Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=1)=O.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:24][C:21]([O:20][C:18]([N:12]1[CH2:17][CH2:16][N:15]([CH2:1][C:3]2[CH:4]=[C:5]([B:9]([OH:11])[OH:10])[CH:6]=[CH:7][CH:8]=2)[CH2:14][CH2:13]1)=[O:19])([CH3:22])[CH3:23]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(B(O)O)c2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To the solution of (3-formylphenyl)boronic acid (3.0 g, 20.0 mmol) in DCM (100 mL) was added 1,1-dimethylethyl 1-piperazinecarboxylate (3.91 g, 21.0 mmol), and NaBH(OAc)3 (6.36 g, 30.0 mmol), and the mixture stirred at room temperature for 17 h. The organic layer was diluted with EtOAc (100 mL), washed with H2O (30 mL), dried over Na2SO4, filtered and concentrated to afford 7.72 g (quantitative) of the title compound. LC-MS m/z 321 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([F:10])[CH:3]=1.C([Li])CCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>>[F:10][C:4]1[CH:3]=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1F
Agent: [Li]CCCC
Product: COc1ccc(B(O)O)cc1F

Procedure:
The title compound was prepared by reacting 4-bromo-2-fluoroanisole (10 g, 0.049 mol) with n-butyl lithium (23.4 mL of 2.5 M solution in hexane, 0.059 mol) followed by triisopropyl borate (45.2 mL, 36.9 g, 0.196 mol) according to method F to yield 7.1 g (85.2%) of a white solid-MS (ESI) m/z 169 (M−H)−: 1H NMR (DMSO-d6): δ 3.84 (3H, s), 7.10-7.16 (1H, m), 7.51-7.60 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=1.Cl.O1CCOC[CH2:22]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:19]=[CH:18][C:14]([C:15]([O:17][CH3:22])=[O:16])=[CH:13][N:12]=1
Reactant: C1COCCO1
Reactant: O=C(O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)nc1
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(-c2cc([N+](=O)[O-])ccc2Cl)nc1

Procedure:
75 mL of (5-methylpyridin-2-yl)zinc(II) bromide was reacted with 4 g of 1-chloro-2-iodo-4-nitrobenzene via Procedure B. To 935 mg of 2-(2-chloro-5-nitrophenyl)-5-methylpyridine in 5 mL of Sulfuric Acid was slowly added 2.25 g of Chromium (III) Oxide and the reaction was stirred for several hours at room temperature until complete. Icewater was added to dilute the reaction and the aqueous layer was extracted 3 times with Ethyl Acetate. The organic layers were combined, dried over Magnesium Sulfate, filtered and concentrated to give 6-(2-chloro-5-nitrophenyl)nicotinic acid. 704 mg of 6-(2-chloro-5-nitrophenyl)nicotinic acid was esterified with 3.1 mL of 4N HCl in Dioxane in 20 mL of MeOH. The reaction was concentrated and subjected to basic workup, dried over Magnesium Sulfate, filtered and concentrated to give methyl 6-(2-chloro-5-nitrophenyl)nicotinate. 681 mg of methyl 6-(2-chloro-5-nitrophenyl)nicotinate was treated with 2.1 g of Tin (II) Chloride and 1 mL of HCl in 25 mL of EtOH. Upon completion, EtOH was concentrated and the reaction was extracted with Ethyl Acetate and water with TEA to decrease emulsions. The organic layer was dried over Magnesium Sulfate, filtered and concentrated to give crude methyl 6-(5-amino-2-chlorophenyl)nicotinate. 296 mg of methyl 6-(5-amino-2-chlorophenyl)nicotinate was coupled to 266 mg of 4-(methylsulfonylmethyl)benzoic acid via Procedure G. To 518 mg of methyl 6-(2-chloro-5-(4-(methylsulfonylmethyl)benzamido)phenyl)nicotinate at 0° C. in 20 mL of EtOH was slowly added 640 mg of Sodium Borohydride. The reaction was subsequently refluxed for 1 hour until complete, quenched with water and extracted with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate, filtered, concentrated and purified by reverse phase HPLC to give pure N-(4-chloro-3-(5-(hydroxymethyl)pyridin-2-yl)phenyl)-4-(methylsulfonylmethyl)benzamide. MS (Q1) 431.1 (M)+.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([OH:23])=O)[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2].Cl.[CH3:25][O:26][C:27]1[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[C:33]2[C:28]=1[CH2:29][CH2:30][NH:31][CH2:32]2>>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:20]=[C:19]([C:21]([N:31]3[CH2:30][CH2:29][C:28]4[C:33](=[CH:34][CH:35]=[C:36]([O:37][CH3:38])[C:27]=4[O:26][CH3:25])[CH2:32]3)=[O:23])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Reactant: COc1ccc2c(c1OC)CCNC2
Agent: Cl
Product: COc1ccc2c(c1OC)CCN(C(=O)c1nc(-c3ccc(NC(C)=O)cc3)nc3ccccc13)C2
Yield: 7 %

Procedure:
Reaction of 2-(4-acetamidophenyl)quinazoline-4-carboxylic acid with 5,6-dimethoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 63 (7% yield) as a yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 2.09 (s, 3H), 2.73 and 2.98 (2t, 2H), 3.49 and 4.02 (2t, 2H), 3.68-3.81 (4s, 6H), 4.41 and 4.93 (2s, 2H), 6.63 and 7.01 (2d, 1H), 6.80 and 7.08 (2d, 1H), 7.65-7.80 (m, 3H), 7.84-7.95 (2d, 1H), 8.03-8.13 (m, 2H), 8.41-8.49 (m, 2H), 10.23 (s, 1H); MS (ESI) m/z 483 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:18][CH3:19])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([OH:17])=O)[CH:10]=2)=[N:6][CH:7]=1.CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>CN(C)C=O>[Cl:1][C:2]1[C:3]([NH:18][CH3:19])=[N:4][C:5]([NH:8][C:9]2[N:13]([CH3:14])[N:12]=[C:11]([C:15]([N:53]3[CH2:58][CH2:57][O:56][CH2:55][CH2:54]3)=[O:17])[CH:10]=2)=[N:6][CH:7]=1
Reactant: C1COCCN1
Reactant: CNc1nc(Nc2cc(C(=O)O)nn2C)ncc1Cl
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CNc1nc(Nc2cc(C(=O)N3CCOCC3)nn2C)ncc1Cl
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask equipped with a stir bar was added 0.116 g of 5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazole-3-carboxylic acid, 0.19 g of o-benzotriazol-1-yl-tetramethyluronium hexafluorophosphate, 0.14 mL of diisopropylethylamine and 2 mL of dimethylformamide. After pre-activating for 10 minutes, 0.05 mL of morpholine was added and the reaction stirred at room temperature for 2 hours. The reaction was concentrated and purified by preparative reverse phase HPLC to yield 53.2 mg of (5-(5-chloro-4-(methylamino)pyrimidin-2-ylamino)-1-methyl-1H-pyrazol-3-yl)(morpholino)methanone. LCMS (Method A): [MH+]=352.0 at 2.80 min. 1H-NMR (DMSO): δ 9.47 (s, 1H), 7.86 (s, 1H), 7.15 (s, 1H), 6.78 (s, 1H), 3.74 (s, 3H), 3.61 (m, 8H), 2.88 (d, 3H). K1=0.16.
Reaction SMILES: [NH2:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[C:10]([O:21][CH3:22])[CH:9]=3)=[CH:4][CH:3]=1.N1C=CC=CC=1.[CH3:31][S:32](Cl)(=[O:34])=[O:33].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:31][S:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:16])[CH:15]=2)=[C:12]([O:17][CH3:18])[C:11]([O:19][CH3:20])=[C:10]([O:21][CH3:22])[CH:9]=3)=[CH:23][CH:24]=1)(=[O:34])=[O:33]
Reactant: COc1cc2oc(-c3ccc(N)cc3)cc(=O)c2c(OC)c1OC
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1cc2oc(-c3ccc(NS(C)(=O)=O)cc3)cc(=O)c2c(OC)c1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
The aminoflavone 10a (0.13 g, 0.40 mmol) was dissolved in 5 mL of dry methylene chloride, then 2 mL of freshly distilled pyridine was added. The solution was cooled to 0° C. then was dropwise added freshly distilled methanesulfonyl chloride (0.6 mmol). The reaction mixture was stirred at 0° C. for 1 h and at room temperature for an additional hour, then poured into 30 mL saturated NaHCO3. The resulting mixture was extracted with methylene chloride. The combined organic layers were washed with 5% HCl to remove pyridine, dried over Na2SO4 and concentrated. The residue was purified by column chromatography on silica gel (acetone:toluene=1:5) to give 10e (0.12 g, 74%). 1H NMR (400 MHz, Acetone) δ 3.11 (s, 3H), 3.81 (s, 3H), 3.87 (s, 3H), 4.00 (s, 3H), 6.60 (s, 1H), 7.11 (s, 1H), 7.50 (d, J=8.8 Hz, 2H), 8.02 (d, J=8.8 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:7])[C:5]#[CH:6])[CH3:2].[CH2:8]([OH:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17].CN1CCOCC1>C(OCC)C>[CH2:1]([O:3][C:4](=[O:7])/[CH:5]=[CH:6]/[O:18][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]=[CH2:17])[CH3:2]
Reactant: C=CCCCCCCCCO
Reactant: C#CC(=O)OCC
Solvent: CN1CCOCC1
Solvent: CCOCC
Product: C=CCCCCCCCCO/C=C/C(=O)OCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 91.2 %

Procedure:
The reaction was performed in standard glassware under an atmosphere of N2. To 150 ml of diethylether were added 9.8 g (0.1 mol) propiolic acid ethyl ester, 15.6g (0.1 mol) dec-9-en-1-ol and 10.1 g (0.1 mol) N-methylmorpholine. This solution was kept without stirring at room temperature for 24 hours. The mixture was evaporated under vacuum and the residue purified by bulb to bulb distillation (bp: 85-90° C.; 0.006 mbar) to yield 23.2 g (916%) of an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[C:18]([O:22][C:23](=[O:39])[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][C:32]=2[F:38])[CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].Cl.C(N=C=NCCCN(C)C)C.ClCCl>CN(C)C1C=CN=CC=1.O>[C:18]([O:22][C:23](=[O:39])[NH:24][CH:25]1[CH2:30][CH2:29][N:28]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:7](=[O:9])[C:6]3[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:33][C:32]=2[F:38])[CH2:27][CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)cc2F)CC1
Reactant: COCCOCOc1ccc(Cl)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: COCCOCOc1ccc(Cl)cc1C(=O)Nc1ccc(N2CCC(NC(=O)OC(C)(C)C)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.9 %

Procedure:
A mixture of 5-chloro-2-(2-methoxyethoxymethoxy)benzoic acid (compound of Reference Example 140; 0.18 g, 0.7 mmol), [1-(4-amino-2-fluorophenyl)piperidin-4-yl]carbamic acid tert-butyl ester (compound of Reference Example 90; 0.28 g, 0.9 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.17 g, 0.9 mmol), 4-dimethylaminopyridine (0.01 g) and dichloromethane (5 ml) was stirred at room temperature for 18 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporation of the solvent under reduced pressure was purified by column chromatography on silica gel (n-hexane:ethyl acetate=1:1) to give the title compound (0.27 g, 70%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19][CH3:20])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.ClC1C=CC=C(C(OO)=[O:31])C=1>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:22]=[CH:21][C:15]4[N:16]=[C:17]([S:19]([CH3:20])=[O:31])[O:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: CSc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2o1
Temperature: 0 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To a stirred solution of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylthio)benzo[d]oxazole (595 mg, 1.89 mmol) from the previous step in DCM (10 mL) at 0° C. was added 70% meta-chloroperbenzoic acid (425 mg, 2.46 mmol). The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed sequentially with aq sodium sulfite and brine. The organic layer was separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 50% ethyl acetate in petroleum ether to afford 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]oxazole (509 mg, 82%). 1H NMR (300 MHz, DMSO-d6): δ 8.73 (s, 1H), 8.40 (s, 2H), 7.53 (d, J=7.2 Hz, 1H), 7.37 (s, 1H), 7.15 (d, J=4.5 Hz, 1H), 5.69 (s, 2H), 3.18 (s, 3H); LCMS (ESI) m/z 331 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=2)[CH2:9][CH2:10][N:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2CN2C3C=CC=CC=3COC3C=CC=CC2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.N1CC[C@H]([OH:41])C1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[OH:41][C@H:13]1[CH2:14][CH2:15][N:11]([CH2:10][CH2:9][C:8]2[CH:32]=[CH:33][CH:34]=[C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:7]=2)[CH2:12]1
Reactant: O[C@H]1CCNC1
Reactant: c1cc(CCN2CCC[C@@H]2CN2c3ccccc3COc3ccccc32)cc(N2CCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Temperature: 100 °C

Procedure:
3-Pyrrolidinophenethyl mesylate (1.80 g, 4.00 mmol) synthesized in Example 21, (S)-3-pyrrolidinol hydrochloride (0.50 g, 4.05 mmol) and potassium carbonate (1.70 g, 12.3 mmol) were added to acetonitrile (20 ml), and they were heated at 100° C. for 12 hours. Acetonitrile was evaporated under reduced pressure, and the residue was distributed into water and ethyl acetate. The intended product was extracted from the ethyl acetate layer with 1 M hydrochloric acid. The extract was neutralized and then the product was extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure to obtain (S)-3-hydroxy-1-(3-pyrrolidinophenethyl)pyrrolidine in the form of a light yellow solid (1.04 g, 100%).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH3:11])=[O:9])=[C:6]([C:12]([Cl:15])([F:14])[F:13])[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[C:3]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21].Cl.[NH2:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29].C(N(CC)CC)C>CN(C=O)C>[Cl:15][C:12]([F:13])([F:14])[C:6]1[N:5]=[C:4]([C:16]([F:17])([F:19])[F:18])[C:3]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:2]([NH:26][CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)(F)Cl)c(C(=O)OC)c1Cl
Reactant: CCOC(=O)CN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CNc1c(C(=O)OCC)c(C(F)(F)F)nc(C(F)(F)Cl)c1C(=O)OC
Yield: 82.4 %

Procedure:
This compound was prepared as described in Example 37: 5.0 g (0.013 mol) of product of Example 28, 1.82 g (0.013 mol) of ethyl glycinate hydrochloride, 2.63 g (0.026 mol) of triethylamine in 30 ml of DMF were reacted at room temperature for 16 hours affording a residue which was kugelrohr distilled at 67 Pa, pot temperature 150° C., to give 4.96 g of solid. Recrystallization in hot hexane afforded 4.60 g (75.3%) of product as a beige solid; mp 60°-61.5° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C@@H:11]1[C@@H:14]([CH2:15][C:16](=[O:37])[CH:17]=P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[NH:13][C:12]1=[O:38])[CH3:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:39]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1[CH:50]=O)=[O:44])[CH:40]=[CH2:41].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH2:39]([O:42][C:43]([N:45]1[CH2:49][CH2:48][CH2:47][C@H:46]1/[CH:50]=[CH:17]/[C:16](=[O:37])[CH2:15][C@H:14]1[NH:13][C:12](=[O:38])[C@@H:11]1[C@H:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:2])[CH3:3])[CH3:10])=[O:44])[CH:40]=[CH2:41]
Reactant: C[C@@H](O[Si](C)(C)C(C)(C)C)[C@H]1C(=O)N[C@@H]1CC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: C=CCOC(=O)N1CCC[C@H]1C=O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1CCC[C@H]1/C=C/C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 63 %

Procedure:
A solution of (3S,4R)-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-4-(3-triphenylphosphoranylidene-2-oxopropyl)-2-oxoazetidine (572 mg) and (2S)-1-allyloxycarbonyl-2-formylpyrrolidine (201.5 mg) in toluene (5 ml) was heated to reflex for three hours. Evaporation of the solvent gave a residue, which was taken up into ethyl acetate. The resultant precipitate was filtered off and washed with ethyl acetate. The filtrate and the washings were combined and evaporated in vacuo. The residue was chromatographed on silica gel (50 ml) eluting with a mixture of n-hexane and ethyl acetate (2:1-1:1-1:3 V/V) to give (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (297.7 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:21])=[C:4]([C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([Cl:20])[CH:18]=3)[NH:13][CH:12]=2)=[O:10])[C:5]([F:8])=[CH:6][CH:7]=1.[F:22][C:23]1[CH:24]=[C:25]([S:30](Cl)(=[O:32])=[O:31])[CH:26]=[C:27]([F:29])[CH:28]=1.N1C=CC=CC=1>O1CCCC1>[Cl:20][C:17]1[CH:18]=[C:19]2[C:11]([C:9]([C:4]3[C:3]([F:21])=[C:2]([NH:1][S:30]([C:25]4[CH:24]=[C:23]([F:22])[CH:28]=[C:27]([F:29])[CH:26]=4)(=[O:32])=[O:31])[CH:7]=[CH:6][C:5]=3[F:8])=[O:10])=[CH:12][NH:13][C:14]2=[N:15][CH:16]=1
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Reactant: Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(Cl)cc23)c1F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(c1c(F)ccc(NS(=O)(=O)c2cc(F)cc(F)c2)c1F)c1c[nH]c2ncc(Cl)cc12
Temperature: 130 °C

Procedure:
Into a microwave reaction vessel were combined (3-amino-2,6-difluoro-phenyl)-(5-chloro-1H-pyrrolo[2,3-b]pyridin-3-yl)-methanone (56, 50 mg, 0.16 mmol), 3,5-difluorobenzenesulfonyl chloride (57, 103 mg, 0.49 mmol), pyridine (0.5 mL, 6.1820 mol) and tetrahydrofuran (3.0 mL). The reaction was warmed in the CEM microwave at 300 watts, 130° C. for 10 minutes. The reaction mixture was partitioned between ethyl acetate and brine. The organic layer was collected, dried over Na2SO4, filtered and concentrated. The compound (58) was isolated using column chromatography (silica, hexane:ethyl acetate 70:30) to obtain 36 mg (46%) compound. MS=482.0.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][C:7]=1[C:8]([CH3:11])([CH3:10])[CH3:9].[F:13][C:14]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[C:15]=1[C:16]([NH:18][NH2:19])=O.Cl.C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]2[N:4]([C:16]([C:15]3[C:20]([F:24])=[CH:21][CH:22]=[CH:23][C:14]=3[F:13])=[N:18][N:19]=2)[N:3]=1
Reactant: CC(C)(C)c1cc(Cl)nnc1Cl
Reactant: NNC(=O)c1c(F)cccc1F
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc2nnc(-c3c(F)cccc3F)n2nc1Cl
Yield: 13.3 %

Procedure:
A mixture of 3,6-dichloro-4-(1,1-dimethylethyl)pyridazine (2 g, 9.75 mmol), 2,6-difluorobenzoic acid hydrazide (2.52 g, 14.6 mmol) (WO 95/24403) and triethylamine hydrochloride (2.01 g, 14.6 mmol) in 1,4-dioxane (10 ml) was stirred and heated at reflux for 3.5 days. Upon cooling, the volatiles were removed in vacuo and the residue was triturated with dichloromethane. Any undissolved solid was removed by filtration. The residue was purified by chromatography on silica gel eluting with 0%→25% ethyl acetate in dichloromethane to give the required product (0.42 g). Data for the title compound: 1H NMR (250 MHz, CDCl3) δ1.57 (9H, s), 7.09-7.16 (2H, m), 7.51-7.63 (1H, m), 8.19 (1H, s); MS (ES30) m/e 323 (MH+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:6][CH:5]=1.[C:24]1(=O)[CH2:28][CH2:27][CH2:26][CH2:25]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:23])[C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]2[CH:22]=[CH:21][C:15]3[CH2:16][CH2:17][N:18]([CH:24]4[CH2:28][CH2:27][CH2:26][CH2:25]4)[CH2:19][CH2:20][C:14]=3[CH:13]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCCC1
Reactant: COC(=O)c1ccc(COc2ccc3c(c2)CCNCC3)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: COC(=O)c1ccc(COc2ccc3c(c2)CCN(C2CCCC2)CC3)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
4-(2,3,4,5-Tetrahydro-1H-benzo[d]azepin-7-yloxymethyl)-benzoic acid methyl ester (D4) (2.83 g, 9.1 mmol) and cyclopentanone (1.6 ml, 18.2 mmol) were dissolved in dichloromethane (30 ml) and acetic acid (0.5 ml). Sodium triacetoxy borohydride (3.85 g, 18.2 mmol) was added and the solution was stirred at room temperature for 4 hours. The reaction mixture was washed with a saturated solution of sodium carbonate, the organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by column chromatography eluting with a mixture of 0.880 ammonia:ethanol:dichloromethane (1:9:90) to afford the title compound (E88); MS (ES+) m/e 380 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:11][S:10][C@@H:5]2[C@H:6]([NH2:9])[C:7](=[O:8])[N:4]2[C:3]=1[C:12]([OH:14])=[O:13].[CH:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)C=C[C:16]=1[OH:25].[OH-].[NH4+]>O>[CH3:11][C:2]1([CH3:1])[S:10][C@@H:5]2[C@H:6]([NH:9][C:16]([CH2:15][C:24]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:25])[C:7](=[O:8])[N:4]2[C@H:3]1[C:12]([OH:14])=[O:13]
Reactant: Oc1ccc2ccccc2c1
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Product: CC1(C)S[C@@H]2[C@H](NC(=O)Cc3ccccc3)C(=O)N2[C@H]1C(=O)O
Temperature: 25 °C

Procedure:
The pH value of a mixture (slurry) of D-PGA.1/2H2SO4 (74.7 g, 0.375 mol), 7-ADCA (21.4 g, 0.10 mol), and 2-naphthol (10.8 g, 0.075 mol, particle size <100 μm) in approximately 300 ml of water was adjusted to 6.7 by addition of 4M ammonium hydroxide. Water was added to 400 ml followed by immobilized E. coli Penicillin G acylase prepared as described above (50 g on dry basis suspended in water to a total of 100 ml), and the mixture was stirred at 25° C.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH2:14])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]1([N:29]=[C:30]=[S:31])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>O1CCOCC1>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[C:13]([NH:14][C:30]([NH:29][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)=[S:31])=[CH:12][CH:11]=[CH:10][N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ncccc1N
Reactant: S=C=Nc1cccc2ccccc12
Solvent: C1COCCO1
Product: CC(C)(C)c1ccccc1Oc1ncccc1NC(=S)Nc1cccc2ccccc12
Temperature: 60 °C

Procedure:
A solution of 1b (40 mg, 0.17 mmol) and 1-naphtylisothiocyanate (34 mg, 0.18 mmol) in dioxane (2 mL) was heated at 60° C. for 6 h. More 1-naphtylisothiocyanate (34 mg, 0.18 mmol) was added and the mixture was heated at 60° C. for 8 days. The mixture was concentrated and the residue was purified by column chromatography on silica gel using a continuous gradient from 0% to 40% ethyl acetate in hexanes as eluent to afford 102a which was directly used in the next step. [M−H]−=426.18.