Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[Si]([O:26][C:27]1[CH:57]=[CH:56][C:30]([CH2:31]/[C:32](=[C:37](\[C@H:42]2[CH2:47][CH2:46][C@@H:45]([O:48][Si:49]([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50])[CH2:44][CH2:43]2)/[C:38]([O:40][CH3:41])=[O:39])/[C:33]([O:35][CH3:36])=[O:34])=[CH:29][CH:28]=1)(C(C)(C)C)(C)C>C1COCC1>[Si:49]([O:48][C@@H:45]1[CH2:46][CH2:47][C@H:42](/[C:37](=[C:32](\[CH2:31][C:30]2[CH:29]=[CH:28][C:27]([OH:26])=[CH:57][CH:56]=2)/[C:33]([O:35][CH3:36])=[O:34])/[C:38]([O:40][CH3:41])=[O:39])[CH2:43][CH2:44]1)([C:52]([CH3:55])([CH3:54])[CH3:53])([CH3:51])[CH3:50]
Reactant: COC(=O)/C(Cc1ccc(O[Si](C)(C)C(C)(C)C)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)/C(Cc1ccc(O)cc1)=C(\C(=O)OC)[C@H]1CC[C@@H](O[Si](C)(C)C(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 1.0 M tetrabutyl ammonium fluoride solution in THF (0.29 ml, 0.29 mmol) was added dropwise to a solution of dimethyl 2-(4-((tert-butyldimethylsilyl)oxy)benzyl)-3-(cis-4-((tert-butyldimethylsilyl)oxy)cyclohexyl)maleate (55 mg, 0.10 mmol) in THF (1.0 ml) at 0° C., and the mixture was stirred at room temperature for 5 hr. The solvent was removed by distillation under reduced pressure, and the residue was chromatographed on silica gel column (hexane:ethyl acetate=85:15) to give the title compound as a yellow oil (35 mg, yield 80%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:16]([NH:23][CH2:24][CH2:25][OH:26])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.O>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH:13]([CH3:15])[CH3:14])[C:10]([N:23]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:24][CH2:25][OH:26])=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: OCCNCc1ccccc1
Reactant: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)[C@@H](NC(=O)OC(C)(C)C)C(=O)N(CCO)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
To a solution of (R)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (2.0 g, 9.20 mmol) in CH2Cl2 (40 mL) were added 2-(benzylamino)ethanol (1.3 g, 8.80 mmol), HATU (5.30 g, 13.8 mmol) and Et3N (2.80 g, 27.6 mmol) under N2. The mixture was stirred at rt overnight. The mixture was diluted with water (20 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, concentrated and purified by column chromatography on silica gel to afford (R)-tert-butyl(1-(benzyl(2-hydroxyethyl)amino)-3-methyl-1-oxobutan-2-yl)carbamate (2.80 g, 88% yield) as a white solid. LC-MS m/z 351.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:28]=[CH:27][C:8]([NH:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[O:17])[CH2:12][CH2:11]2)=[CH:7][CH:6]=1.C([Si]([O:46][C:47]1[CH:52]=[CH:51][C:50]([O:53][CH2:54][CH:55]2[CH2:57][O:56]2)=[CH:49][CH:48]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[F:26][C:23]1[CH:22]=[CH:21][C:20]([CH2:19][NH:18][C:16]([N:13]2[CH2:14][CH2:15][CH:10]([NH:9][C:8]3[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][NH:1][CH2:57][C@H:55]([OH:56])[CH2:54][O:53][C:50]4[CH:51]=[CH:52][C:47]([OH:46])=[CH:48][CH:49]=4)=[CH:28][CH:27]=3)[CH2:11][CH2:12]2)=[O:17])=[CH:25][CH:24]=1
Reactant: NCCOc1ccc(NC2CCN(C(=O)NCc3ccc(F)cc3)CC2)cc1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(NCc1ccc(F)cc1)N1CCC(Nc2ccc(OCCNC[C@H](O)COc3ccc(O)cc3)cc2)CC1
Yield: 11.5 %

Procedure:
4-[4-(2-Aminoethoxy)anilino]-N-(4-fluorobenzyl)-1-piperidinecarboxamide (0.63 g, 1.4 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.53 g, 1.3 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.125 g, 0.15 mmol).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:3]=1[NH:4][CH2:5][CH:6]=[O:7].C(=O)([O-])[O-].[Na+].[Na+].C1C=CC=CC=1.[Cl:26][CH2:27][C:28](Cl)=[O:29]>O>[Cl:26][CH2:27][C:28]([N:4]([CH2:5][CH:6]=[O:7])[C:3]1[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:29]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C#N)cc1NCC=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O
Product: Cc1ccc(C#N)cc1N(CC=O)C(=O)CCl
Temperature: 25 °C

Procedure:
The dimethyl acetal of 2-(2-methyl-5-cyanoanilino)-acetaldhyde (0.1 mole), sodium carbonate (0.06 mole) dissolved in water (50 ml) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and cooling means. The mixture is cooled to a temperature of about 0°C and α-chloroacetyl chloride (0.11 mole) is incrementally added with stirring. After the addition is completed stirring is continued and the reaction mixture is permitted to warm to room temperature. After this time the mixture is filtered, washed with dilute hydrochloric acid and stripped of solvent to yield the desired product the dimethyl acetal of 2-(N-α-chloroacetyl-2-methyl-5-cyanoanilino)acetaldehyde.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2.[CH2:11]([O:15][C:16](=[O:19])[CH2:17]Cl)[CH2:12][CH2:13][CH3:14].C(OCC)(=O)C>C(=O)([O-])[O-].[K+].[K+]>[CH2:11]([O:15][C:16]([CH2:17][S:1][C:2]1[S:3][C:4]2[C:9]([N:10]=1)=[CH:8][CH:7]=[CH:6][N:5]=2)=[O:19])[CH2:12][CH2:13][CH3:14]
Reactant: Sc1nc2cccnc2s1
Reactant: CCCCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCCCOC(=O)CSc1nc2cccnc2s1
Temperature: 25 °C
Yield: 99 %

Procedure:
Twenty-four (24) g of 2-mercaptothiazolo[5,4-b]pyridine was dissolved in 300 ml of N,Ndimethylformamide, and 43.3 g of potassium carbonate and 23.65 g of chloroacetic acid n-butyl ester were added to the solution, followed by one-hour stirring at room temperature. Seven hundred (700) ml of ethyl acetate was added to the solution, which was then washed with water three times, dehydrated over magnesium sulfate, dried and distilled to remove the solvent to obtain the title compound (39.9 g, 99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([O:34][Si](CC)(CC)CC)[C:17]2[C:12](=[CH:13][C:14](I)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:27][C@H:26]([N:28]([CH2:31][CH3:32])[CH2:29][CH3:30])[CH2:25]2)[C:10]1=[O:33].[NH:42]1[CH:46]=[CH:45][N:44]=[N:43]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].CNCCNC>CN(C)C=O.[Cu](I)I.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([OH:34])[C:17]2[C:12](=[CH:13][C:14]([N:42]3[CH:46]=[CH:45][N:44]=[N:43]3)=[CH:15][C:16]=2[C:18]([F:21])([F:20])[F:19])[N:11]([CH2:23][C@H:24]2[CH2:25][C@H:26]([N:28]([CH2:29][CH3:30])[CH2:31][CH3:32])[CH2:27]2)[C:10]1=[O:33]
Reactant: c1c[nH]nn1
Reactant: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O[Si](CC)(CC)CC)(c3ccc(Cl)cc3Cl)c3c2cc(I)cc3C(F)(F)F)C1
Agent: I[Cu]I
Agent: CNCCNC
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(CC)[C@H]1C[C@H](CN2C(=O)C(O)(c3ccc(Cl)cc3Cl)c3c2cc(-n2ccnn2)cc3C(F)(F)F)C1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
To a solution of the compound of Example 14-1 (75 mg, 0.101 mmol) in N,N-dimethylformamide (1 mL) were added triazole (7.0 mg, 0.101 mmol), potassium phosphate (43 mg, 0.202 mmol), N,N′-dimethylethylenediamine (15 mg, 0.170 mmol) and copper iodide (1) (1.0 mg, 0.01 mmol) under nitrogen, and the mixture was stirred at 100° C. for 8 hours. To the reaction solution was added water, and the mixture was extracted with ethyl acetate, and then the organic layer was washed with saturated saline, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography (chloroform/methanol/28% ammonia water=100/5/1) to give the titled compound (20 mg, 63%).
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([S:9]([CH:12]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]2)[CH3:13])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[CH3:29][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.[NH4+].[Cl-]>CCOCC.O.O1CCCC1>[CH3:13][C:12]([CH:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[CH2:18][CH2:19]1)([S:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:1])([F:27])[F:28])[CH:4]=1)(=[O:10])=[O:11])[CH3:29]
Reactant: CC(C1CCN(C(=O)OC(C)(C)C)CC1)S(=O)(=O)c1cccc(C(F)(F)F)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(C)(C)S(=O)(=O)c2cccc(C(F)(F)F)c2)CC1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
To a 100 ml round bottom flask was added tert-butyl 4-(1-{[3-(trifluoromethyl)phenyl]sulfonyl}ethyl)piperidine-1-carboxylate (5.4 g, 12.8 mmol) and 30 ml tetrahydrofuran. The resulting solution was cooled to −78° C. Sodium bis(trimethylsilyl)amide (NaHMDS) tetrahydrofuran solution (1M, 15.4 ml) was added via a syringe. The reaction mixture turned deep orange-red. It was stirred at −78 C for 5 minutes. MeI (0.96 ml, 15.4 mmol) was then added dropwise with a syringe until reaction mixture turned light yellow. More NaHMDS (1M, 3 ml tetrahydrofuran solution) was added. The reaction mixture was stirred at −78° C. for 5 more minutes and 0.3 ml MeI was added. NH4Cl (60 ml) was added at −78° C. to quench the reaction. The resulting mixture was diluted with 120 ml ether and 60 ml water. The layers were separated, and the organics were dried over sodium sulfate, filtered and concentrated. The residue was purified on silica gel column eluted with 1:4 to 1:2 ethylacetate/hexane to give desired product which was used for the next directly.
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Br:15])[C:5]2[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:21](OCC)(=[O:24])[C:22]#[CH:23]>C(O)C>[Cl:20][C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:23]=[CH:22][C:21](=[O:24])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Br:15])[C:5]=2[CH:16]=1
Reactant: NC1=Nc2ccc(Cl)cc2C(c2ccccc2Br)=NC1
Reactant: C#CC(=O)OCC
Solvent: CCO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Br)c1cc(Cl)ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-chloro-5-(o-bromophenyl)-3H-1,4-benzodiazepine, ethyl propiolate, and ethanol were refluxed. The mixture was chromatographed to give 9-chloro-7-(o-bromophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]1[C:32]2[CH:31]=[C:30]([CH:33]=O)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)(Cl)Cl.CO>[O:23]1[C:32]2[CH:31]=[C:30]([CH2:33][NH:1][CH:2]3[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]4[C:19]5[C:14](=[CH:15][CH:16]=[C:17]([O:20][CH3:21])[CH:18]=5)[CH:13]=[CH:12][C:11]4=[O:22])[CH2:4][CH2:3]3)[N:29]=[CH:28][C:27]=2[O:26][CH2:25][CH2:24]1
Reactant: COc1ccc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Reactant: O=Cc1cc2c(cn1)OCCO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1ccc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCO5)CC3)c2c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 1-[2-(4-aminopiperidin-1-yl)ethyl]-7-methoxyquinolin-2(1H)-one (Intermediate 1, crude, 60 mg, 0.20 mmol) and 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carbaldehyde (WO 2004/058144) (33 mg, 0.20 mmol) in dry chloroform/methanol (5 mL, 1:1) was heated over 3 Å molecular sieves at 70° C. for 3 hours. The reaction mixture was cooled to 0° C., and sodium triacetoxy borohydride (127 mg, 0.6 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes and then was filtered through a 0.45 μm membrane and concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane (50 mL) and saturated aqueous sodium hydrogen carbonate solution (5 mL). The pH of the aqueous phase was adjusted to a pH of 10 with 1M aqueous sodium hydroxide solution. The aqueous phase was back extracted twice with dichloromethane (2×20 mL) and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. Chromatography on silica gel with dichloromethane/methanol (8:1 to 4:1) gave the free base of the title compound as a colorless oil. The free base was taken up in dichloromethane (2 mL), ethanol (7 mL) was added, followed by addition of 1M HCl in ether (0.3 mL). The colorless precipitate was collected by filtration and gave 50 mg (48%) of the bis-hydrochloride salt of the product, mp 243° C.
Reaction SMILES: CS([C:5]1[N:6]=[CH:7][C:8]2[CH:13]=[CH:12][S:11][C:9]=2[N:10]=1)(=O)=O.N[CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1.CN1CCCC1=O>CCOC(C)=O.O>[O:20]1[CH2:21][CH2:22][N:17]([CH2:16][CH2:15][C:5]2[N:6]=[CH:7][C:8]3[CH:13]=[CH:12][S:11][C:9]=3[N:10]=2)[CH2:18][CH2:19]1
Reactant: CS(=O)(=O)c1ncc2ccsc2n1
Reactant: NCCN1CCOCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN1CCCC1=O
Product: c1cc2cnc(CCN3CCOCC3)nc2s1
Temperature: 25 °C
Yield: 87.6 %

Procedure:
A solution of 2-(methylsulfonyl)thieno[2,3-d]pyrimidine (1.0 g, 4.67 mmol), 4-(2-aminoethyl)morpholine (1.8 g, 14.02 mmol), and 1-methyl-2-pyrrolidinone (1.5 mL) was heated to 100° C. overnight. The reaction mixture was cooled to RT and diluted with EtOAc (200 mL)/water (75 mL). The layers were separated, and the organic layer was washed successively with water (4×75 mL) and brine (1×75 mL). The organic layer was then dried over MgSO4, filtered and concentrated to give (1.2 g) of the crude product. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 5% to 95% MeOH in DCM to provide the title compound (1.02 g) MS (ES+): 265 (M+H)+.
Reaction SMILES: [O:1]1[CH2:4][CH:3]([OH:5])[CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[N:26]1[C:34](=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]1=[O:36].N(/C(OC(C)C)=O)=N\C(OC(C)C)=O>>[O:1]1[CH2:4][CH:3]([O:5][N:26]2[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])[CH2:2]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: OC1COC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: O=C1c2ccccc2C(=O)N1OC1COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 13.5 %

Procedure:
To a solution of oxetan-3-ol (1.0 g, 13.50 mmol) were added triphenylphosphine (4.25 g, 16.20 mmol) and 2-hydroxyisoindoline-1,3-dione (2.42 g, 14.85 mmol). After stirring at rt for 10 min, (E)-diisopropyl diazene-1,2-dicarboxylate (3.28 g, 16.20 mmol) was added. After stirring at 30° C. overnight, the reaction mixture was quenched with NH4Cl (aq), extracted with EtOAc, washed with NH4Cl (aq), dried over Na2SO4, filtered and concentrated in vacuo to give the crude product, which was purified with column chromatography on silica gel (gradient hexanes:EtOAc) to give a colorless oil 2-(oxetan-3-yloxy)isoindoline-1,3-dione (400 mg, 6%). LCMS (method B): [MH]+=220, tR=1.67 min.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)#[N:2].[OH:40]O.[OH-].[Na+].Cl>C(O)C.O>[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][O:13]1)[N:7]=[C:6]2[C:18]1[CH:19]=[C:20]([NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]2)=[O:26])[CH:21]=[CH:22][CH:23]=1)(=[O:40])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C#N)cc34)c2)CC1
Reactant: OO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cccc(-c3nn(C4CCCCO4)c4ccc(C(N)=O)cc34)c2)CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl 4-{N-[3-(5-cyano-1-perhydro-2H-pyran-2-yl-1H-indazol-3-yl)phenyl]carbamoyl}piperidinecarboxylate in 3 mL of ethanol, was added 3 mL of 30% commercially available H2O2 solution followed by 0.280 mL of 6.0 N aqueous NaOH solution. Within 30 min, the formation of an abundant white precipitate was observed. The mixture was acidified using a 6.0 N aqueous solution of HCl. Upon addition of water (20 mL), the formation of a precipitate was observed. The solid was collected by filtration, washed with small portions of water and dried in a vacuum oven overnight. The desired product was isolated as a pure white solid (0.277 g, 40% over 2 steps): ES-MS (m/z) 548 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([NH:9][C:10]1[NH:11][C:12]2[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=2[N:14]=1)=[S:8].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)(Cl)Cl>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]1[S:8][N:11]2[C:10](=[N:14][C:13]3[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=32)[N:9]=1
Reactant: S=C(Nc1nc2ccccc2[nH]1)c1cnccn1
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: c1ccc2c(c1)nc1nc(-c3cnccn3)sn12
Reaction time: 15 h

Procedure:
To 0.51 g. of 2-(2-pyrazinylthiocarbonylamino)-benzimidazole [(IV), R = 2-pyrazinyl] in 200 ml. of chloroform at 20°-30°C. (room temperature) is added 0.5 g. of m-chloroperbenzoic acid. The reaction mixture is allowed to stand for 15 hours (overnight) and washed with 20 ml. of potassium bicarbonate solution, 20 ml. of water and dried over magnesium sulfate. The chloroform is evaporated and the residue is recrystallized from methanol-chloroform to yield 2-(2-pyrazinyl)-1,2,4-thiadiazolo-[2,3-a]-benzimidazole [(I), R = 2-pyrazinyl].
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][C:6]([NH2:8])=[O:7])#[N:4].[C:9]([O:13][C:14](=[O:39])[NH:15][C:16]1([C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)/[C:27](/[C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[CH:28]/N(C)C)=[CH:22][CH:21]=2)[CH2:19][CH2:18][CH2:17]1)([CH3:12])([CH3:11])[CH3:10].CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>CN(C=O)C.CO.O>[C:9]([O:13][C:14](=[O:39])[NH:15][C:16]1([C:20]2[CH:21]=[CH:22][C:23]([C:26]3[C:27]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:28][C:5]([C:3]#[N:4])=[C:6]([OH:7])[N:8]=3)=[CH:24][CH:25]=2)[CH2:17][CH2:18][CH2:19]1)([CH3:12])([CH3:10])[CH3:11]
Reactant: CN(C)/C=C(/C(=O)c1ccc(C2(NC(=O)OC(C)(C)C)CCC2)cc1)c1ccccc1
Reactant: N#CCC(N)=O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(O)c(C#N)cc3-c3ccccc3)cc2)CCC1
Temperature: 40 °C
Yield: 92.6 %

Procedure:
To a suspension of sodium hydride (3.58 g, 0.089 mol) in DMF (150 ml) at 0° C. was added a solution of 2-cyanoacetamide (3.48 g, 0.041 mol) and (E)-tert-butyl(1-(4-(3-(dimethylamino)-2-phenylacryloyl)phenyl)cyclobutyl)carbamate (15 g, 0.0357 mol) in methanol (5.5 ml) and DMF (150 ml). The resulting mixture was heated at 40° C. for 16 h. After cooled down to room temperature, the mixture was added to a solution of acetic (50 ml) in water (300 ml) slowly. The resulting precipitate was filtered and the filter cake was partitioned between water (250 ml) and dichloromethane (150 ml). The layers were separated and the aqueous phase extracted into dichloromethane (150 ml). The combined organic phases were washed with water (200 ml) and brine (150 ml), dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give the title compound as a yellow solid (14.6 g, 93%). LCMS (Method A): RT=6.59 min, M+1=442. 1H NMR (500 MHz, CDCl3): 7.89 (1H, s), 7.37-7.32 (2H, m), 7.22-7.16 (5H, m), 7.03-6.98 (2H, m), 2.50-2.37 (4H, m), 2.06-1.97 (1H, m), 1.82-1.77 (1H, m), 1.45-1.05 (9H, br).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:25])[F:24])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27](Cl)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].CCN(CC)CC.[CH3:37][N:38]([CH3:47])[CH2:39][CH2:40][N:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]([O:16][C:17]3[CH:22]=[CH:21][C:20]([C:23]([F:26])([F:24])[F:25])=[CH:19][CH:18]=3)[CH3:15])[CH2:12][N:11]([C:27]([N:44]3[CH2:45][CH2:46][N:41]([CH2:40][CH2:39][N:38]([CH3:47])[CH3:37])[CH2:42][CH2:43]3)=[O:28])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CN(C)CCN1CCNCC1
Reactant: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)Cl)CC1c1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(Oc1ccc(C(F)(F)F)cc1)C1CN(C(=O)N2CCN(CCN(C)C)CC2)CC1c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 63 %

Procedure:
To a stirred solution of (3RS,4SR)-3-(3,4-dichloro-phenyl)-4-[(RS)-1-(4-trifluoromethyl-phenoxy)-ethyl]-pyrrolidine-1-carbonyl chloride (58 mg, 0.12 mmol) in CH2Cl2 (2 ml) were added Et3N (0.02 mL, 0.15 mmol) and dimethyl-(2-piperazin-1-yl-ethyl)-amine (0.03 mL) (commercially available). Stirring was continued overnight, and the reaction mixture was concentrated under vacuo and directly purified by flash chromatography (SiO2, CH2Cl2/MeOH/NH3, 9/4/1) to yield 46 mg (63%) of the title compound as light yellow oil. ES-MS m/e: 587.3 (M+H+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=1.[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([CH:26]=[C:27]([F:29])[CH:28]=1)[NH2:25])[CH3:19]>>[CH2:18]([S:20][CH2:21][C:22]1[CH:23]=[C:24]([NH:25][C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=3[O:15][CH3:16])[C:5]([F:17])=[CH:4][N:3]=2)[CH:26]=[C:27]([F:29])[CH:28]=1)[CH3:19]
Reactant: CCSCc1cc(N)cc(F)c1
Reactant: COc1cc(F)ccc1-c1nc(Cl)ncc1F
Product: CCSCc1cc(F)cc(Nc2ncc(F)c(-c3ccc(F)cc3OC)n2)c1

Procedure:
Intermediate 42.3 was prepared under similar conditions as described in the preparation of Intermediate 20.1 using 2-chloro-5-fluoro-4-(4-fluoro-2-methoxyphenyl)pyrimidine and 3-[(ethylsulfanyl)methyl]-5-fluoroaniline. The batch was purified by chromatography (hexane to hexane/ethyl acetate 30%) to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21][CH:22]=O.C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[C:31]([CH3:34])[CH:32]=[O:33])C=CC=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:11]([CH3:12])=[C:10]2[C:6]([C:7](=[O:13])[O:8][CH2:9]2)=[C:5]([O:14][CH2:15][O:16][CH2:17][CH2:18][O:19][CH3:20])[C:4]=1[CH2:21]/[CH:22]=[C:31](\[CH3:34])/[CH:32]=[O:33]
Reactant: CC(C=O)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COCCOCOc1c(CC=O)c(OC)c(C)c2c1C(=O)OC2
Solvent: Cc1ccccc1
Product: COCCOCOc1c(C/C=C(\C)C=O)c(OC)c(C)c2c1C(=O)OC2

Procedure:
A solution of 2-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy -7-methyl-3-oxoisobenzofuran-5-yl)acetaldehyde (10.3 g) and 2-(triphenyl-phosphoranylidene)-propionaldehyde (11.6 g) in toluene (250 ml) was refluxed for 7 hours. The solvent was removed under vacuum and the residue was chromatographed on silica gel, eluting with 9:1 hexane:ethyl acetate, to afford (E)-4-(1,3-dihydro-6-methoxy-4-methoxyethoxymethoxy-7-methyl -3-oxoisobenzofuran-5-yl)-2-methylbut-2-enaldehyde, mp 67°-68° C., (methylene chloride/hexane).