Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:39]([CH3:40])=[CH:38][CH:37]=[CH:36][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH2:34][OH:35])[CH:27]=4)[CH:24]=3)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].[CH3:41][S:42](Cl)(=[O:44])=[O:43].C(N(CC)CC)C>C(Cl)Cl>[CH3:41][S:42]([O:35][CH2:34][CH2:33][O:32][C:28]1[CH:29]=[CH:30][CH:31]=[C:26]([CH2:25][N:23]2[CH:24]=[C:20]([C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:14]=3[CH2:13][CH2:12][CH2:11][N:10]4[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]3[CH:36]=[CH:37][CH:38]=[C:39]([CH3:40])[C:2]=3[CH3:1])[CH:21]=[N:22]2)[CH:27]=1)(=[O:44])=[O:43]
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCO)c5)c4)cccc32)c1C
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCOS(C)(=O)=O)c5)c4)cccc32)c1C
Temperature: 0 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a solution of 4-(2,3-dimethylphenoxy)-1-(5-(1-(3-(2-hydroxyethoxy)benzyl)-1H-pyrazol-4-yl)-3,4-dihydroquinolin-1(2H)-yl)butan-1-one (0.07 g, 0.13 mmol) in CH2Cl2 (2 mL) at 0° C. was added methanesulfonyl chloride (0.019 g, 0.17 mmol) and triethylamine (0.029 mL, 0.21 mmol) dropwise. The reaction mixture was stirred at 0° C. for 2 h and then quenched with saturated NaHCO3. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with 1 N HCl, saturated NaHCO3, and brine, dried and concentrated to afford the title compound (80 mg, 100%). LCMS, [M+H]+=618.4.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:19][CH2:18][CH:15]([CH2:16][CH2:17]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24](=O)[NH:25][CH:26]([C:35]#[N:36])[CH2:27][C:28]3[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=3)[N:23]=[C:12]21)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(Cl)(Cl)[Cl:49].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(#N)C>[CH2:1]([O:8][C:9](=[O:47])[NH:10][C:11]12[CH2:17][CH2:16][CH:15]([CH2:18][CH2:19]1)[CH2:14][N:13]1[C:20](=[O:46])[C:21]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[C:22]([C:24]3[NH:25][C:26]([CH2:27][C:28]4[CH:29]=[CH:30][C:31]([F:34])=[CH:32][CH:33]=4)=[C:35]([Cl:49])[N:36]=3)[N:23]=[C:12]21)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: N#CC(Cc1ccc(F)cc1)NC(=O)c1nc2n(c(=O)c1OCc1ccccc1)CC1CCC2(NC(=O)OCc2ccccc2)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: O=C(NC12CCC(CC1)Cn1c2nc(-c2nc(Cl)c(Cc3ccc(F)cc3)[nH]2)c(OCc2ccccc2)c1=O)OCc1ccccc1
Temperature: 45 °C
Reaction time: 16 h
Yield: 42 %

Procedure:
To a solution of benzyl(3-(benzyloxy)-2-((1-cyano-2-(4-fluorophenyl)ethyl)carbamoyl)-4-oxo-6,7,8,9-tetrahydro-7,10-ethanopyrimido[1,2-a]azepin-10(4H)-yl)carbamate, Intermediate 5 (140 mg, 0.220 mmol) in acetonitrile (4 mL) was added carbon tetrachloride (0.053 mL, 0.551 mmol), followed by triphenylphosphine (144 mg, 0.551 mmol) and the mixture was heated at 45° C. After stirring for 16 h, the mixture was cooled to room temp and concentrated in vacuo. The residue was then treated with dichloromethane (10 mL) and 0.5 N NaOH (20 mL). The mixture was then poured into water and extracted with dichloromethane (×4), dried (Na2SO4), filtered and concentrated. The crude product was then purified by silica gel chromatography (40-100% EtOAc/hexane) to afford the title compound (90 mg, 42% yield) as a yellow solid. 1H NMR (500 MHz, CDCl3) δ ppm 1.65-1.74 (m, 2H) 1.92-2.03 (m, 4H) 2.47 (br. s., 1H) 2.71-2.86 (m, 2H) 3.74 (s, 2H) 4.13 (d, J=3.66 Hz, 2H) 5.12 (s, 2H) 5.29 (s, 2H) 6.92 (d, J=7.63 Hz, 4H) 7.08 (br. s., 1H) 7.29-7.37 (m, 8H) 7.39-7.46 (m, 2H) 10.08 (br. s., 1H). (M+H)=654.28.
Reaction SMILES: B#B.[C:3]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([Br:29])=[CH:23][N:22]=1)(=[O:19])=[O:18])(=O)[CH3:4]>C1COCC1>[CH2:3]([NH:6][C:7]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[C:12]2[S:17]([NH:20][C:21]1[C:26]([O:27][CH3:28])=[N:25][C:24]([Br:29])=[CH:23][N:22]=1)(=[O:19])=[O:18])[CH3:4]
Reactant: COc1nc(Br)cnc1NS(=O)(=O)c1cccc2c(NC(C)=O)cccc12
Agent: B#B
Solvent: C1CCOC1
Product: CCNc1cccc2c(S(=O)(=O)Nc3ncc(Br)nc3OC)cccc12
Yield: 32.7 %

Procedure:
A 1.0M solution of diborane in THF (6.65 ml) was added to a solution of 5-acetamido-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.725 g) in dry THF (60 ml) at 0° C. under argon. The solution was heated under reflux for 24 hours and then volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with ethyl acetate/hexane (7:13 v/v), to give 5-ethylamino-N-(5-bromo-3-methoxy-2-pyrazinyl)-1-naphthalenesulphonamide (0.23 g), m.p. 216-218° C. (after trituration with ether); 1H NMR (d6 -DMSO): 1.3 (t,3H), 3.25 (q,2H), 3.9 (s,3H), 6.6 (d,1H), 7.4-7.6 (m,2H), 7.75 (s,1H), 7.95 (d,1H), 8.25 (d,1H), 8.5 (d,1H), 11.3-11.5 (br, 1H); mass spectrum (+ve FAB, methanol/NBA): 438 (M+H)+.
Reaction SMILES: C([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C@H:16]([NH:17][C:18](=[O:27])[C:19](=[N:25][OH:26])[C:20]3[S:21][CH:22]=[CH:23][CH:24]=3)[C:15](=[O:28])[N:10]2[C:11]=1[C:12]([O-:14])=[O:13])(=O)C.[Na+:29].[OH-].[Na+].CC(C)=O>O>[OH:26][N:25]=[C:19]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)[C:18]([NH:17][C@@H:16]1[C:15](=[O:28])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][OH:4])[CH2:7][S:8][C@H:9]12)=[O:27].[Na+:29]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)[C@@H](NC(=O)C(=NO)c3cccs3)[C@H]2SC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)C(=NO)c3cccs3)C(=O)N12
Reaction time: 4 h

Procedure:
A solution of sodium 3-acetoxymethyl-7β-[2-hydroxyimino-2-(thien-2-yl)acetamido]ceph-3-em-4-carboxylate (syn-isomer) (2.0 g) in water (160 ml) was warned to 37° and defatted wheat germ (15 g.) was added. The mixture was stirred at 37° for 4 hours, the pH being kept between 6.5 and 6.9 by the addition of 2N sodium hydroxide solution (total 2.3 ml). The mixture was poured into acetone (200 ml) and then filtered through kieselguhr. Acetone was removed under reduced pressure and the aqueous solution was again filtered through kieselguhr, washed with ethyl acetate, then covered with ethyl acetate and taken to ph 2.7 by the careful addition of concentrated hydrochloric acid. The layers were separated and the aqueous layer was re-extracted with ethyl acetate. The combined extracts were washed with water and the pH was taken to 7.0 by the addition of 2N-sodium hydroxide. The organic layer was further extracted with water and the combined aqueous solution was washed with ethyl acetate and ether, degassed and lyophilised to give the title oxime as a brown solid (1.43 g; 79%), [α]D + 76° (c 0.46, DMSO), λmax. (pH 6 phosphate) 261.5 nm (ε 10,600), λinflex. 284 nm (ε 6,500), νmax. (Nujol) 1760 (β-lactam), 1560 (CO-2), 1650 and 1520 cm-1 (COHN), τ (D2O) values include 2.41, 2.63 and 2.83 (doublet, doublet and triplet respectively, J 4 Hz; thienyl protons)
Reaction SMILES: C(O[K])(C)(C)C.[CH3:7][O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]([C:25]3[CH:30]=[CH:29][C:28]([O:31]C(=O)C(C)(C)C)=[CH:27][CH:26]=3)[CH:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:15]=[CH:16]2)=[CH:11][CH:10]=1.[Cl-].[NH4+]>CS(C)=O>[OH:31][C:28]1[CH:27]=[CH:26][C:25]([C:13]2[C:12]3[C:17](=[CH:18][C:9]([O:8][CH3:7])=[CH:10][CH:11]=3)[CH2:16][CH2:15][C:14]=2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:30][CH:29]=1
Reactant: COc1ccc2c(c1)C=CC(c1ccccc1)C2c1ccc(OC(=O)C(C)(C)C)cc1
Agent: CC(C)(C)O[K]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CS(C)=O
Product: COc1ccc2c(c1)CCC(c1ccccc1)=C2c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69 %

Procedure:
To a dimethyl sulfoxide (0.6 mL) solution of tertiary butoxy potassium (40.3 mg, 0.359 mmol), a dimethyl sulfoxide (0.8 mL) solution of 7-methoxy-3-phenyl-4-(4-pivaloyloxyphenyl)-3,4-dihydronaphthalene (6, 29.3 mg, 0.0710 mmol) was added, and stirred at room temperature for one day and night. After adding saturated ammonium chloride (10 mL) to the reaction mixture with much stirring, extraction was carried out three times with diethyl ether. The organic layers were combined, washed with a saturated sodium chloride solution (10 mL), and after drying with anhydrous sodium sulphate, concentrated. The residue was purified with thin layer chromatography (toluene:ethyl acetate=10:1), to obtain the subject compound (7, 16.0 mg; yield=69%).
Reaction SMILES: CS[CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]1=[O:19].S(Cl)([Cl:23])(=O)=O>ClCCl>[Cl:23][CH2:3][N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]=[C:6]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:5]1=[O:19]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)c1nc2ccccc2n(CSC)c1=O
Solvent: ClCCl
Product: CCOC(=O)c1nc2ccccc2n(CCl)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
2.1 g (7.5 mmol) of ethyl 1-(methylthiomethyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate was dissolved in dichloromethane (10 mL), and 1.3 g (9.8 mmol) of sulfuryl chloride was added dropwise at or below 10° C. The mixture was stirred for 2 hours at room temperature. After completion of the reaction, the solvent was distilled off under reduced pressure, to obtain ethyl 1-(chloromethyl)-2-oxo-1,2-dihydroquinoxaline-3-carboxylate. The chloromethylation product thus obtained was used in the subsequent reaction without purification.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([N:15]2[C:19]([NH:20][C:21](=[O:36])[C:22]3[CH:27]=[C:26]([C:28]4[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=4)[CH:25]=[CH:24][C:23]=3[Cl:35])=[CH:18][C:17]([C:37](OCC)=[O:38])=[N:16]2)[CH:12]=[CH:13][CH:14]=1)C1C=CC=CC=1.[NH3:42].B(Cl)(Cl)Cl>CO>[Cl:35][C:23]1[CH:24]=[CH:25][C:26]([C:28]2[C:33]([F:34])=[CH:32][CH:31]=[CH:30][N:29]=2)=[CH:27][C:22]=1[C:21]([NH:20][C:19]1[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([OH:8])[CH:10]=2)[N:16]=[C:17]([C:37]([NH2:42])=[O:38])[CH:18]=1)=[O:36]
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(OCc3ccccc3)c2)n1
Reactant: N
Agent: ClB(Cl)Cl
Solvent: CO
Product: NC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2cccc(O)c2)n1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 6 %

Procedure:
To a solution of ethyl 1-(3-(benzyloxy)phenyl)-5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1H-pyrazole-3-carboxylate (Example 128, 220 mg, 0.385 mmol) in methanol (3 mL) was added 880 ammonia (7 mL) and the reaction was heated at 60° C. for 18 hours in a Reactivial™. The reaction was cooled, concentrated in vacuo and dissolved in DCM (5 mL). The solution was cooled to 0° C. and boron trichloride (1M in DCM, 3.41 mL, 3.41 mmol) was added dropwise. The reaction was stirred at room temperature for 30 minutes before being quenched by the addition of methanol (20 mL) and stirred for 18 hours. The reaction was concentrated in vacuo azeotroping with MeOH. The residue was purified using preparative HPLC followed by trituration with TBME to afford the title compound (12 mg, 6%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)(=O)=O)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([NH:26][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[C:5]([C:12]#[N:13])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:3]=1
Reactant: CS(=O)(=O)c1nc(N)nc(-c2ccccc2)c1C#N
Reactant: NC1CCCCC1
Solvent: COCCOC
Product: N#Cc1c(NC2CCCCC2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-methanesulfonyl-6-phenyl-pyrimidine-5-carbonitrile and cyclohexylamine in DME. ES-MS m/e (%): 294 (M+H+, 100).
Reaction SMILES: [CH3:1][Ge:2]([CH3:17])([CH3:16])[C:3]1[CH:4]=[C:5]([C:13](=[O:15])[CH3:14])[CH:6]=[C:7]([Ge:9]([CH3:12])([CH3:11])[CH3:10])[CH:8]=1.[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][CH:21]=1)=O.[OH-].[K+].Cl>C(O)(C)C.O1CCCC1>[CH3:11][Ge:9]([CH3:10])([CH3:12])[C:7]1[CH:6]=[C:5]([C:13](=[O:15])[CH:14]=[CH:18][C:20]2[CH:29]=[CH:28][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=2)[CH:4]=[C:3]([Ge:2]([CH3:16])([CH3:1])[CH3:17])[CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cc([Ge](C)(C)C)cc([Ge](C)(C)C)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: C[Ge](C)(C)c1cc(C(=O)C=Cc2ccc(C(=O)O)cc2)cc([Ge](C)(C)C)c1
Yield: 53.7 %

Procedure:
3',5'-Bis(trimethylgermyl)acetophenone 163 mg (0.46 mmol) and 96 mg (0.58 mmol) of methyl 4-formylbenzoate was dissolved in 4 ml of a mixture of isopropanol and tetrahydrofuran (1:1). To the mixture was added 2.5 ml of 0.75N aqueous potassium hydroxide solution with stirring and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted to pH3.8 with 0.2N hydrochloric acid and extracted with AcOEt. The extract was evaporated. The residue was purified by column chromatography on silicagel [eluent: methylene chloride-MeOH (10:1)] and recrystallized from a mixture of methylene chloride, MeOH and n-hexane to give 120 mg of yellow prisms, m.p.194°-195.5° C. (dec.).
Reaction SMILES: [CH3:1][CH:2]([CH3:44])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34]OS(C)(=O)=O)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1.[NH:45]1[CH:49]=[CH:48][CH:47]=[N:46]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C(=O)C.O>[CH3:44][CH:2]([CH3:1])[CH2:3][N:4]([C:26]([C:28]1[N:32]([CH2:33][CH2:34][N:45]2[CH:49]=[CH:48][CH:47]=[N:46]2)[C:31]2[CH:40]=[CH:41][CH:42]=[CH:43][C:30]=2[N:29]=1)=[O:27])[C@H:5]1[CH2:10][C@@H:9]([C:11]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[O:12])[CH2:8][N:7]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:6]1
Reactant: CC(C)CN(C(=O)c1nc2ccccc2n1CCOS(C)(=O)=O)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Reactant: c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)CN(C(=O)c1nc2ccccc2n1CCn1cccn1)[C@H]1C[C@@H](C(=O)N2CCOCC2)CN(C(=O)OC(C)(C)C)C1
Temperature: 60 °C
Reaction time: 72 h
Yield: 59.3 %

Procedure:
To a solution of tert-butyl (3S,5R)-3-{(2-methylpropyl) [(1-{2-[(methylsulfonyl)oxy]ethyl}-1H-benzimidazol-2-yl)carbonyl]amino}-5-(morpholin-4-ylcarbonyl)piperidine-1-carboxylate (127 mg) and pyrazole (41 mg) in N,N-dimethylacetamide (3 ml) was added cesium carbonate (326 mg), and the mixture was stirred at 60° C. for 3 days. The to reaction mixture was diluted with water, and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate was concentrated under reduced pressure to give the object product (72 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:6]([OH:8])=[O:7].[Br:14]Br.O>Cl>[Br:14][C:9]1[CH:10]=[C:11]([O:12][CH3:13])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: BrBr
Reactant: COc1ccc(C(=O)O)cc1OC
Agent: Cl
Solvent: O
Product: COc1cc(Br)c(C(=O)O)cc1OC
Reaction time: 1 h
Yield: 96.2 %

Procedure:
3,4-Dimethoxybenzoic acid (25.0 g) was suspended in concentrated hydrochloric acid (35%) (500 mL), and bromine (23.0 g, 1.05 equivalents) was added dropwise to the resultant suspension at 25° C. Subsequently, the resultant mixture was stirred for seven hours. Water (500 mL) was added to the mixture, and the mixture was stirred for one hour. Thereafter, the precipitated crystals were filtrated, and then dried under reduced pressure, to thereby produce crude crystals of 2-bromo-4,5-dimethoxybenzoic acid (34.47 g) (yield: 96.2%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[H-].[Na+].[CH2:11](Cl)[O:12][CH3:13]>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:11][O:12][CH3:13])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.4 %

Procedure:
To a solution of 4-bromophenol (1.0 g, 5.8 mmol) in anhydrous THF (10 mL) was added NaH (60%, 254 mg, 6.4 mmol) at 0° C. After being stirred at the temperature for 0.5 h, MOM-Cl (698 mg, 8.7 mmol) was added to the mixture. The mixture was stirred at 0° C. for 0.5 h, warmed to room temperature for 2 h, quenched with water, and extracted with EtOAc. The organic layer was dried over Na2SO4, concentrated in vacuo, and purified by column chromatography (PE:EtOAc=50:1) to give 1-bromo-4-(methoxymethoxy)benzene (1 g, yield 80%).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([CH3:14])=[O:13].[OH-].[Na+].Cl>O>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:11]/[C:12](=[O:13])[CH3:14]
Reactant: O=Cc1ccc(F)cc1Br
Reactant: CC(C)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)/C=C/c1ccc(F)cc1Br
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a 500 mL recovery flask was added 2-bromo-4-fluorobenzaldehyde (1A, 10.0 g, 49.3 mmol, 1.0 eq.) and acetone (22.9 g, 394 mmol, 8.0 eq.). The mixture was cooled to 0° C. in an ice bath. H2O (200 mL) was added and the mixture became a thick suspension. Solid NaOH (2.16 g, 54.2 mmol, 1.1 eq.) was added and the reaction was gradually warmed to room temperature and stirred overnight. The reaction was acidified with 1N HCl and extracted with EtOAc (3×100 mL). The organic phases were combined and washed with saturated aqueous NaCl. The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated to give a dark yellow oil that was carried on to the next step without further purification (11.9 g, 99%). ESI-MS: m/z 243.2 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1I.[NH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]#[CH:18])=[CH:13][N:12]=1.C(N(CC)CC)C>CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH3:8])[C:3]=1[C:18]#[C:17][C:14]1[CH:15]=[CH:16][C:11]([NH2:10])=[N:12][CH:13]=1
Reactant: C#Cc1ccc(N)nc1
Reactant: Cc1nccc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nccc(Cl)c1C#Cc1ccc(N)nc1

Procedure:
The title compound is synthesized according to general procedure GP1 starting from 1.0 g (4.0 mmol) 4-chloro-3-iodo-2-methyl-pyridine and 513 mg (4.3 mmol) 2-amino-5-ethynyl-pyridine using 75 mg (0.40 mmol) CuI, 276 mg (0.40 mmol) PdCl2(PPh3)2 and 5.4 mL (39.5 mmol) triethylamine in 40 mL dry DMF. After completion of the reaction the solvent is removed under vacuum and the product is purified by chromatography on silica gel using a DCM/MeOH gradient (100:0 to 90:10). Yield: 617 mg (64%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[Br:13][CH2:14][CH2:15]Br>>[Br:13][CH2:14][CH2:15][O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2
Reactant: BrCCBr
Reactant: Cc1ccc2c(O)cccc2n1
Product: Cc1ccc2c(OCCBr)cccc2n1
Yield: 91 %

Procedure:
The title compound was prepared from 5-hydroxy-2-methylquinoline and 1,2-dibromoethane using a similar procedure to Description 16, in 91% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]3[CH:17]=[CH:16][S:15][CH:14]=3)[C:6]=2[CH:20]=1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:2]2[CH:3]=[CH:4][C:5]3[NH:11][C:10](=[O:12])[CH2:9][O:8][C:7]([CH2:18][CH3:19])([C:13]4[CH:17]=[CH:16][S:15][CH:14]=4)[C:6]=3[CH:20]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CCC1(c2ccsc2)OCC(=O)Nc2ccc(Br)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CCC1(c2ccsc2)OCC(=O)Nc2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
Prepared from 7-bromo-5-ethyl-5-thien-3-yl-1,5-dihydro-4,1-benzoxazepin-2(3H)-one and 3-chloro-4-fluorobenzeneboronic acid using the coupling procedure described in example 1. 1H-NMR (DMSO-d6) δ 10.03 (s, 1H), 7.84 (dd, J=6.9, 2.2 Hz, 1H), 7.62 (m, 2H), 7.56 (dd, J=5.2, 3.0 Hz, 1H), 7.48 (m, 2H), 7.27 (m, 1H), 7.24 (d, J=8.5 Hz, 1H), 7.16 (dd, J=5.2, 1.4 Hz, 1H), 4.04 (d, J=15.4 Hz, 1H), 3.94 (d, J=15.4 Hz, 1H), 2.53 (m, 1H), 2.35 (m, 1H), 0.75 (t, J=7.1 Hz, 3H); MS (ES) m/z 402 (M+H)+;
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]O.P(Br)(Br)[Br:12].O>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5][Br:12]
Reactant: OCc1ccc(F)c(Br)c1
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Product: Fc1ccc(CBr)cc1Br
Yield: 242.5 %

Procedure:
20.5 g (0.1 mol) of 3-bromo-4-fluoro-benzyl alcohol were dissolved in 100 ml of anhydrous toluene, and 10 g of phosphorus tribromide were added dropwise at 0° to 10° C., while stirring. The mixture was then stirred at room temperature for 2 hours. The reaction batch was subsequently poured into 500 ml of water, the organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. The residue was distilled in vacuo. 24 g (89.6% of theory) of 3-bromo-4-fluoro-benzyl bromide with a boiling point of 99°-100° C./3 mbars were obtained.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[NH:9][N:8]=2)=[CH:3][CH:2]=1.[H-].[Na+].[CH3:20][N:21]([CH3:25])[C:22](Cl)=[O:23]>O1CCCC1>[CH3:20][N:21]([CH3:25])[C:22]([N:8]1[C:7]([C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[N:11][C:10]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[N:9]1)=[O:23]
Reactant: CN(C)C(=O)Cl
Reactant: c1cc(-c2n[nH]c(-c3ccncc3)n2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(C)C(=O)n1nc(-c2ccncc2)nc1-c1ccncc1

Procedure:
To 2.13 g. (0.01 mole) of 3,5-di(4-pyridyl)-1,2,4-triazole in 200 ml. of tetrahydrofuran is added 57% sodium hydride in mineral oil (0.42 g., 0.01 moles). The reaction mixture is heated at reflux for 1 hour, cooled and a solution of dimethylcarbamoyl chloride (1g., 0.01 mole) in 10 ml. of tetrahydrofuran is added dropwise. The reaction mixture is heated at reflux for 4 hours, cooled, filtered and concentrated to an oil which solidifies. After recrystallization from benzene 1.2 g. of 1-dimethylcarbamoyl-3,5-di(4-pyridyl)-1,2,4-triazole melting at 140°-141.5°C. is obtained.
Reaction SMILES: Cl[CH2:2][C:3](=O)[C:4](=[N:36][O:37][CH2:38][C:39]([O:41][CH3:42])=[O:40])[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6].[NH2:44][C:45]([NH2:47])=[S:46].C([O-])(=O)C.[Na+]>O1CCCC1.O>[CH3:42][O:41][C:39]([CH2:38][O:37][N:36]=[C:4]([C:3]1[N:44]=[C:45]([NH2:47])[S:46][CH:2]=1)[C:5]([NH:7][CH:8]1[C:34](=[O:35])[N:10]2[C:11]([C:18]([O:20][CH:21]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:12](/[CH:15]=[CH:16]/[Cl:17])[CH2:13][S:14][C@H:9]12)=[O:6])=[O:40]
Reactant: COC(=O)CON=C(C(=O)CCl)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12
Reactant: NC(N)=S
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C/Cl)CS[C@H]12)c1csc(N)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of benzhydryl 7-(4-chloro-2-methoxycarbonylmethoxyimino-3-oxobutyramido)-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (1.65 g) in a mixture of tetrahydrofuran (10 ml) and water (10 ml) were added thiourea (0.39 g) and sodium acetate (1.05 g). The mixture was stirred at ambient temperature for 2 hours and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium chloride and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with diisopropyl ether and collected by filtration to give benzhydryl 7-[2-methoxycarbonylmethoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[(E)-2-chlorovinyl]-3-cephem-4-carboxylate (syn isomer) (1.45 g).