Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C@H:9]1[NH:14][C@@H:13]([CH3:15])[CH2:12][N:11]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:32]=[N:33][C:34]([NH2:37])=[N:35][CH:36]=2)[N:19]=3)[CH2:10]1.[C:43](OC(=O)C)(=[O:45])[CH3:44]>C(Cl)Cl>[C:43]([N:14]1[C@@H:9]([CH3:8])[CH2:10][N:11]([C:16]2[N:17]([CH2:38][C:39]([F:42])([F:41])[F:40])[C:18]3[C:23]([N:24]=2)=[C:22]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:21]=[C:20]([C:31]2[CH:36]=[N:35][C:34]([NH2:37])=[N:33][CH:32]=2)[N:19]=3)[CH2:12][C@H:13]1[CH3:15])(=[O:45])[CH3:44]
Reactant: C[C@@H]1CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@H](C)N1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1[C@H](C)CN(c2nc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc3n2CC(F)(F)F)C[C@@H]1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 93.4 %

Procedure:
Triethylamine (73.8 μl, 0.53 mmol) was added to a methylene chloride solution (9.0 ml) of 5-[8-(cis-3,5-dimethylpiperazin-1-yl)-6-morpholin-4-yl-9-(2,2,2-trifluoroethyl)-9H-purin-2-yl]pyrimidin-2-amine (108.7 mg, 0.22 mmol) at room temperature followed by the addition of acetic anhydride (25.0 μl, 0.26 mmol) with ice cooling. The resulting mixture was stirred at room temperature for 3 days followed by the addition of acetic anhydride (8.3 μl, 0.09 mmol) and the resulting mixture was stirred for 1 day. Acetic anhydride (4.2 μl, 0.04 mmol) was further added to the resulting mixture, the resulting mixture was stirred for 1 day, and the reaction mixture was poured into methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure and the resulting residue was purified by preparative thin layer silica gel chromatography (methylene chloride:methanol=10:1) to give the title compound (109.8 mg, 93%) as a pale yellow solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6](=[O:8])[CH3:7].[CH3:9]C1C=CC(S(O)(=O)=O)=CC=1.[CH3:20][OH:21]>>[CH3:20][O:21][C:6]([C:2]1[S:1][CH:5]=[CH:4][N:3]=1)([O:8][CH3:9])[CH3:7]
Reactant: CO
Reactant: CC(=O)c1nccs1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Product: COC(C)(OC)c1nccs1
Yield: 75.6 %

Procedure:
A mixture of 1-(1,3-thiazol-2-yl)ethanone (35 g, 0.28 mol), anhydrous p-TsOH (50 g, 0.29 mol) and trimethyl ortheformate (175 ml) in methanol (500 ml) was refluxed for 18 h. After concentration, the residue was partitioned between sat. NaHCO3 and ether. The organic layers were washed with brine, dried over Na2SO4 and concentrated to give 36 g (75.6%) of 2-(1,1-dimethoxyethyl)-1,3-thiazole as an oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[C:18]1(C)[CH:23]=CC([Mg]Br)=[CH:20][CH:19]=1.[CH2:27]1[CH2:31][O:30][CH2:29][CH2:28]1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([C:29]([C:28]3[CH:27]=[CH:31][C:19]([CH3:20])=[CH:18][CH:23]=3)=[O:30])[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Cc1ccc([Mg]Br)cc1
Reactant: C1CCOC1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Product: Cc1ccc(C(=O)c2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 37 %

Procedure:
A 25-mL round bottom flask, with stirrer bar, was charged with 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (97 mg, 0.38 mol, 1.0 eq.) and THF (5.0 mL). A solution of 4-tolylmagnesium bromide (1.14 mL, 1.0M in THF, 1.14 mmol, 3.0 eq.) was added dropwise over 1 minute at room temperature. After stirring for 2 hrs at room temperature the reaction was heated to reflux for 2.5 hrs. The reaction was cooled to room temperature and was quenched with 2N HCl and diluted with ethyl acetate (50 mL). The organic layer was washed with sat. sodium chloride (3×5 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue (227 mg) was purified by chromatography on silica gel using hexanes/ethyl acetate (10:0 to 8:2) as the eluent, to afford (2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(p-tolyl)methanone (49 mg, 37% yield) as a yellow solid. MW=348.83. 1H NMR (DMSO-d6, 500 MHz) δ 8.31-8.26 (m, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.62-7.53 (m, 2H), 7.41 (d, J=8.0 Hz, 2H), 3.12 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.0 Hz, 2H), 2.43 (s, 3H), 2.06 (quintet, J=7.5 Hz, 2H).
Reaction SMILES: [H-].[Na+].[CH3:3][OH:4].[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:13]#[N:14])=[N:10][C:11]=1Cl.[O:15]1[CH2:19]CCC1>>[Br:5][C:6]1[CH:7]=[CH:8][C:9]([C:13](=[NH:14])[O:15][CH3:19])=[N:10][C:11]=1[O:4][CH3:3]
Reactant: C1CCOC1
Reactant: CO
Reactant: N#Cc1ccc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COC(=N)c1ccc(Br)c(OC)n1
Reaction time: 0.92 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 3.57 g, 93.8 mmol) was added portion-wise over a 20 minute period to a stirred solution of methanol (7.1 mL) in tetrahydrofuran (123 mL) under argon; the reaction was then stirred for an additional 55 minutes. A solution of 5-bromo-6-chloropyridine-2-carbonitrile (C28) (8.16 g, 37.5 mmol) in tetrahydrofuran (71 mL) was then added drop-wise and the reaction mixture was stirred for 18 hours. After being quenched with saturated aqueous ammonium chloride solution (200 mL), the mixture was extracted with ethyl acetate (2×400 mL). The combined organic layers were washed with saturated aqueous sodium chloride solution (200 mL), dried over magnesium sulfate and concentrated in vacuo to give the crude title compound (9.42 g, quantitative) as an orange solid, which was used in the next step without further purification, as it was found to be unstable on silica gel. LCMS m/z 247.1 (M+1). 1H NMR (400 MHz, CDCl3) δ 3.99 (s, 3H), 4.09 (s, 3H), 7.32 (d, J=7.8 Hz, 1H), 7.90 (d, J=7.8 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH:25]1[CH2:34][CH2:33][CH2:32][C@H:26]1[C:27]([O:29][CH2:30][CH3:31])=[O:28]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([N:25]2[CH2:34][CH2:33][CH2:32][C@H:26]2[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H]1CCCN1
Product: CCOC(=O)[C@@H]1CCCN1C(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and ethyl L-prolinate and suitable processing produces ethyl N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-prolinate (oil), saponification of which and processing of the reaction product yields N-[N-p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-proline (M.P. 129° to 131°).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][CH3:40])(=[O:38])[CH2:34][C:35]([CH3:37])=O>CS(C)=O.C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:11]2[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C@H:5]2[CH2:4][N:1]2[C:35]([CH3:37])=[C:34]([C:33]([O:39][CH3:40])=[O:38])[N:3]=[N:2]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: COC(=O)CC(C)=O
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN=[N+]=[N-])C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1nnn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6S,7R)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMSO (2 mL) were added potassium carbonate (276 mg) and methyl acetoacetate (0.08 mL) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (149 mg).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([C:8](=[N:18][OH:19])[C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])[CH:5]=[CH:4][N:3]=1>Cl>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9](=[O:10])[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([O:10][CH:9]([CH3:11])[CH3:8])[CH:7]=2)=[N:18][OH:19])=[CH:12][CH:13]=1
Reactant: O=C(C(=NO)c1ccnc(F)c1)c1ccc(F)cc1
Agent: Cl
Product: CC(C)Oc1cc(C(=NO)C(=O)c2ccc(F)cc2)ccn1

Procedure:
A solution of 22b (200 mg; 0.76 mmol) in HCl-saturated isopropanol (15 ml) was stirred under reflux for 2.5 h. The solution was concentrated and the yellowish-white residue was triturated with a little ethanol, filtered off and dried.
Reaction SMILES: [NH2:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][C:7]2[NH:15][C:14]3[C:13](=[O:16])[N:12]([CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[F:24])[C:11](=[O:25])[N:10]([CH2:26][CH2:27][CH2:28][CH3:29])[C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][C:35]=1[S:42](Cl)(=[O:44])=[O:43]>>[CH2:26]([N:10]1[C:9]2[N:8]=[C:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([NH:1][S:42]([C:35]4[CH:36]=[C:37]([O:40][CH3:41])[CH:38]=[CH:39][C:34]=4[O:33][CH3:32])(=[O:44])=[O:43])=[CH:31][CH:30]=3)[NH:15][C:14]=2[C:13](=[O:16])[N:12]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[F:24])[C:11]1=[O:25])[CH2:27][CH2:28][CH3:29]
Reactant: COc1ccc(OC)c(S(=O)(=O)Cl)c1
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(N)cc3)nc21
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NS(=O)(=O)c4cc(OC)ccc4OC)cc3)nc21

Procedure:
Prepared from 8-(4-amino-benzyl)-3-butyl-1-(2-fluoro-benzyl)-3,7-dihydro-purine-2,6-dione and 2,5-dimethoxy-benzenesulfonyl chloride. Purity (ELSD, based on MW=621.7)=90%.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:12])[CH:8]=2)[N:3]=1.[OH:13][C:14]1[CH:26]=[CH:25][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([O:13][C:14]1[CH:15]=[CH:16][C:17]([O:18][CH:19]([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:25][CH:26]=1)[CH:11]=[N:10]2
Reactant: Clc1ccc2nc(Cl)cnc2c1
Reactant: COC(=O)C(C)Oc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C(C)Oc1ccc(Oc2cnc3cc(Cl)ccc3n2)cc1

Procedure:
In 150 ml of acetonitrile, 2.0 g (0.01 mole) of 2,6-dichloroquinoxaline, 2.0 g (0.01 mole) of methyl 2-(4'-hydroxyphenoxy)propionate and 2.0 g (0.014 mole) of potassium carbonate were added and the mixture was refluxed for 24 hours.
Reaction SMILES: COC1C=CC([N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[N:11](O)[C:10]2=[S:21])=CC=1.C(=S)([O-:24])N>C(Cl)Cl>[C:14]1([C:12]2[NH:11][C:10](=[S:21])[N:9]([OH:24])[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COc1ccc(-n2cc(-c3ccccc3)n(O)c2=S)cc1
Reactant: NC([O-])=S
Solvent: ClCCl
Product: On1cc(-c2ccccc2)[nH]c1=S

Procedure:
The thiohydroxamine acid, 3-(p-methoxyphenyl)-5-phenyl-1-hydroxy-1,2-dihydroimidazole-2-thione, was prepared from the thiocarbamate in a manner similar to that used in Example I. The 3-(p-methoxyphenyl)-5-phenyl-1-hydroxy-1,2-dihydroimidazole-2-thione was recrystallized from methylene chloride/hexane to give white crystalline material. mp: 168° C. (dec); IR (CH2Cl2): 2800-1756-1510-1383-1361-1241-1133 cm-1 ; 1H NMR (200 MHz, CDCl3 : DMSO 1:1): 3.82 (3H, OCH3, s); 6.5 (2H, d); 7.15 (1H, CH=, s); 7.4 (3H, m); 7.54 (2H, d); 7.71 (2H, d); 11.85 (1H, OH, br); 13C NMR (CDCl3 : DMSO 1:1): 54 (OCH3): 110.6 (CH=); 112.6 (CH); 125.6 (CH); 125.7 (CH); 127 (CH); 127.2 (CH); 129.5 (Cq); 157.6 (CH); Anal. Calcd for C16H14N2O2 5: C, 64.40; H, 4.73; N, 9.39; S,10.74 Found C, 64.48; H, 4.24; N,9.43; S, 10.68.
Reaction SMILES: [CH3:1][C:2]1([CH3:31])[C:10]2[C:5](=[CH:6][C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])=[CH:8][CH:9]=2)[NH:4][CH2:3]1.Cl[CH2:33][C:34](Cl)=[O:35].[CH3:37][NH:38][CH3:39]>ClCCCl>[CH3:37][N:38]([CH3:39])[CH2:33][C:34]([N:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([N:11]3[C:15](=[O:16])[C:14]([CH3:17])([CH3:18])[N:13]([CH2:19][C:20]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[N:23]=[CH:22][CH:21]=4)[C:12]3=[O:30])[CH:6]=2)[C:2]([CH3:31])([CH3:1])[CH2:3]1)=[O:35]
Reactant: CNC
Reactant: CC1(C)CNc2cc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)ccc21
Reactant: O=C(Cl)CCl
Solvent: ClCCCl
Product: CN(C)CC(=O)N1CC(C)(C)c2ccc(N3C(=O)N(Cc4ccnc5ccccc45)C(C)(C)C3=O)cc21
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 50 mg 3-(3,3-dimethyl-2,3-dihydro-1H-indol-6-yl)-5,5-dimethyl-1-quinolin-4-ylmethyl-imidazolidine-2,4-dione in 1 ml 1,2-dichloroethane 0.04 ml ethyl-diisopropyl-amine and 13.7 mg chloroacetylchloride were added at 0° C. After stirring for 1 hour at 0° C. 5.5 mg dimethyl-amine were added and the reaction mixture was stirred for 2 days at room temperature. After removing of the solvent under reduced pressure the residue was purified by preparative HPLC (C18 reverse phase column, elution with a water/acetonitrile gradient with 0.1% trifluoroacetic acid). After lyophilization of the solution the resulting crude product was purified in addition by flash chromatography on silica gel with a dichloro-methane/methanol gradient. The fractions containing the product were evaporated to yield a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=2)[S:7](=[O:28])(=[O:27])[C:8]2[CH:22]=[C:21](OC)[C:20](OC)=[CH:19][C:9]=2[C:10]=1OS(C(F)(F)F)(=O)=O)=[O:4].[O:39]1[C:43]2[CH:44]=[CH:45][C:46]([S-:48])=[CH:47][C:42]=2[O:41][CH2:40]1.[Na+].O1C2C=CC(S)=CC=2OC1.[H-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:29][C:30]2[CH:38]=[CH:37][C:33]3[O:34][CH2:35][O:36][C:32]=3[CH:31]=2)[S:7](=[O:28])(=[O:27])[C:8]2[CH:22]=[CH:21][CH:20]=[CH:19][C:9]=2[C:10]=1[S:48][C:46]1[CH:45]=[CH:44][C:43]2[O:39][CH2:40][O:41][C:42]=2[CH:47]=1)=[O:4]
Reactant: [S-]c1ccc2c(c1)OCO2
Reactant: COC(=O)C1=C(OS(=O)(=O)C(F)(F)F)c2cc(OC)c(OC)cc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Agent: Sc1ccc2c(c1)OCO2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C1=C(Sc2ccc3c(c2)OCO3)c2ccccc2S(=O)(=O)N1Cc1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To 2-Benzo[1,3]dioxol-5-ylmethyl-4-hydroxy-1,1-dioxo-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester in dichloromethane (6 mL) and pyridine (0.65 mL, 7.75 mmol) was added trifluoromethanesulfonic anhydride (0.32 mL, 1.71 mmol). This mixture was stirred at room temperature for 30 minutes. Diluted with ethyl acetate (100 mL), washed with 1N HCl (2×50 mL), brine (50 mL), dried with magnesium sulfate and then evaporated in vacuo to afford the crude 2-benzo[1,3]dioxol-5-ylmethyl-6,7-dimethoxy-1,1-dioxo-4-(trifluoro-methanesulfonyloxy)-1,2-dihydro-1λ6 -benzo[e][1,2]thiazine-3-carboxylic acid methyl ester. A solution of this ester, in DMF (3 mL), was added to sodium 1,3-benzodioxole-5-thiolate (0.31 g, 2.0 mmol) {prepared by dissolving 1,3-benzodioxole-5-thiol (0.31 g, 2.0 mmol) in DMF (3 mL) and stirring with sodium hydride (0.081 g, 2.0 mmol) for 5 minutes} in DMF (3 mL). After stirring at room temperature for 16 hours the mixture was diluted with ethyl acetate (100 mL), washed with 1N NaOH(2×50 mL), brine (50 mL), dried with magnesium sulfate, and evaporated in vacuo. Silica gel column chromatography eluting with 25% ethyl acetate in hexane afforded the title compound as a foam (0.64 g, 79%);
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]([S:19][CH2:20][C:21]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:23][CH2:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][OH:18])[CH:12]=1>CCOC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C@@H:10]([S:19][CH2:20][C:21]1([CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:22][CH2:23]1)[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=[O:18])[CH:12]=1
Reactant: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(CO)c2)CC1
Agent: O=[Mn]=O
Solvent: CCOC(C)=O
Product: COC(=O)CC1(CS[C@H](CCc2ccccc2Br)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 86.5 %

Procedure:
A mixture of the benzylic alcohol of Step 7 (1.176 g, 2.54 mmol) and activated MnO2 (4.6 g, 20 equiv.) in 25 mL of EtOAc was stirred at room temperature for 4 hr. Another batch of MnO2 (1.1 g) was added and the mixture was stirred 20 min. It was filtered through celite to afford 1.014 g (87%) of the title aldehyde.
Reaction SMILES: [F:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:17]CCCCCCCCCCCN>>[F:1][C:2]1[C:3]([O:11][CH2:12][C:13]([F:15])([F:16])[F:14])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([O:9][CH3:17])=[O:8]
Reactant: CCCCCCCCCCCCN
Reactant: O=C(O)c1cnc(OCC(F)(F)F)c(F)c1
Product: COC(=O)c1cnc(OCC(F)(F)F)c(F)c1
Yield: 55 %

Procedure:
The title compound is prepared in 55% yield (1.74 g, white solid) from 5-fluoro-6-(2,2,2-trifluoroethoxy)nicotinic acid (3.0 g, 12.6 mmol, Step-1) in a similar manner to Step-2 of Amine-12.
Reaction SMILES: C([O:3][C:4](=O)[CH:5](Br)[CH2:6][CH3:7])C.[OH:10][CH:11]([CH2:21][OH:22])[CH2:12][NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[OH:20].[H-].[Na+]>CN(C)C=O.C(Cl)(Cl)Cl>[CH2:6]([CH:5]1[C:4](=[O:3])[N:13]([CH2:12][CH:11]([OH:10])[CH2:21][OH:22])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20]1)[CH3:7]
Reactant: CCOC(=O)C(Br)CC
Reactant: OCC(O)CNc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCC1Oc2ccccc2N(CC(O)CO)C1=O
Yield: 55 %

Procedure:
This same compound is prepared in a yield of 55 % by the action of ethyl-2-bromobutyrate on 2-(2,3-dihydroxypropylamino) -phenol (Method D): 4.8 g of a suspension of sodium hydride in oil are slowly added to a solution of 18 g of 2-(2,3-dihydroxypropylamino)-phenol in dimethylformamide, followed by the addition 30 minutes afterwards of 20 g of ethyl-2-bromobutyrate. The mixture is then heated for 2 hours to 60°C and then kept for a few hours at the reflux temperature of the solvent. The solvent is then eliminated under reduced pressure, the residue dissolved in chloroform and the organic phase washed with a normal aqueous solution of soda and then with water. After drying over magnesium sulphate, the chloroform is eliminated under reduced pressure and the crude product obtained is purified by recrystallisation from cyclohexane.
Reaction SMILES: C[N:2](C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=1)=O.[NH:26]([C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=1)N>>[O:13]=[C:12]1[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:21]([F:24])([F:23])[F:22])[CH:15]=2)[N:8]=[C:7]1[C:5]1[N:26]([C:28]2[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[CH:30][CH:29]=2)[N:2]=[CH:3][CH:4]=1
Reactant: NNc1ccc(C(=O)O)cc1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2cccc(OC(F)(F)F)c2)ccc1=O
Product: O=C(O)c1ccc(-n2nccc2-c2nn(-c3cccc(OC(F)(F)F)c3)ccc2=O)cc1

Procedure:
Reaction of 3-((E)-3-Dimethylamino-acryloyl)-1-(3-trifluoromethoxy-phenyl)-1H-pyridazin-4-one (A-6) and 4-hydrazino-benzoic acid according to example 43 gave the desired product. MS: M=442.9 (M)+
Reaction SMILES: [Li+].[OH-:2].COC(=O)[C@@H:6]([NH:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=2)=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C1[CH2:32][O:31]CC1>>[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:15]([NH:14][C:6]1[CH:7]=[CH:8][CH:13]=[CH:12][C:11]=1[CH:10]([CH3:9])[C:32]([OH:31])=[O:2])=[O:16])=[CH:25]2
Reactant: [OH-]
Reactant: C1CCOC1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Li+]
Product: CC(C(=O)O)c1ccccc1NC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
Aqueous 2M LiOH (33.10 ml) was added to a solution of (2S)-[(5-chloro-1H-indole-2carbonyl)-amino]-3-phenyl-propionic acid methyl ester (21.47 g, 60 mmol) in THF (140 ml) at 0-5° C. After 0.5 hour, the mixture was partially concentrated, acidified to pH 1-2 with 6N HCl, concentrated to dryness, and the solids washed with water and then ether to yield a colorless solid (18.78 g, 91%): mp 248-255° C.; HPLC (60/40) 5.21 minutes (98%); TSPMS 343/345 (MH+, 100%).
Reaction SMILES: [O:1]=[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)[C@@H:3]([NH:11]C(=O)OC(C)(C)C)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:11][C@@H:3]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]([N:19]1[C:27]2[C:22](=[CH:23][CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=3)[CH:26]=2)[CH2:21][CH2:20]1)=[O:1]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccncc3)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@@H](Cc1ccccc1)C(=O)N1CCc2ccc(-c3ccncc3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a 25 ml flask was added (S)-tert-butyl 1-oxo-3-phenyl-1-(6-(pyridin-4-yl)indolin-1-yl)propan-2-ylcarbamate 50.D (300 mg, 0.68 mmole) 10 ml of CH2Cl2, and 5 ml of TFA. The reaction was stirred at room temperature for 3 hour at which time the solvent was removed with a stream of nitrogen. The crude was resuspended and the solvent was removed as before. This procedure was repeated one more time to give (S)-2-amino-3-phenyl-1-(6-(pyridin-4-yl)indolin-1-yl)propan-1-one 50.E of as a light yellow oil (300 mg, 21% yield).
Reaction SMILES: BrC1C=CC2N(C=C(C3C(C4C=CC=CC=4)=NOC=3C)N=2)C=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:25]=1[C:35]1[N:36]=[C:37]2[CH:42]=[CH:41][C:40]([C:43]#[C:44][Si](C)(C)C)=[CH:39][N:38]2[CH:49]=1>>[C:43]([C:40]1[CH:41]=[CH:42][C:37]2[N:38]([CH:49]=[C:35]([C:25]3[C:26]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[N:27][O:28][C:24]=3[CH3:23])[N:36]=2)[CH:39]=1)#[CH:44]
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2cc(C#C[Si](C)(C)C)ccc2n1
Agent: Cc1onc(-c2ccccc2)c1-c1cn2cc(Br)ccc2n1
Product: C#Cc1ccc2nc(-c3c(-c4ccccc4)noc3C)cn2c1
Yield: 60.5 %

Procedure:
As described for Example 45, 6-bromo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine (100 mg, 0.28 mmol) instead of 7-bromo-2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine, was converted to 2-(5-methyl-3-phenyl-isoxazol-4-yl)-6-trimethylsilanylethynyl-imidazo[1,2-a]pyridine (39 mg, 37% MS: m/e=372.1 [M+H]+) and then to the title compound (19 mg, 69%) which was obtained as a light yellow foam. MS: m/e=300.3 [M+H]+.