Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([P:7]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C@H:8]2[CH2:16][C@@H:11]3[O:12][C:13](=[O:15])[CH2:14][C@@H:10]3[C@H:9]2[CH2:17][P:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B.C1N2CCN(CC2)C1>C1(C)C=CC=CC=1>[C:31]1([P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:8]2[CH2:16][CH:11]3[O:12][C:13](=[O:15])[CH2:14][CH:10]3[CH:9]2[CH2:17][P:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C1C[C@@H]2[C@@H](CP(c3ccccc3)c3ccccc3)[C@@H](P(c3ccccc3)c3ccccc3)C[C@@H]2O1
Agent: B
Agent: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: O=C1CC2C(CC(P(c3ccccc3)c3ccccc3)C2CP(c2ccccc2)c2ccccc2)O1
Temperature: 40 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a 25 mL-recovery flask were added (3aR,4S,5S,6aS)-(5-diphenylphosphanyl-4-[(diphenylphosphanyl)methyl]hexahydrocyclopenta[b]furan-2-one-borane complex (Compound 3, 1.0 mmol) and 1,4-diazobicyclo[2,2,2]octane (DABCO, 0.25 g, 2.2 mmol), and the atmosphere in the flask was substituted with nitrogen. The mixture was added with 10 mL of deoxygenized toluene, and stirred at 40° C. for 3 hours. The solvent was concentrated in an evaporator, and the residue was purified by silica gel column chromatography (toluene/ethyl acetate=20/1 to 4/1) to obtain (3aR,4S,5S,6aS)-(5-diphenylphosphanyl-4-[(diphenylphosphanyl)methyl]hexahydrocyclopenta[b]furan-2-one (CLPL-S, yield: 85%).
Reaction SMILES: Br[C:2]1[N:7]2[CH:8]=[N:9][N:10]=[C:6]2[C:5]([N:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][CH:3]=1.[O:24]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25]1.C([O-])([O-])=O.[Cs+].[Cs+].O1CCOCC1>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.O>[O:24]1[CH:28]=[CH:27][C:26]([C:2]2[N:7]3[CH:8]=[N:9][N:10]=[C:6]3[C:5]([N:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)=[N:4][CH:3]=2)=[CH:25]1
Reactant: OB(O)c1ccoc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ncc(Br)n3cnnc23)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCN(c2ncc(-c3ccoc3)n3cnnc23)CC1
Temperature: 100 °C
Yield: 97.3 %

Procedure:
A 50 mL round bottom flask was charged with tert-butyl 4-(5-bromo-[1,2,4]triazolo[4,3-a]pyrazin-8-yl)piperazine-1-carboxylate (800 mg, 2.08 mmol), furan-3-ylboronic acid (349 mg, 3.12 mmol), Pd(PPh3)4 (240 mg, 0.312 mmol), Cs2CO3 (1.00 g, 3.12 mmol), 1,4-dioxane (11 mL) and water (4 mL). The resulting mixture was heated under N2 at 100° C. overnight. Work-up: the reaction mixture was filtered. The filter cake was washed with EtOAc (10 mL) and the filtrate was extracted with more EtOAc (10 mL×3). The combined organic solutions were washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel with 2% methanol in dichloromethane, to afford 0.75 g (97%) of the product as a yellow solid. MS m/z: 371 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:17][N:18]1[CH:22]=[N:21][CH:20]=[N:19]1)[C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=1.[CH3:23]I.[H-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=1)[N:17]([CH3:23])[N:18]1[CH:22]=[N:21][CH:20]=[N:19]1
Reactant: Fc1ccc(C(Nn2cncn2)c2ccc(Cl)cc2Cl)cc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(c1ccc(F)cc1)c1ccc(Cl)cc1Cl)n1cncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
A solution of 40.0 g (0.119 mol) of N-[1-(2,4-dichlorophenyl)-1-(4-fluorophenyl)methyl]-1H-1,2,4-triazol-1-amine and 40 mL (0.64 mol) of methyl iodide in 250 mL dimethyl formamide was cooled to 0° C. Sodium hydride (4.5 g; 0.19 mol, freed from oils) was added portionwise. The reaction mixture was warmed to room temperature, stirred 1 h and quenched by dropwise addition of aqueous ammonium chloride. The mixture was diluted with ether, and washed three times with water and with brine. Drying (MgSO4) and removal of solvent gave product as an oil. Crystallization from hexanes afforded 27.7 g (66% yield) of the desired product as a white solid; mp 118°-119° C.
Reaction SMILES: [C:1]([NH:6][C:7]1[NH:8][C:9](=[O:34])[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[C@@H:16]([O:17][CH2:18][S:19][CH3:20])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3].[C:35]1([N:41]([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.C(N(CC)C(C)C)(C)C>N1C=CC=CC=1>[C:1]([NH:6][C:7]1[N:8]=[C:9]([O:34][C:42](=[O:43])[N:41]([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:10]2[N:11]=[CH:12][N:13]([C:32]=2[N:33]=1)[C@@H:14]1[O:31][C@H:21]([CH2:22][O:23][Si:24]([C:27]([CH3:29])([CH3:28])[CH3:30])([CH3:25])[CH3:26])[C@@H:16]([O:17][CH2:18][S:19][CH3:20])[CH2:15]1)(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: CSCO[C@H]1C[C@H](n2cnc3c(=O)[nH]c(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: CSCO[C@H]1C[C@H](n2cnc3c(OC(=O)N(c4ccccc4)c4ccccc4)nc(NC(=O)C(C)C)nc32)O[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80 %

Procedure:
To 1.0 g N2-isobutyryl-3′-O-(methylthimethyl)-5′-O-(tert-butyldimethylsilyl)-2′-deoxyguanosine (11, 1.95 mmol) dissolved in 22 mL dry pyridine were added diphenylcarbamoyl chloride (0.677 g, 2.92 mmol) and 1.02 mL N,N-diisopropylethylamine, and stirred at room temperature for 3 h under nitrogen atmosphere. The reaction mixture became dark red during this time. The solvent was removed under high vacuum, and product was then purified by silica gel column chromatography using EtOAc:hex/1:1 to 7:3 as mobile phase. The product 12 was isolated as yellowish powder (1.09 g, ˜80% yield; Rf=0.7, EtOAc:hex (1:1)). HR-MS: Obs. m/z 707.3068 calcd. for C35H47O6N6SiS 707.3047 [M+H]+. 1H-NMR (CDCl3): δH 8.25 (s, 1H), 7.94 (brs, 1H), 7.47-7.37 (m, 10H), 6.42 (m, 1H), 4.75 (m, 2H), 4.71 (m, 1H), 4.18 (m, 1H), 3.88-3.70 (m, 2H), 2.80 (m, 1H), 2.60 (m, 1H), 2.19 (s, 3H), 1.30 (d, J=7.2 Hz, 6H), 0.93 (s, 9H) and 0.14 (s, 6H) ppm.
Reaction SMILES: [C:1]([O:4][C@@H:5]([C@H:9]([O:40][C:41](=[O:43])[CH3:42])[C@H:10]([O:36][C:37](=[O:39])[CH3:38])[C@@H:11]([NH:17][C:18](=[O:35])[C@H:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:6](O)=[O:7])(=[O:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.[NH2:59][C@H:60]([C:67]1[CH:72]=[CH:71][C:70]([CH3:73])=[CH:69][CH:68]=1)[CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63].C(N(CC)CC)C>C(#N)C>[C:1]([O:4][C@@H:5]([C@H:9]([O:40][C:41](=[O:43])[CH3:42])[C@H:10]([O:36][C:37](=[O:39])[CH3:38])[C@@H:11]([NH:17][C:18](=[O:35])[C@H:19]([CH2:31][CH:32]([CH3:34])[CH3:33])[NH:20][C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH2:12][O:13][C:14](=[O:16])[CH3:15])[C:6]([NH:59][C@H:60]([C:67]1[CH:68]=[CH:69][C:70]([CH3:73])=[CH:71][CH:72]=1)[CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])=[O:7])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H](NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)C(=O)O
Reactant: CCOC(=O)C[C@H](N)c1ccc(C)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C[C@H](NC(=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](COC(C)=O)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To a solution of [(2S,3R,4R,5S)-2,3,4,6-tetraacetoxy-5-(N-benzyloxycarbonyl-L-leucyl)aminohexanoic acid (250 mg) in acetonitrile (10 ml) were added N-hydroxy-5-norbornene-2,3-dicarboxyimide (110 mg) and N,N′-dicyclohexylcarbodimide (110 mg) and the mixture was stirred at room temperature for 1 hour. After addition of a solution of ethyl (S)-3-amino-3-(4-methylphenyl)propionate (150 mg) and triethylamine (0.13 ml) in acetonitrile (10 ml), the whole was stirred at room temperature for 18 hours. The formed insoluble solid was filtrated off and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and washed with saturated brine (50 ml×2), followed by drying over anhydrous sodium sulfate. After concentration under reduced pressure, the residue was passed through silica gel column chromatography, followed by elution with ethyl acetate-hexane (2:1). The effective fractions were combined and concentrated under reduced pressure to afford the title compound (184 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:23]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:22][C:21]([NH2:30])=[C:20]([CH2:31][NH2:32])[N:19]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C1N=CN([C:39](N2C=NC=C2)=[O:40])C=1>C1COCC1>[C:1]([O:5][C:6](=[O:33])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:23]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)=[CH:22][C:21]4[NH:30][C:39](=[O:40])[NH:32][CH2:31][C:20]=4[N:19]=3)=[CH:16][CH:17]=2)[CH2:9][CH2:10][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc(CN)c(N)cc3-c3ccccc3)cc2)CCC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)NC4)cc2)CCC1
Reaction time: 1 h
Yield: 60.4 %

Procedure:
To a solution of tert-butyl(1-(4-(5-amino-6-(aminomethyl)-3-phenylpyridin-2-yl)phenyl)cyclobutyl)carbamate (113 mg, 0.25 mmol) in dry THF (2 ml) was added CDI (41 mg, 0.25 mmol) under nitrogen. The resulting mixture was stirred for 1 h at 60 C and concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 5% MeOH in DCM) to give the title compound (71 mg, 59%). 1H NMR (500 MHz, CDCl3): 8.91 (1H, br s), 7.19-7.11 (7H, m), 7.00-6.97 (3H, m), 5.73 (1H, s), 4.93 (1H, s), 4.65 (2H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([O:18][CH2:19][CH2:20][CH2:21][N:22]4[CH2:23][CH2:24][N:25]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:26][CH2:27]4)=[CH:15][CH:16]=3)[C:11](=[O:28])[C:10]=2[C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([F:37])[CH:30]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCNCC4)cc3C2=O)cc1F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCCN4CCN(S(C)(=O)=O)CC4)cc3C2=O)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 47 %

Procedure:
To a solution of 3-(3,5-difluorophenyl)-2-(3-fluoro-4-methoxyphenyl)-6-(3-(piperazin-1-yl)propoxy)-1H-inden-1-one (70 mg, 1.2 eq, 0.1 mmol) obtained in Step 2 in CH2Cl2 at 0° C. was added triethylamine (1.5 eq) and methylsulfonyl chloride (1.0 eq). The mixture was stirred for 1 h at room temperature and diluted with CH2Cl2. The mixture was washed with H2O and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexanes=1:1) to obtain the title compound (47%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([O:13]CC)=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9].C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1.[OH-].[Na+]>[F:1][C:2]1[CH:3]=[C:4]([C:10](=[O:16])[C:11]([OH:13])=[O:12])[CH:5]=[CH:6][C:7]=1[S:8][CH3:9]
Reactant: CCOC(=O)C(=O)c1ccc(SC)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CSc1ccc(C(=O)C(=O)O)cc1F
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetate (5.5 g, 0.02 mol) in toluene (55 mL, 10 times), 3 M sodium hydroxide solution (9.09 mL) was added at 50° C. and the reaction mixture was stirred for 3 h at the same temperature. Progress of the reaction was monitored by TLC (30% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, the contents were cooled to 0° C., the mixture was acidified with diluted HCl and the solid precipitated was filtered. The crude product 2-(3-fluoro-4-(methylthio)phenyl)-2-oxoacetic acid obtained as an yellow colored solid (4.5 g, crude) was directly used for the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=[O:6].CS(C)=O.C(=O)([O-])[O-].[K+].[K+].[CH2:22](Cl)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33]>O.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([O:7][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])=[O:6]
Reactant: CCCCCCCCCCCCCl
Reactant: Nc1cc(C(=O)O)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCOC(=O)c1ccc(Cl)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95 %

Procedure:
17.2 g (0.1 mol) of 3-amino-4-chlorobenzoic acid was added to 50 ml of dimethylsulfoxide.. Then 13.8 g (0.1 mol) of potassium carbonate was added to the solution obtained above, and the resulting mixture was stirred in the temperature range of from 20 to 30° C. for 30 min. 22.5 g (0.11 mol) of dodecyl chloride was poured into the solution thus obtained, and the resulting solution was heated to 100° C., and allowed to react at the temperature for 1 hour. After completing the reaction, 50 ml of ethyl acetate, and 50 ml of water were added to the reaction mixture, and the organic layer obtained was separated, concentrated, diluted with 100 ml of methanol, and then cooled to precipitate crystals. The crystals were separated by filtration, and then dried to obtain 32.3 g (yield 95%) of the desired product. Purity 99% or higher. Melting point 58.0-59.2° C. A result of the elemental analysis of this sample was as follows:
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH:11]2[CH:14]([CH3:25])[NH:15][CH:16]([C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=3)[CH:10]2[C:9]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:33](OC(=O)C)(=[O:35])[CH3:34]>C(#N)C>[C:33]([N:15]1[CH:14]([CH3:25])[CH:11]2[CH:10]([C:9](=[O:26])[N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:12]2=[O:13])[CH:16]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1)(=[O:35])[CH3:34]
Reactant: CC1NC(c2ccc(C#N)cc2)C2C(=O)N(Cc3ccccc3)C(=O)C12
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)N1C(C)C2C(=O)N(Cc3ccccc3)C(=O)C2C1c1ccc(C#N)cc1
Reaction time: 1.5 h
Yield: 83 %

Procedure:
4.B)c) A solution of 3.46 g (10 mmol) of (1RS,3SR,3aRS,6aSR)-4-(5-benzyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile in acetonitrile (10 ml) was treated with pyridine (20 mmol). Acetic anhydride (20 mmol) was slowly added dropwise while cooling with ice. The cooling was removed and the reaction mixture was stirred for a further 1.5 hours. Thereafter, the reaction mixture was poured into saturated NaCl solution and extracted with dichloromethane. The solvent was removed and the residue was separated chromatographically (hexane:ethyl acetate=1:1). (1RS,3SR,3aRS,6aSR)-4-(2-Acetyl-5-benzyl-3-methyl-4,6-dioxo-octahydro-pyrrolo[3,4-c]pyrrol-1-yl)-benzonitrile (83%) was isolated as a colourless solid. M.p.: 107°-109° C. EI-MS: 387 ([M]+, 72); 344 (35); 320 (28); 254 (18); 183 (16); 169 (17); 158 (53); 91 (86); 43 (100).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[CH:15])=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:3])[CH3:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](I)=[CH:23][CH:22]=1>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[C:15][C:24]2[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=2)=[CH:10][C:9]=1[N+:16]([O-:18])=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: Fc1ccc(I)cc1
Reactant: C#Cc1ccc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])c1
Product: CC(C)(C)OC(=O)Nc1ccc(C#Cc2ccc(F)cc2)cc1[N+](=O)[O-]
Yield: 111.3 %

Procedure:
Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester (Example F2) (525 mg, 2.0 mmol) and 1-fluoro-4-iodobenzene (0.35 mL, 3 mmol) according to the general procedure F. Obtained as a yellow solid (793 mg).
Reaction SMILES: [N+:1](=[C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:12])=[N-:2].[C:13]1([C:19]([C:21]#[CH:22])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:19]([C:21]1[CH:22]=[C:3]2[N:1]([C:4](=[O:12])[NH:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=32)[N:2]=1)(=[O:20])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: [N-]=[N+]=C1C(=O)Nc2ccccc21
Reactant: C#CC(=O)c1ccccc1
Product: O=C(c1ccccc1)c1cc2c3ccccc3[nH]c(=O)n2n1

Procedure:
6.23 g (0.039 mole) of diazooxindole and 6.6 g (0.051 mole or 1.3 equiv) of the phenylethynyl ketone prepared as in part A above (dried on a porous plate before being weighed out) are suspended in benzene (275 ml) and the mixture is refluxed under N2 for 19 hours. The reaction mixture is cooled and the precipitates that form are filtered off, washed well with anhydrous ether (150 ml) and dried in a vacuum oven at ~70° for 11/2 hours. Yield: 10.3 g, m.p. 308°-311°. Additional product of 400 mg is obtained on refluxing the filtrate for another 24 hours. Total crude yield: 94.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:31]CN(CC)CC.C=O.C(O)(=O)C.C([BH3-])#N.[Na+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[S:15][C:14]3=[N:16][CH:17]=[C:18]([C:19]4[CH:20]=[N:21][C:22]([N:25]5[CH2:26][CH2:27][N:28]([CH3:31])[CH2:29][CH2:30]5)=[N:23][CH:24]=4)[N:13]3[N:12]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CCN(CC)CC
Reactant: COc1ccc(-c2nn3c(-c4cnc(N5CCNCC5)nc4)cnc3s2)cc1OC
Agent: C=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-c2nn3c(-c4cnc(N5CCN(C)CC5)nc4)cnc3s2)cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 12.1 %

Procedure:
To a mixture of 2-(3,4-Dimethoxy-phenyl)-5-(2-piperazin-1-yl-pyrimidin-5-yl)-imidazo[2,1-b][1,3,4]thiadiazole (52 mg, 0.113 mmol, 1 eq), Et3N (0.032 mL, 0.226 mmol, 2 eq), formaldehyde (0.102 mL, 1.36 mmol, 12 eq) and acetic acid (0.02 mL, 0.136 mmol, 1.2 eq) in MeOH (2 mL) was added Sodium cyanoborohydride (0.1 g, 1.58 mmol, 14 eq). The reaction mixture was stirred at rt for 2 h. Solvents were evaporated to dryness and the residue was dissolved in sat NaHCO3/EtOAc. Layers were separated and the aqueous layer was extracted once with EtOAc. The combined organic layers were dried, filtered and evaporated. The residue was purified by HPLC to give the desired product (6 mg, 12%). HPLC-MS: (5-40% B in 8 min, 0.8 mL/min, 50° C.): tR=4.64 min, [M+H]+ m/z 438.2; 1H NMR (300 MHz, DMSO) δ 8.98 (s, 2H), 7.70 (s, 1H), 7.56 (dd, J=8.4, 2.0 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H), 7.16 (d, J=8.5 Hz, 1H), 3.90 (s, 3H), 3.86 (s, 3H), 3.80 (m, 4H), 2.38 (m, 4H), 2.22 (s, 3H).
Reaction SMILES: Cl.[CH3:2][NH:3][CH3:4].[Cl-].C[Al+]C.C(O[C:12]([C:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]([CH2:22][CH2:23][O:24][CH3:25])[N:15]=1)=[O:13])C.O>C1(C)C=CC=CC=1>[CH3:2][N:3]([CH3:4])[C:12]([C:14]1[C:18]([N+:19]([O-:21])=[O:20])=[CH:17][N:16]([CH2:22][CH2:23][O:24][CH3:25])[N:15]=1)=[O:13]
Reactant: CNC
Reactant: CCOC(=O)c1nn(CCOC)cc1[N+](=O)[O-]
Agent: C[Al+]C
Agent: Cl
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: O
Product: COCCn1cc([N+](=O)[O-])c(C(=O)N(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Under inert gas atmosphere, dimethylamine hydrochloride (73 mg, 0.89 mmol) was dissolved in toluene (1.0 ml). Dimethylaluminium chloride (990 μl, 0.9M heptane solution) was added and the reaction mixture was stirred for 10 min. at ambient temperature. 1-(2-Methoxyethyl)-4-nitro-1H-pyrazole-3-carboxylic acid ethyl ester (70 mg, 0.29 mmol) was added and the reaction mixture was heated to 90° C. overnight. After cooling-down to ambient temperature, a small amount of water was added and the resulting suspension was stirred vigorously for 5 min. All volatiles were removed and the product was obtained after purification by silica gel chromatography using a heptane/ethyl acetate gradient as light brown oil (65 mg, 93%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH:13]=[CH:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CO.[Pd]>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:28][CH2:29][S:30][CH3:31])[NH:5][C:6](=[O:27])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[CH:9][C:8]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: COC(=O)[C@H](CCSC)NC(=O)c1ccc(C=Cc2cccnc2)cc1-c1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)[C@H](CCSC)NC(=O)c1ccc(CCc2cccnc2)cc1-c1ccccc1
Reaction time: 8 h
Yield: 71.2 %

Procedure:
A mixture of the {4-[2-(pyrid-3-yl)ethenyl]-2-phenylbenzoyl}methionine methyl ester prepared in Example 210 (160 mg, 0.36 mmol) and palladium (10%) on carbon (460 mg, 0.43 mmol of palladium) in methanol was flushed with hydrogen, and stirred under a positive hydrogen pressure for 8 hours. The mixture was then filtered through Celite, rinsed with ethyl acetate, and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate) give {4-[2-(pyrid-3-yl)ethyl]-2-phenylbenzoyl}methionine methyl ester (115 mg, 71%). 1H NMR (300 MHz, CDCl3) δ 8.45 (m, 2H), 7.64 (d, 1H), 7.40 (m, 7H), 7.22 (dd, 2H), 7.10 (d, 1H), 5.87 (br d, 1H), 4.68 (m, 1H), 3.67 (s, 3H), 2.99 (m, 4H), 2.08 (m, 2H), 2.02 (s, 3H), 1.93 (m, 1H), 1.76 (m, 1H). MS (APCI+) m/e 449 (M+H)+.
Reaction SMILES: Br.C(O)(=O)C.[CH:6]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH2:22][CH2:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)(=[O:10])=[O:9])=[CH2:7].[CH3:28][S:29](C)=O>>[CH3:28][S:29][CH2:7][CH2:6][S:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24](=[O:27])[NH:25][N:26]=2)=[CH:17][CH:16]=1)(=[O:9])=[O:10]
Reactant: CS(C)=O
Reactant: C=CS(=O)(=O)NCCCc1ccc(C2=NNC(=O)CC2)cc1
Agent: Br
Solvent: CC(=O)O
Product: CSCCS(=O)(=O)NCCCc1ccc(-c2ccc(=O)[nH]n2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 64.4 %

Procedure:
1.7 g of dimethylsulfoxide was added to a 25% hydrogen bromide-acetic acid suspension (50 ml) containing 5.30 g of 6-[4-(3-vinylsulfonylaminopropyl)phenyl]-4,5-dihydropyridazin-3(2H)-one, and the mixture was stirred at room temperature for 4.5 hours. After hydrogen bromide and acetic acid were removed, a 15% aqueous sodium methyl mercaptide solution (100 ml) was added to the residue, and the mixture was stirred at 60° C. for 1.5 hours. After cooling, the mixture was neutralized with hydrochloric acid, and crystal was collected by filtration, washed with water, dried and then recrystallized from acetonitrile to obtain 3.90 g of 6-[4-(3-(2-methylthioethyl)sulfonylaminopropyl)phenyl]pyridazin-3(2H)-one.