Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[OH:33]>N1C=CC=CC=1>[F:23][C:24]1[CH:29]=[C:28]([N+:30]([O-:32])=[O:31])[CH:27]=[CH:26][C:25]=1[O:33][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][C:16]3([C:19]([O:21][CH3:22])=[O:20])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(O)c(F)c1
Reactant: COC(=O)C1(COc2cc3nccc(Cl)c3cc2OC)CC1
Solvent: c1ccncc1
Product: COC(=O)C1(COc2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3cc2OC)CC1
Temperature: 110 °C
Yield: 55432.1 %

Procedure:
A mixture of Methyl 1-((4-chloro-6-methoxyquinolin-7-yloxy)methyl)cyclopropane-carboxylate (29.2 g, US12036244) and 2-fluoro-4-nitrophenol (20.5 mg) in pyridine (50 ml) was heated at 110° C. for 4 hours and cooled. The reaction was evaporated and water (300 ml) was added and further sonicated for 20 minutes. The solid was filtered and washed with water followed by acetone to give the product as methyl 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropanecarboxylate (32 g). This product (3.9 g) was mixed with LiOH (0.82 g) in THF/H2O (40 ml/20 ml) and the mixture was refluxed for 4 hours. The solution was evaporated and acidified with AcOH, the precipitated was filtered and washed with water followed by acetone to give the product as 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclo-propanecarboxylic acid. This acid (1 g) was mixed with DIPEA (0.53 ml) in acetone (50 ml) and cooled at 0° C. To the reaction mixture was added isobutylchloroformate slowly and further stirred for 1 hour at 0° C. To the reaction was added NaN3 (1.52 g) in water (2 ml) and further stirred for 2 hours at 0° C. EtOAc (100 ml) was added to the reaction and washed with brine, dried over Na2SO4. The solution was evaporated to around 10 ml and toluene (70 ml) was added followed by addition of 4-methoxybenzyl alcohol. The solution was refluxed for 4 hours and cooled, EtOAc (50 ml) and water (50 ml) were added and further extracted with EtOAc two times. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated and purified with silica gel column to give 4-methoxybenzyl 1-((4-(2-fluoro-4-nitrophenoxy)-6-methoxyquinolin-7-yloxy)-methyl)cyclopropyl-carbamate (850 mg) that was mixed with Fe power (1 g) and NH4Cl (100 mg) in EtOH/H2O (20 ml, 16 ml/4 ml). The solution was refluxed for two hours and filtered through the Celite and washed with MeOH. The filtrate was evaporated and partitioned with water and DCM, the aqueous layer was further extracted with DCM twice. The combined organic layer was washed with water, brine and dried over Na2SO4. The solution was evaporated to give 4-methoxybenzyl 1-((4-(2-fluoro-4-aminophenoxy)-6-methoxyquinolin-7-yloxy)methyl)cyclopropylcarbamate (650 mg) for next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C@H:12]([NH:14][C:15]([C@@H:17]3[CH2:22][CH2:21][CH2:20][N:19]([C:23](=[O:34])[C@@H:24]([NH:26][C:27](=[O:33])[C@@H:28]([OH:32])[CH:29]([CH3:31])[CH3:30])[CH3:25])[NH:18]3)=[O:16])[CH3:13])=[N:9]2)=[CH:4][CH:3]=1.[CH:35]([C:37]1([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]1)=[CH2:36].C(N(CC)CC)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:32][C@@H:28]([CH:29]([CH3:31])[CH3:30])[C:27]([NH:26][C@@H:24]([CH3:25])[C:23]([N:19]1[CH2:20][CH2:21][CH2:22][C@@H:17]([C:15]([NH:14][C@@H:12]([C:8]2[CH:7]=[CH:6][C:5]3[C:10](=[CH:11][C:2](/[CH:36]=[CH:35]/[C:37]4([C:44]([OH:46])=[O:45])[CH2:43][O:42][CH2:41][CH2:40][O:39][CH2:38]4)=[CH:3][CH:4]=3)[N:9]=2)[CH3:13])=[O:16])[NH:18]1)=[O:34])=[O:33]
Reactant: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(Br)cc3n2)N1
Reactant: C=CC1(C(=O)O)COCCOC1
Agent: [Pd]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(C)[C@H](O)C(=O)N[C@@H](C)C(=O)N1CCC[C@@H](C(=O)N[C@H](C)c2ccc3ccc(/C=C/C4(C(=O)O)COCCOC4)cc3n2)N1
Temperature: 50 °C

Procedure:
A mixture of (S)-1-[(S)-2-((S)-2-hydroxy-3-methyl-butyrylamino)-propionyl]-hexahydro-pyridazine-3-carboxylic acid [(R)-1-(7-bromo-quinolin-2-yl)-ethyl]-amide (68 mg, 0.128 mmol), 6-vinyl-[1,4]dioxepane-6-carboxylic acid (22 mg, 0.128 mmol), triethylamine (39 mg, 54 μL, 0.384 mmol) and tri(o-tolyl)phosphine (8 mg, 0.026 mmol) in 1,4-dioxane (2 mL) was deoxygenated by bubbling nitrogen through for 5 minutes and then warmed to 50° C. under nitrogen with stirring. Tris(dibenzylideneacetone)dipalladium(0) (12 mg, 0.013 mmol) was added and the mixture was refluxed for 40 minutes and then allowed to cool. The suspension was filtered and the filtrate was evaporated to give crude title compound which was used directly in the next stage. LCMS (m/z) 626.2 [M+H], Tr=1.67 min.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=1.[CH3:17][C:18]([CH3:34])([CH3:33])[CH2:19][N:20]1[C:28]2[C:23](=[C:24]([CH2:30][CH2:31][CH3:32])[C:25]([OH:29])=[CH:26][CH:27]=2)[CH:22]=[CH:21]1>>[CH3:17][C:18]([CH3:33])([CH3:34])[CH2:19][N:20]1[C:28]2[C:23](=[C:24]([CH2:30][CH2:31][CH3:32])[C:25]([O:29][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:16]=[CH:15][C:10]([C:11]([OH:13])=[O:12])=[CH:9][CH:8]=3)=[CH:26][CH:27]=2)[CH:22]=[CH:21]1
Reactant: CCCc1c(O)ccc2c1ccn2CC(C)(C)C
Reactant: COC(=O)c1ccc(OCCCCBr)cc1
Product: CCCc1c(OCCCCOc2ccc(C(=O)O)cc2)ccc2c1ccn2CC(C)(C)C

Procedure:
Similar procedures as outlined in examples 1 & 26 were followed using methyl 4-(4-bromobutoxy)benzoate and 1-(2,2-dimethylpropyl)-4-propyl-1H-indol-5-ol. 1H NMR (500 MHz, DMSO) δ 12.64 (s, 1H), 7.92 (d, 2H), 7.24 (d, 1H), 7.20 (s, 1H), 7.02 (d, 2H), 6.87 (d, 1H), 6.37 (d, 1H), 4.14 (t, 2H), 4.01 (t, 2H), 3.90 (s, 2H), 2.77 (t, 2H), 1.95 (m, 2H), 1.88 (m, 2H), 1.59 (m, 2H), 0.92 (s, 9H), 0.90 (t, 3H). MS (ESI): 438 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[C:4]#[N:5].O=[C:17]([CH3:24])[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[CH2:10][CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[N:1]=[C:17]([CH3:24])[C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CC(C)(C)CCc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(CCC(C)(C)C)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(3,3-dimethylbutyl)benzonitrile (Example 21b) and ethyl 3-oxobutanoate as a white solid (95%). 1H NR (400 MHz, DMSO-d6) δ 0.93 (s, 9H), 1.32 (t, J=7.2 Hz, 3H), 1.42-1.46 (m, 1H), 2.55 (s, 3H), 3.11-3.15 (m, 2H), 4.33 (q, J=7.2 Hz, 2H), 7.12 (s, 2H), 7.19-7.21 (m, 1H), 7.46-7.52 (m, 2H). MS 315 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4].[Cl:14][S:15](O)(=[O:17])=[O:16]>>[CH3:1][O:2][C:3]([C:5]1([C:8]2[CH:13]=[CH:12][C:11]([S:15]([Cl:14])(=[O:17])=[O:16])=[CH:10][CH:9]=2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=S(=O)(O)Cl
Reactant: COC(=O)C1(c2ccccc2)CC1
Product: COC(=O)C1(c2ccc(S(=O)(=O)Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57 %

Procedure:
Chlorosulfonic acid (10 mL) was cooled to 0° C. Then compound 36A (6.80 g, 38.6 mmol) was added over 30 min. The mixture was stirred at RT for 3 h and was poured into ice (˜500 g). The cloudy solution was extracted with ether (2×200 mL). The extracts were dried with magnesium sulfate and concentrated to give a brown oil which was passed through a short pad of silica gel to afford the desired product 36B (6.05 g, 57%) as white plates. MS: 239 (M−Cl)+.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=1.CS(C)=O>C(#N)C>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Solvent: CC#N
Solvent: CS(C)=O
Product: O=C(NCc1cccnc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
A solution of 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Step B (0.28 mmol), and 3-aminomethylpyridine (0.59 mmol), in dimethylsulfoxide (1.5 mmol) and acetonitrile (2.5 mL) was stirred at 80° C. for 18 hours. The solvent was evaporated and the residue dissolved in dichloromethane, washed with water, dried over anhydrous sodium sulfate, and evaporated. The material was purified by HPLC (Normal phase, Luna CN bonded packing) and crystallized from ethyl acetate/hexane. (0.103 g; 75%), m.p. 169-171° C.
Reaction SMILES: Cl[CH2:2][C:3]#[C:4][CH3:5].[CH3:6][O:7][C:8]([CH:10]1[CH:15]([CH3:16])[O:14][CH:13]([CH3:17])[CH2:12][N:11]1[S:18]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)(=[O:20])=[O:19])=[O:9]>>[CH3:6][O:7][C:8]([C@H:10]1[C@H:15]([CH3:16])[O:14][C@@H:13]([CH3:17])[CH2:12][N:11]1[S:18]([C:21]1[CH:22]=[CH:23][C:24]([O:27][CH2:2][C:3]#[C:4][CH3:5])=[CH:25][CH:26]=1)(=[O:20])=[O:19])=[O:9]
Reactant: CC#CCCl
Reactant: COC(=O)C1C(C)OC(C)CN1S(=O)(=O)c1ccc(O)cc1
Product: CC#CCOc1ccc(S(=O)(=O)N2C[C@H](C)O[C@@H](C)[C@@H]2C(=O)OC)cc1

Procedure:
The title compound was prepared in a manner similar to Preparation 3 from 1-chloro-but-2-yne and 4-(4-Hydroxy-benzenesulfonyl)-2,6-dimethyl-morpholine-3-carboxylic acid methyl ester. 1HNMR (400 MHz, CDCl3): δ=7.66 (d, J=8.9 Hz, 2H), 6.98 (d, J=8.9 Hz, 2H), 4.65 (bs, 2H), 4.47 (q, J=6.4 Hz, 1H), 4.23 (s, 1H), 3.92 (m, 1H), 3.50 (s, 3H), 2.93 (dd, J=12.2 and 11.0 Hz, 1H), 1.79(t, J=2.3 Hz, 3H), 1.40 (d, J=6.6 Hz, 3H), 1.01(d, J=6.0, 3H). MS: Calculated for C18H23NO6S (M+H): 382.13. Found: 382.0.
Reaction SMILES: Cl[C:2]1[C:3]2[S:22][CH2:21][CH2:20][C:4]=2[N:5]=[C:6]([N:8]2[CH2:13][CH2:12][N:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:10][CH2:9]2)[N:7]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH2:31])[CH:28]=[CH:29][CH:30]=1.C(N(C(C)C)CC)(C)C>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:2]2[C:3]3[S:22][CH2:21][CH2:20][C:4]=3[N:5]=[C:6]([N:8]3[CH2:13][CH2:12][N:11]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH2:10][CH2:9]3)[N:7]=2)[CH:28]=[CH:29][CH:30]=1
Reactant: Clc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Reactant: COc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc(Nc2nc(N3CCN(c4ccccc4)CC3)nc3c2SCC3)c1

Procedure:
0.320 g (0.96 mmol) of 4-chloro-2-(4-phenylpiperazin-1-yl)-6,7-dihydrothieno[3,2-d]pyrimidine (V), 1.5 mL (13.1 mmol) of 3-methoxyphenylamine, and 0.33 mL (1.92 mmol) of diisopropylethylamine are combined, and reacted for 0.5 hours at 130° C. in the microwave. Then the reaction mixture is purified by chromatography using HPLC through an RP column (column: Microsorb, RP-C18, 300 Å, 10 μm, 21.4*250 mm, eluant: acetonitrile+0.1% formic acid (A), water+0.13% formic acid (B)).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.S(=O)(=O)(O)O.[C:24](=O)(O)[O-].[Na+]>CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:12])[C:9]([O:11][CH3:24])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C([O-])O
Reactant: CC(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)C(C)c1ccc(-c2ccccc2)c(F)c1
Temperature: 40 °C
Reaction time: 2.5 h

Procedure:
2-(2-Fluoro-biphenyl-4-yl)-propionic acid (104.2 g) was dissolved in methanol (410 ml) and then conc. sulfuric acid (60.2 g) was added, after which the resulting mixture was stirred at 40° C. for 2.5 hours. The mixture was cooled to room temperature, diluted with toluene, then neutralized with a saturated aqueous sodium bicarbonate solution, and thereafter subjected to extraction with ethyl acetate. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure, to obtain methyl 2-(2-fluoro-biphenyl-4-yl)-propionate (110.2 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[CH2:32][CH2:33][CH2:34][O:35][CH3:36]>O>[CH3:36][O:35][CH2:34][CH2:33][CH2:32][O:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][N:9]=[C:10]([CH3:16])[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[C:4]([N+:17]([O-:19])=[O:18])[CH:3]=1
Reactant: COCCCBr
Reactant: CCOC(=O)C(C)=NNc1ccc(O)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)=NNc1ccc(OCCCOC)cc1[N+](=O)[O-]
Temperature: 60 °C
Reaction time: 15 h
Yield: 42.4 %

Procedure:
To a mixture of ethyl 2-[(4-hydroxy-2-nitrophenyl)hydrazono]propanoate (6.81 g), potassium carbonate (3.52 g) and N,N-dimethylformamide (100 mL) was added 1-bromo-3-methoxypropane (3.90 g) at 60° C., and the mixture was stirred at 60° C. for 15 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-1:1, volume ratio) to give the title compound (3.67 g, yield 42%) as orange crystals.
Reaction SMILES: O([C:8]([N:10]1[CH2:14][CH2:13][CH2:12][C:11]1=[O:15])=[O:9])C1C=CC=CC=1.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][NH2:27])=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[CH3:16][O:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][CH2:25][CH2:26][NH:27][C:8]([N:10]2[CH2:14][CH2:13][CH2:12][C:11]2=[O:15])=[O:9])=[CH:20][CH:19]=1
Reactant: COc1ccc(NCCN)cc1
Reactant: O=C1CCCN1C(=O)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COc1ccc(NCCNC(=O)N2CCCC2=O)cc1
Yield: 91.4 %

Procedure:
A mixture of 4.0 g (19.5 mmol) of 1-phenoxycarbonyl-2-oxopyrrolidine and 3.4 g (20.4 mmol) of 2-(4-methoxyphenylamino)ethylamine was heated at 115°-120° C. for 4 hr. The reaction solution was refined by silica gel column chromatography, whereby 4.94 g (87.0%) of the objective product (I a-1) was obtained from the eluate with toluene-ethyl acetate (3/1 v/v). The needles melting at 83.5°-84.5° C. were obtained by recrystallizing from ethanol.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(OCC)=O.[OH-].[NH4+:24].[Cl-].[NH4+]>O1CCCC1.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14](=[O:16])[NH2:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(N)=O
Reaction time: 0.58 h

Procedure:
58 g of (2S, 4R)-1-(t-butoxycarbonyl)-4-hydroxy-2-pyrrolidinecarboxylic acid [prepared as described in step (1) aboveπ were dissolved in 850 ml of dry tetrahydrofuran, and then 38.2 ml of triethylamine were added to the mixture at -15° to -20° C. A solution of 26.3 ml of ethyl chloroformate in 240 ml of dry tetrahydrofuran was then added dropwise to the mixture at -15° to -20° C., and the mixture was stirred at the same temperature for 35 minutes. At the end of this time, 258 ml of 28% w/v aqueous ammonium hydroxide were added to the mixture at -15° to -20° C., and the mixture was allowed to stand overnight at room temperature. Ammonium chloride was then added to the reaction mixture, which was then extracted with tetrahydrofuran. The extract was dried and freed from the solvent by distillation under reduced pressure. The resulting residue was triturated with diethyl ether to cause crystallization. The crystals were collected by filtration and washed with diethyl ether to afford 49.7 g of the title compound as colorless crystals, melting at 146°-148° C.
Reaction SMILES: [CH2:1]([N:3]([CH2:33][CH3:34])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([O:31]C)=[O:30])(=[O:17])=[O:16])=[O:8])[CH3:2].O.O.[OH-].[Li+].Cl>O1CCOCC1>[CH2:33]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15]([NH:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]=1[C:29]([OH:31])=[O:30])(=[O:17])=[O:16])=[O:8])[CH3:34]
Reactant: CCN(CC)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC)CCNC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)O
Temperature: 60 °C
Reaction time: 8 h

Procedure:
A solution of Example 299A (244 mg, 0.505 mmol) in dioxane (8 mL) and distilled water (4 mL) was treated with lithium hydroxide monohydrate (212 mg, 5.05 mmol), stirred at 60° C. overnight, cooled to room temperature, treated with 1N HCl, and extracted with ethyl acetate two times. The combined organic fractions were washed with brine, dried (MgSO4), filtered, and concentrated. The resulting residue was purified by preparative HPLC to provide the desired product. MS (ESI(+)) m/e 470 (M+H)+; (ESI(−)) m/e 468 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 9.73 (br s, 1H), 9.10 (br s, 1H), 9.01 (t, 1H), 7.99 (t, 2H), 7.92 (dd, 1H), 7.84 (dd, 1H), 7.76 (dt, 1H), 7.70-7.45 (m, 5H), 3.65 (m, 4H), 3.25 (m, 4H), 1.24 (t, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:15][CH2:14][N:13](C#N)[CH2:12][CH2:11]3)[C:9](=[O:18])[NH:8][C:5]2=[CH:6][CH:7]=1.[OH-].[Na+]>C(O)CO.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:11][CH2:12][NH:13][CH2:14][CH2:15]3)[C:9](=[O:18])[NH:8][C:5]2=[CH:6][CH:7]=1
Reactant: N#CN1CCC2(CC1)C(=O)Nc1ccc(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: OCCO
Product: O=C1Nc2ccc(Br)cc2C12CCNCC2
Temperature: 130 °C
Yield: 59.3 %

Procedure:
5-Bromo-1,2-dihydro-2-oxospiro[3H-indole-3,4′-piperidine]-1′-cyano 12 (3.3 g, 10.8 mmol) was suspended in ethylene glycol (10 ml). The mixture was treated in NaOH (1.8 g, 45 mmol) and heated to 130° C. for 15 min. It was diluted with methylene chloride (500 ml) and washed with 10% aqueous K2CO3 (2×100 m). The organic layer was dried (Na2SO4) and concentrated and residue purified by silica gel chromatography (30% MeOH/CH2Cl2) to gave 13 as a light ceramic white solid 1.8 g (60%), mp 256-258° C. 1HNMR (DMSO-d6, 400 MHz) δ 10.6 (br s, 1H, NH), 7.57 (d, J=1.84 Hz, 1H), 7.36 (d, J=8.2 Hz, 1H), 6.79 (d, J=8.2 Hz, 1H), 4.05 (br s, 1H, NH), 3.06 (m, 2H), 2.84 (m, 2H), 1.64 (m, 2H), 1.55 (m, 2H), 13C NMR (DMSO-d6, 100 MHz) δ 180.93, 140.64, 137.98, 130.42, 126.75, 113.20, 111.45, 46.24, 40.92, 32.94. Anal. Calcd for C12H13BrN2O: C, 51.26; H, 4.66; N, 9.9. Found: C, 50.87; H, 4.91; N, 9.67.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:8]=[C:9]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[S:34]([CH3:37])(=[O:36])=[O:35])[CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][NH:15][S:16]([C:19]1[CH:24]=[C:23]([C:25]#[N:26])[CH:22]=[CH:21][C:20]=1[OH:27])(=[O:18])=[O:17])C.[OH-].[Na+].Cl>C(O)C>[C:25]([C:23]1[CH:22]=[CH:21][C:20]([OH:27])=[C:19]([S:16]([NH:15][CH2:14][CH2:13][C:12]2[CH:11]=[CH:10][C:9]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[S:34]([CH3:37])(=[O:36])=[O:35])=[CH:8][C:7]=2[O:6][CH2:5][C:4]([OH:38])=[O:3])(=[O:17])=[O:18])[CH:24]=1)#[N:26]
Reactant: CCOC(=O)COc1cc(-c2ccccc2S(C)(=O)=O)ccc1CCNS(=O)(=O)c1cc(C#N)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)O)c1
Yield: 101.9 %

Procedure:
To a stirred solution of 154 g of ethyl[4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate in 1.23 L of ethanol was added 275 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the mixture was stirred under ice-cooling for 1.5 hours. To the reaction mixture was added drop wise 275 mL of 2 mol/L hydrochloric acid, and ethanol was removed under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with brine. The solvent was dried over anhydrous magnesium sulfate, and removed under reduced pressure to give 149 g of [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][O:11][C:12](=[O:41])[C:13](=O)[CH:14](Br)[CH:15]([CH3:38])[CH:16]2[CH:19]([CH:20]([O:22][Si](C(C)(C)C)(C)C)[CH3:21])[C:18](=[O:30])[N:17]2[Si](C(C)(C)C)(C)C)=[CH:6][CH:5]=1)([O-:3])=[O:2].[SH:42][C@H:43]1[CH2:47][O:46][C@@H:45]([CH2:48][OH:49])[CH2:44]1.O1CCCC1>C(N(CC)CC)C>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][O:11][C:12]([C:13]2[N:17]3[CH:16]([CH:15]([CH3:38])[C:14]=2[S:42][CH:43]2[CH2:44][CH:45]([CH2:48][OH:49])[O:46][CH2:47]2)[CH:19]([CH:20]([OH:22])[CH3:21])[C:18]3=[O:30])=[O:41])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OC[C@H]1C[C@@H](S)CO1
Reactant: CC(O[Si](C)(C)C(C)(C)C)C1C(=O)N([Si](C)(C)C(C)(C)C)C1C(C)C(Br)C(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(O)C1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(SC3COC(CO)C3)C(C)C12

Procedure:
The title compound is prepared by the procedure of Example 104 using 0.166 g of product from Example 103, 0.0396 g of product from Example 77, 2.3 ml of dry tetrahydrofuran and 0.0413 ml of triethylamine to obtain the crude β-lactam. The subsequent cyclization uses the above product, 1.48 ml of 1M solution in methylene chloride of titanium tetrachloride and 1.6 ml of dry tetrahydrofuran to give 0.053 g of the desired product as a white solid.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14](O)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH:24]([O:27][C:28]1[N:33]=[C:32]2[S:34][C:35]([NH2:37])=[N:36][C:31]2=[CH:30][CH:29]=1)([CH3:26])[CH3:25].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CN1CCOCC1>CN(C=O)C>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([O:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[C:14]([NH:37][C:35]3[S:34][C:32]4[C:31]([N:36]=3)=[CH:30][CH:29]=[C:28]([O:27][CH:24]([CH3:26])[CH3:25])[N:33]=4)=[O:15])=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: O=C(O)C(OC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)Oc1ccc2nc(N)sc2n1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc2nc(NC(=O)C(OC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)sc2n1
Yield: 38.9 %

Procedure:
The compound of example A82 was obtained by similar method described in example A75 using (4-cyclopropanesulfonyl-phenyl)-[(tetrahydro-pyran-4-yloxy)]-acetic acid (Preparation 14) (0.100 g,0.29 mmol), 5-iso-propoxy-thiazolo[5,4-b]pyridin-2-ylamine (0.067 g, 0.32 mmol), HOBt (0.047 g, 0.35 mmol), and EDCI (0.067 g, 0.35 mmol), N-methyl morpholine (0.065 g, 0.58 mmol) in DMF (5 mL) to provide the title compound (0.060 g).