Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:4][CH2:5][CH:6]1[CH2:12][CH:11]=[CH:10][CH2:9][N:8]([S:13]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)(=[O:15])=[O:14])[CH:7]1[C:24]([OH:26])=O)(=[O:3])[CH3:2].C([Si](C)(C)[O:32][NH2:33])(C)(C)C.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CN(C)C=O.C(OCC)(=O)C>[OH:32][NH:33][C:24]([CH:7]1[CH:6]([CH2:5][O:4][C:1](=[O:3])[CH3:2])[CH2:12][CH:11]=[CH:10][CH2:9][N:8]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:26]
Reactant: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)O)cc1
Reactant: CC(C)(C)[Si](C)(C)ON
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(S(=O)(=O)N2CC=CCC(COC(C)=O)C2C(=O)NO)cc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 31.4 %

Procedure:
To a solution of 3-Acetoxymethyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepine-2-carboxylic acid (101 mg, 0.263 mmoL) in 3 mL dimethylformamide at -20° C. under an argon blanket was added O-(tert-Butyldimethyl-silyl)hydroxylamine (50 mg, 0.342 mmoL) followed by N,N-Diisopropylethylamine (0.069 mL, 0.342 mmoL). (O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (110 mg, 0.289 mmoL) was added in and the temperature was kept at -20° C. for 40 minutes before allowing to warm to ambient temperature. The reaction was allowed to stir for 19 hours at which time it was diluted with ethyl acetate. 10% citric acid was added in and stirred for 30 minutes, the reaction was then washed sequentially with water, 0.5N HCL, dilute sodium bibarbonate, and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the solvent removed under reduced pressure. The residue was purified by column chromatography (silica: 0.5% to 3% methanol in dichloromethane) to yield (33 mg, 31%) of Acetic acid 2-hydroxycarbamoyl-1-(4-methoxy-benzenesulfonyl)-2,3,4,7-tetrahydro-1H-azepin-3-ylmethyl ester; MS: (M+H)+ =399, (M+NH4)+ =416.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N+:4]([O-])[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[N+:12]([O-])=O>[Ni].CO>[NH2:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:11]=1[NH2:12]
Reactant: Nc1c[n+]([O-])c2c(c1[N+](=O)[O-])CCCC2
Agent: [Ni]
Solvent: CO
Product: Nc1cnc2c(c1N)CCCC2
Yield: 86.4 %

Procedure:
A mixture of 5.00 g of Compound 4 obtained in the above step (4) and 12.9 g of Raney nickel in methanol is hydrogenated at ordinary temperature under atmospheric pressure. The catalyst is filtered off, and the filtrate is concentrated in vacuo to remove the solvent. The residue is chromatographed on an alumina column, eluting with 5% methanol/chloroform. The product is recrystallized from methylene chloride-ethyl acetate to give 3.37 g of the titled compound (IIla) as crystals. Yield: 86%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[C:19]1[S:20][C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=1.[I-].[Na+]>CN(C)C=O.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][O:15][C:19]2[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CO)C1
Reactant: Clc1nc2ccccc2s1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC(COc2nc3ccccc3s2)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 95 %

Procedure:
1-(tert-Butoxycarbonyl)piperidin-3-ylmethanol (300 mg, 1.39 mmol) was dissolved in N,N-dimethylformamide (5 mL). While this solution was chilled in an ice bath, 60% sodium hydride in oil (83.6 mg, 2.09 mmol) was added. The reaction mixture was stirred for 10 min while ice-chilled and for another 10 min at room temperature. 2-chlorobenzothiazole (0.344 mL, 2.78 mmol) and sodium iodide (208 mg, 1.39 mmol) were then added and the mixture was stirred at room temperature for 5 hours. Subsequently, water was added and the mixture was extracted with ethyl acetate. The extract washed with brine. The washed product was then dried over magnesium sulfate and the solvent was evaporated. Purification of the resulting residue by silica gel column chromatography (hexane:ethyl acetate=20:1->5:1) gave 460 mg (95%) of the desired compound as a colorless powder.
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[C:17](Cl)[CH:18]=[C:13]3[C:12](I)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(S([N:30]2[C:34]3=[N:35][CH:36]=[CH:37][CH:38]=C3C(I)=[CH:31]2)(=O)=O)C=CC=CC=1>>[C:1]1([S:7]([N:10]2[C:14]3=[N:15][CH:16]=[CH:17][CH:18]=[C:13]3[C:12]([CH2:38][C:37]3[CH:36]=[N:35][C:34]([S:7]([CH3:1])(=[O:9])=[O:8])=[N:30][CH:31]=3)=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cccnc21
Reactant: O=S(=O)(c1ccccc1)n1cc(I)c2cc(Cl)cnc21
Product: CS(=O)(=O)c1ncc(Cc2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cn1

Procedure:
was prepared following the protocol of Scheme 191, substituting 1 benzenesulfonyl-5-chloro-3-iodo-1H-pyrrolo[2,3-b]pyridine 581 with 1-benzenesulfonyl-3-iodo-1H-pyrrolo[2,3-b]pyridine in Step 1.
Reaction SMILES: O.Cl.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([O:20]C)=[CH:17][CH:18]=3)[CH2:13][C:12]([N:22]([CH3:24])[CH3:23])=[N:11]2)=[CH:6][CH:5]=1.[BrH:25]>>[BrH:25].[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:19]3[C:14](=[CH:15][C:16]([OH:20])=[CH:17][CH:18]=3)[CH2:13][C:12]([N:22]([CH3:24])[CH3:23])=[N:11]2)=[CH:8][CH:9]=1
Reactant: COc1ccc2c(c1)CC(N(C)C)=NC2c1ccc(Cl)cc1
Agent: Br
Agent: Cl
Solvent: O
Product: CN(C)C1=NC(c2ccc(Cl)cc2)c2ccc(O)cc2C1

Procedure:
A solution of 1-(4-chlorophenyl)-3-dimethylamino-6-methoxy-1,4-dihydroisoquinoline hydrochloride hydrate (1.5 g) in 48% aqueous hydrobromic acid (200 ml) was heated at 120° C. for 2.5 h. The solution was evaporated to dryness in in vacuo and recrystallised from ethanol-ether to give the title compound, (2.53 g),
Reaction SMILES: [OH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12.[CH3:12]I>[OH-].[Na+].O>[OH:1][C:2]1[N:7]=[C:6]([S:8][CH3:12])[N:5]=[C:4]2[NH:9][N:10]=[CH:11][C:3]=12
Reactant: CI
Reactant: Oc1nc(S)nc2[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1nc(O)c2cn[nH]c2n1
Temperature: 5 °C
Reaction time: 0.29 h

Procedure:
4-hydroxy-6-mercapto-pyrazolo[3,4-d]pyrimidine (14 g) was dissolved in a solution of sodium hydroxide (10 g) in water (300 mL). The solution was cooled to 5° C. and shaken with of methyl iodide (12 g). After 15-20 minutes the solution was charcoaled, filtered and acidified with acetic acid to yield crude product. Re-crystallization in acid gave the desired product MS (ES+): 183.0 (M+1)+.
Reaction SMILES: [CH:1]1([N:4]2[CH2:16][C@@H:7]3[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]3[C:5]2=[O:17])[CH2:3][CH2:2]1.[CH3:18]C(C)CN>>[CH2:1]([N:4]1[CH2:16][C@@H:7]2[C@H:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][N:6]2[C:5]1=[O:17])[CH:3]([CH3:2])[CH3:18]
Reactant: COC(=O)[C@@H]1NCCN2C(=O)N(C3CC3)C[C@H]12
Reactant: CC(C)CN
Product: COC(=O)[C@@H]1NCCN2C(=O)N(CC(C)C)C[C@H]12

Procedure:
Compound 101-C was prepared in analogy to compound 82-C by using 2-methylpropan-1-amine instead of cyclopropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=O)[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7].Cl.[CH3:36][O:37][NH2:38]>>[Cl:1][C:2]1[C:14]([Cl:15])=[C:13]([CH2:16][CH2:17][C:18](=[N:38][O:37][CH3:36])[C:19]2[S:20][C:21]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=3)=[CH:22][CH:23]=2)[CH:12]=[CH:11][C:3]=1[O:4][C:5]([CH3:10])([CH3:9])[C:6]([OH:8])=[O:7]
Reactant: CON
Reactant: CC(C)(Oc1ccc(CCC(=O)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O
Agent: Cl
Product: CON=C(CCc1ccc(OC(C)(C)C(=O)O)c(Cl)c1Cl)c1ccc(-c2ccc(C(F)(F)F)cc2)s1

Procedure:
2-(2,3-Dichloro-4-(3-(methoxyimino)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methylpropanoic acid is prepared from 2-(2,3-dichloro-4-(3-oxo-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)phenoxy)-2-methyl propanoic acid and O-methylhydroxylamine hydrochloride according to general procedure I.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[O:21])[CH2:13][CH:14]2CC(O)=O)=[CH:10][CH:9]=1>ClCCl>[F:7][C:8]1[CH:16]=[C:15]2[C:11]([C:12](=[O:21])[CH2:13][CH:14]2[CH2:1][C:2]([Cl:4])=[O:3])=[CH:10][CH:9]=1
Reactant: O=C(O)CC1CC(=O)c2ccc(F)cc21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C(Cl)CC1CC(=O)c2ccc(F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Oxalyl chloride (4.5 g, 0.035 mol, Aldrich) was added to an ice cold stirring mixture of 2-(6-fluoro-3-oxo-1-indanyl)acetic acid (5.0 g, 0.024 mol) in dichloromethane (200 ml) under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirring was continued for 48 hrs. The volatiles were removed from the solution by spin evaporation in vacuo with the addition of dichloromethane (3×50 ml) to give 2-(6-fluoro-3-oxo-1-indanyl)acetyl chloride which was used without purification or analysis.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:6][CH2:7][CH2:8][CH2:9][CH2:10]Br.[H-].[Na+]>C1COCC1>[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: c1c[nH]cn1
Reactant: BrCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: BrCCCCn1ccnc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of imidazole (500 mg, 7.35 mmol) and 1,4-dibromobutane (2.6 mL, 22.0) in THF (50 mL) was added 60% NaH (356 mg, 8.81 mmol), and the resultant mixture was refluxed for 2 h and stirred at room temperature overnight. The mixture was quenched with H2O (50 mL) and diluted with CH2Cl2 (75 mL). The aqueous phase was separated and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated to dryness. Purification by flash chromatography on silica gel (CH2Cl2/MeOH, 97:3) resulted in partial decomposition of 1-(4-Bromo-butyl)-1H-imidazole. This material was used without any further purification. Using General Procedure A: 3,3″-Dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (94.4 mg, 0.353 mmol), impure 1-(4-Bromo-butyl)-1H-imidazole (145 mg), KI (6.0 mg, 0.035 mmol), DIPEA (0.18 mL, 1.02 mmol), and DMF (3.5 mL) were stirred for 48 h at 60° C. Purification of the crude material by radial chromatography on a 1 mm TLC grade silica gel plate (CH2Cl2/MeOH/NH4OH, 96:2:2) afforded the free base of the title compound (47 mg, 34% over 2 steps) as a colorless oil.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:38])[NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH2:36][OH:37])[CH:31]=3)=[O:28])[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2>O1CCOCC1.[O-2].[Mn+4].[O-2]>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:38])[NH:11][C@H:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([CH:36]=[O:37])[CH:31]=3)=[O:28])[CH:20]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:2]2
Reactant: O=C(COc1cccc([C@@H](NC(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)c1)Nc1cccc(CO)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1COCCO1
Product: O=Cc1cccc(NC(=O)COc2cccc([C@@H](NC(=O)O[C@H]3CN4CCC3CC4)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (R)-quinuclidin-3-yl((S)-(3-(2-((3-(hydroxymethyl)-phenyl)amino)-2-oxoethoxy)phenyl)(phenyl)methyl)carbamate (0.35 g, 0.68 mmol) in 1,4-dioxane (25 mL) was added manganese (IV) oxide (0.58 g, 6.8 mmol) and the reaction mixture stirred at room temperature for 2 hours and then at 50° C. for 15 hours. The suspension was filtered through a pad of celite. The solvent was evaporated at reduced pressure to afford the crude material. This material was used in the next step without further purification.
Reaction SMILES: F[C:2]1[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]2[S:13][C:12]([NH:14][C:15]3[CH:16]=[C:17]4[C:22](=[CH:23][CH:24]=3)[N:21]=[CH:20][CH:19]=[CH:18]4)=[N:11][C:10]=2[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CN1C(=O)CCC1>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:29]=[CH:28][C:5]([C:6]([NH:8][C:9]3[S:13][C:12]([NH:14][C:15]4[CH:16]=[C:17]5[C:22](=[CH:23][CH:24]=4)[N:21]=[CH:20][CH:19]=[CH:18]5)=[N:11][C:10]=3[C:25]([NH2:27])=[O:26])=[O:7])=[CH:4][CH:3]=2)[CH2:33][CH2:32]1
Reactant: CN1CCNCC1
Reactant: NC(=O)c1nc(Nc2ccc3ncccc3c2)sc1NC(=O)c1ccc(F)cc1
Solvent: CN1CCCC1=O
Product: CN1CCN(c2ccc(C(=O)Nc3sc(Nc4ccc5ncccc5c4)nc3C(N)=O)cc2)CC1
Temperature: 150 °C
Yield: 45.7 %

Procedure:
A mixture of 5-(4-fluorobenzamido)-2-(quinolin-6-ylamino)thiazole-4-carboxamide (90 mg, 0.22 mmol) and 1-methyl-piperazine (110 mg, 1.10 mmol) in NMP (3 mL) was heated at 150° C. for 1.5 h. The reaction mixture was diluted with ice-water (5 mL), and the resulting solids were collected by filtration and washed successively with water, ether and dried to give 0.049 g (45% yield) of the titled compound.
Reaction SMILES: O[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]3[N:39]=[C:40]([NH:43]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:41][CH:42]=3)=[N:17]\[O:18]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:12](=[O:64])[N:7]2[C:8]=1[C:9]([O-:11])=[O:10].[Na+].[C:66]([CH2:69][S:70][C:71]1[S:72][C:73]([SH:76])=[N:74][N:75]=1)(=[NH:68])[NH2:67]>CN(C=O)C>[C:66]([CH2:69][S:70][C:71]1[S:72][C:73]([S:76][CH2:2][C:3]2[CH2:4][S:5][C@@H:6]3[C@H:13]([NH:14][C:15](=[O:63])/[C:16](/[C:38]4[N:39]=[C:40]([NH2:43])[S:41][CH:42]=4)=[N:17]\[OH:18])[C:12](=[O:64])[N:7]3[C:8]=2[C:9]([OH:11])=[O:10])=[N:74][N:75]=1)(=[NH:67])[NH2:68]
Reactant: N=C(N)CSc1nnc(S)s1
Reactant: O=C([O-])C1=C(CO)CS[C@@H]2[C@H](NC(=O)/C(=N\OC(c3ccccc3)(c3ccccc3)c3ccccc3)c3csc(NC(c4ccccc4)(c4ccccc4)c4ccccc4)n3)C(=O)N12
Agent: [Na+]
Solvent: CN(C)C=O
Product: N=C(N)CSc1nnc(SCC2=C(C(=O)O)N3C(=O)[C@@H](NC(=O)/C(=N\O)c4csc(N)n4)[C@H]3SC2)s1
Yield: 27.2 %

Procedure:
To a solution containing 906 mg of sodium 3-hydroxymethyl-7β-[2-(2-tritylaminothiazol-4-yl)-(Z)-2-trityloxyiminoacetamido]-3-cephem-4-carboxylate and 309 mg of 2-amidinomethylthio -5-mercapto-1,3,4-thiadiazole in 7 ml of DMF was added 1.01 g of ethyl o-phenylenephosphate under ice-cooling and stirring. The reaction mixture was stirred at room temperature for 4 hours and subjected to a column chromatography on silica gel (100 g), being washed with acetone and eluted with acetone/water (9:1). The eluate was concentrated to dryness under reduced pressure, and there was added 20 ml of formic acid. The mixture was stirred at room temperature for 16 hours and then distilled to remove formic acid. To the residue was added a mixture of water and THF. The solution was washed with ethyl acetate, concentrated under reduced pressure and then subjected to a column chromatography on XAD-II (140 ml), being washed with water and eluted with 20% aqueous ethanol. The eluate was concentrated to 10 ml and the resultant precipitate was collected by filtration to give 160 mg of the title compound as pale yellow crystals.
Reaction SMILES: [NH:1]1[C:51](=[O:52])[C@H:50]2[CH2:53][CH2:54][CH2:55][CH2:56][N:49]2[C:47](=[O:48])[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:38][C:36](=[O:37])[C@H:31]([CH2:32][C:33](=[O:35])[OH:34])[NH:30][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:23])[NH:8]S(C1C(C)=C(C)C(OC)=CC=1C)(=O)=O>C(O)(C(F)(F)F)=O.ClCCl.C1(S)C=CC=CC=1>[NH:1]1[C:51](=[O:52])[C@H:50]2[CH2:53][CH2:54][CH2:55][CH2:56][N:49]2[C:47](=[O:48])[C@@H:39]([CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[NH:38][C:36](=[O:37])[C@H:31]([CH2:32][C:33](=[O:34])[OH:35])[NH:30][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C@@H:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:23]
Reactant: COc1cc(C)c(S(=O)(=O)NC(=N)NCCC[C@@H]2NC(=O)[C@H]3CCCCN3C(=O)[C@@H](Cc3ccccc3)NC(=O)[C@H](CC(=O)O)NC(=O)CNC2=O)c(C)c1C
Agent: Sc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N=C(N)NCCC[C@@H]1NC(=O)[C@H]2CCCCN2C(=O)[C@@H](Cc2ccccc2)NC(=O)[C@H](CC(=O)O)NC(=O)CNC1=O
Reaction time: 4 h

Procedure:
A solution of 0.28 g of cyclo-(Arg(Mtr)-Gly-Asp-DPhe-DhPro) [obtainable by cyclization according to Ex. 1] in 8.4 ml of TFA, 1.7 ml of dichloromethane and 0.9 ml of thiophenol is allowed to stand at room temperature for 4 hours, then concentrated, and the residue is diluted with water and then freeze-dried. Gel filtration on Sephadex G 10 (acetic acid/water 1:1) and subsequent purification by preparative HPLC under the conditions indicated give cyclo-(Arg-Gly-Asp-DPhe-DhPro); FAB-MS (M+H): 587.
Reaction SMILES: [O:1]([CH2:8][CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:11](Cl)(=[O:15])[C:12]([Cl:14])=[O:13]>C(Cl)Cl>[O:1]([CH2:8][CH2:9][O:10][C:11](=[O:15])[C:12]([Cl:14])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: OCCOc1ccccc1
Solvent: ClCCl
Product: O=C(Cl)C(=O)OCCOc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-phenoxyethanol (536 mg, 3.9 mmol) in DCM (total volume: 0.5 mL) was added to a solution of oxalyl chloride (0.5 mL, 5.8 mmol) in DCM (total volume 1.0 mL) at 0° C. and the resulting mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo and the resulting residue was dissolved in DCM (3.9 mL) to yield a 1.0M solution in DCM.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][NH:14][CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[F:25][C:26]1([F:35])[CH2:31][CH2:30][CH:29]([C:32](O)=[O:33])[CH2:28][CH2:27]1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:24])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:32]([CH:29]3[CH2:30][CH2:31][C:26]([F:35])([F:25])[CH2:27][CH2:28]3)=[O:33])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CNC[C@H]1c1ccc(Cl)cc1
Reactant: O=C(O)C1CCC(F)(F)CC1
Product: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCC(F)(F)CC2)C[C@H]1c1ccc(Cl)cc1

Procedure:
In analogy to the procedure described for the synthesis of example 44 (step c), the title compound [(3S,4R)-4-(4-chloro-phenyl)-1-(4,4-difluoro-cyclohexanecarbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester was prepared from [(3S,4R)-4-(4-chloro-phenyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester using 4,4-Difluoro-cyclohexanecarboxylic acid instead of 1-methylcyclopropane-1-carboxylic acid and was obtained as an off-white solid. MS m/e: 494.2 [M]+.
Reaction SMILES: [CH3:1][C:2]1[NH:7][C:6]2=[CH:8][C:9]([C:11]3[CH:12]=[CH:13][CH2:14][CH2:15][CH:16]=3)=[N:10][C:5]2=[C:4]([C:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH:18]=2)[N:3]=1>C(O)C.O=[Pt]=O>[CH:17]1([C:4]2[N:3]=[C:2]([CH3:1])[NH:7][C:6]3=[CH:8][C:9]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)=[N:10][C:5]=23)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Cc1nc(C2=CCCCC2)c2nc(C3=CCCC=C3)cc-2[nH]1
Agent: O=[Pt]=O
Solvent: CCO
Product: Cc1nc(C2CCCCC2)c2nc(-c3ccccc3)cc-2[nH]1

Procedure:
A solution of 2-methyl-4-(1-cyclohexenyl)-5H-6-phenylpyrrolo[3,2-d]pyrimidine (Example 59) (96 mg, 0.33 mmol) in ethanol (5 mL) was agitated on a Parr Apparatus at room temperature in the presence of PtO2 (Aldrich Chemical Company) (20 mg, 0.088 mmol) under H2 (70 psi) for 30 h. The reaction mixture was filtered through a pad of Celite and concentrated on a rotary evaporator. Chromatography on silica gel with a gradient eluant of EtOAc (0-20%):hexanes (100-80%) afforded 55 mg (57%) of the title compoud as an off-white solid. Mp: >280° C. 1H NMR (CDCl3; 400 MHz): δ 1.44-1.49 (m, 2), 1.81-1.88 (m, 4), 1.93-2.01 (m, 4), 2.99 (m, 1), 6.86 (d, 1, J=1.4), 7.44 (t, 1, J=6.1), 7.51 (t, 2, J=6.1), 7.74 (d, 2, J=6.1), 8.40 (s, 1). MS m/z: 292 (M+1), 290 (M−1). HRMS: Calcd for M+H: 292.1814. Found: 292.1806.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([OH:20])=[N:8][C:9]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[N:10]2)=[CH:5][CH:4]=1.C([O:23][C:24]([C:26]12[CH2:43][CH:42]1[CH:41]=[CH:40][CH2:39][CH2:38][CH2:37][CH2:36][N:35]([CH3:44])[C:34](=[O:45])[N:33]1[CH:29]([CH2:30][CH:31](O)[CH2:32]1)[C:28](=[O:47])[NH:27]2)=[O:25])C>>[CH3:1][O:2][C:3]1[C:12]([CH3:13])=[C:11]2[C:6]([C:7]([O:20][CH:31]3[CH2:30][CH:29]4[N:33]([C:34](=[O:45])[N:35]([CH3:44])[CH2:36][CH2:37][CH2:38][CH2:39][CH:40]=[CH:41][CH:42]5[C:26]([C:24]([OH:25])=[O:23])([NH:27][C:28]4=[O:47])[CH2:43]5)[CH2:32]3)=[N:8][C:9]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[N:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)C12CC1C=CCCCCN(C)C(=O)N1CC(O)CC1C(=O)N2
Reactant: COc1ccc2c(O)nc(-c3ccccc3)nc2c1C
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccccc3)nc2c1C
Yield: 17 %

Procedure:
Quinazolinol derivative (83) (449 mg, 1.7 mmol) was coupled to compound 51 (400 mg, 1.1 mmol) followed by hydrolysis of the ethyl ester as described in example 52, which gave the title compound (112 mg, 17%).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7](Br)[CH:8]=[CH:9][C:10]=1[O:11][C:12](=[O:14])[CH3:13])(=[O:3])[CH3:2].[C:16]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:27]=1)[CH:23]=[CH2:24])(=[O:18])[CH3:17].C(=O)([O-])[O-].[K+].[K+].C(=NO)(C1C=CC=CC=1)C>[Pd]>[C:16]([O:19][C:20]1[CH:21]=[C:22](/[CH:23]=[CH:24]/[C:7]2[CH:8]=[CH:9][C:10]([O:11][C:12](=[O:14])[CH3:13])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)[CH:25]=[C:26]([O:28][C:29](=[O:31])[CH3:30])[CH:27]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)Oc1ccc(Br)cc1OC(C)=O
Reactant: C=Cc1cc(OC(C)=O)cc(OC(C)=O)c1
Agent: [Pd]
Agent: CC(=NO)c1ccccc1
Agent: O=C([O-])[O-]
Product: CC(=O)Oc1cc(/C=C/c2ccc(OC(C)=O)c(OC(C)=O)c2)cc(OC(C)=O)c1
Temperature: 150 °C
Reaction time: 19 h

Procedure:
A 10 ml Schlenk tube equipped with magnetic stirrer is charged with 218 mg (0.8 mmol) 3,4-diacetoxybromobenzene, 176 mg (0.84 mmol) 3,5-diacetoxystyrene, 187 mg potassium carbonate (0.9 mmol) and 0.22 mg (0.1 mol %) of the acetophenon-oxim derived palladium catalyst CAS No. 32679-19-9 as used in Example 9. The tube was evacuated and flushed with argon three times and 1 ml de-aerated DMF was added under inert conditions. The reaction was carried out with stirring for 19 hours at 150° C. Work-up was conducted following the procedure of Example 5 and to give (E)-3,3′, 4′,5-tetraacetoxystilbene.