Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)O[C@H:6]1[CH2:10][C@@H:9]([N:11]2[CH:19]=[N:18][C:17]3[C:12]2=[N:13][C:14]([Cl:35])=[N:15][C:16]=3[NH:20][CH2:21][CH:22]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:8]=[CH:7]1)C.[CH3:37][C:38]1[CH:39]=[N:40][NH:41][CH:42]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[Cl:35][C:14]1[N:13]=[C:12]2[C:17]([N:18]=[CH:19][N:11]2[C@@H:9]2[CH2:10][C@H:6]([N:40]3[CH:39]=[C:38]([CH3:37])[CH:42]=[N:41]3)[CH:7]=[CH:8]2)=[C:16]([NH:20][CH2:21][CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[N:15]=1
Reactant: CCOC(=O)O[C@@H]1C=C[C@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(Cl)nc32)C1
Reactant: Cc1cn[nH]c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: Cc1cnn([C@@H]2C=C[C@H](n3cnc4c(NCC(c5ccccc5)c5ccccc5)nc(Cl)nc43)C2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Carbonic acid (1S,4R)-4-[2-chloro-6-(2,2-diphenyl-ethylamino)-purin-9-yl]-cyclopent-2-enyl ester ethyl ester (Intermediate AA) (2.00 g, 3.97 mmol) is placed in an oven-dried flask under an atmosphere of argon. Dry deoxygenated THF (20 mL) is added followed by 4-methyl-pyrazole (0.36 g, 4.37 mmol) and triphenylphosphine (0.16 g, 0.60 mmol). Tetrakis(triphenyl-phosphine)palladium(0) (0.23 g, 0.20 mmol) is then added and the reaction mixture is stirred at room temperature for 18 hours. The solvent is removed in vacuo and the title compound is obtained after purification by flash column chromatography (silica, iso-hexane/ethyl acetate 1:2). 1H nmr (CDCl3, 400 MHz); 8.10 (br s, 1H), 7.35-7.15 (m, 12H), 6.25 (m, 1H), 6.10 (m, 1H), 5.80 (m, 1H), 5.70 (m, 1H), 5.35 (m, 1H), 4.35 (t, 1H), 4.25 (m, 2H), 3.25 (m, 1H), 2.20 (m, 1H), 2.05 (s, 3H), MS (ES+) m/e 496 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[NH:20][CH2:19][CH:18]([CH2:21][CH3:22])[O:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9].N1C=CC=CC=1>C(Cl)Cl>[C:8]([C:10]1[CH:11]=[C:12]([CH:16]2[N:20]([C:1](=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4])[CH2:19][CH:18]([CH2:21][CH3:22])[O:17]2)[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: CC(C)CC(=O)Cl
Reactant: CCC1CNC(c2cccc(C#N)c2)O1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC1CN(C(=O)CC(C)C)C(c2cccc(C#N)c2)O1
Reaction time: 8 h

Procedure:
Two and five-tenths grams of isovaleroyl chloride in 10 ml of methylene chloride was added dropwise to 6.5 g of 2-(m-cyanophenyl)-5-ethyl-1,3-oxazolidine in 25 ml of methylene chloride containing 1.9 g of pyridine. The mixture was allowed to stir overnight, washed with 50 ml of 5% NaOH and 200 ml of water, dried over anhydrous MgSO4 and stripped on the rotary evaporator. The yield was 3.7 g, nD30 1.5455. The structure was confirmed by NMR and infrared spectroscopy.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[N:6]=1.CCN(CC)CC.[CH3:32][C:33](OC(C)=O)=[O:34]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:33]([NH:1][CH2:2][CH2:3][CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[C:8]2[CH:21]=[CH:22][CH:23]=[CH:24][C:7]=2[N:6]=1)(=[O:34])[CH3:32]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)c1ccc(Cn2c(CCCN)nc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Cn2c(CCCNC(C)=O)nc3ccccc32)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 34.8 %

Procedure:
To a round bottom flask charged with methyl 4-((2-(3-aminopropyl)-1H-benzo[d]imidazol-1-yl)methyl)benzoate 34 (135 mg, 0.417 mmol) in DCM (5 mL) was added Et3N (0.076 mL, 0.543 mmol) and catalytic DMAP (5 mg, 0.042 mmol). The reaction was cooled to 0° C. and then Ac2O (0.051 mL, 0.543 mmol) was added dropwise. The resulting solution was allowed to warm to RT and stirred for 18 h after which the reaction was quenched with H2O (10 mL) and extracted with chloroform (3×10 mL). Combined extracts were washed with brine (20 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified using automated column chromatography method 2 and isolated as a white, waxy solid (53 mg, 35%). 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J=8.0 Hz, 2H), 7.73 (d, J=7.6 Hz, 1H), 7.24 (m, 3H), 7.07 (d, J=8.0 Hz, 2H), 6.73 (br s, 1H), 5.38 (s, 2H), 3.88 (s, 3H), 3.33 (m, 2H), 2.89 (t, J=7.2H, 2H), 2.05 (m, 2H), 1.86 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 170.44, 166.32, 154.48, 141.76, 140.60, 134.98, 130.26, 129.91, 126.00122.81, 122.49, 118.89, 109.42, 52.12, 46.60, 38.91, 26.42, 24.92, 22.97. ESI-LRMS: [M+H]+=366 m/z.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9](O)[C:10]([OH:12])=[O:11])=[CH:7][CH:6]=1.[CH:16]1[C:21](O)=[CH:20][CH:19]=[C:18]([CH3:23])[CH:17]=1>O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:15]=[CH:14][C:8]([CH:9]2[C:16]3[CH:17]=[C:18]([CH3:23])[CH:19]=[CH:20][C:21]=3[O:12][C:10]2=[O:11])=[CH:7][CH:6]=1
Reactant: Cc1ccc(O)cc1
Reactant: O=C(O)C(O)c1ccc(OCCO)cc1
Solvent: O
Product: Cc1ccc2c(c1)C(c1ccc(OCCO)cc1)C(=O)O2
Yield: 58 %

Procedure:
A suspension of 8.5 g (40.0 mmol) of 4-(2-hydroxyethoxy)mandelic acid (compound (201), Example 10, Table 2) and 12.0 g (110 mmol) of p-cresol is maintained at 180° C. under a nitrogen atmosphere for 75 minutes, during which the water formed distils off. Excess p-cresol is then distilled off in a vacuum rotary evaporator. Chromatography of the residue on silica gel using the eluent system 9:1 dichloromethane/ethyl acetate gives 6.6 g (58%) of 3-[4-(2-hydroxyethoxy)phenyl]-5-methylbenzofuran-2-one, a yellowish resin (compound (119), Table 1).
Reaction SMILES: [CH:1]([C:4]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:5]=1[CH:6]=[O:7])([CH3:3])[CH3:2].CCO.[BH4-].[Na+].CCCCCCC>CCOC(C)=O>[CH:1]([C:4]1[CH:11]=[CH:10][C:9]([CH:12]([CH3:14])[CH3:13])=[CH:8][C:5]=1[CH2:6][OH:7])([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(C(C)C)c(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)c1ccc(C(C)C)c(CO)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 63.6 %

Procedure:
In a 2-neck RBF equipped with magnetic stir bar and N2 inlet, 2,5-diisopropylbenzaldehyde (1.7 g, 9 mmol) was dissolved into 30 mL of EtOH and NaBH4 (0.37 g, 10 mmol) was added over 20 min (portion-wise). After 18 h stirring at RT, ˜95% of solvent was removed on a rotary evaporator and then 5 mL of 0.5 M HCl was added and product was extracted with 25 mL of EtOAc. Organic layer was washed with 15 mL of H2O and 15 mL of brine, dried over Na2SO4, filtered and concentrated to dryness to obtain crude product. This material was subjected to chromatography using heptane: EtOAc as mobile phase to provide 1.1 g of pure product. Yield 65%. 1H NMR (300 MHz, CDCl3) δ 1.2-1.3 (d, 12H), 2.8 (septet, 1H), 3.2 (septet, 1H), 5.7 (s, 2H), 7.1-7.3 (m, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12>>[Br:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:16]2[C:12](=[O:22])[C:13]3[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:15]2=[O:17])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: OCCSc1cccc(Br)c1
Product: O=C1c2ccccc2C(=O)N1CCSc1cccc(Br)c1

Procedure:
Mitsunobu coupling of 2-(3-bromophenylthio)ethanol (125) with phthalimide according to the method used in Example 17, followed by flash chromatography (5-20% ethyl acetate/hexanes gradient) gave 2-(2-(3-bromophenylthio)ethyl)isoindoline-1,3-dione (126) as a white solid. Yield (4.04 g, 72%): 1H NMR (400 MHz, CDCl3) δ 7.77-7.84 (m, 2H), 7.66-7.72 (m, 2H), 7.50 (t, J=2.0 Hz, 1H), 7.30 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.19 (ddd, J=0.8, 1.6, 7.6 Hz, 1H), 7.07 (t, J=7.6 Hz, 1H), 3.93 (t, J=7.2 Hz, 2H), 3.22 (J=7.2 Hz, 2H).
Reaction SMILES: IC.[CH3:3][C:4]1[C:5](=[O:10])[NH:6][CH:7]=[CH:8][CH:9]=1.[C:11](=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:11][N:6]1[CH:7]=[CH:8][CH:9]=[C:4]([CH3:3])[C:5]1=[O:10]
Reactant: Cc1ccc[nH]c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: Cc1cccn(C)c1=O
Temperature: 55 °C
Reaction time: 16 h
Yield: 78.6 %

Procedure:
Iodomethane (10.62 mL, 111.6 mmol) was added to a mixture of 3-methyl-2-pyridone (4.06 g, 37.20 mmol) and potassium carbonate (15.43 g, 111.6 mmol) in acetone (150 mL) in a sealable flask. The mixture was vigorously stirred in an oil bath at 55° C. for 16 hours. The reaction mixture was cooled to ambient temperature then filtered through glass fiber filter paper and the filtrate was concentrated under vacuum until a solid formed (5.4 g). The solid was partitioned between water (50 mL) and dichloromethane (100 mL). The aqueous phase was extracted once more with dichloromethane (50 mL). The combined organic phases were dried over magnesium sulfate and concentrated under vacuum to give 1,3-dimethylpyridin-2(1H)-one as an oil (3.6 g).
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:18][C:19]1[CH:31]=[CH:30][C:22]2[C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:24][O:25][C:21]=2[CH:20]=1>CO>[NH2:1][C@@H:2]([CH3:17])[C:3]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[OH:18][C:19]1[CH:31]=[CH:30][C:22]2[C@H:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][O:25][C:21]=2[CH:20]=1
Reactant: O=C(O)Cc1coc2cc(O)ccc12
Agent: C[C@H](N)C(O)(c1ccccc1)c1ccccc1
Solvent: CO
Product: O=C(O)C[C@@H]1COc2cc(O)ccc21

Procedure:
A solution of (6-hydroxy-1-benzofuran-3-yl)acetic acid (S)-2-amino-1,1-diphenylpropan-1-ol salt (19.64 g) and dichloro[(+)-1,2-bis((2R,5R)-2,5-diisopropylphosphorano)benzene]ruthenium (II)-N,N-dimethylformamide complex (2.3 mg) in dehydrated methanol (90 ml) was stirred at 35° C. for 22 hr under a hydrogen atmosphere (1.1 MPa). To the reaction solution was added methanol (9 mL) to give a methanol solution of the title compound. 81.3% de
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]2[NH:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:25])[CH3:24])=[CH:18][CH:17]=1.[Cl:26][C:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]>ClCCl.CO>[Cl:26][C:27]1[CH:32]=[C:31]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[CH:7][C:6]([C:12](=[O:14])[CH3:13])=[C:5]3[NH:15][C:16]2[CH:21]=[CH:20][C:19]([CH2:22][N:23]([CH3:24])[CH3:25])=[CH:18][CH:17]=2)[CH:30]=[C:29]([Cl:42])[C:28]=1[OH:43]
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Br)cc2c1Nc1ccc(CN(C)C)cc1
Solvent: CO
Solvent: ClCCl
Product: CC(=O)c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(CN(C)C)cc1
Yield: 122.7 %

Procedure:
Following general procedure F, 1-(6-bromo-4-(4-((dimethylamino)methyl)phenylamino)quinolin-3-yl)ethanone (2.0 g, 5.09 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (2.2 g, 7.6 mmol) to obtain the free base. The purified product was suspended in dichloromethane/methanol (1:1, 40 mL) and HBr gas was bubbled through the suspension until a solution formed. The solution was concentrated to dryness and the resultant solid was triturated with diethyl ether. The mixture was filtered, washed with diethyl ether, and dried to obtain desired product (3.0 g, 94% over two steps) as a yellow solid: 1H NMR (300 MHz, DMSO) δ 11.93 (s, 1H), 10.59 (s, 1H), 9.81 (s, 1H), 9.24 (s, 1H), 8.37 (m, 2H), 8.11 (d, J=8.8 Hz, 1H), 7.66 (d, J=8.5 Hz, 2H), 7.56 (s, 2H), 7.51 (d, J=8.5 Hz, 2H), 4.39 (d, J=4.0 Hz, 2H), 2.74 (d, J=4.0 Hz, 6H), 2.54 (s, 3H). APCI MS m/z 480 [C26H23Cl2N3O2+H]+; HPLC>99% (AUC), tR=4.79 min.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].I[CH:17]([CH3:19])[CH3:18]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH:17]([CH3:19])[CH3:18])[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Oc1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 3,5-difluorophenol (1.0 equiv.) in DMF (0.26 M) was added potassium carbonate (2.2 equiv.) followed by 2-iodopropane (1.1 equiv.) and the reaction was stirred overnight at room temperature. The reaction was poured into a separatory funnel and diluted with a 3:1 (v/v) solution of EtOAc:heptanes. The organic phase was washed with water, then sat′d NaHCO3. The remaining organic phase was dried over MgSO4, filtered and concentrated in vacuo to provide 1,3-difluoro-5-isopropoxybenzene in 88% yield. 1H NMR (400 MHz, <cdcl3>) δ ppm 1.33 (d, J=6.26 Hz, 6 H), 4.48 (dt, J=11.93, 6.16 Hz, 1 H), 6.31-6.47 (m, 3 H).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1I)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[F:28][C:29]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:31][C:32]2[NH:37][CH2:36][CH2:35][O:34][C:33]=2[CH:38]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(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:1]([O:5][C@@H:6]([C:12]1[C:13]([CH3:27])=[N:14][C:15]2[N:16]([N:19]=[C:20]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:21]=2)[C:17]=1[C:30]1[C:29]([F:28])=[CH:38][C:33]2[O:34][CH2:35][CH2:36][NH:37][C:32]=2[CH:31]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(c2cc3c(cc2F)OCCN3)OC1(C)C
Reactant: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(I)n2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(-c3cc4c(cc3F)OCCN4)n2n1
Temperature: 100 °C
Reaction time: 0.08 h

Procedure:
A mixture of (S)-ethyl 6-(1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-iodo-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (300 mg, 0.613 mmol), 7-fluoro-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-2H-benzo[b][1,4]oxazine (prepared according to the procedure described in WO 2009/062285; 205 mg, 0.736 mmol) and 2N Na2CO3 (0.613 mL, 1.226 mmol) in DMF (6 mL) was degassed for 15 min. Tetrakis(triphenylphosphine)palladium(0) (49.6 mg, 0.043 mmol) was added and the degassing was continued for another 5 min. The mixture was then heated at 100° C. for 16 h. At this point LCMS indicated completion of reaction and presence of desired product. After cooling to room temperature, water was added (50 mL) and the mixture was extracted with ethyl acetate (2×100 mL), washed with brine (100 mL), dried (Na2SO4), filtered and concentrated. The crude was then purified by prep-HPLC to afford ethyl 6-((S)-1-(tert-butoxy)-2-ethoxy-2-oxoethyl)-7-(7-fluoro-3,4-dihydro-2H-benzo[b][1,4]oxazin-6-yl)-5-methylpyrazolo[1,5-a]pyrimidine-2-carboxylate (approx 10-15% of minor atrope isomer present by LCMS and NMR). 1H NMR (500 MHz, CDCl3) δ 7.11 (s, 1H), 6.74 (dd, J=8.3, 1.8 Hz, 2H), 5.17 (s, 1H), 4.48-4.33 (m, 4H), 4.24 (t, J=7.0 Hz, 2H), 3.83 (br. s., 1H), 3.51-3.41 (m, 2H), 2.70 (s, 3H), 1.43-1.39 (m, 3H), 1.31-1.26 (m, 3H), 1.05 (s, 9H). LCMS (M+H)=515.4.
Reaction SMILES: [C:1]([Cl:6])(=[O:5])[C:2](Cl)=[O:3].[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1OCC(O)=O>ClCCl.CN(C)C=O>[CH3:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[O:3][CH2:2][C:1]([Cl:6])=[O:5]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccccc1OCC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccccc1OCC(=O)Cl
Reaction time: 16 h

Procedure:
Oxalyl chloride (2.2 mL, 25 mM) was added to a stirred solution of (2-methylphenoxy)acetic acid (3.32 g, 20 mM) in dichloromethane (10 mL). Dry N,N-dimethylformamide (1 drop) was added to catalyse the reaction and the mixture was stirred for 16 hours. The solvent was removed by evaporation to leave (2-methylphenoxy)acetyl chloride as a pale yellow oil, which was used without further purification.
Reaction SMILES: C(O[CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[CH:16]([NH2:17])[C:15](=[O:18])[N:10]2[C:11]=1[C:12]([OH:14])=[O:13])(=O)C.[NH2:19][C:20]1[CH:25]=[C:24]([NH2:26])[N:23]([CH3:27])[C:22](=[S:28])[N:21]=1.CO.N>C(#N)C>[NH2:17][CH:16]1[C:15](=[O:18])[N:10]2[C:11]([C:12]([O-:14])=[O:13])=[C:6]([CH2:5][S:28][C:22]3[N:21]=[C:20]([NH2:19])[CH:25]=[C:24]([NH2:26])[N+:23]=3[CH3:27])[CH2:7][S:8][C@H:9]12
Reactant: Cn1c(N)cc(N)nc1=S
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(N)[C@H]2SC1
Agent: N
Solvent: CC#N
Solvent: CO
Product: C[n+]1c(N)cc(N)nc1SCC1=C(C(=O)[O-])N2C(=O)C(N)[C@H]2SC1
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Under an anhydrous condition, a solution containing 2.72 g of 3-acetoxymethyl-7-amino-3-cephem-4-carboxylic acid and 1.56 g of 4,6-diamino-1-methyl-2-(1H)pyrimidinethione suspended in 20 ml of dry acetonitrile was cooled to 0° C.; and 3.6 ml of boron trifluoride diethylether was added. The temperature of the reaction solution was increased to a room temperature, e.g., 18°-20° C.; the solution was stirred for three hours; and then 10 ml of methyl alcohol was added. The resultant solution was stirred for 10 minutes and was added with 30 ml of ice water. The pH of the solution was adjusted to 7.1 by adding aqueous ammonia solution After concentration under a reduced pressure, e.g., about 20 mmHg, the solution was adjusted to pH 3.7 with 2N-aqueous hydrochloric acid; and allowed to stand at a room temperature for 24 hrs. The precipitates resulted from the reaction solution were filtered, washed with 10 ml of distilled water and with 10 ml of methyl alcohol, and dried to give 2.69 g of the title compound as a solid.
Reaction SMILES: B([O-])([O-])O[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14])=[C:5]([Cl:15])[CH:4]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[N:28]([CH:29]=[O:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]3[CH:39]=[CH:38][C:37]([CH2:40][N:41]([CH3:48])[CH:42]4[CH2:47][CH2:46][O:45][CH2:44][CH2:43]4)=[CH:36][CH:35]=3)=[O:32])=[CH:24][C:23]=2[CH:49]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O.C1(C)C=CC=CC=1.C(OCC)(=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>[Cl:15][C:5]1[CH:4]=[C:3]([C:19]2[CH:20]=[CH:21][C:22]3[N:28]([CH:29]=[O:30])[CH2:27][CH2:26][C:25]([C:31]([NH:33][C:34]4[CH:35]=[CH:36][C:37]([CH2:40][N:41]([CH3:48])[CH:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:38][CH:39]=4)=[O:32])=[CH:24][C:23]=3[CH:49]=2)[CH:8]=[CH:7][C:6]=1[O:9][CH2:10][CH2:11][O:12][CH2:13][CH3:14]
Reactant: CCOCCOc1ccc(OB([O-])[O-])cc1Cl
Reactant: CN(Cc1ccc(NC(=O)C2=Cc3cc(Br)ccc3N(C=O)CC2)cc1)C1CCOCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(CN(C)C4CCOCC4)cc2)CCN3C=O)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
In a mixture of water ethanol:toluene (1:1:10; v/v, 18.0 ml) were dissolved 3-chloro-4-(2-ethoxy)ethoxyphenyl borate (280 mg) and 7-bromo-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (380 mg). To the solution was added potassium carbonate (253 mg), and the mixture was stirred under argon atmosphere at room temperature for 30 minutes. To the mixture was added tetrakistriphenylphosphinepalladium (35 mg), and the mixture was heated to reflux under argon atmosphere for 10 hours. The mixture was diluted with ethyl acetate, and washed with water and saturated brine, and the organic layer was dried with anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified with silica gel column chromatography (25 g, ethyl acetate→ethyl acetate:ethanol=10:1→ethyl acetate:ethanol:triethylamine=100:10:0.5) and recrystallized from ethanol to give 7-[3-chloro4-(2-ethoxy)ethoxyphenyl]-1-formyl-N-[4-[[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl]phenyl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 21) (342 mg, 73%) as white crystals.
Reaction SMILES: [O:1]([CH2:8][C@@H:9]1[CH2:13][CH2:12][CH2:11][N:10]1[S:14]([C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][C:21](=[O:26])[C:20]2=[O:27])(=[O:16])=[O:15])[C:2]1[CH:7]=C[CH:5]=[CH:4][CH:3]=1.C(OC([N:35]1CCCC1COC1C=NC=CC=1)=O)(C)(C)C>>[N:35]1[CH:5]=[CH:4][CH:3]=[C:2]([O:1][CH2:8][CH:9]2[CH2:13][CH2:12][CH2:11][N:10]2[S:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[NH:22][C:21](=[O:26])[C:20]3=[O:27])(=[O:15])=[O:16])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1COc1cccnc1
Reactant: O=C1Nc2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccccc3)cc2C1=O
Product: O=C1Nc2ccc(S(=O)(=O)N3CCCC3COc3cccnc3)cc2C1=O
Yield: 82 %

Procedure:
5-(2-(Pyridin-3-yl-oxymethyl)-pyrrolidine-1-sulfonyl)-1H-indole-2,3-dione (20) was prepared according to the same procedure for compound 10, except using compound 19, and the crude product was recrystallized from ethyl acetate to afford 1.75 g (82%) of 20 as a yellow solid, mp 215.9-217.8° C. 1H NMR (300 MHz, DMSO) δ 11.42 (s, 1H), 8.26 (d, J=3.0 Hz, 1H), 8.16 (d, J=4.5 Hz, 1H), 8.02 (d, J=8.4 Hz, 1H), 7.78 (s, 1H), 7.38 (m, 1H), 7.33 (m, 1H), 7.05 (d, J=8.4 Hz, 1H), 4.15-4.02 (m, 2H), 3.90 (m, 1H), 3.34 (m, 1H), 3.12 (m, 1H), 1.87 (m, 2H), 1.67-1.54 (m, 2H). LCMS m/e: 387.8 (M+H). Anal. Calcd for C18H17N3O5S.0.5H2O: C, 54.54, H, 4.58; N, 10.60. Found: C, 54.56, H, 4.70; N, 10.04.
Reaction SMILES: CCOC(/N=N/C(OCC)=O)=O.[Br:13][C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1.[Br:21][CH2:22][CH2:23][CH2:24]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Br:21][CH2:22][CH2:23][CH2:24][O:20][C:16]1[CH:15]=[C:14]([Br:13])[CH:19]=[CH:18][CH:17]=1
Reactant: OCCCBr
Reactant: Oc1cccc(Br)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: BrCCCOc1cccc(Br)c1
Temperature: 25 °C
Yield: 67 %

Procedure:
Diethylazodicarboxylate (0.77 g, 3.8 mmol) was added to solution of 3-bromophenol (0.50 g, 3.2 mmol), 3-bromopropanol (0.53 g, 3.8 mmol), triphenylphosphine (1.0 g, 3.8 mmol) and THF (10 mL). The solution was maintained at RT for 16 h and then concentrated in vacuo. The residue was partitioned between methylene chloride and 10% NaHCO3 aq. solution and layers separated. The aqueous layer was extracted with methylene chloride (2×10 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash column chromatography (100 g silica gel 60, 230-400 mesh, 9:1 hexane:ethyl acetate as eluent) to give 0.63 g (71%) of the title compound as a pale yellow liquid. MS (ESI) 293.0 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12](=[O:40])[C@@H:13]([NH:19][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:25]=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=2)=[O:21])[CH2:14]CC(O)=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:41]([O:43]C(N1CCN(C(=O)[C@@H](NC(C2C=C(OC3CCCC3)N=C(C3C=CC=CC=3)N=2)=O)CCCC(O)=O)CC1)=O)C>>[CH2:1]([O:3][C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12](=[O:40])[C@@H:13]([NH:19][C:20]([C:22]2[CH:27]=[C:26]([O:28][CH:29]3[CH2:33][CH2:32][CH2:31][CH2:30]3)[N:25]=[C:24]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:23]=2)=[O:21])[CH2:14][CH2:41][OH:43])[CH2:10][CH2:11]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Reactant: CCOC(=O)N1CCN(C(=O)[C@H](CCCC(=O)O)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCO)NC(=O)c2cc(OC3CCCC3)nc(-c3ccccc3)n2)CC1

Procedure:
The compounds of Examples 12 and 13 were prepared using a method analogous to that of Example 11, starting from 4-{(S)-4-carboxy-2-[(6-cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid ethyl ester and 4-{(S)-5-carboxy-2-[(6-cyclopentyloxy-2-phenyl-pyrimidine-4-carbonyl)-amino]-pentanoyl}-piperazine-1-carboxylic acid ethyl ester respectively.