Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[N:6][C:7]=1[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C.[ClH:50].[N:51]1([CH2:57][C:58](O)=[O:59])[CH2:56][CH2:55][O:54][CH2:53][CH2:52]1.C(N(CC)CC)C>>[ClH:50].[ClH:50].[CH3:1][C:2]1[C:3]([N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27][C:58](=[O:59])[CH2:57][N:51]4[CH2:56][CH2:55][O:54][CH2:53][CH2:52]4)[CH:23]=3)[CH:18]2[CH3:28])=[N:4][C:5]([NH:9][C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(O)ccc3C2C)c1C
Reactant: O=C(O)CN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2ccc(F)cc2)nc(N2CCc3cc(OC(=O)CN4CCOCC4)ccc3C2C)c1C

Procedure:
The same procudures as in Example 167 were repeated using 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-6-hydroxy-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine(50 mg, 0.132 mmol), 1-hydroxybenzotriazole(26.8 mg, 0.198 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide(32.9 mg, 0.171 mmol), 4-morpholineacetic acid hydrochloride (28.8 mg, 0.158 mmol), and triethylamine (46 μl, 0.330 mmol) to afford the titled compound.
Reaction SMILES: [CH3:1][C@@]1(O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O)O.[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[O:25][C@@H:23]1[OH:24])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(Cl)C1C=CC=CC=1.[OH-].[K+]>O>[CH2:14]([O:21][C@@H:22]1[C@@H:28]([O:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:27]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[C@@H:26]([CH2:45][O:46][CH2:47][C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[O:25][C@@H:23]1[O:24][CH3:1])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: C[C@]1(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Reactant: O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: ClCc1ccccc1
Solvent: O
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1

Procedure:
Preparation of 2,3,4,6-Tetra-O-benzyl-α-D-glucopyranose Methyl-α-D-glucopyranose (100 g, 0.516 mol) is suspended in benzyl chloride (400 mL, 3.5 mol) with KOH pellets (336 g, 6 mol), and the mixture is stirred using a mechanical stirrer at 120°-130° C. for 3 h. The reaction mixture is cooled and water (800 mL) is added to dissolve the crystalline mass, which is extracted with ether (2×200 mL). The combined organic layer is washed with water (2×500 mL) and dried (Na2SO4). The solvents are removed by vacuum distillationto give the crude methyl 2,3,4,6-tetra-O-benzyl-α-D-glucopyranoside for the next reaction.
Reaction SMILES: C([O:5][C:6](=[O:43])[CH2:7][CH2:8][C@H:9]([NH:13][C:14]([C:16]1[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]2[CH2:29][CH2:28][CH2:27][C@H:26]2[C:30](=[O:36])[NH:31][CH2:32][CH:33]2[CH2:35][CH2:34]2)=[O:24])[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[N:17]=1)=[O:15])[C:10](O)=[O:11])(C)(C)C.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][NH:85][CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]>CN(C=O)C>[CH2:77]([O:79][C:80]([N:82]1[CH2:87][CH2:86][N:85]([C:10](=[O:11])[C@@H:9]([NH:13][C:14]([C:16]2[CH:20]=[C:19]([O:21][CH2:22][C:23]([N:25]3[CH2:29][CH2:28][CH2:27][C@H:26]3[C:30](=[O:36])[NH:31][CH2:32][CH:33]3[CH2:35][CH2:34]3)=[O:24])[N:18]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[N:17]=2)=[O:15])[CH2:8][CH2:7][C:6]([OH:43])=[O:5])[CH2:84][C@H:83]1[CH3:88])=[O:81])[CH3:78]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1cc(OCC(=O)N2CCC[C@H]2C(=O)NCC2CC2)n(-c2ccccc2)n1)C(=O)O
Reactant: CCOC(=O)N1CCNC[C@H]1C
Agent: CN(C)C(On1nnc2cccnc21)=[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: CCOC(=O)N1CCN(C(=O)[C@H](CCC(=O)O)NC(=O)c2cc(OCC(=O)N3CCC[C@H]3C(=O)NCC3CC3)n(-c3ccccc3)n2)C[C@H]1C
Reaction time: 16 h

Procedure:
To a solution of 100 mg (S)-2-({5-[2-((S)-2-(Cyclopropylmethyl-carbamoyl)-pyrrolidin-1-yl)-2-oxo-ethoxy]-1-phenyl-1H-pyrazole-3-carbonyl}-amino)-pentanedioic acid 5-tert-butyl ester in 6 ml DMF were added 28 μl DIPEA, 64 mg HATU and 29 mg (R)-2-Methyl-piperazine-1-carboxylic acid ethyl ester. After stirring for 16 h the solution was concentrated, the residue dissolved in 1.5 ml dichloromethane and treated with 560 μl TFA. After stirring for 16 h the solvents were removed under reduced pressure and the residue purified by preparative HPLC (C18 reverse phase column, elution with a water/MeCN gradient with 0.1% TFA). The fractions containing the product were lyophilized to yield the pure product. Yield: 65 mg MS (ES+): m/e=696.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]([CH3:11])[C:3]1=[O:12].[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](Cl)=[O:19]>>[Cl:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]([CH3:11])[C:3](=[O:12])[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:19]
Reactant: Cn1c(=O)n(C)c2ccccc21
Reactant: O=C(Cl)CCCCCl
Product: Cn1c(=O)n(C)c2cc(C(=O)CCCCCl)ccc21
Yield: 70.7 %

Procedure:
Using 1,3-dimethyl-1,3-dihydro-2H-benzimidazol-2-one (3.00 g) and 5-chlorovaleryl chloride (5.74 g) according to the same method as that of Reference Example 1, the title compound (3.67 g) was obtained as colorless crystals.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([OH:54])=O)=[CH:40][CH:41]=2)[N:36]=1.Cl.[CH2:56]1[C:65]2[C:60](=[C:61]([O:66][CH2:67][C:68]3[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=3)[C:71]#[N:72])[CH:62]=[CH:63][CH:64]=2)[CH2:59][CH2:58][NH:57]1>CN(C)C=O>[NH2:34][C:35]1[N:44]=[C:43]([N:45]2[CH2:50][CH2:49][N:48]([CH3:51])[CH2:47][CH2:46]2)[C:42]2[C:37](=[CH:38][C:39]([C:52]([N:57]3[CH2:58][CH2:59][C:60]4[C:65](=[CH:64][CH:63]=[CH:62][C:61]=4[O:66][CH2:67][C:68]4[CH:69]=[C:70]([CH:73]=[CH:74][CH:75]=4)[C:71]#[N:72])[CH2:56]3)=[O:54])=[CH:40][CH:41]=2)[N:36]=1
Reactant: N#Cc1cccc(COc2cccc3c2CCNC3)c1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(c2nc(N)nc3cc(C(=O)N4CCc5c(cccc5OCc5cccc(C#N)c5)C4)ccc23)CC1
Reaction time: 2 h
Yield: 93.7 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (20 mg, 0.05 mmol) and N,N-diisopropylethylamine (10 uL, 0.07 mmol) were added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (10 mg, 0.03 mmol) and 3-[(1,2,3,4-tetrahydroisoquinolin-5-yloxy)methyl]benzonitrile HCl salt (30 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) at r.t. The reaction was stirred for 2 h. and the product was purified without workup by RP-HPLC (pH=10) to afford the desired compound (0.015 g, 33%) as an amorphous white solid. 1H NMR (500 MHz, DMSO): δ 7.79 (s, 1H), 7.71 (m, 2H.), 7.67 (d, 1H), 7.52 (t, 1H), 7.20 (s, 1), 7.05 (t, 1H), 6.96 (d, 1H), 6.83 (d, 1H), 6.70 (bs, 1H.), 6.02 (s, 2H.), 5.10 (s, 2H), 4.61 (m, 2H), 3.54 (m, 4H), 2.96 (s, 4H), 2.74 (m, 2H.), 2.44 (m, 2H.), 2.18 (s, 3H). (NMR sample heated to 90 c); Analytical LCMS (M+H)+: m/z=534.1.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][C:13]3=[O:18])=[N:9]2)=[CH:4][C:3]=1[C:19]#[N:20].[CH3:21][C:22]1[C:30]2[CH2:29][O:28][C:27](=[O:31])[C:26]=2[CH:25]=[CH:24][C:23]=1[C@@H:32]1[CH2:34][O:33]1>CCO>[OH:33][C@H:32]([C:23]1[CH:24]=[CH:25][C:26]2[C:27](=[O:31])[O:28][CH2:29][C:30]=2[C:22]=1[CH3:21])[CH2:34][N:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[C:3]([C:19]#[N:20])[CH:4]=3)[N:9]=2)[C:13](=[O:18])[CH2:14]1
Reactant: Cc1c([C@@H]2CO2)ccc2c1COC2=O
Reactant: Cc1cc2nc(N3CCNCC3=O)ccc2cc1C#N
Solvent: CCO
Product: Cc1cc2nc(N3CCN(C[C@H](O)c4ccc5c(c4C)COC5=O)CC3=O)ccc2cc1C#N
Temperature: 140 °C

Procedure:
A mixture of 7-Methyl-2-(2-oxopiperazin-1-yl)quinoline-6-carbonitrile [I-3] (125 mg, 0.47 mmol) and 4-methyl-5-[(2R)-oxiran-2-yl]-2-benzofuran-1(3H)-one (134 mg, 0.70 mmol) in EtOH (1.5 mL) in a 5 mL microwave tube was heated to 140° C. for 20 minutes. LC showed formation of the desired product, which was purified by mass-directed reverse phase HPLC (AcCN-Water with 0.1% TFA). LC-MS (IE, m/z): 457 [M+1]+.
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:15][C:14]([NH2:16])=[N:13][C:12]=1[CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1>[C:23]([NH:16][C:14]1[S:15][C:11]([C:9]([NH:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[C:12]([CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[N:13]=1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CCN(CC)Cc1nc(N)sc1C(=O)NCc1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)Cc1nc(NC(=O)c2ccccc2)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Yield: 31.1 %

Procedure:
To a solution of 2-amino-4-diethylaminomethylthiazole-5-carboxylic acid benzylamide (0.052 g, 0.16 mmol) in tetrahydrofuran (5 mL) at 0° C. were added benzoyl chloride (0.04 mL, 0.34 mmol), 4-dimethylaminopyridine (catalytical amount) and triethylamine (0.3 mL, 2.10 mmol). The reaction mixture was allowed to warm to ambient temperature over 18 h then concentrated in vacuo. The crude product was purified by flash column chromatography eluting with methanol/dichloromethane (1/40 to 20/80) to afford the title compound (0.021 g); MS (ES+) m/z 423 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:31][C:32]1[CH:33]=[C:34]([CH:37]=[CH:38][C:39]=1B1OC(C)(C)C(C)(C)O1)[CH:35]=[O:36].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.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>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:39]2[CH:38]=[CH:37][C:34]([CH:35]=[O:36])=[CH:33][C:32]=2[CH3:31])[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: Cc1cc(C=O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)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: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)cc2C)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 100 °C
Yield: 69.3 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (400 mg, 0.84 mmol) and 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (310 mg, 1.26 mmol) in dioxane (2 mL), aqueous 2M Na2CO3 solution (1.5 mL, 3.03 mmol) was added and solution was purged with argon for 15 min. Then Pd(PPh3)4 (97 mg, 0.08 mmol) was added and argon was purged again for 15 min. Reaction mass was heated at 100° C. for 4 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM (3 times). Combined organic layer was dried over sodium sulphate. Removal of the solvent under reduced pressure followed by column chromatographic purification afforded the desired compound (300 mg, 69.28%).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([O:20][CH3:21])[C:11]([O:18][CH3:19])=[N:12]2>CN(C)C=O>[N:1]([CH2:6][C:7]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]2[C:8]=1[N:9]=[C:10]([O:20][CH3:21])[C:11]([O:18][CH3:19])=[N:12]2)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1nc2cc(F)cc(CBr)c2nc1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc2cc(F)cc(CN=[N+]=[N-])c2nc1OC
Reaction time: 5 h

Procedure:
1.73 g (26.6 mmol) of sodium azide are added at room temperature to 4.0 g (13.3 mmol) of 5-bromomethyl-2,3-dimethoxy-7-fluoroquinoxaline in 50 ml of dimethylformamide and stirred for 5 h. The reaction mixture is poured onto water, extracted with diethyl ether and washed with water and brine. The organic phase is dried using Na2SO4, filtered off on a suction filter and concentrated. The title compound is obtained as white crystals of m.p. 75-78° C.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([C:15]([F:18])([F:17])[F:16])=[C:10]([C:12]([OH:14])=O)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.[CH2:50]([O:52][C:53]([CH:55]1[CH2:60][CH2:59][N:58]([C:61]2[CH:66]=[CH:65][C:64]([NH2:67])=[CH:63][CH:62]=2)[CH2:57][CH2:56]1)=[O:54])[CH3:51]>CN(C=O)C>[CH2:50]([O:52][C:53]([CH:55]1[CH2:56][CH2:57][N:58]([C:61]2[CH:66]=[CH:65][C:64]([NH:67][C:12]([C:10]3[N:11]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[O:8][C:9]=3[C:15]([F:18])([F:17])[F:16])=[O:14])=[CH:63][CH:62]=2)[CH2:59][CH2:60]1)=[O:54])[CH3:51]
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCN(c2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 2-phenyl-5-trifluoromethyl-oxazole-4-carboxylic acid (926 mg, 3.6 mmol), triethylamine (910 mg, 1.25 mL, 9.0 mmol), bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP, 2.51 g, 5.4 mmol) and 1-(4-amino-phenyl)-piperidine-4-carboxylic acid ethyl ester (3.6 mmol, prepared above) in DMF (10 mL) was stirred at room temperature overnight. The reaction mixture was diluted with. EtOAc, and washed twice with water. The organic phase was then dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (gradient elution with 10-50% ethyl acetate in hexanes) to provide 1-{4-[(2-phenyl-5-trifluoromethyl-oxazole-4-carbonyl)-amino]-phenyl}-piperidine-4-carboxylic acid ethyl ester. HRMS calcd for C25H24F3N3O4 (M+H) 488.1792, obsd 488.1792.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[CH2:10]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:17]=[C:18]1[C:23]2=[CH:24][NH:25][C:26]([CH:27]=O)=[C:22]2[CH2:21][CH2:20][NH:19]1.N1CCCCC1>C(O)C>[O:16]=[C:11]1[C:10](=[CH:27][C:26]2[NH:25][CH:24]=[C:23]3[C:22]=2[CH2:21][CH2:20][NH:19][C:18]3=[O:17])[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=2)[NH:12]1
Reactant: O=Cc1[nH]cc2c1CCNC2=O
Reactant: O=C1Cc2cc(-c3ccccc3)ccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1Nc2ccc(-c3ccccc3)cc2C1=Cc1[nH]cc2c1CCNC2=O
Temperature: 80 °C

Procedure:
A mixture of 5-phenyl-1,3-dihydro-indol-2-one (41.8 mg, 0.2 mmol), 4-oxo-4,5,6,7-tetrahydro-2H-pyrrolo[3,4-c]pyridine-1-carbaldehyde (1 equivalent) and 0.1 mL of piperidine in ethanol (1 mL) was heated in a sealed tube at 80° C. for 3 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give the title compound as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.N1C=CC=CC=1.[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([C:27](=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][Br:21])[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCNCC1
Reactant: O=C(Cl)CCCCCBr
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccccc1N1CCN(C(=O)CCCCCBr)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.1 %

Procedure:
To a stirred mixture of 1-(2-methoxyphenyl)piperazine (21.34 mmol) and pyridine (25.6 mmol) in 60 mL of dry dichloromethane was added dropwise a solution of 6-bromohexanoyl chloride (23.52 mmol) in 20 mL of dichloromethane at 0° C. under nitrogen. After addition, the mixture was allowed to warm to room temperature and stirred for 1-2 hours. The mixture was quenched with 10% potassium carbonate in water, and extracted with dichloromethane. The organic phase was washed with brine and water, dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography using 5% methanol, 0.5% ammonium hydroxide in ethyl acetate to give 1-(2-methoxyphenyl)-4-(6-bromohexanoyl)piperazine (6.00 g, 76%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:16]([CH2:18][CH2:19][C@@H:20]([NH:28]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:17])=[N+:2]=[N-:3].C(NCC)C>C(Cl)Cl>[NH2:28][C@H:20]([CH2:19][CH2:18][C:16](=[O:17])[NH:15][CH2:14][CH2:13][O:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22]
Reactant: CC(C)(C)OC(=O)[C@@H](CCC(=O)NCCOCCOCCOCCN=[N+]=[N-])NC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: ClCCl
Solvent: CCNCC
Product: CC(C)(C)OC(=O)[C@H](N)CCC(=O)NCCOCCOCCOCCN=[N+]=[N-]
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.2 %

Procedure:
Compound 103 (2.7 g, 4.3 mmol) was dissolved in 30 ml methylene chloride and 30 ml diethylamine was added. The reaction mixture was stirred at room temperature for 2 h, and then concentrated to an oil under reduced pressure. The residue was dissolved with diethyl ether and ethyl acetate (ca. 50 ml ea.) and extracted with 10% citric acid. The aqueous layer was neutralized to pH13 with 10N NaOH and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and concentrated under reduced pressure to give 1.6 g of a brown oil, 4.0 mmol, 92% (compound 104).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([CH3:21])[CH3:20])[O:15][C:14]2=[O:22])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:32][CH:33]=[CH:34][CH3:35]>CN(C)C=O.O>[F:1][C:2]1[C:12]([N:13]2[C:17](=[O:18])[C:16](=[C:19]([CH3:20])[CH3:21])[O:15][C:14]2=[O:22])=[CH:11][C:5]2[N:6]([CH2:32][CH:33]=[CH:34][CH3:35])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC=CCBr
Reactant: CC(C)=C1OC(=O)N(c2cc3c(cc2F)OCC(=O)N3)C1=O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC=CCN1C(=O)COc2cc(F)c(N3C(=O)OC(=C(C)C)C3=O)cc21
Temperature: 70 °C

Procedure:
To a solution of 3-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-5-isopropylidene-1,3-oxazolidine-2,4-dione (1.1 g), potassium carbonate (0.3 g) and potassium iodide (0.1 g) in N,N-dimethylformamide (50 ml), 1-bromo-2-butene (0.5 g) was added, followed by heating at 70° C. for 4 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography to give Compound No. 8 (1.0 g).
Reaction SMILES: [I:1][CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].ClC1C=CC=C(C(OO)=[O:68])C=1.O>C(Cl)Cl>[I:1][CH2:2][C:3]1[CH2:4][S:5](=[O:68])[C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35][C:36]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS(=O)[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 99.3 %

Procedure:
A mixture of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate (VIIa) (1.10 g, 1.19 mmoles) and m-chloroperbenzoic acid (m-CPBA) (322 mg, 1.30 mmoles) in CH2Cl2 (22 ml) was stirred at 0° C. for 15 minutes, poured into H2O (50 ml), and then extracted with CHCl3 (50 ml×3). The combined extracts were washed with saturated aqueous NaHCO3 (50 ml) and NaCl successively, dried and evaporated to afford the title compound (VIIa 1-oxide) (1.12 g, quantitative) as an amorphous powder.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4]1.[Cl:15][C:16]1[CH:24]=[C:23]2[C:19]([CH:20]=[C:21]([C:25](O)=[O:26])[NH:22]2)=[CH:18][CH:17]=1>>[C:11]([O:10][C:8]([N:5]1[CH2:6][CH2:7][C@H:3]([CH2:2][NH:1][C:25]([C:21]2[NH:22][C:23]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[C:16]([Cl:15])[CH:24]=3)=[O:26])[CH2:4]1)=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=C(O)c1cc2ccc(Cl)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](CN)C1
Product: CC(C)(C)OC(=O)N1CC[C@H](CNC(=O)c2cc3ccc(Cl)cc3[nH]2)C1

Procedure:
68.1 Using general procedure E, (R)-3-aminomethyl-1-N-tert-butoxycarbonyl-pyrrolidine was coupled with 6-chloro-1H-indole-2-carboxylic acid to give (R)-3-{[(6-chloro-1H-indole-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid tert-butyl ester. Pale yellow solid. MS376.1 ([M−H]−)
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:31]([CH2:33][C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1)[CH3:32])[CH2:29][CH3:30]>>[CH2:28]([N:31]([CH2:33][C:34]1[CH:35]=[CH:36][C:37]([NH:38]/[C:17](=[C:6]2\[C:5](=[O:27])[NH:4][C:12]3[C:7]\2=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=3)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:39][CH:40]=1)[CH3:32])[CH2:29][CH3:30]
Reactant: CCCN(C)Cc1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: CCCN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc(C(=O)OC)ccc32)c2ccccc2)cc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and 4-((N-propyl-N-methyl-amino)-methyl)-aniline Rf value: 0.5 (silica gel, methylene chloride/methanol 9:1) C28H29N3O3
Reaction SMILES: FC1C=CC(C(Cl)=O)=CC=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]([C:45](=[O:48])[CH2:46]C)[CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]([C:29]([C:31]3[CH:43]=[CH:42][C:34]([O:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=3)=[O:30])[CH:21]([CH3:44])[CH2:20]2)=[CH:14][CH:13]=1>>[C:45]([N:18]([C:15]1[CH:14]=[CH:13][C:12]([Cl:11])=[CH:17][CH:16]=1)[C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]([C:29]([C:31]2[CH:43]=[CH:42][C:34]([O:35][CH2:36][CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=2)=[O:30])[C@@H:21]([CH3:44])[CH2:20]1)(=[O:48])[CH3:46]
Reactant: CCC(=O)N(c1ccc(Cl)cc1)C1CC(C)N(C(=O)c2ccc(OCCCC(=O)O)cc2)c2ccccc21
Agent: O=C(Cl)c1ccc(F)cc1
Product: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(=O)O)cc2)c2ccccc21

Procedure:
(2S,4R)-4-(4-{4-[Acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid was prepared was made following general procedure C, substituting 4-methoxybenzoyl chloride for 4-fluorobenzoyl chloride. Further elaboration to the acid was done following the same procedure as described for (±)-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid.