Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].P(Cl)(Cl)(Cl)(Cl)Cl.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH2:17]>ClCCl>[C:1]([CH2:3][C:4]([NH:17][C:16]1[CH:18]=[CH:19][C:20]([N+:21]([O-:23])=[O:22])=[C:14]([CH3:13])[CH:15]=1)=[O:6])#[N:2]
Reactant: N#CCC(=O)O
Reactant: Cc1cc(N)ccc1[N+](=O)[O-]
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(NC(=O)CC#N)ccc1[N+](=O)[O-]
Yield: 60.3 %

Procedure:
Cyanoacetic acid (1.5 g; 17.6 mmol) and phosphorus pentachloride (4.1 g; 19.4 mmol) are heated under reflux in dichloromethane (40 ml) for 1 hour. 3-Methyl-4-nitroaniline (1.6 g; 10.6 mmol) is added and the mixture is heated for a further hour under reflux conditions. After cooling, the solid is filtered and stirred with water for a further hour, the mixture is filtered and the filtrate is brought to dryness under reduced pressure. 2-Cyano-N-(3-methyl-4-nitrophenyl)acetamide (1.4 g; 64%) is thus obtained.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li]CCCC.CN([CH:18]=[O:19])C>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:18]=[O:19]
Reactant: CN(C)C=O
Reactant: c1ccc2scnc2c1
Agent: [Li]CCCC
Product: O=Cc1nc2ccccc2s1
Reaction time: 1 h

Procedure:
To a solution of benzo[d]thiazole (1 g, 7 mmol) in DMF (10 mL) was added n-BuLi (8.4 mL, 21 mmol) over 15 min at −78° C. and the mixture was stirred at this temperature for 1 hour. The reaction was quenched with water, extracted with EtOAc and dried over anhydrous sodium sulfate. The solution was then concentrated under vacuum to give benzo[d]thiazole-2-carbaldehyde as a light yellow solid (500 mg).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][CH3:3].[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16](Cl)=[O:17])=[CH:11][CH:10]=1)(=[O:7])[CH3:6]>O.C(OCC)C>[CH2:1]([NH:4][C:16](=[O:17])[CH2:15][C:12]1[CH:11]=[CH:10][C:9]([O:8][C:5](=[O:7])[CH3:6])=[CH:14][CH:13]=1)[CH2:2][CH3:3]
Reactant: CCCN
Reactant: CC(=O)Oc1ccc(CC(=O)Cl)cc1
Solvent: CCOCC
Solvent: O
Product: CCCNC(=O)Cc1ccc(OC(C)=O)cc1
Temperature: 0 °C

Procedure:
To an ice-cold solution of 1-propylamine (9 g) in water (50 ml) was added solution of 4-acetoxyphenylacetyl chloride (10.6 g) in diethyl ether (100 ml), keeping the temperature of the mixture between 15° and 25° C. with external cooling. The ether layer was separated, washed with brine and evaporated to give N-(1-propyl)-4-acetoxyphenylacetamide as a pale yellow oil, essentially pure by TLC, which was used without further purification or characterisation.
Reaction SMILES: C(OC(=O)[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:37])[N:25]([CH2:31][CH2:32][CH2:33][C:34](=[O:36])[NH2:35])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>ClCCl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:34]([CH2:33][CH2:32][CH2:31][N:25]([CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30]1)[C:24](=[O:37])[C:19]1[CH:18]=[C:17]([O:16][CH2:15][CH2:14][NH:7][C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH:22]=[C:21]([Cl:23])[CH:20]=1)(=[O:36])[NH2:35]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCC(N)=O)C2CCCC2)c1)c1ccncc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C1CCCC1
Reaction time: 2 h

Procedure:
A solution of (2-{3-[(3-carbamoyl-propyl)-cyclopentyl-carbamoyl]-5-chloro-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester (0.040 g) in a mixture of dichloromethane (1 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 2 h and then concentrated under reduced pressure to give the title compound (0.040 g) as a colourless gum.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:38]1[CH2:43][CH2:42][N:41]([CH2:44][CH2:45][C@@H:46]([NH:55][C:56]2[CH:61]=[CH:60][C:59]([S:62]([NH2:65])(=[O:64])=[O:63])=[CH:58][C:57]=2[N+:66]([O-:68])=[O:67])[CH2:47][S:48][C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:40][CH2:39]1>>[Si:1]([O:8][C@@H:9]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=1)[CH:10]1[CH2:15][CH2:14][N:13]([C:16]2[CH:24]=[CH:23][C:19]([C:20]([NH:65][S:62]([C:59]3[CH:60]=[CH:61][C:56]([NH:55][C@H:46]([CH2:45][CH2:44][N:41]4[CH2:40][CH2:39][O:38][CH2:43][CH2:42]4)[CH2:47][S:48][C:49]4[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=4)=[C:57]([N+:66]([O-:68])=[O:67])[CH:58]=3)(=[O:64])=[O:63])=[O:22])=[CH:18][CH:17]=2)[CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: NS(=O)(=O)c1ccc(N[C@H](CCN2CCOCC2)CSc2ccccc2)c([N+](=O)[O-])c1
Reactant: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)O)cc2)CC1
Product: CC(C)(C)[Si](C)(C)O[C@@H](c1ccccc1-c1ccc(Cl)cc1)C1CCN(c2ccc(C(=O)NS(=O)(=O)c3ccc(N[C@H](CCN4CCOCC4)CSc4ccccc4)c([N+](=O)[O-])c3)cc2)CC1
Yield: 74.9 %

Procedure:
The title product (346.6 mg, yield: 75%) was prepared using a procedure similar to the one described for the synthesis of INTERMEDIATE 33. (R)-4-(4-((tert-Butyldimethylsilyloxy)(4′-chlorobiphenyl-2-yl)methyl)piperidin-1-yl)benzoic acid (INTERMEDIATE 13, 250.7 mg, 0.47 mmol) and (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-nitrobenzenesulfonamide (INTERMEDIATE 74, 229.0 mg, 0.49 mmol) were used as starting materials. The resulting product was purified by column chromatography (ISCO, 12 g silica gel column, eluting with 0→10% MeOH/DCM), providing the title product.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1.[C:21](B1OC(C)(C)C(C)(C)O1)([CH3:23])=[CH2:22]>>[CH:21]([C:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=2)[N:3]=1)([CH3:23])[CH3:22]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COc1cccc2c(Cl)nc(Nc3cc(C)[nH]n3)cc12
Product: COc1cccc2c(C(C)C)nc(Nc3cc(C)[nH]n3)cc12

Procedure:
Similar procedure as described in example 330 was used, starting from (1-Chloro-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and isopropenylboronic acid pinacol ester to give (1-Isopropyl-5-methoxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 297(MH+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1([NH:9][CH:10]=[C:11]([C:17](=[O:28])[C:18]2[CH:23]=[C:22]([F:24])[C:21]([F:25])=[C:20]([F:26])[C:19]=2F)[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7][CH2:6][CH2:5]1.[H-].[Na+].O>C1COCC1>[F:26][C:20]1[CH:19]=[C:18]2[C:23](=[C:22]([F:24])[C:21]=1[F:25])[N:9]([C:4]1([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6][CH2:7][CH2:8]1)[CH:10]=[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:17]2=[O:28]
Reactant: CCOC(=O)C(=CNC1(CCO)CCCC1)C(=O)c1cc(F)c(F)c(F)c1F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C2(CCO)CCCC2)c2c(F)c(F)c(F)cc2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65.3 %

Procedure:
To an iced solution of ethyl 3-[1-(2-hydroxyethyl)-cyclopentylamino]-2-(2,3,4,5-tetrafluorobenzoyl)acrylate (22.7 g, 56.3 mmol) in THF (200 mL) was added NaH (3.60 g, 90.0 mmol), and the mixture was stirred at room temperature for 1 hour. Water was added to the mixture portionwise at 0° C. The resulting mixture was extracted with ethyl acetate, and the combined organic extracts were concentrated in vacuo. Flash chromatography (AcOEt:Hexane=2:1) of the residue give the title compound as a colorless solid (14.1 g, 65%). 1H-NMR (400 MHz, DMSO-d6) δ 1.27 (3H, t, J=7.3 Hz), 1.53-1.75 (4H, m), 2.10-2.26 (4H, m), 2.31-2.44 (2H, m), 4.23 (2H, q, J=7.3 Hz), 4.55-4.60 (1H, m), 7.99-8.07 (1H, m), 8.80 (1H, s).
Reaction SMILES: C(OC)(OC)(OC)C.[CH2:9]([O:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][C@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C@H:23](O)[CH2:24][OH:25])=[CH:19][C:18]=1[F:37])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N(CC)CC)C.C(Br)(=O)C.[OH-].[K+]>C(Cl)Cl.CO.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[CH2:9]([O:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][C@H:22]([NH:27][C:28](=[O:34])[O:29][C:30]([CH3:31])([CH3:33])[CH3:32])[C@H:23]2[CH2:24][O:25]2)=[CH:19][C:18]=1[F:37])[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H](O)CO
Agent: CC(=O)Br
Agent: COC(C)(OC)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)c(F)c1)[C@H]1CO1
Reaction time: 1 h
Yield: 72.2 %

Procedure:
Trimethyl orthoacetate (0.94 mL, 7.4 mmol) is added to a suspension of compound 16 (2.9 g, 7.2 mmol) in 30 mL of CH2Cl2 stirred under nitrogen. Pyridinium p-toluenesulfonate (18 mg, 0.07 mmol) is added and the resulting pale yellow solution is stirred for 30 min and then concentrated to a white solid. This solid is dissolved in 30 mL of CH2Cl2, triethylamine (0.10 mL, 0.72 mmol) is added, and the mixture, under nitrogen, is cooled in an ice bath. Freshly distilled acetyl bromide (0.55 mL, 7.4 mmol) is added dropwise over 3-4 min with stirring. After 1 h, the ice bath is removed and aqueous 1 N NaHCO3 and CH2Cl2 are added. The aqueous phase is extracted with additional CH2Cl2 and the combined organic phases are dried over MgSO4 and concentrated to a white solid. This solid is suspended in 25 mL of methanol and 6 mL of THF, and cooled in an ice bath, under nitrogen. Pulverized KOH (0.60 g, 11 mmol) in 6 mL of methanol is added all at once. After 15 min the ice bath is removed and the mixture is allowed to come to ambient temperature over 70 min. The mixture is concentrated and taken up in ethyl acetate and aqueous 1N KH2PO4. The organic phase is washed with 1N NaHCO3 and then brine, dried over Na2SO4, and concentrated. Chromatography over silica gel, eluting with 20% ethyl acetate and 5% to 10% CH2Cl2 in heptane affords 2.0 g (5.2 mmol, 72%) of compound 17 as a white solid: 1H NMR (CDCl3) δ 7.45-7.30 (m, 5H), 6.99-6.86 (m, 3H), 5.12 (s, 2H), 4.43 (br, 1H), 3.63 (br, 1H), 2.90 (m, 2H), 2.79 (m, 2H), 2.74 (m, 1H), 1.39 (s, 9H); MS (CI) m/z 410.3 (MNa+), 388.3 (MH+).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([S:14][C:15]1[N:19]([CH3:20])[N:18]=[CH:17][C:16]=1[C:21]([NH:23][OH:24])=[O:22])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH2:25](Br)[CH:26]=[CH2:27].Cl>O.C1(C)C=CC=CC=1>[CH2:27]([O:24][NH:23][C:21]([C:16]1[CH:17]=[N:18][N:19]([CH3:20])[C:15]=1[S:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:22])[CH:26]=[CH2:25]
Reactant: C=CCBr
Reactant: Cn1ncc(C(=O)NO)c1SCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=CCONC(=O)c1cnn(C)c1SCc1ccccc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 82.4 %

Procedure:
In a solution of potassium carbonate (1.3 g, 9.4 mmol) in water (10 ml), a solution of 5-benzylthio-1-methylpyrazole-4-carbohydroxamic acid (2.0 g, 7.6 mmol) and allyl bromide (1.1 g, 9.1 mmol) in toluene (10 ml) were added, and stirred at 50° C. for 4 hours. After cooling to room temperature, the mixture was adjusted to pH 1 by adding 35% hydrochloric acid and extracted with ethyl acetate. The resulting ethyl acetate solution was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off to obtain the aimed product (1.9 g). Oily substance. Proton nuclear magnetic resonance chemical shift values δ (ppm) (in CDCl3) 3.42 (s, 3H), 3.95 (s, 2H), 4.49 (d, J=6.3 Hz, 2H), 5.33-5.43 (m, 2H), 6.00-6.16 (m, 1H), 6.93-7.00 (m, 2H), 7.21-7.30 (m, 3H), 8.08 (s, 1H), 9.68 (brs, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[C:11]([OH:18])[C:10]=1[N+:19]([O-])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(O)(=O)C.[Zn]>[NH2:19][C:10]1[C:11]([OH:18])=[C:12]([C:15](=[O:17])[CH3:16])[CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(OCc2ccccc2)c([N+](=O)[O-])c1O
Agent: [Zn]
Solvent: CC(=O)O
Product: CC(=O)c1ccc(OCc2ccccc2)c(N)c1O
Reaction time: 2 h

Procedure:
Zinc dust (5.5 g) was added portionwise to a suspension of 1-(4-(benzyloxy)-2-hydroxy-3-nitrophenyl)ethanone (example 11, step b) (5.5 g) in acetic acid (55 mL) over 15 minutes, whilst maintaining the internal temperature below 40° C. with an ice bath. The mixture was allowed to attain ambient temperature and stirred for 2 h. The mixture was filtered through Celite (Caution: Gets hot—do not allow to dry), washed with acetic acid, and the filtrate poured onto ice/water (500 mL). The resulting precipitate was filtered off, washed with water, and dried under vacuum at 40° C. to afford the subtitled compound as a light brown solid. Yield 4.8 g.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1.[CH3:17][CH:18]([CH3:34])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1)=[O:20]>>[N:8]1([CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][N:31]2[CH2:32][CH2:33][CH:28]([C:25]3[CH:26]=[CH:27][C:22]([NH:21][C:19](=[O:20])[CH:18]([CH3:17])[CH3:34])=[CH:23][CH:24]=3)[CH2:29][CH2:30]2)[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1
Reactant: CC(C)C(=O)Nc1ccc(C2CCNCC2)cc1
Reactant: ClCCCCCCn1ccc2ccccc21
Product: CC(C)C(=O)Nc1ccc(C2CCN(CCCCCCn3ccc4ccccc43)CC2)cc1

Procedure:
Prepared by Procedure AH and Scheme P using 1-(6-chlorohexyl)-1H-indole and 2-methyl-N-[4-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 446.3 (M+H)+.
Reaction SMILES: O1CCC[CH2:2]1.[CH3:6][O:7][C:8](=[O:25])[C@H:9]([CH2:21][CH2:22]SC)[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].C(Br)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O>[CH3:6][O:7][C:8](=[O:25])[C@@H:9]1[CH2:21][CH2:22][CH2:2][N:10]1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: C1CCOC1
Reactant: COC(=O)[C@H](CCSC)NC(=O)OCc1ccccc1
Agent: BrCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Product: COC(=O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a tetrahydrofuran solution (1 ml) of the compound prepared in Example 7 (146 mg), were successively added dropwise at 0° C. in a nitrogen atmosphere benzyl bromide (0.114 ml, 0.96 mmol) and a tetrahydrofuran solution of tetrabutyl ammonium fluoride (0.48 ml, 0.48 mmol). The mixture was stirred for 1 hour at 0° C., poured into water and extracted with ether. The ether layer was dried over anhydrous magnesium sulfate and concentrated under vacuum. The resulting reaction mixture was subjected to column chromatography on silica gel and eluted with a 1:1 mixture of ether and hexane to give the titled compound in an amount of 94 mg (yield, 75% based on the starting materials used in Example 7).
Reaction SMILES: CS(C)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[C:18]([C:20]1[CH:25]=[CH:24][C:23]([C:26]2[S:27][C:28]([C:32]([N:34]([C@H:38]([CH3:55])[C@:39]([C:47]3[CH:52]=[CH:51][C:50]([F:53])=[CH:49][C:48]=3[F:54])([OH:46])[CH2:40][N:41]3[CH:45]=[N:44][CH:43]=[N:42]3)[CH2:35][CH2:36][OH:37])=[O:33])=[C:29]([CH3:31])[N:30]=2)=[CH:22][CH:21]=1)#[N:19].C(N(CC)CC)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:54][C:48]1[CH:49]=[C:50]([F:53])[CH:51]=[CH:52][C:47]=1[C@:39]1([CH2:40][N:41]2[CH:45]=[N:44][CH:43]=[N:42]2)[O:46][CH:36]([OH:37])[CH2:35][N:34]([C:32]([C:28]2[S:27][C:26]([C:23]3[CH:24]=[CH:25][C:20]([C:18]#[N:19])=[CH:21][CH:22]=3)=[N:30][C:29]=2[CH3:31])=[O:33])[C@@H:38]1[CH3:55]
Reactant: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N(CCO)[C@H](C)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CS(C)=O
Product: Cc1nc(-c2ccc(C#N)cc2)sc1C(=O)N1CC(O)O[C@@](Cn2cncn2)(c2ccc(F)cc2F)[C@H]1C
Temperature: -40 °C
Reaction time: 1 h

Procedure:
To a cooled (-78° C.) solution of DMSO (0.29 mL, 4.17 mmol) in CH2Cl2 (10 mL) was added a solution of trifluoroacetic anhydride (0.30 mL, 2.09 mmol) in CH2Cl2 (1 mL) dropwise. After ten minutes, a solution of (1R,2R)-2-(4-cyanophenyl)-N-[2-(2,4-difluorophenyl)-2-hydroxy-1-methyl-3-(1H-1,2,4-triazol-1-yl)propyl]-N-(2-hydroxyethyl)-4-methylthiazole-5-carboxamide (0.9 g, 1.67 mmol, obtained in example 82) in CH2Cl2 (3 mL) was added. The mixture was stirred for 1 h, and then triethylamine (1.1 mL, 8.3 mmol) was added. The reaction mixture was allowed to warm up to -40° C. and was stirred at this temperature for 1.5 h and then at -10° C. for 30 min. 10% aqueous NaHCO3 solution was added, the organic phase was separated and the aqueous phase was extracted with chloroform. The combined organic extracts were washed with water, dried over anhydrous Na2SO4, filtered and concentrated to a crude product. Purification by flash chromatography afforded the title compound as a white solid: mp 225°-228° C.; 1H NMR (300 MHz, CDCl3) δ (TMS) 8.06 and 8.05 (d, J=8.4, 2H, arom), 7.77 (s, 1H, triazole), 7.76 (d, J=8.4, 2H, arom), 7.35 (dt, Jd =6.5, Jt =8.8, 1H, arom), 7.30 (s, 1H, triazole), 7.0-6.7 (m, 2H, arom), 5.83 (m, 1H, OCHOH), 5.8-3.2 (several broad signals), 2.57 and 2.55 (s, 3H, Me-thiazole), 1.14 (d, J=6.8, 3H, MeCH); [α]D =-79.8° (c 1, CHCl3). Analysis calculated for C26H22F2N6O3S.1/2H2O: C 57.24; H 4.21; N 15.40; S 5.86. Found: C 57.49; H 4.03; N 15.08; S 5.69.
Reaction SMILES: [Br:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11](=O)[NH:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].P(Cl)(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O.[N+:36]([CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])#[C-:37]>CN(C)C=O.C(O)(=O)C.CCCCCC>[Br:1][C:2]1[C:7]2[C:8](=[O:16])[N:9]3[CH2:15][CH2:14][C@H:10]3[C:11]3[N:12]([CH:37]=[N:36][C:38]=3[C:39]([O:41][CH2:42][CH3:43])=[O:40])[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: O=C1Nc2cccc(Br)c2C(=O)N2CC[C@@H]12
Agent: O=P(Cl)(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)c1ncn2c1[C@@H]1CCN1C(=O)c1c(Br)cccc1-2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
30 g (106.7 mmol) of (S)-5-bromo-1,10a-dihydro-2H-azeto[2,1-c][1,4]benzodiazepine-4,10(9H)-dione were dissolved in 50 ml of N,N-dimethylformamide, treated at -20° with 5.6 g (128 mmol) of sodium hydride dispersion (55% in oil) (washed with hexane) and deprotonized at -30° to -20° for 30 minutes. A solution of 43 g (160 mmol) of diphenyl chlorophosphate in 25 ml of N,N-dimethylformamide was added thereto at -60° and the mixture was stirred at max. -45° for 35 minutes. In the meanwhile and separately, 12 g (107 mmol) of potassium tert.-butylate were dissolved in 20 ml of N,N-dimethylformamide and treated at -60° with 12.1 g (107 mmol) of ethyl isocyanoacetate. The reaction mixture is added dropwise to the deprotonized ethyl isocyanoacetate at max. -65° within 11/4 hours. The mixture was stirred for 1 hour in an acetone/dry-ice bath, neutralized with 10 ml of acetic acid and poured into 500 ml of ice-water. The mixture was extracted five times with methylene chloride (a total of 1.21), dried over magnesium sulfate and evaporated to dryness. By recrystallization of the residue from ethanol and ether there were obtained 23.7 g (49%) of ethyl (S)-8-bromo-9-oxo-12,12a-dihydro-9H,11H-azeto[2,1-c]imidazo[1,5-a]-[1,4]-benzodiazepine-1-carboxylate of m.p. 184°-185°.
Reaction SMILES: [C:1]1([C:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:8][CH:9]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]([CH:22]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:19][CH2:20][CH3:21])=[O:18]>C(O)C>[CH2:20]([O:19][C:17](=[O:18])/[CH:22]=[CH:9]\[CH:8]=[C:7]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:21]
Reactant: O=CC=C(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCO
Product: CCOC(=O)/C=C\C=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Yield: 16.8 %

Procedure:
A solution of 3,3-diphenyl-2-propenal (18.73 g) and (carbethoxymethylene)triphenylphosphorane (33.1 g) in ethanol (100 mL) was stirred at room temperature for 1 hour. The solvent was removed in vacuo and the residual solid was refluxed in a mixture of ether (125 mL) and hexane (250 mL) for 10 minutes. The mixture was cooled to room temperature and the precipitated triphenylphosphine oxide (25 g) was removed by filtration and was washed with ether-hexane (1:2; 2×50 mL). The filtrates were evaporated and the residue was passed through a short column of silica gel (200 g) made up in dichloromethane to remove residual triphenylphosphine oxide and starting ylid. After evaporation of the appropriate eluates, the resulting mixture of esters was separated by using HPLC (dichloromethane-hexane; 1:1). The fractions containing the less polar material were combined and evaporated to yield 4.2 g of (Z)-5,5-diphenyl-2,4-pentadienoic acid ethyl ester as an oil which crystallized on standing, mp 36°-37° C.
Reaction SMILES: O.[C:2](S)(C)([CH3:4])[CH3:3].[CH3:7][C:8](N=N[C:14]([C:17]#N)([CH3:16])[CH3:15])([C:10]#[N:11])C.[C:19](#N)C=C>>[C:10](#[N:11])[CH:8]=[CH2:7].[CH2:19]=[CH:17][C:14]1[CH:15]=[CH:4][CH:2]=[CH:3][CH:16]=1
Reactant: CC(C)(C#N)N=NC(C)(C)C#N
Reactant: CC(C)(C)S
Solvent: O
Solvent: C=CC#N
Product: C=Cc1ccccc1
Temperature: 65 °C

Procedure:
168.7 Parts of demineralized water were added to a reactor. The reactor was sealed and purged with nitrogen. To a separate container were added 26.9 parts of demineralized water, 1.5 parts GAFAC RE-610 and 0.02 part citric acid monohydrate, and the components were mixed until dispersed. To a third container were added 21.6 parts styrene and 67 parts acrylonitrile and the components were mixed for 10 minutes. The aqueous solution of GAFAC RE-610 and citric acid were then added to the reactor by vacuum and the contents of the reactor heated with agitation. 15.2 Parts of elastomer were then added by vacuum followed by 20.3 parts demineralized rinse water. While heating, the reactor was purged with nitrogen. A mixture of monomer precharge consisting of 0.4 part styrene and 8.43 parts of acrylonitrile were added to the reactor by vacuum, and this was followed by the addition of 20.3 parts of demineralized water. The nitrogen purge was again repeated, and the final pressure in the reactor was maintained at a vacuum of 10 inches of Hg. After the temperature of the reactor was stabilized at 60°C, 0.1 part of Vazo 52 dissolved in 1.0 part acrylonitrile was added to the reactor with vacuum, followed by 0.33 part acrylonitrile as a rinse. 0.75 Part of water was then used to rinse the acrylonitrile into the reactor, and reaction time was measured subsequent to this point. After fifteen minutes of reaction time, the balance of the monomer mixture and the t-butyl mercaptan were pumped into the reactor through separate lines over a period of 360 minutes. At 165 minutes of reaction time, 0.3 parts of Vazo 52 dissolved in 0.33 parts of acrylonitrile were added to the reaction mixture by means of a vacuum, and this was followed by 0.33 parts of acrylonitrile and 0.75 parts of water. At 285 minutes of reaction time, the above addition of Vazo 52 and acrylonitrile was repeated, and the temperature was then raised to 65°C after 315 minutes. After all the monomers and the mercaptan had been added, the lines were purged with 0.75 part demineralized water and the temperature was maintained at 65°C for an additional 30 minutes.