 500 mg (80%) of 2,3-bis(4-methoxyphenyl)quinoxaline-6-sulfonic acid as a brown solid.
Reaction SMILES: [C:1]12(O)[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[C:2]2O.C(=O)=O.[C:13]([O:16]C(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([OH:16])(=[O:15])[CH3:14].[C:13]([OH:16])(=[O:15])[CH3:14].[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]=[CH:2]2
Reactant: OC1=CC2CCC1(O)C2
Reactant: CC(=O)OC(C)=O
Agent: O=C=O
Solvent: c1ccncc1
Product: C1=CC2CCC1C2
Product: CC(=O)O
Temperature: 0 °C
Reaction time: 16 h

Procedure:
A solution of 11 grams of norbornene diol prepared as in Example 2 in 100 ml pyridine was cooled by dry ice. 45 ml of acetic anhydride was added to the cooled solution. The solution was held in the dry ice bath for about 30 minutes then allowed to sit at room temperature for about 16 hours, poured into an ice water slurry, extracted with chloroform and washed sequentially with 10% HCl, a saturated sodium bicarbonate solution, a sodium chloride solution, twice with water, then dried over sodium sulfate, and crystallized from a mixture of toluene and hexane to produce about 10 grams of norbornene diacetate.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](Cl)=[N:7][C:8]([Cl:12])=[N:9][C:10]=1[CH3:11])=[O:4].C[O-].[Na+].C[C:18](O)=[O:19]>CO>[CH3:1][O:2][C:3]([C:5]1[C:6]([O:19][CH3:18])=[N:7][C:8]([Cl:12])=[N:9][C:10]=1[CH3:11])=[O:4]
Reactant: COC(=O)c1c(C)nc(Cl)nc1Cl
Reactant: CC(=O)O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1c(C)nc(Cl)nc1OC

Procedure:
To a solution of 2,4-dichloro-6-methyl-pyrimidine-5-carboxylic acid methyl ester (15.3 g, 69.6 mmol) in methanol (150 mL) at 0° C. under nitrogen with magnetic stirring is added 0.5 M NaOMe in MeOH (139 mL, 69.6 mmol) in dropwise fashion over 1 h. HOAc (2 mL) is added and the reaction mixture is evaporated at reduced pressure. The resulting residue is treated with sat. NaHCO3 (100 mL) and extracted with EtOAc (120 mL×3). The combined organic layers are washed with water (75 mL) and brine (75 mL), dried over magnesium sulfate, filtered and evaporated at reduced pressure to obtain a cream-colored solid. Purification by chromatography on silica gel (1:3 ether/hexanes) affords the title compound a s a white solid (less polar of two isomeric addition products formed) and 4-chloro-2-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester. 2-Chloro-4-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3) δ=4.03 (s, 3H), 3.92 (s, 3H), 2.48 (s, 3H). 4-Chloro-2-methoxy-6-methyl-pyrimidine-5-carboxylic acid methyl ester 1H NMR (CDCl3) δ=4.03 (s, 3H), 3.95 (s, 3H), 2.50 (s, 3H).
Reaction SMILES: S(=O)(=O)(O)O.[C:6]([OH:25])(=[O:24])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[S:13][S:14][C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=O.[C:26]([O-])(O)=O.[Na+].[CH3:31][OH:32]>>[CH3:31][O:32][C:17]([C:16]1[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=1[S:14][S:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[C:6]([O:25][CH3:26])=[O:24])=[O:19]
Reactant: CO
Reactant: O=C(O)c1ccccc1SSc1ccccc1C(=O)O
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1ccccc1SSc1ccccc1C(=O)OC
Temperature: 25 °C
Yield: 82 %

Procedure:
6 mL Sulphuric acid is added to ‘2,2’-dithiodibenzoic acid (20 g, 65.3 mmol) in 150 mL methanol. The reaction mixture is refluxed 3 days. The reaction mixture is cooled to room temperature and saturated aqueous NaHCO3 is added. Methanol is removed in vacuo. The resulting heterogeneous mixture is extracted with ethyl acetate. The organic phase is washed with brine, dried with MgSO4 and concentrated in vacuo to give 17.8 g (82%) of the title compound as a solid, which is used without further purification.
Reaction SMILES: C(Cl)CCl.C1C=NC2N(O)N=NC=2C=1.[NH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][C:21]=1[C@H:22]1[CH2:27][C@@H:26]([NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])[C@@H:25]([C:36]#[N:37])[C@@H:24]([CH3:38])[CH2:23]1.[F:39][C:40]1[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:41]=1[C:47]1[N:52]=[C:51]([C:53]([OH:55])=[O:54])[CH:50]=[CH:49][C:48]=1[F:56]>CN(C=O)C.O>[C:36]([C@H:25]1[C@@H:24]([CH3:38])[CH2:23][C@@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:53](=[O:54])[C:51]2[CH:50]=[CH:49][C:48]([F:56])=[C:47]([C:41]3[C:40]([F:39])=[CH:45][CH:44]=[CH:43][C:42]=3[F:46])[N:52]=2)[CH2:27][C@H:26]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:32])([CH3:33])[CH3:34])#[N:37].[C:36]([C@@H:25]1[C@H:24]([CH3:38])[CH2:23][C@H:22]([C:21]2[CH:20]=[CH:19][N:18]=[CH:17][C:16]=2[NH:15][C:53](=[O:55])[C:51]2[CH:50]=[CH:49][C:48]([F:56])=[C:47]([C:41]3[C:42]([F:46])=[CH:43][CH:44]=[CH:45][C:40]=3[F:39])[N:52]=2)[CH2:27][C@@H:26]1[NH:28][C:29](=[O:35])[O:30][C:31]([CH3:34])([CH3:33])[CH3:32])#[N:37]
Reactant: C[C@H]1C[C@@H](c2ccncc2N)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Reactant: O=C(O)c1ccc(F)c(-c2c(F)cccc2F)n1
Agent: On1nnc2cccnc21
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H]1C[C@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@H](NC(=O)OC(C)(C)C)[C@@H]1C#N
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1C#N
Temperature: 25 °C
Reaction time: 8 h
Yield: 27 %
Yield: 25 %

Procedure:
EDC (1.1 equiv.) and HOAt (1.1 equiv.) were added to a solution of (+/−)-tert-butyl (1R,2S,3S,5R)-5-(3-aminopyridin-4-yl)-2-cyano-3-methylcyclohexylcarbamate (1.0 equiv.) and 6-(2,6-difluorophenyl)-5-fluoropicolinic acid (1.5 equiv.) in DMF (0.11 M). The mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined extracts were washed sequentially with 1M aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered, concentrated and purified by ISCO SiO2 chromatography. Purification was completed via SFC (15% IPA, 100 mL/min, IA column) to yield tert-butyl (1R,2S,3S,5R)-2-cyano-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate (25% yield, 99% ee) and tert-butyl (1S,2R,3R,5S)-2-cyano-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate (27% yield, 99% ee). LC/MS (m/z)=566.2 (MH+), Rt=0.90 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:16](=[O:18])(=[O:17])[CH2:15][CH2:14][C:13]([C:19]([O:21]C)=[O:20])=[CH:12][C:11]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].Cl>C1COCC1.CO>[CH3:1][O:2][C:3]1[CH:27]=[CH:26][CH:25]=[CH:24][C:4]=1[CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[S:16](=[O:17])(=[O:18])[CH2:15][CH2:14][C:13]([C:19]([OH:21])=[O:20])=[CH:12][C:11]=2[CH:23]=1
Reactant: COC(=O)C1=Cc2cc(OCc3ccccc3OC)ccc2S(=O)(=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1COc1ccc2c(c1)C=C(C(=O)O)CCS2(=O)=O
Temperature: 60 °C
Reaction time: 20 h
Yield: 77.6 %

Procedure:
Into a solution of methyl 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (230 mg) in THF-methanol (5-2.5 ml) was added at room temperature an aqueous solution (1.0 ml) of potassium carbonate (164 mg), and the resulting mixture was stirred at 60° C. for 20 hours. After cooling to room temperature, the reaction mixture was mixed with 1 N hydrochloric acid (10 ml) and was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After concentration under reduced pressure, the precipitated crystals were collected by filtration. The crystals were washed with diisopropyl ether to obtain 7-[(2-methoxybenzyl)oxy]-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (172 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9](I)[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[CH3:13][N:14](C=O)C>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.[C-]#N.[Zn+2].[C-]#N>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:13]#[N:14])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Clc1ccnc2ccc(I)cc12
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2nccc(Cl)c2c1
Temperature: 50 °C
Reaction time: 17 h

Procedure:
A pyrex reaction tube was charged with Pd(PPh3)4 (200 mg, 173 μmol), 4-chloro-6-iodoquinoline (1.00 g, 3454 μmol), zinc cyanide (406 mg, 3454 μmol) and DMF. The tube was purged with argon, sealed, and the heterogeneous mixture was stirred at 50° C. for 17 h. The mixture was poured into water and the resulting solids were filtered, washed with water, and dried. The crude material was purified by silica gel chromatography, 0-5% MeOH/DCM to provide 4-chloroquinoline-6-carbonitrile as a white solid. MS: [M+H]=189.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([Cl:30])C(=O)C1>CN(C=O)C.CCOC(C)=O>[NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11](=[O:22])[NH:10][N:9]=2)=[CH:4][C:3]=1[Cl:30]
Reactant: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1ccc(C2=NNC(=O)Cc3cc4c(cc32)OCO4)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 47.4 %

Procedure:
To a solution of 1-(4-aminophenyl)-7,8-methylenedioxy-3,5-dihydro-2,3-benzodiazepin-4(4H)-one (118 mg, 0.400 mmol) in DMF (3 mL) was added NCS (51 mg, 0.38 mmol). The mixture was stirred at room temperature for 20 h, diluted with EtOAc (50 mL), washed with water and brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by chromatography (1:1 hexane/EtOAc) to afford the title compound as a tan solid (60 mg, 0.18 mmol, 45%), mp: 256°-258° C. 1H NMR (CDCl3) 8.50 (s, 1H), 7.54 (s, 1H), 7.32(d, J=8.3, 1H), 6.82 (s, 1H), 6.77 (d, J=8.3, 1H), 6.69 (s, 1H), 6.04 (s, 2H), 4.33 (s, 2H), 3.42 (s, 2H).
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][OH:17])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.[H+].[CH2:24](Cl)Cl>>[C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][O:17][CH3:24])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCCCCCCCCO
Agent: F[B-](F)(F)F
Agent: [H+]
Product: COCCCCCCCCNC(=O)OC(C)(C)C
Temperature: 0 °C

Procedure:
To a vigorously stirred mixture of BocNH(CH2)8OH (392 mg, 1.6 mmol) and fluoroboric acid (210 μL, 1.6 mmol) in DCM (8 mL), the TMS CHN2 (800 μL, 1.6 mmol) was added dropwise at 0° C. The solution was stirred at 0° C. and three further additions of TMS CHN2 (400 μL, 0.8 mmol and 200 μL×2, 0.4 mmol) were added at 15-minute intervals. The mixture was stirred for a further 4 hours after which starting material was still visible by t.l.c. but no further evolution of the reaction was however apparent.
Reaction SMILES: [C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13]O)=[CH:11][N:10]=[C:9]2[CH3:15])=[CH:5][CH:4]=1)#[N:2].S(Cl)([Cl:20])=O>>[ClH:20].[C:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][N:8]2[C:12]([CH2:13][Cl:20])=[CH:11][N:10]=[C:9]2[CH3:15])=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1ncc(CO)n1Cc1ccc(C#N)cc1
Reactant: O=S(Cl)Cl
Product: Cc1ncc(CCl)n1Cc1ccc(C#N)cc1
Product: Cl
Reaction time: 8 h

Procedure:
A mixture of 1-(4-cyanobenzyl)-5-hydroxymethyl-2-methylimidazole (3.45 g, 15.2 mmol) and thionyl chloride (30 mL, 411 mmol) was stirred at room temp. overnight under a calcium chloride drying tube. The resultant mixture was concentrated under vacuum, and residual thionyl chloride was removed by co-evaporation with toluene. The residue was triturated with anhydrous diethyl ether, filtered, washed with ether to provide the title compound as white solid.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:14]=[C:13](C)C=C[C:6]=1S([O-])(=O)=O)(=[O:3])[CH3:2].C(O)(=[O:18])C>>[OH:18][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH:14]=[CH2:13]
Reactant: CC(=O)Oc1cc(C)ccc1S(=O)(=O)[O-]
Reactant: CC(=O)O
Product: C=CC(CO)OC(C)=O

Procedure:
Alternatively, the acetoxy-tosylate could be prepared by initial reaction of EpB with acetic acid under palladium(0) catalysis to afford 1-hydroxy-2-acetoxy-3-butene. Tosylation under normal conditions (p-TsCl, Et3N, CH2Cl2, 88%) afforded the desired product. However, the isomeric inconsistency of the monoacetate material (acetyl migration during distillative purification) and the inseparability of the positional isomers of two intermediates posed significant problems, since the unwanted isomers complicated the enzymatic hydrolysis. Therefore, the former (diol) preparation is preferred.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].[CH3:18][C:19]1[C:24]([CH2:25]O)=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=[C:21]([C:31]2[CH:36]=[CH:35][C:34]([O:37][C:38]([F:41])([F:40])[F:39])=[CH:33][CH:32]=2)[N:20]=1.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>O1CCCC1>[CH2:1]([O:3][C:4](=[O:17])[C:5]([CH3:6])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:25][C:24]2[C:19]([CH3:18])=[N:20][C:21]([C:31]3[CH:32]=[CH:33][C:34]([O:37][C:38]([F:40])([F:39])[F:41])=[CH:35][CH:36]=3)=[CH:22][C:23]=2[C:27]([F:28])([F:30])[F:29])=[CH:11][C:10]=1[CH3:16])[CH3:7])[CH3:2]
Reactant: Cc1nc(-c2ccc(OC(F)(F)F)cc2)cc(C(F)(F)F)c1CO
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2c(C(F)(F)F)cc(-c3ccc(OC(F)(F)F)cc3)nc2C)cc1C
Temperature: 0 °C
Reaction time: 14 h
Yield: 75 %

Procedure:
To an ice cold solution of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (35 mg, 147 μmol; described in WO 02/092590), [2-methyl-6-(4-trifluoromethoxy-phenyl)-4-trifluoromethyl-pyridin-3-yl]-methanol (52 mg, 148 μmol, example 112E]) and tributylphosphine (50 μl, 178 μmol) in tetrahydrofuran (3.5 ml) was added N,N,N′,N′-tetramethyl azodicarboxamide (30 mg, 178 mmol). The cooling bath was removed and stirring continued for 14 h. The mixture was filtered over celite and the solvent removed under reduced pressure to give a yellow oil which was purified by column chromatography (silica gel, heptane/AcOEt) to give 63 mg (110 μmol, 75%) of the title compound as colorless oil.