Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[N:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:11])[N:3]([CH3:8])[CH2:4][C:5]([OH:7])=[O:6].[CH3:20][CH:21](O)[CH3:22]>Cl>[ClH:19].[NH2:1][C:2](=[N:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=1)=[O:11])[N:3]([CH3:8])[CH2:4][C:5]([O:7][CH:21]([CH3:22])[CH3:20])=[O:6]
Reactant: CC(C)O
Reactant: CN(CC(=O)O)C(N)=NC(=O)Nc1cccc(Cl)c1
Agent: Cl
Product: CC(C)OC(=O)CN(C)C(N)=NC(=O)Nc1cccc(Cl)c1
Reaction time: 24 h
Yield: 55 %

Procedure:
A 5.0 g sample of N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycine was stirred in 200 ml of 4% hydrogen chloride in 2-propanol for 30 minutes. The undissolved solid was removed by filtration. The filtrate was stirred for 24 hours at 25°. The solution was cooled and the precipitated white crystalline 2-propyl N-{amino[(3-chlorophenyl)aminocarbonyl]iminomethyl}-N-methylglycinate, 3.5 g (55% yield), was collected and dried, m.p. 185° C. (d).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([CH3:23])[CH:17]=2)=[CH:11][C:10]=1[CH3:24])(C)(C)C.C([O-])([O-])=O.[Cs+].[Cs+].CN(C=O)C.[F:37][C:38]([F:48])([F:47])[C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Br)=[CH:41][CH:40]=1>O>[CH3:24][C:10]1[CH:11]=[C:12]([S:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:43][C:42]3[CH:41]=[CH:40][C:39]([C:38]([F:37])([F:47])[F:48])=[CH:46][CH:45]=3)=[C:18]([CH3:23])[CH:17]=2)[CH:13]=[CH:14][C:9]=1[O:8][CH2:7][C:6]([OH:5])=[O:25]
Reactant: Cc1cc(Sc2ccc(OCC(=O)OC(C)(C)C)c(C)c2)ccc1O
Reactant: FC(F)(F)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(Sc2ccc(OCc3ccc(C(F)(F)F)cc3)c(C)c2)ccc1OCC(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.9 %

Procedure:
An oven-dried 100 mL round-bottomed flask was charged with compound 1.1 (400 mg, 1.1 mmol), finely powdered Cs2CO3 (405 mg, 1.2 mmol), and anhydrous DMF (2 mL). 4-(Trifluoromethyl)benzyl bromide (298 mg, 1.1 mmol, Aldrich) was added, and the reaction was stirred vigorously overnight at room temperature. The reaction mixture was poured into 60 mL of water and extracted with 3×20 mL of methylene chloride. The combined organics were washed with 2×50 mL of water, dried over Na2SO4, and concentrated to a slightly yellow oil (422 mg). This crude material was dissolved in methylene chloride (2.5 mL), and trifluoroacetic acid (1.2 mL) was slowly added. The reaction was stirred for 4 h, after which the volatile components were removed in vacuo to reveal a crude pink oil. The crude pink oil was purified using flash chromatography (SiO2 gel 60, eluted with 60% EtOAc/hexanes), and the resulting white solid was recrystallized from methylene chloride/hexanes to give fine white crystals (213 mg). MS ESI m/e: 461.1 (M−H). 1H NMR (400 MHz) (CDCl3) δ 7.65 (2H, d, J=8.4 Hz); 7.54 (2H, d, J=8.4 Hz); 7.20 (1H, s); 7.17-7.14 (2H, d, m); 7.10 (1H, dd, J=13.0, 2.4 Hz); 6.77 (1H, d, J=8.4 Hz); 6.65 (1H, d, J=8.4 Hz); 5.12 (2H, s); 4.66 (2H, s); 2.25 (3H, s); 2.24 (3H, s).
Reaction SMILES: [NH2:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4].[C:44]([NH:54][C@H:55]([C:57](O)=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]>ClCCl>[C:44]([NH:54][C@H:55]([C:57]([NH:1][CH2:2][C:3]([C@@H:5]1[C@@H:10]([OH:11])[C@H:9]([OH:12])[C@@H:8]([CH2:13][OH:14])[O:7][C@@:6]1([NH2:43])[N:15]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])[C:16](=[O:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:4])=[O:58])[CH3:56])([O:46][CH2:47][C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)=[O:45]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CN
Solvent: ClCCl
Product: CCCCCCCCCCCCCCN(C(=O)CCCCCCCCCCC)[C@]1(N)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1C(=O)CNC(=O)[C@H](C)NC(=O)OCc1ccccc1
Yield: 94 %

Procedure:
from N-(2-glycyl-amino-2-deoxy-β-D-glucopyranosyl)-N-tetradecyl-dodecanamide and N-carbobenzoxy-L-alanine. Yield 94%. [α]D =+16.3° (c=1.12, dichloromethane). m.p. 103-105°.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.[Cl:25][C:26]1[CH:31]=[CH:30][C:29](O)=[CH:28][CH:27]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([O:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCO)c3ccccc23)CC1
Reactant: Oc1ccc(Cl)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCOc3ccc(Cl)cc3)c3ccccc23)CC1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
tert-Butyl 6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.533 g, 1.61 mmol), p-chlorophenol (0.224 g, 1.74 mmol, 1.08 equiv.) and triphenylphosphine (0.445 g, 1.70 mmol, 1.05 equiv.) was dissolved in THF (10 mL) and stirred at rt under N2. Diethyl azodicarboxylate (0.30 mL, 0.337 g, 1.93 mmol, 1.2 equiv.) was added, and the reaction mixture was stirred for 2.5 h. The reaction mixture was concentrated to give crude product (1.85 g), which was chromatographed (SiO2 175 g, eluted with 4:1 hexane:EtOAc) to give tert-butyl 6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.622 g) in 88% yield. 1H NMR (300 MHz, CD3OD) δ 1.48, 2.96-3.03, 3.05-3.14, 3.63-3.78, 4.15, 4.48, 6.70, 7.11, 7.15-7.20, 7.17, 7.27-7.31, 7.46-7.51; MS (ESI+) for C25H29ClN2O3 m/z 440.9 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.[CH2:19]([N:26]1[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[NH:29][CH:28]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:27]1=[O:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH2:19]([N:26]1[C:30]2([CH2:31][CH2:32][N:33]([S:15]([C:12]3[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=3)(=[O:17])=[O:16])[CH2:34][CH2:35]2)[NH:29][CH:28]([CH2:36][C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:27]1=[O:43])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: O=C1C(Cc2ccccc2)NC2(CCNCC2)N1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1C(Cc2ccccc2)NC2(CCN(S(=O)(=O)c3ccc(Cl)cc3)CC2)N1Cc1ccccc1
Temperature: 25 °C

Procedure:
Triethylamine (0.12 ml, 0.89 mmol) and subsequently 4-chlorobenzenesulfonyl chloride (314 mg, 1.49 mmol) were added to a solution of 1,3-dibenzyl-1,4,8-triaza-spiro[4,5]decan-2-one (249 mg, 0.75 mmol) in CH2Cl2 (6.7 ml) with stirring under a blanket of nitrogen at RT. The reaction mixture was stirred overnight. The organic phase was rendered alkaline using saturated aqueous sodium carbonate solution (20 ml) and the aqueous phase was extracted with CH2Cl2 (15 ml). The combined organic phases were dried over Na2SO4. After filtration, removal of the solvent and column chromatography, the desired product 1,3-dibenzyl-8-(4-chlorobenzene-sulfonyl)-1,4,8-triazaspiro[4,5]decan-2-one was obtained in a yield of 382 mg (100% of theory).
Reaction SMILES: [F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13](O)=[O:14])=[CH:10][C:4]=2[O:3]1.C(Cl)(=O)C(Cl)=O.[NH3:23]>O1CCCC1.CN(C)C=O>[F:1][C:2]1([F:16])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=[CH:12][C:13]([NH2:23])=[O:14])=[CH:10][C:4]=2[O:3]1
Reactant: N
Reactant: O=C(O)C=Cc1ccc2c(c1)OC(F)(F)O2
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)C=Cc1ccc2c(c1)OC(F)(F)O2
Reaction time: 2 h
Yield: 90 %

Procedure:
To a suspension of 8.00 g (35.1 mmol) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylic acid in 40 ml tetrahydrofurane and 0.4 ml N,N-dimethyl formamide, 3.86 ml (45.0 mmol) oxalyl chloride was added dropwise at 0° C. within 10 min. Stirring was continued at 0–5° C. for 30 min. and 2 h at room temperature thereafter. The resulting solution was cooled to 0–5° C. again and then added within 15 min. to 34 ml of an 25% aqueous solution of ammonia. After stirring for 30 min. the precipitated amide was collected, washed with water and dried at 40° C. in vacuo. 7.20 g (90%) 3-(2,2-Difluoro-benzo[1,3]dioxol-5-yl)-acrylamide were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:15][CH:16]=[C:17]([F:18])[C:12]2=[N:11]1)[CH:5]=[O:6].[BH4-].[Na+].Cl>C(O)C.C1COCC1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([Cl:28])[C:9]=1[N:10]1[CH:27]=[C:13]2[C:14]([NH:19][C:20]3[CH:25]=[C:24]([CH3:26])[N:23]=[CH:22][N:21]=3)=[N:15][CH:16]=[C:17]([F:18])[C:12]2=[N:11]1
Reactant: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(C=O)cc4Cl)cc23)ncn1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(Nc2ncc(F)c3nn(-c4c(Cl)cc(CO)cc4Cl)cc23)ncn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a solution of 3,5-dichloro-4-[7-fluoro-4-(6-methylpyrimidin-4-ylamino)pyrazolo[4,3-c]pyridin-2-yl]benzaldehyde (125 mg, 0.3 mmol) in ethanol (IMS grade, 5 mL) and THF (2 mL) was added sodium borohydride (14 mg, 0.36 mmol) and the reaction mixture was stirred at room temperature for 2 hours. The resultant mixture was partitioned between ethyl acetate and water and the layers were separated. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (0-1% methanol in ethyl acetate) to yield a solid, to which was added HCl (1.25 N in propan-2-ol, 10 mL) and the mixture was stirred at room temperature for 1 hour. The solid obtained was collected by filtration and dried to afford the title compound as an off-white solid (62 mg, 45% yield). 1H NMR (400 MHz, DMSO-d6): δ 9.35 (br s, 1H), 8.97 (s, 1H), 8.36 (br s, 1H), 8.10 (d, J=3.5 Hz, 1H), 7.75 (s, 2H), 4.68 (s, 2H), 2.57 (s, 3H). LCMS (Method B): RT=2.89 min, m/z: 419 [M+H+].
Reaction SMILES: C([O:4][C@H:5]1[CH2:10][C@H:9]([O:11]C(=O)C)[CH2:8][CH:7]([O:15][Si:16]([C:29]([CH3:32])([CH3:31])[CH3:30])([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]1[CH3:33])(=O)C.C[Mg]Br.[Cl-].[NH4+]>C1COCC1>[CH3:30][C:29]([Si:16]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[O:15][CH:7]1[CH2:8][C@@H:9]([OH:11])[CH2:10][C@H:5]([OH:4])[CH:6]1[CH3:33])([CH3:31])[CH3:32]
Reactant: CC(=O)O[C@@H]1CC(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C(C)[C@@H](OC(C)=O)C1
Agent: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C[C@@H](O)C[C@@H]1O
Yield: 60 %

Procedure:
469 mg (1 mmol) of 16 is dissolved in 10 ml of THF and mixed at 0° C. with 3.4 ml of methylmagnesium bromide solution (3M in THF). After 3 hours at this temperature, it is hydrolyzed with ammonium chloride solution, extracted with ethyl acetate and dried on sodium sulfate. The solvent is removed, and the residue is purified on silica gel (mobile solvent: EE:H=8.2), whereby 231 mg (0.6 mmol) of title compound 17 is obtained.
Reaction SMILES: S(=O)(=O)(O)O.[OH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[C:17](=[O:18])[CH2:16][CH:15]([C:19]([OH:21])=[O:20])[CH2:14]2)=[CH:9][CH:8]=1.[CH3:22]O>>[OH:6][C:7]1[CH:8]=[CH:9][C:10]([N:13]2[C:17](=[O:18])[CH2:16][CH:15]([C:19]([O:21][CH3:22])=[O:20])[CH2:14]2)=[CH:11][CH:12]=1
Reactant: O=C(O)C1CC(=O)N(c2ccc(O)cc2)C1
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)C1CC(=O)N(c2ccc(O)cc2)C1
Yield: 89 %

Procedure:
A catalytic amount of concentrated sulfuric acid is added to a solution of 1-(4-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylic acid a50 (3.7 g, 16.7 mmol, 1 eq) in methanol (100 ml) and the mixture is heated at reflux overnight. The solvent is then removed under vacuum, and the residue is dissolved into ethyl acetate. The organic layer is washed with a saturated solution of aqueous sodium hydrogenocarbonate, dried over magnesium sulfate and concentrated under vacuum to afford 3.5 g of methyl 1-(4-hydroxyphenyl)-5-oxopyrrolidine-3-carboxylate a51.
Reaction SMILES: [OH-].[Na+].[CH3:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].Cl>C1COCC1.O>[S:14]([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)([O:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH3:3])(=[O:16])=[O:15]
Reactant: COCCOCCOCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COCCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In an oven dried 12 L three-necked roundbottom flask, equipped with a magnetic stir bar and a 1000 mL pressure-equalizing dropping funnel, a solution of NaOH (440.0 g, 11.0 mol) is added to 1800 mL water and the mixture is cooled to approximately 0° C. A solution of triethylene glycol monomethyl ether, Formula A, (656.84 g, 4.0 mol) in THF (1000 mL) is added. The clear solution is stirred vigorously at 0° C. for 15 min and a solution of tosyl chloride (915.12, 4.8 mol) in THF (2.0 L) added dropwise over a 1 h period. The reaction mixture is stirred for an additional 1 h at O° C., and 10% HCl (5.0 L) is added to quench the reaction (to pH 5-7). The two-phase mixture is transferred to a 4 L separatory funnel the organic layer removed, and the aqueous layer extracted with t-butylmethyl ether (3×250 mL). The combined organic extracts are washed with brine (2×350 mL), dried (MgSO4), and evaporated under reduced pressure to afford Formula B, 1217.6 g (95%) as a light colored oil. This material is taken to the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:10]1=[O:31])[C:6]([CH3:8])=[CH2:7])=[O:4].C(N(CC)CC)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]([N:9]1[CH:12]([S:13][N:14]2[C:18](=[O:19])[CH2:17][CH2:16][C:15]2=[O:20])[CH:11]([NH:21][C:22](=[O:30])[CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:10]1=[O:31])=[C:6]([CH3:8])[CH3:7])=[O:4]
Reactant: C=C(C)C(C(=O)OC)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(=C(C)C)N1C(=O)C(NC(=O)Cc2ccccc2)C1SN1C(=O)CCC1=O
Temperature: 65 °C
Reaction time: 0.42 h

Procedure:
A mixture of 2.25 g (5 mmoles) of 1-(1-methoxycarbonyl-2-methylprop-2-enyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one (prepared as described in Example 2) and 1.4 ml (10 mmoles) of triethylamine in 100 ml of tetrahydrofuran was stirred at 65°C for 25 minutes. The reaction mixture was evaporated, treated with 25 ml of ethyl acetate and evaporated once more. The residual foam was dissolved in 50 ml of ethyl acetate, treated with charcoal and concentrated to a small volume. The desired product crystallized upon cooling. There was obtained 1-(1-methoxycarbonyl-2-methylpropenyl)-3-phenylacetamido-4-succinimidothio-azetidin-2-one.
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][CH:25]=[CH:24][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:19]=[C:18](O)[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=2)=[N:6]1.P(Cl)(Cl)([Cl:30])=O.O.C(=O)([O-])O.[Na+]>S1(CCCC1)(=O)=O>[Cl:30][C:18]1[C:17]([N+:21]([O-:23])=[O:22])=[CH:16][N:15]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:24]=[CH:25][CH:26]=[CH:27][C:2]=3[F:1])[N:6]=2)[N:19]=1
Reactant: O=[N+]([O-])c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1O
Reactant: O=P(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: O=S1(=O)CCCC1
Product: O=[N+]([O-])c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1Cl
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
109.00 g (249.95 mmol) of the compound from example 78A were initially charged in sulfolane (490 ml), then 55.92 ml (599.88 mmol) of phosphoryl chloride were added and the mixture was heated to 120° C. for 1 h. After cooling, the mixture was added cautiously to water (3 l) and stirred for 15 min. Sodium hydrogencarbonate was added in portions until the pH was 6. The precipitate formed was filtered off with suction and washed with water. The residue was stirred with 200 ml of dichloromethane/methanol (v/v=4:1) for 30 min, filtered off with suction, washed with dichloromethane, acetone and petroleum ether and dried under high vacuum. This gave 63.00 g (62% of theory) of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:15][CH2:14]2)=[CH:4][CH:3]=1.Cl.[C:33]1([N:39]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)N)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:39]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[C:33]3[C:34]([C:9]=2[CH2:10][CH2:11][CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19]4[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=4)[CH2:15][CH2:14]2)=[CH:35][CH:36]=[CH:37][CH:38]=3)=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccc(F)cc3)CC2)c1
Reactant: NN(c1ccccc1)c1ccccc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccc(F)cc4)n(-c4ccccc4)c4ccccc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(4-fluorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 1,1-diphenylhydrazine hydrochloride: ESMS m/e: 548.2 (M+H)+.
Reaction SMILES: [CH3:1][C@@H:2]([OH:6])[CH2:3][C:4]#[CH:5].[F:7][C:8]1[C:9](I)=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]>CN(C=O)C.CCN(CC)CC.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>[F:7][C:8]1[C:9]([C:5]#[C:4][CH2:3][C@H:2]([OH:6])[CH3:1])=[C:10]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])/[C:11]/2=[CH:18]\[C:19]1[NH:23][CH:22]=[N:21][C:20]=1[CH3:24]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CC[C@@H](C)O
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CC[C@@H](C)O)c21

Procedure:
Using Method C above, (R)-pent-4-yn-2-ol (68 mg, 0.82 mmol) (see Example 78 below) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (100 mg, 0.27 mmol) (Starting Material 3 supra) using (Ph3P)4Pd (31 mg, 0.03 mmol) and CuI (6 mg) in a mixture of DMF (5 mL) and Et3N (5 mL) as solvent at 80° C. for 4 hrs. Upon completion, the reaction mixture was concentrated and the residue was chromatographed on a silica gel column with neat CH3CN then THF and finally MeOH as elution solvent. The resulting (R)-(Z)-1,3-Dihydro-5-fluoro-4-(4-hydroxy-1-pentynyl)-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one was triturated with Et2O and then recrystalized from superheated EtOH. (Yield 18 mg, 20%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)(O)[CH:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C(C)=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)=[C:9]([C:11]2[N:15]([CH3:16])[N:14]=[N:13][N:12]=2)[CH3:10])=[CH:4][CH:3]=1
Reactant: CC(c1nnnn1C)C(O)(c1ccc(F)cc1)c1ccc(F)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1C
Product: CC(=C(c1ccc(F)cc1)c1ccc(F)cc1)c1nnnn1C
Yield: 90.9 %

Procedure:
A slurry of 1,1-bis(4-fluorophenyl)-2-(1-methyl -1H-tetrazol-5-yl)propanol (8.25 g, 0.025 mole) [prepared in Step B] and 100 mg of p-toluene sulfonic acid monohydrate in xylene (60 mL) was heated to reflux with a Dean & Stark water collecting apparatus for a period of 12 hours. The reaction mixture was washed with 1N NaOH (10 mL) while it was warm and with water (100 mL). Concentration of the organic layer gave off-white crystals of product. This was purified by recrystallization from ethanol-hexane to give 7.1 g (91%) of the title compound as white crystals; m.p.=146°-147° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([O:5][C:6](=[O:21])[C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)c1ccc(O)cc1
Reaction time: 3 h
Yield: 94.6 %

Procedure:
0.36 g of 10% palladium on activated carbon were added to a solution of 1.2 g (4.3 mmol) of 4-benzyloxy-benzoic acid tert-butyl ester in 45 mL of ethanol and this mixture was hydrogenated at 20 psi for 3 hours. After filtering over celite and removing the solvent under reduced pressure 0.79 g (95% yield) of 4-hydroxy-benzoic acid tert-butyl ester were obtained.
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([NH:13][C@H:14]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]2)[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:33]([C:35](OCC)=[O:36])[NH2:34]>CCOC(C)=O>[O:36]=[C:35]1[NH:33][N:34]=[C:1]([C:3]2[N:4]=[C:5]([NH:13][C@H:14]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15]3)[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CCOC(=O)NN
Reactant: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(C#N)cc3ccccc23)C1
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(-c3n[nH]c(=O)[nH]3)cc3ccccc23)C1
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (S)-tert-butyl 3-((3-cyanoisoquinolin-1-yl)amino)pyrrolidine-1-carboxylate (717 mg) was added NMP (2 mL) and ethyl hydrazinecarboxylate (883 mg, 8.484 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with aqueous NH4Cl. The organic layer was separated and concentrated to give the title compound, which was used directly in the next step.
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].N[C:23]1[CH:27]=[CH:26][O:25][N:24]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:23]1[CH:27]=[CH:26][O:25][N:24]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccon1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2ccon2)c1=O
Temperature: 25 °C
Reaction time: 96 h
Yield: 64.3 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in ethanol (4 mL), 3-aminoisoxazol (70 mg, 0.834 mmol) was added. The resulting mixture was stirred at room temperature for four days and the final product was collected by filtration and washed with diethylether to yield the title compound (58 mg, 63.7% yield).