Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)([Cl:3])=O.[CH:5]1([C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)O)[CH2:7][CH2:6]1>>[Cl:3][CH2:7][CH2:6][CH:5]=[C:8]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CC1
Reactant: O=S(Cl)Cl
Product: ClCCC=C(c1ccccc1)c1ccccc1

Procedure:
Thionyl chloride (8.9 ml) is added slowly to cyclopropyldiphenylcarbinol (25 g) and the mixture is stirred until gas evolution ceases. Vacuum distillation affords 4-chloro-1,1-diphenylbutene. Conversion of the chloride to the cyanide is accomplished using the method of R. A. Smiley and C. Arnold, J. Org. Chem. 1960, 25, 257. The resulting nitrile (14.72 g) is reduced with Raney-Cobalt (4 g) in tetrahydrofuran (150 ml) and triethylamine (4 ml) at 15°-130° C. and 1450-2100 PSIG. The olefinic moiety is then reduced at room temperature in methanol (150 ml) with concentrated sulfuric acid (3.5 ml) and 20% Pd-C (5 g, added portionwise during the course of the reaction) at room temperature and 50 PSIG hydrogen.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14]CC)=O)[N:6]=[CH:5]2.[NH2:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1.C(N(C(C)C)CC)(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([NH:17][C@H:18]1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19]1)=[O:14])[N:6]=[CH:5]2
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CCOC(=O)c1ncc2cc(Cl)ccc2n1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](NC(=O)c2ncc3cc(Cl)ccc3n2)C1
Temperature: 150 °C
Reaction time: 20 h
Yield: 24.7 %

Procedure:
To a solution of ethyl 6-chloroquinazoline-2-carboxylate (0.200 g, 0.85 mmol, 1 eq) in 0.42 mL of NMP was added (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (0.16 g, 0.86 mmol, 1 eq) and diisopropylethylamine (0.6 mL, 3.4 mmol, 4 eq). After stirring at 150° C. for 20 h, the mixture was concentrated and purified via silica gel flash chromatography to provide (S)-tert-butyl 3-(6-chloroquinazoline-2-carboxamido)pyrrolidine-1-carboxylate (0.08 g, 0.21 mmol, 25%).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[N:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH2:22])[S:20][CH:21]=1>>[Br:16][C:17]1[C:18]([C:23]2[NH:27][N:26]=[CH:25][N:24]=2)=[C:19]([NH:22][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][N:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:20][CH:21]=1
Reactant: O=C(O)CN1C(=O)CCc2cnccc21
Reactant: Nc1scc(Br)c1-c1ncn[nH]1
Product: O=C(CN1C(=O)CCc2cnccc21)Nc1scc(Br)c1-c1ncn[nH]1

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydro-1,6-naphthyridin-1(2H)-yl)acetic acid (40 mg, 0.195 mmol) and 4-bromo-3-(1H-1,2,4-triazol-5-yl)thiophen-2-amine (24 mg, 0.0979 mmol) according to protocol A. Retention time (min)=8.108, method [6], MS (ESI) 433.0 (M+H); 1H NMR (300 MHz, CD3OD) δ 8.61-8.48 (m, 3H), 7.51 (d, J=6.8 Hz, 1H), 7.16 (s, 1H), 5.08 (s, 2H) 3.29-3.25 (m, 2H), 2.98-2.93 (m, 2H).
Reaction SMILES: F[C:2](F)(F)[C:3]([N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][C:9]([S:15](Cl)(=[O:17])=[O:16])=[CH:10][CH:11]=2)[CH2:6]1)=O.[NH2:21][CH2:22][CH2:23][CH:24]1[CH2:28][CH2:27][CH2:26][N:25]1[CH3:29]>CO.Cl>[CH:2]1([CH2:3][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][C:9]([S:15]([NH:21][CH2:22][CH2:23][C@@H:24]4[CH2:28][CH2:27][CH2:26][N:25]4[CH3:29])(=[O:17])=[O:16])=[CH:10][CH:11]=3)[CH2:6]2)[CH2:11][CH2:12][CH2:7][CH2:8][CH2:9]1
Reactant: CN1CCCC1CCN
Reactant: O=C(N1CCc2ccc(S(=O)(=O)Cl)cc2C1)C(F)(F)F
Agent: Cl
Solvent: CO
Product: CN1CCC[C@H]1CCNS(=O)(=O)c1ccc2c(c1)CN(CC1CCCCC1)CC2

Procedure:
WO2005/118547 describes a general method of synthesis which is difficult to transpose to the industrial scale for production in large quantities. This method of synthesis entails reacting 2-(2,2,2-trifluoroacetyl)-1,2,3,4-tetrahydro-isoquinoline-7-sulfonyl chloride with (+/−)-2-(2-aminoethyl)-1-methylpyrrolidine, which product is deprotected in methanol and hydrochloric acid. The enantiomers are next separated by chiral chromatography. The resulting N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide undergoes reductive amination with cyclohexanecarboxaldehyde in the presence of a palladium catalyst. 2-(Cyclohexylmethyl)-N-{2-[(2S)-1-methylpyrrolidin-2-yl]ethyl}-1,2,3,4-tetrahydroisoquinoline-7-sulfonamide is isolated as the free base and converted to a salt.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:13][C:8]3([NH:12][CH2:11][CH2:10][NH:9]3)[C:6]=2[CH:7]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18]Cl>CO>[ClH:1].[Cl:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH2:18][S:13][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][C:6]=1[C:8]1[NH:12][CH2:11][CH2:10][N:9]=1
Reactant: Clc1ccc2c(c1)C1(NCCN1)S2
Reactant: ClCc1cccc(Cl)c1
Solvent: CO
Product: Cl
Product: Clc1cccc(CSc2ccc(Cl)cc2C2=NCCN2)c1

Procedure:
32 Parts of 4-chlorobenzothietane-2-spiro-2'-imidazolidine is reacted with 26 parts of 3-chlorobenzyl chloride in 300 parts of methanol, as described in Example 11. The yield is 49 parts (85% of theory ) and the melting point is 255° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[CH2:12][N:11](C(OC(C)(C)C)=O)[C:10](=[O:20])[CH2:9]2)=[CH:4][C:3]=1[OH:21].C([O-])([O-])=[O:23].[K+].[K+].Br.Br[CH2:30][C:31]1[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=1>C(O)C>[ClH:1].[NH2:11][CH2:12][C@@H:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([O:21][CH2:30][C:31]2[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=2)[CH:4]=1)[CH2:9][C:10]([OH:20])=[O:23]
Reactant: BrCc1ccncc1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](c2ccc(Cl)c(O)c2)CC1=O
Reactant: O=C([O-])[O-]
Agent: Br
Agent: [K+]
Solvent: CCO
Product: Cl
Product: NC[C@H](CC(=O)O)c1ccc(Cl)c(OCc2ccncc2)c1
Temperature: 90 °C

Procedure:
To a solution of tert-butyl (4R)-4-(4-chloro-3-hydroxyphenyl)-2-oxopyrrolidinecarboxylate (68a) (1.0 equiv.) in ethanol (0.4M) was added K2CO3 (2 equiv.) followed by an appropriate electrophile (1.5 equiv., e.g. 4-bromomethylpyridine hydrobromide). The reaction mixture was heated overnight at 90° C. The mixture was cooled to room temperature and the solvent removed. The crude residue was treated with a 6N HCl aqueous solution (0.1M) and heated for 3 h at 90° C. The title compound (68) was obtained following purification by HPLC purification. 1H-NMR (400 MHz, CD3OD): δ 2.60-2.66 (dd, J=16.4, 7.6 Hz, 1H), 2.74-2.78 (dd, J=16.4, 7.2 Hz, 1H), 3.17-3.24 (m, 1H), 5.28 (s, 2H), 8.53-8.54 (d, J=4.0 Hz, 1H), 7.56-7.57 (d, J=4 Hz, 1H), 7.40 (d, J=8.0 Hz, 1H), 7.09-7.09 (d, J=2.0 Hz, 1H), 6.92-6.95 (d, J=4.0 Hz, 1H); MS (ESI) m/z 321.01 (M+H)+.
Reaction SMILES: [CH2:1]([N:5]1[CH:10]2[CH2:11][C:12](=O)[CH2:13][CH:6]1[CH2:7][O:8][CH2:9]2)[CH2:2][CH2:3][CH3:4].N1C=CC=CC=1.Cl.[NH2:22][OH:23].C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:1]([N:5]1[CH:10]2[CH2:11][C:12](=[N:22][OH:23])[CH2:13][CH:6]1[CH2:7][O:8][CH2:9]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1C2COCC1CC(=O)C2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: CCCCN1C2COCC1CC(=NO)C2
Reaction time: 0.5 h

Procedure:
To a solution of 9-(n-butyl)-3-oxa-9-azabicyclo-[3.3.1]-nonan-7-one (28 g) in ethanol (150 ml) were added in turn pyridine (18.0 ml) and hydroxylamine hydrochloride (11.9 g) and the mixture was heated under reflux for 40 minutes. To the reaction solution were added water (29 ml) and potassium carbonate (57.9 g), the mixture was stirred for 30 minutes and dried over potassium carbonate. The solvent was distilled off under reduced pressure to give the crude 9-(n-butyl)-3-oxa-9-azabicyclo[3.3.1]nonan-7-one oxime. This product was employed for the sebsequent reaction without any purification.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:33][C:34]1[CH:41]=[CH:40][CH:39]=[CH:38][C:35]=1[CH2:36][NH2:37].O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:37][CH2:36][C:35]2[CH:38]=[CH:39][CH:40]=[CH:41][C:34]=2[Cl:33])[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1Cl
Reactant: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)OC1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NCc4ccccc4Cl)ncnc32)[C@]1(C)F
Temperature: 25 °C
Reaction time: 15 h
Yield: 40.9 %

Procedure:
To a stirred solution of ((2R,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added 2-chlorobenzylamine (about 0.62 ml, 5.19 mmol) and stirred at room temperature for about 15 hours. Completion of the reaction mixture monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compound (0.1 g) as a colorless gummy mass. Yield: 41%; 1H NMR (300 MHz, CDCl3): δ 8.42 (s, 1H), 8.06-7.99 (m, 3H), 7.47-7.02 (m, 7H), 6.55 (d, 1H, J=23.1 Hz), 6.28 (bs, 1H), 4.98-4.91 (m, 2H), 4.83-4.78 (m, 2H), 4.49-4.45 (m, 1H), 2.16 (s, 3H), 1.89 (d, 3H, J=2.4 Hz), 1.45 (d, 3H, J=23.1 Hz); Mass: [M+1]+ 568 (100%); IR cm−: 3414, 2931, 1751, 1619, 1276, 1230, 951, 712; HPLC: 95.2%.
Reaction SMILES: C(OC([CH2:11][C@H:12]([NH2:29])[C@@H:13]([F:28])[C:14]([NH:16][CH2:17][C:18]([O:20]CC1C=CC=CC=1)=[O:19])=[O:15])=O)C1C=CC=CC=1>CO.[Pd]>[NH2:29][C@@H:12]([CH3:11])[C@@H:13]([F:28])[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: N[C@@H](CC(=O)OCc1ccccc1)[C@@H](F)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: C[C@H](N)[C@@H](F)C(=O)NCC(=O)O
Reaction time: 18 h
Yield: 97.4 %

Procedure:
To a solution of benzyl N-(benzyloxycarbonyl-3-(S)-amino-2-(R)-fluorobutanoyl)glycinate (8.50 g, 21.1 mmol) in 200 mL of methanol is added 850 mg of 10% palladium on carbon. The mixture is connected to a Parr hydrogenation apparatus and hydrogenated at 50 psi for 18 hours. The mixture is then filtered through celite to remove the catalyst. Evaporation of the solvent leaves 3.66 g of the desired product as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:14][C:15]([NH:17][C:18]([CH3:22])([CH3:21])[CH2:19][OH:20])=[S:16])[CH:6]=[CH:7][C:8]=1[N:9]=[CH:10][N:11](C)C)#[N:2].[CH3:23][C:24]1[CH:25]=[C:26](N)[CH:27]=[CH:28][C:29]=1[O:30][C:31]1[CH:32]=[CH:33][C:34]2[O:38][C:37]([CH3:39])=[N:36][C:35]=2[CH:40]=1.C(O)(=O)C>C(OC(C)C)(=O)C>[OH:20][CH2:19][C:18]([NH:17][C:15]([NH:14][C:5]1[CH:4]=[C:3]2[C:8](=[CH:7][CH:6]=1)[N:9]=[CH:10][N:11]=[C:1]2[NH:2][C:26]1[CH:27]=[CH:28][C:29]([O:30][C:31]2[CH:32]=[CH:33][C:34]3[O:38][C:37]([CH3:39])=[N:36][C:35]=3[CH:40]=2)=[C:24]([CH3:23])[CH:25]=1)=[S:16])([CH3:21])[CH3:22]
Reactant: CN(C)C=Nc1ccc(NC(=S)NC(C)(C)CO)cc1C#N
Reactant: Cc1nc2cc(Oc3ccc(N)cc3C)ccc2o1
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)C
Product: Cc1nc2cc(Oc3ccc(Nc4ncnc5ccc(NC(=S)NC(C)(C)CO)cc45)cc3C)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.7 %

Procedure:
To a solution of 1-(3-cyano-4-((dimethylamino)methyleneamino)phenyl)-3-(1-hydroxy-2-methylpropan-2-yl)thiourea (275 mg, 0.861 mmol) and 3-methyl-4-(2-methylbenzo[d]oxazol-5-yloxy)benzenamine (241 mg, 0.947 mmol) in isopropyl acetate (2 mL) was added acetic acid (0.2 mL, 3.44 mmol). After stirring at room temperature for 16 hours, hexanes was added and stirred with the mixture for 30 minutes. The mixture was filtered to provide the crude product (281 mg, 62%) as yellow solid.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1([CH2:16][N:17]2[CH2:26][CH2:25][C:24]3[C:19](=[CH:20][C:21]([C:31]45[CH2:40][CH:35]6[CH2:36][CH:37]([CH2:39][CH:33]([CH2:34]6)[CH2:32]4)[CH2:38]5)=[C:22]([O:27][CH:28]([CH3:30])[CH3:29])[CH:23]=3)[CH2:18]2)[CH2:13][O:12]C(C)(C)[O:10][CH2:9]1)(C)(C)C.C(OC1C=C(C2ON=C(C3C=CC=C4C=3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)N=2)C=CC=1OCC)C>>[NH2:7][C:8]([CH2:16][N:17]1[CH2:26][CH2:25][C:24]2[C:19](=[CH:20][C:21]([C:31]34[CH2:38][CH:37]5[CH2:39][CH:33]([CH2:34][CH:35]([CH2:36]5)[CH2:40]3)[CH2:32]4)=[C:22]([O:27][CH:28]([CH3:30])[CH3:29])[CH:23]=2)[CH2:18]1)([CH2:13][OH:12])[CH2:9][OH:10]
Reactant: CC(C)Oc1cc2c(cc1C13CC4CC(CC(C4)C1)C3)CN(CC1(NC(=O)OC(C)(C)C)COC(C)(C)OC1)CC2
Agent: CCOc1ccc(-c2nc(-c3cccc4c3CCN4CC3(NC(=O)OC(C)(C)C)COC(C)(C)OC3)no2)cc1OCC
Product: CC(C)Oc1cc2c(cc1C13CC4CC(CC(C4)C1)C3)CN(CC(N)(CO)CO)CC2
Yield: 77 %

Procedure:
When the product of Step G was substituted for tert-butyl 5-((4-(5-(3,4-diethoxyphenyl)-1,2,4-oxadiazol-3-yl)indolin-1-yl)methyl)-2,2-dimethyl-1,3-dioxan-5-ylcarbamate in Example 34, Step E, the identical process afforded the title compound in 77% yield, as pale paste. 1H-NMR (CDCl3) 1.26 (d, 6H, J=6.07 Hz); 1.65 (m, 6H); 1.94 (m, 3H); 1.67 (m, 6H); 2.52 (m, 2H); 2.75 (m, 4H); 3.38-3.47 (m, 4H); 3.59 (s, 2H); 4.48-4.52 (m, 1H); 6.46 (s, 1H); 6.72 (s, 1H).
Reaction SMILES: CO[C:3]1[CH2:4][C@@H:5]([CH3:15])[C@H:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[N:7]=1.[Cl-:16].[NH4+:17]>CO>[ClH:16].[CH3:15][C@H:5]1[C@H:6]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:7][C:3](=[NH:17])[CH2:4]1
Reactant: COC1=N[C@@H](Cc2ccccc2)[C@H](C)C1
Reactant: [Cl-]
Reactant: [NH4+]
Solvent: CO
Product: C[C@@H]1CC(=N)N[C@H]1Cc1ccccc1
Product: Cl

Procedure:
A solution of the title product of Example 63 (300 mg, 1.4 mmol) in MeOH (20 mL) was reacted with ammonium chloride (77 mg, 1.6 mmol) by the method of Example 5 followed by chromatography to generate the title material (240 mg, 75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([S:12][CH3:13])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=O.[NH2:14][C:15]1[NH:16][C:17](=[O:23])[NH:18][C:19](=[O:22])[C:20]=1[NH2:21].O>CN(C)C=O>[NH2:14][C:15]1[NH:16][C:17](=[O:23])[NH:18][C:19](=[O:22])[C:20]=1[NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][C:10]([S:12][CH3:13])=[CH:11][C:3]=1[O:2][CH3:1]
Reactant: Nc1[nH]c(=O)[nH]c(=O)c1N
Reactant: COc1cc(SC)ccc1C(=O)O
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(SC)ccc1C(=O)Nc1c(N)[nH]c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Twenty grams of 2-methoxy-4-methylmercapto-benzoic acid is dissolved in 260 ml of dimethylformamide, mixed with 13 gm of N,N'-carbonyl-diimidazole, and stirred for 30 minutes at ambient temperature. Then, 13 gm of 4,5-diamino-pyrimidin-2,6-dione are added, and the reaction mixture is refluxed for three hours with stirring. After cooling, it is poured into 1 liter of water. The product precipitated is suction filtered, washed with water, and dried at 70° C. in a circulating air drier.
Reaction SMILES: [NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([OH:17])=O)[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9].[NH:28]1[CH2:67][CH2:66][CH2:65][C@H:29]1[C:30]([NH:32][C@H:33]([C:44]([NH:46][C@H:47]([C:52]([NH:54][C@H:55]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH3:1].[NH:1]([C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C@H:2]([C:15]([N:28]1[CH2:67][CH2:66][CH2:65][C@H:29]1[C:30]([NH:32][C@H:33]([C:44]([NH:46][C@H:47]([C:52]([NH:54][C@H:55]([C:60]([O:62][CH2:63][CH3:64])=[O:61])[CH2:56][CH:57]([CH3:59])[CH3:58])=[O:53])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])[CH2:34][C:35]1[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[NH:37][CH:36]=1)=[O:31])=[O:17])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1)C(C)(C)C
Reactant: CC(C)(C)OC(=O)NCCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@H](CC(C)C)NC(=O)[C@@H](NC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCCNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1)C(C)(C)C
Product: N
Temperature: 0 °C
Reaction time: 1 h
Yield: 147.4 %
Yield: 0.1 %

Procedure:
Z-Lys(BOC) (0.75 g, 1.98 mmol), Pro-Trp-Tle-Leu-OEt (Seq ID No: 7), (1.0 g, 1.8 mmol) (prepared by catalytic hydrogenation of Z-Pro-Tle-Leu-OEt (Seq ID No: 7) over palladium on charcoal), and NMM (0.36 mL) is dissolved in 15 mL DMF, cooled to 0° C., and treated with TBTU (0.635 g, 1.98 mmol). The reaction is stirred at 0° C. for 1 hour then removed from the ice bath and stirred at room temperature for 3 hours. The mixture is poured into 150 mL of a saturated solution of sodium carbonate which is then extracted with two 150 mL portions of ethyl acetate. The combined organic extracts are washed with 150 mL of 1 M KHSO4, water and brine, and then dried over sodium sulfate. The solvents are removed under reduced pressure and the residue is chromatographed on silica gel. (2% MeOH in chloroform with 0.1% NH3) to give Z-Lys(BOC)-Pro-Trp-Tle-Leu-OEt (Seq ID No: 9) (1.34 g). FABMS M+1 818 (M-tBu)
Reaction SMILES: [C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[N+:19]([O-])=O)(=[O:3])[CH3:2].[CH3:22][C:23]1[N:24]=[N:25][C:26]2[CH:27]=[CH:28][CH:29]=[C:30](N)[C:31]=2[CH:32]=1>C(O)C>[C:1]([C:4]1[C:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:8][N:7]([CH2:16][CH3:17])[C:6](=[O:18])[C:5]=1[NH:19][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]2[C:31]=1[CH:32]=[C:23]([CH3:22])[N:24]=[N:25]2)(=[O:3])[CH3:2]
Reactant: Cc1cc2c(N)cccc2nn1
Reactant: CCn1nc(-c2ccccc2)c(C(C)=O)c([N+](=O)[O-])c1=O
Solvent: CCO
Product: CCn1nc(-c2ccccc2)c(C(C)=O)c(Nc2cccc3nnc(C)cc23)c1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.5 %

Procedure:
To a stirred solution of 80 mg (0.278 mmol) of 5-acetyl-2-ethyl-4-nitro-6-phenylpyridazin-3(2H)-one (Dal Piaz, V et al, J. Med. Chem. 1997, 40, 1417) in 4 ml of ethanol, 66 mg (0.417 mmol) of 3-methylcinnolin-5-amine was added. The resulting mixture was stirred at room temperature for one day. The final product was collected by filtration and purified by column chromatography (silica gel, ethyl acetate/hexane 2:1) to yield the title compound (65 mg, 58.6% yield).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:28](C1N=C(Cl)C2N=NN(CC3C=CC=CC=3Cl)C=2N=1)(C)(C)C.Cl.N1CCC[C@@H](O)C1>>[C:1]([C:5]1[N:6]=[C:7]([N:22]2[CH2:27][CH2:26][CH2:28][C@@H:24]([OH:25])[CH2:23]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[Cl:21])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Agent: Cl
Agent: O[C@@H]1CCCNC1
Product: CC(C)(C)c1nc(N2CCC[C@@H](O)C2)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and (R)-piperidin-3-ol hydrochloride and isolated as colorless gum (8.3 mg, 44%). MS (m/e): 401.4 (MH+).
Reaction SMILES: C(=O)=[O:2].[CH3:4][N:5]([CH3:9])[CH2:6][CH2:7][OH:8].[CH2:10]1[O:12][CH2:11]1>O>[OH-:2].[OH:8][CH2:7][CH2:6][N+:5]([CH2:10][CH2:11][OH:12])([CH3:9])[CH3:4]
Reactant: O=C=O
Reactant: C1CO1
Reactant: CN(C)CCO
Solvent: O
Product: C[N+](C)(CCO)CCO
Product: [OH-]
Reaction time: 96 h

Procedure:
A two-liter three-necked flask equipped with a thermometer, magnetic stirrer, dry ice condenser, cooling bath, and nitrogen inlet was charged with about 267 grams of dimethylethanolamine (DMEA) and 330 grams of de-ionized water. About 128 grams of ethylene oxide was fed slowly through a feeding tube into the reaction mixture using moderate agitation, and the reaction temperature was maintained below 20° C. After the ethylene oxide addition was completed, the reaction was allowed to digest for an additional hour. The reaction mixture was then purged with nitrogen for one hour. The product is a clear and colorless solution. However, after about four days of standing at room temperature, the product darkened somewhat.
Reaction SMILES: [Br-].[Br:2][C:3]1[C:4]([NH:31][C:32](=O)[C:33]([F:36])([F:35])[F:34])=[C:5]([CH2:11][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[C:7]([C:9]#[N:10])[CH:8]=1>CN(C=O)C>[CH3:8][CH2:3][CH2:4][CH:5]([CH3:11])[CH3:6].[F:34][C:33]([F:36])([F:35])[C:32]1[NH:31][C:4]2[C:5]([CH:11]=1)=[CH:6][C:7]([C:9]#[N:10])=[CH:8][C:3]=2[Br:2]
Reactant: N#Cc1cc(Br)c(NC(=O)C(F)(F)F)c(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: [Br-]
Solvent: CN(C)C=O
Product: CCCC(C)C
Product: N#Cc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Temperature: 130 °C
Reaction time: 3 h
Yield: 72.3 %

Procedure:
({3-bromo-5-cyano-2-[(trifluoroacetyl)amino]phenyl}methyl)(triphenyl)phosphonium bromide (37.2 g, crude) was dissolved in DMF (150 mL) and the reaction mixture was heated to 130° C. stirring for 3 hrs. The reaction mixture was allowed to cool to room temperature then quenched with water (400 mL). The reaction mixture was then extracted with ethyl acetate (3×300 mL). The organic extract was washed with a 1:1 mixture of water:brine (2×600 mL), dried (MgSO4), filtered and the solvent was removed. The resulting residues were then purified by filtration through a pad of silica gel eluting with 2-10% EtOAc: isoHexane to give the title compound as an off-white solid (6 g);
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[C:19]1([NH2:26])[C:20]([NH2:25])=[CH:21][CH:22]=[CH:23][CH:24]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O.C(O)(=O)C>[NH:25]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:26]=[C:15]1[CH2:14][C:9]1[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]2[CH2:2][CH2:3][O:4][CH2:5][CH2:6]2)[N:8]=1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Reactant: Nc1ccccc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: O=c1cc(N2CCOCC2)nc(Cc2nc3ccccc3[nH]2)[nH]1
Yield: 21 %

Procedure:
The product is prepared according to the procedure described in Example 3, using 300 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 248 mg of benzene-1,2-diamine and 330 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 2.5 ml of pyridine and 2.5 ml of dimethylformamide and then in 5 ml of acetic acid. After refluxing for one hour and purification by silica column chromatography, eluent: CH2Cl2/MeOH: gradient from 100/0 to 90/10, 75 mg of 2-(1H-benzimidazol-2-ylmethyl)-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a beige powder, the characteristics of which are the following: