Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[O:11][CH3:12].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.[CH3:44][N:45]1[C:49]2[C:50]3[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=3[O:56][C:57]3([CH2:62][CH2:61][NH:60][CH2:59][CH2:58]3)[C:48]=2[CH:47]=[N:46]1>CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:60]2[CH2:61][CH2:62][C:57]3([C:48]4[CH:47]=[N:46][N:45]([CH3:44])[C:49]=4[C:50]4[CH:51]=[CH:52][CH:53]=[CH:54][C:55]=4[O:56]3)[CH2:58][CH2:59]2)=[O:8])=[CH:4][C:3]=1[O:11][CH3:12]
Reactant: Cn1ncc2c1-c1ccccc1OC21CCNCC1
Reactant: COc1cc(C(=O)O)ccc1Br
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)ccc1Br
Reaction time: 0.17 h

Procedure:
To a 100 mL round bottom flask was added 4-bromo-3-methoxy-benzoic acid (860 mg, 3.7 mmol), HATU (1.4 g, 3.7 mmol), DMF (6 mL) and triethylamine (1.4 mL, 10 mmol). The reaction mixture was allowed to stir for 10 minutes. 1-Methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine] (860 mg, 3.4 mmol) dissolved in DMF (6 mL) was added, and the mixture was allowed to stir at 25° C. After 2 h, the reaction was quenched with brine and was extracted with ethyl acetate. The combined organic layers were washed with brine 3 times. The combined organic layer were dried over sodium sulfate and evaporated. The residue was purified via silica gel chromatography (5-90% EtOAc:hexanes) to give (4-bromo-3-methoxyphenyl)(1-methyl-1H-spiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone as white foam. ESI-MS m/z calc. 467.1, found 468.2 (M+1)+. Retention time: 3.04 minutes (4 min run).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([NH:8][NH2:9])=[CH:6][CH:7]=1.[C:10](O)([C:12]([F:15])([F:14])[F:13])=O>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[N:4]([C:10]([C:12]([F:15])([F:14])[F:13])=[N:9][N:8]=2)[N:3]=1
Reactant: O=C(O)C(F)(F)F
Reactant: NNc1ccc(Cl)nn1
Product: FC(F)(F)c1nnc2ccc(Cl)nn12
Temperature: 85 °C

Procedure:
A mixture of 3-chloro-6-hydrazinylpyridazine (3.3 g, 22.8 mmol) in TFA (60 mL) was heated to 85° C. for 18 h. The reaction mixture was cooled to room temperature and TFA was removed in vacuo. The residue was partitioned between DCM and saturated aqueous sodium bicarbonate and the organic layer was washed with a saturated solution of sodium bicarbonate (3×), dried over sodium sulfate, and evaporated to dryness to afford 2.8 g of 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine as a beige solid. 1H NMR (300 MHz, DMSO-d6) δ 8.72 (d, 1H), 7.78 (d, 1H).
Reaction SMILES: [C:1]([C:4]1[C:12]2[CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][C:7]=2[S:6][C:5]=1[NH:20][C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)=[O:22])(=[O:3])[NH2:2].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[Cl:30][C:27]1[CH:26]=[CH:25][C:24]([NH:23][C:21](=[O:22])[NH:20][C:5]2[S:6][C:7]3[CH2:8][NH:9][CH2:10][CH2:11][C:12]=3[C:4]=2[C:1]([NH2:2])=[O:3])=[CH:29][CH:28]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(sc(NC(=O)Nc3ccc(Cl)cc3)c2C(N)=O)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)c1c(NC(=O)Nc2ccc(Cl)cc2)sc2c1CCNC2

Procedure:
A stirred suspension of tert-butyl 3-carbamoyl-2-[3-(4-chlorophenyl)ureido]-4,5-dihydrothieno[2,3-c]pyridine-6(7H)-carboxylate (697 mg, 1.55 mmol) in 6 mL of DCM at rt was treated with 3 mL of TFA. The resultant solution was stirred at rt for 25 min whereupon it was concentrated in a rotary evaporator. The product was taken up in MeOH and the solution concentrated in vacuo (×2) to afford the title compound as a tan solid in quantitative yield. LRMS [M+H]351.
Reaction SMILES: Br[CH:2]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:3]([NH:5][C:6]1[S:7][C:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[Cl:18])=[CH:9][N:10]=1)=[O:4].[CH3:25][NH:26][CH3:27]>CN(C)C=O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][C:8]1[S:7][C:6]([NH:5][C:3](=[O:4])[CH:2]([N:26]([CH3:27])[CH3:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:10][CH:9]=1
Reactant: O=C(Nc1ncc(Cc2ccccc2Cl)s1)C(Br)c1ccccc1
Reactant: CNC
Solvent: CN(C)C=O
Product: CN(C)C(C(=O)Nc1ncc(Cc2ccccc2Cl)s1)c1ccccc1

Procedure:
2-Bromo-N-[5-(2-chloro-benzyl)-thiazol-2-yl]-2-phenyl-acetamide (42 mg, 0.10 mmol) was dissolved in 0.5 mL of N,N-dimethylformamide containing dimethylamine (90.2 mg, 2.00 mmol). The reaction vessel was sealed and then subjected to microwave irradiation for 5 minutes at 80° C. The crude mixture was evaporated to dryness and purified by reverse-phase preparative liquid chromatography (13 mg, 0.034, 34%). ESI-MS m/z calc. 385.1. found 386.0 (M+1)+ Retention time 2.40 minutes.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8]CC2C=CC=CC=2)=[CH:6][NH:5][C:4]([C:16]([NH:18][N:19]2[CH2:23][CH2:22][NH:21][C:20]2=[O:24])=[O:17])=[CH:3]1.C[Si](C([Si](C)(C)C)C(N)=O)(C)C>C(#N)C>[OH:8][C:7]1[C:2](=[O:1])[CH:3]=[C:4]([C:16]([NH:18][N:19]2[CH2:23][CH2:22][NH:21][C:20]2=[O:24])=[O:17])[NH:5][CH:6]=1
Reactant: O=C(NN1CCNC1=O)c1cc(=O)c(OCc2ccccc2)c[nH]1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Solvent: CC#N
Product: O=C(NN1CCNC1=O)c1cc(=O)c(O)c[nH]1
Reaction time: 1 h

Procedure:
To a suspension of 12 g (0.0365 mol) of 1,4-dihydro-4-oxo-N-(2-oxo-1-imidazolidinyl)-5-(phenylmethoxy)-2-pyridinecarboxamide in 150 ml of acetonitrile was added 36.1 ml (0.146 mol) of bis(trimethylsilyl)acetamide to form a slightly turbid solution. After filtration, 6 g of 10% palladium on charcoal was added and hydrogen was passed through the stirred reaction mixture. After hydrogenation for 60 minutes, the catalyst was filtered off and 15 ml of methanol and 2 ml of acetic acid were added. Stirring was continued overnight; the title compound crystallized out, yielding 6.6 g, melting point 270°-275° C.
Reaction SMILES: [O:1]=[C:2]1[C:7]2([CH2:11][CH2:10][CH2:9][CH2:8]2)[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:4]2([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[N:3]1[CH2:25][C:26]#[CH:27].I[C:29]1[CH:30]=[C:31]2[C:44](=[CH:45][CH:46]=1)[CH2:43][C@:33]1([C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]1=[O:42])[CH2:32]2.C(N(CC)CC)C>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.[Cu]I>[O:1]=[C:2]1[C:7]2([CH2:8][CH2:9][CH2:10][CH2:11]2)[N:6]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:5][C:4]2([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]2)[N:3]1[CH2:25][C:26]#[C:27][C:29]1[CH:30]=[C:31]2[C:44](=[CH:45][CH:46]=1)[CH2:43][C@:33]1([C:41]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[NH:35][C:34]1=[O:42])[CH2:32]2
Reactant: O=C1Nc2ncccc2[C@]12Cc1ccc(I)cc1C2
Reactant: C#CCN1C(=O)C2(CCCC2)N(C(=O)OC(C)(C)C)CC12CCCCCC2
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2(CCCCCC2)N(CC#Cc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C(=O)C12CCCC2
Temperature: 50 °C

Procedure:
A stirred suspension of tert-butyl 16-oxo-15-prop-2-yn-1-yl-6,15-diazadispiro[4.2.6.2]hexadecane-6-carboxylate (110 mg, 0.294 mmol, described in Intermediate 23), (2R)-5-iodo-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (106 mg, 0.294 mmol, described in Intermediate 27), tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.029 mmol), copper(I)iodide (23 mg, 0.121 mmol), and triethylamine (0.082 mL, 0.588 mmol) in degassed DMF (1.5 mL) was heated at 50° C. for 30 min. The reaction was quenched with water (30 mL), partitioned with saturated NaHCO3 solution (30 mL) and extracted with EtOAc (2×60 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified on silica gel, eluting with a gradient of CH2Cl2:MeOH—100:0 to 90:10, to yield the title compound. MS: m/z=609 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([OH:14])=O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH2:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:26]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:28]=[CH:29][CH:30]=2)[CH2:21][CH2:20]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:30]=[CH:29][CH:28]=[C:27]([NH:31][C:32](=[O:35])[CH2:33][CH3:34])[CH:26]=4)[CH2:21][CH2:20]3)=[O:14])[CH2:9][CH2:10][CH2:11]2)=[CH:6][CH:7]=1
Reactant: CCC(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Product: CCC(=O)Nc1cccc(C2CCN(CCCNC(=O)C3(c4ccc(Cl)cc4)CCC3)CC2)c1

Procedure:
Example 58 was prepared from 1-(4-chlorophenyl)cyclobutanecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}propanamide according to the procedures described in Scheme 10: ESMS m/e: 482.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:28]([C:29]([F:32])([F:31])[F:30])=[CH:27][C:5]([CH2:6][C@H:7]([C:12]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)=[O:13])[CH2:8][C:9]([OH:11])=O)=[CH:4][C:3]=1[Cl:33].[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:46][CH2:45][C:44]3[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=3[NH:42][C:41]2=[O:51])[CH2:36][CH2:35]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:28]([C:29]([F:30])([F:31])[F:32])=[CH:27][C:5]([CH2:6][C@@H:7]([CH2:8][C:9]([N:34]2[CH2:35][CH2:36][CH:37]([N:40]3[CH2:46][CH2:45][C:44]4[CH:47]=[CH:48][CH:49]=[CH:50][C:43]=4[NH:42][C:41]3=[O:51])[CH2:38][CH2:39]2)=[O:11])[C:12]([N:14]2[CH2:15][CH2:16][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]3)[CH2:18][CH2:19]2)=[O:13])=[CH:4][C:3]=1[Cl:33]
Reactant: O=C1Nc2ccccc2CCN1C1CCNCC1
Reactant: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)O)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C2CCN(C(=O)[C@H](CC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)Cc3cc(Cl)c(N)c(C(F)(F)F)c3)CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 6.3 g (12.8 mmol) of (S)-3-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-4-oxo-butanoic acid, 3.16 g (12.9 mmol) of 3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 4.66 g (14.5 mmol) of TBTU, 1.96 g (14.5 mmol) of HOBt, 9.45 mL (68 mmol) of triethylamine and 300 mL DMF was stirred for 12 h at RT. The reaction mixture was evaporated down i. vac., the residue was distributed between EtOAc and saturated NaHCO3 solution. The org. phase was separated off, dried and evaporated down i. vac. The residue was purified by chromatography on silica gel. The yellow oil obtained was triturated with ether and suction filtered. The desired product was obtained in the form of a white solid.
Reaction SMILES: [NH2:1][CH:2]1[C:9](=[O:10])[N:8]2[CH:3]1[S:4](=[O:37])[CH2:5][C:6]([CH:27]=[C:28]([S:30][C:31]1[S:35][C:34]([CH3:36])=[N:33][N:32]=1)[CH3:29])=[C:7]2[C:11]([O:13][CH:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[CH3:38][O:39][N:40]=[C:41]([C:45]1[N:46]=[C:47]([NH:50][C:51]([C:64]2[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=2)([C:58]2[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=2)[C:52]2[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=2)[S:48][CH:49]=1)[C:42](O)=[O:43].C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH:14]([O:13][C:11]([C:7]1[N:8]2[CH:3]([S:4](=[O:37])[CH2:5][C:6]=1[CH:27]=[C:28]([S:30][C:31]1[S:35][C:34]([CH3:36])=[N:33][N:32]=1)[CH3:29])[CH:2]([NH:1][C:42](=[O:43])[C:41](=[N:40][O:39][CH3:38])[C:45]1[N:46]=[C:47]([NH:50][C:51]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)([C:64]3[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=3)[C:52]3[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=3)[S:48][CH:49]=1)[C:9]2=[O:10])=[O:12])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CON=C(C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: CC(=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)C2S(=O)C1)Sc1nnc(C)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=C(C)Sc3nnc(C)s3)CS(=O)C12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 4 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
A solution of the Z form of 7-amino-2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (3.53 g) in methylene chloride (250 cc) is cooled to 4° C. 2-Methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (3.28 g) and dicyclohexylcarbodiimide (1.54 g) are added successively. The mixture is stirred for 11/2 hours at 4° C. and then concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is taken up in ethyl acetate (50 cc) and the insoluble material is filtered off. The solution is washed with a saturated aqueous solution of sodium bicarbonate (100 cc) and then with 0.1N hydrochloric acid (100 cc). It is dried over sodium sulphate and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. The residue is chromatographed on a column of Merck silica gel (0.06-0.2) (80 g) (diameter of the column: 3 cm; height: 64 cm). Elution is carried out with a 35/65 (by volume) ethyl acetate/cyclohexane mixture (300 cc) and then with a 70/30 (by volume) ethyl acetate/cyclohexane mixture (1,200 cc), 60 cc fractions being collected. Fractions 12 to 20 are concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 20° C. This yields the Z form of the syn isomer of 2-benzhydryloxycarbonyl-3-{2-[(2-methyl-1,3,4-thiadiazol-5-yl)-thio]-prop-1-en-1-yl}-7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)-acetamido]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-5-oxide (2 g) in the form of a hard white foam.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15](O)=O)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2].[NH2:21][C:22](=[N:39][OH:40])[C:23]1[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:25]([F:38])[CH:24]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[O:40][N:39]=[C:22]([C:23]3[CH:37]=[CH:36][C:26]([O:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:25]([F:38])[CH:24]=3)[N:21]=2)=[CH:11][C:10]=1[CH2:18][O:19][CH3:20])[CH3:2]
Reactant: CCOC(=O)CCCOc1ccc(C(N)=NO)cc1F
Reactant: CCc1ccccc1-c1ccc(C(=O)O)cc1COC
Product: CCOC(=O)CCCOc1ccc(-c2noc(-c3ccc(-c4ccccc4CC)c(COC)c3)n2)cc1F

Procedure:
The title compound was prepared following procedure described for example 4, step 1, but starting from Intermediate 36 (202.74 mg; 0.75 mmol) and Intermediate 66 (234.54 mg; 0.83 mmol). The reaction mixture was filtered through a SPE NH2 column (10 g) and rinsed with ACN. The filtrate was passed through a SPE SCX column (10 g) and rinsed with ACN. After evaporation of the solvents, the crude product was purified by flash chromatography (c-hex/(DCM/EtOAc 1:1) gradient from 1:0 to 1:1), affording the title compound as a colorless oil. 1H NMR (CDCl3) δ 8.41 (d, J=1.3 Hz, 1H), 8.15 (dd, J=7.9, 1.8 Hz, 1H), 7.95-7.90 (m, 2H), 7.41-7.34 (m, 3H), 7.29-7.23 (m, 1H), 7.12-7.05 (m, 2H), 4.22-4.13 (m, 6H), 3.33 (s, 3H), 2.57 (t, J=7.2 Hz, 2H), 2.50-2.28 (m, 2H), 2.24-2.17 (m, 2H), 1.27 (t, J=7.2 Hz, 3H), 1.05 (t, J=7.5 Hz, 3H). LC/MS (Method B): 519.4 (M+H)+. HPLC (Method A) Rt 6.62 min (Purity: 99.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[C@H:9]([NH:20][C:21](=[O:36])[C@H:22]([CH3:35])[NH:23][C:24](=[O:34])[CH2:25][C:26]3[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=3)[C:8](=[O:37])[NH:7][C:6]=2[CH:38]=1.[H-].[Na+].I[CH3:42]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C@H:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[F:19])[C@H:9]([NH:20][C:21](=[O:36])[C@H:22]([CH3:35])[NH:23][C:24](=[O:34])[CH2:25][C:26]3[CH:27]=[C:28]([F:33])[CH:29]=[C:30]([F:32])[CH:31]=3)[C:8](=[O:37])[N:7]([CH3:42])[C:6]=2[CH:38]=1
Reactant: CI
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)Nc2cc(Cl)ccc2S[C@@H]1c1cc(F)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)N[C@@H]1C(=O)N(C)c2cc(Cl)ccc2S[C@@H]1c1cc(F)ccc1F
Reaction time: 0.08 h
Yield: 83.3 %

Procedure:
To a stirred solution of N1-[(2R,3R)-7-chloro-2-(2,5-difluorophenyl)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepin-3-yl]-N2-[(3,5-difluorophenyl)acetyl]-L-alaninamide (92) (100 mg, 0.177 mmol) in DMF (800 uL) under nitrogen at ambient temperature was added sodium hydride powder (60% in mineral oil) (7 mg, 0.182 mmol). After 5 minutes, iodomethane (25 mg, 0.176 mmol) was added via micro-syringe. After stirring for 3½ hours, the reaction was carefully quenched with 1N aqueous HCl then diluted with water and extracted with ethyl acetate. The organic extracts were combined and evaporated. The residue was purified by flash chromatography on silica gel eluting first with 1:1 (v/v) hexanes:ethyl acetate and finally with ethyl acetate to afford the title compound (85 mg, 82%) as a white solid. 1H NMR (300 MHz, Acetone-d6) δ1.07 (d, 1.5H, J=7.0 Hz), 1.13 (d, 1.5H, J=7.0 Hz), 3.46-3.58 (m, 5H), 4.28 (m, 0.5H), 4.40 (m, 0.5H), 4.87 (m, 1H), 5.52 (m, 1H), 6.80-6.98 (m, 3H), 7.11-7.26 (m, 3H), 7.33 (m, 0.5H), 7.40-7.51 (m, 2.5H), 7.70 (d, 1H, J=2.2 Hz), 7.81 (d, 1H, J=8.3 Hz). MS APCI, m/z=580 (M+1). LC/MS: 2.89 min.
Reaction SMILES: [C:1](O)(=O)/[C:2](=[C:4](\[CH:6]=[O:7])/[Br:5])/[Br:3].Cl.Cl.[CH2:12]([NH:19][NH2:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C(O)C>[CH2:12]([N:19]1[C:6](=[O:7])[C:4]([Br:5])=[C:2]([Br:3])[CH:1]=[N:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NNCc1ccccc1
Reactant: O=C/C(Br)=C(/Br)C(=O)O
Agent: Cl
Solvent: O
Solvent: CCO
Product: O=c1c(Br)c(Br)cnn1Cc1ccccc1
Temperature: 25 °C
Yield: 54.4 %

Procedure:
Alternatively, a suspension of mucobromic acid (80 g., 310 mmol.) and benzylhydrazine dihydrochloride (60 g., 310 mmol.) in ethanol was heated to reflux for 16 hours. It was cooled to r.t. and under vigourous stirring water (50 mL) was added. The suspension was cooled in an ice bath and then filtered. The solid was washed with 95% aqueous ethanol and air dried. It was swished in hexanes (200 mL) and diethyl ether (25 mL), filtered and air dried to yield the title compound(58 g.).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([O:10]C)[CH:3]=1.[Al+3].[Cl-].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([OH:10])[CH:3]=1
Reactant: COc1cc(F)ccc1C#N
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(F)cc1O
Temperature: 130 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A mixture of intermediate 127, 4-fluoro-2-methoxybenzonitrile, (4.53 g, 30 mmol;) and AlCl3 (5.0 g, 37.6 mmol; Aldrich) in anhydrous toluene (30 mL) was stirred at approximately 130° C. for 18 hrs. After cooling, ice water (˜50 mL)was added and the resulting mixture extracted with ether (20 mL×2). The combined extracts were washed sequentially with water and brine, then dried (MgSO4), and concentrated in vacuo to provide the title compound (3.90 g, 28.5 mmol, Yield 95%) as a white solid: 1H NMR (DMSO-d6, 300 MHz) δ ppm: 6.74-6.84 (2H, m, Ar-Hs), 7.71 (1H, dd, J=7 Hz, J=8.5 Hz, Ar—H), 11.64 (1H, s, OH); 13C NMR (DMSO-d6, 75.5 Hz) δ ppm: 95.13 102.45, 102.78, 106.53, 106.83 115.53, 134.68, 134.84, 161.41, 161.58, 163.00, 166.35. HRMS (ESI-) calcd for C7H3NOF (M−H) 136.0199, found 136.0199.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])[CH2:2]C.OO.S(=O)(=O)(O)[OH:13].[I-].[K+].S([O-])([O-])(=O)=S.[Na+].[Na+].C(OO)=O>>[CH2:1]([O:4][CH2:5][CH2:6][C:7]([O:9][OH:13])=[O:8])[CH3:2]
Reactant: CCCOCCC(=O)O
Reactant: O=S(=O)(O)O
Agent: O=COO
Agent: O=S([O-])([O-])=S
Agent: OO
Product: CCOCCC(=O)OO
Reaction time: 96 h

Procedure:
3-Propoxypropionic acid (25.0 g, 189 mmol) was added with 50% aqueous hydrogen peroxide (16.4 mL, 284 mmol) and concentrated sulfuric acid (0.5 mL, 9.4 mmol) and left at room temperature for 4 days. Potassium iodide/sodium thiosulfate titration as described in Example 1 was conducted to determine the concentration of peroxycarboxylic acid 3 (Compound 3) after the 4 days.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH:18]1[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:21]2[C:26]=1[CH:25]=[CH:24][CH:23]=[CH:22]2>ClCCl>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([C:18]2[CH:19]=[C:20]([CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[N:21]3[C:26]=2[CH:25]=[CH:24][CH:23]=[CH:22]3)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)CCCc1ccc2ccccn12
Reactant: CC(=O)Oc1ccc(C(=O)Cl)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCOC(=O)CCCc1cc(C(=O)c2ccc(OC(C)=O)cc2)c2ccccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 37.1 %

Procedure:
4-Acetoxybenzoyl chloride (53.6 g) was added to a suspension of aluminum chloride (36.5 g) in dichloromethane (500 ml). After the mixture was stirred for 20 minutes at room temperature, a solution of ethyl 4-(indolizin-3-yl)butyrate (57.8 g) in dichloromethane (50 ml) was added to the mixture. The mixture was stirred for 2 hours at room temperature and the solvent was evaporated. The residue was dissolved in ethyl acetate (500 ml) and washed with water. N,N-dimethylaminopropylamine (20 ml) was added to the solution. The mixture was washed with diluted hydrochloric acid, water, sodium bicarbonate aqueous solution and water. The solution was dried over magnesium sulfate and the solvent was removed in vacuo. The residue was washed with diisopropyl ether to give ethyl 4-[1-(4-acetoxybenzoyl)indolizin-3-yl]butyrate as yellow powder (36.5 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=3[F:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:21]C.Cl.N1C=CC=CC=1.Cl>CC(=O)CC>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[CH:13][C:12]=3[F:20])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:21]
Reactant: CCOc1ccc(-c2noc3c(Cl)c(OC)ccc23)c(F)c1
Agent: Cl
Solvent: CCC(C)=O
Solvent: c1ccncc1
Product: CCOc1ccc(-c2noc3c(Cl)c(O)ccc23)c(F)c1
Temperature: 180 °C

Procedure:
A mixture of 14.2 g of 7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-methoxy-1,2-benzisoxazole and pyridine hydrochloride is heated at 180° C. for 2 hr. The reaction is worked up with 2-butanone and 5% hydrochloric acid and the product crystallized from toluene to give 7-chloro-3-(4-ethoxy-2-fluorophenyl)-6-hydroxy-1,2-benzisoxazole, mp 170°-172° C. The hydroxy compound is alkylated with 0.045 mole of ethyl bromoacetate and 0.043 mole of potassium carbonate in 75 ml dimethylformamide at 65° C. for 1 hr. Workup with water gives ethyl [7-chloro-3-(2-fluoro-4-ethoxyphenyl)-1,2-benzisoxazol-6-yl]oxy}acetate, mp 118°-119° C., after recrystallization from acetonitrile.