Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH2:10][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([OH:13])[CH3:12])[N:3]=1.[CH3:20][CH2:21][N:22](CC)CC.Cl[C:28](Cl)([O:30]C(=O)OC(Cl)(Cl)Cl)Cl>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[C:4]([N:8]2[CH2:9][CH2:10][C:11]([CH3:12])([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:13][C:28]2=[O:30])[CH:20]=[CH:21][N:22]=1.[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:9][CH2:10][C:11]([CH3:12])([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[O:13][C:28]2=[O:30])[N:3]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(CC)CC
Reactant: CC(O)(CCNc1nccc(Cl)n1)c1ccccc1
Solvent: ClCCl
Product: CC1(c2ccccc2)CCN(c2ccnc(Cl)n2)C(=O)O1
Product: CC1(c2ccccc2)CCN(c2nccc(Cl)n2)C(=O)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %
Yield: 9 %

Procedure:
To a solution of 4-(4-chloro-pyrimidin-2-ylamino)-2-phenyl-butan-2-ol (450 mg, 1.6 mmol) and Et3N (508 mg, 4.8 mmol) in CH2Cl2 (2 ml) was added dropwise a solution of triphosgene (159 mg, 0.54 mmol) in CH2Cl2 slowly at 0° C. under nitrogen atmosphere. The mixture was stirred at rt overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 3-(2-chloropyrimidin-4-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (250 mg, 52%) 1H NMR (CDCl3, 400 MHZ): δ=1.73 (s, 3H), 2.38 (m, 1H), 2.63 (m, 1H), 3.49 (m, 1H), 4.2 (m, 1H), 7.36 (m, 5H), 8.28 (m, 1H), 8.52 (m, 1H) and 3-(4-chloropyrimidin-2-yl)-6-methyl-6-phenyl-1,3-oxazinan-2-one (20 mg, 9%) [Example 57]. 1H NMR (CDCl3, 400 MHZ): δ=1.73 (s, 3H), 2.4 (m, 1H), 2.58 (m, 1H), 3.47 (m, 1H), 4.13 (m, 1H), 7.06 (m, 5H), 7.16-7.55 (m, 5H), 8.54 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:14][CH:15]=[O:16])[CH2:9][C:10](OC)=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH2:22][CH:21]([NH2:25])[CH2:20]1.CCN(C(C)C)C(C)C.CC(O)=O>CO>[CH3:18][C:19]1([CH3:26])[CH2:24][CH2:23][CH2:22][CH:21]([N:25]2[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:14][C:15]2=[O:16])[CH2:20]1
Reactant: CC1(C)CCCC(N)C1
Reactant: COC(=O)CN(CC=O)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Product: CC1(C)CCCC(N2CCN(C(=O)OC(C)(C)C)CC2=O)C1

Procedure:
To a solution (0.19 M) of methyl N-(tert-butoxycarbonyl)-N-(2-oxoethyl)glycinate (prepared as described in Bioorg. Med. Chem. 2007, 15, 2092-2105) in MeOH were added 3,3-dimethylcyclohexanamine hydrochloride (1.5 eq), DIPEA (1.5 eq), NaBH3(CN) (1.5 eq) and AcOH (1.4 eq). After stirring for 2 hours at RT more NaBH3(CN) (1.5 eq) was added and reaction mixture was irradiated at MW for 1 hour at 125° C. MeOH was removed under reduced pressure and the residue purified by filtration on silica with elution of the desired intermediate with EtOAc. Evaporation of the organic solvent yielded tert-butyl 4-(3,3-dimethylcyclohexyl)-3-oxopiperazine-1-carboxylate. MS (ES) C17H30N2O3 requires: 310, found: 311 (M+H)+.
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:7]([CH3:9])[CH3:8])C.[ClH:23].[OH:24][C:25]1[CH:26]=[C:27]([CH:31]=[CH:32][C:33]=1[OH:34])[CH2:28][CH2:29][NH2:30].C(O)CCC>O>[ClH:23].[CH2:13]([O:12][C:10]([N:6]([CH2:5][CH:4]1[C:26]2[C:27](=[CH:31][CH:32]=[C:33]([OH:34])[C:25]=2[OH:24])[CH2:28][CH2:29][NH:30]1)[CH:7]([CH3:8])[CH3:9])=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(CN(C(=O)OCc1ccccc1)C(C)C)OCC
Reactant: NCCc1ccc(O)c(O)c1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: CC(C)N(CC1NCCc2ccc(O)c(O)c21)C(=O)OCc1ccccc1
Yield: 16.6 %

Procedure:
N-benzyloxycarbonyl-N-isopropylaminoacetaldehyde diethyl acetal (9 g) and 3,4-dihydroxyphenethylamine hydrochloride (4.5 g) were added to a mixture of n-butyl alcohol (100 ml) and water (15 ml) and then the mixture was refluxed for 6 hours. The above-mentioned acetal (2 g) was added thereto and the resultant mixture was refluxed for 1.5 hours. The solvent was distilled off from the reaction mixture. To the residue was added a mixed solvent of isopropyl alcohol, methanol and ether. The crystals obtained were recrystallized from the same mixed solvent to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-7,8-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (1.6 g), mp 200° to 205° C. (dec). The mother liquor was concentrated and allowed to stand to give 1-(N-benzyloxycarbonyl-N-isopropylaminomethyl)-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (4.4 g), colorless crystals, mp 207° to 210° C. (dec).
Reaction SMILES: [H-].[Na+].[CH:3]1([OH:8])[CH2:7][CH2:6][CH2:5][CH2:4]1.[NH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[CH2:23][C@H:22]([OH:24])[C@@H:21]([CH2:25][OH:26])[CH2:20]2)=[C:12](Cl)[N:11]=1.Cl>>[NH2:9][C:10]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@H:19]2[CH2:23][C@H:22]([OH:24])[C@@H:21]([CH2:25][OH:26])[CH2:20]2)=[C:12]([O:8][CH:3]2[CH2:7][CH2:6][CH2:5][CH2:4]2)[N:11]=1
Reactant: Nc1nc(Cl)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Reactant: OC1CCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: Nc1nc(OC2CCCC2)c2ncn([C@@H]3C[C@H](CO)[C@@H](O)C3)c2n1
Temperature: 25 °C

Procedure:
Sodium hydride (60% oil dispersion, 113 mg was added to cyclopentanol (7 mL). To the resulting solution, after effervescence had ceased, was added (+)-(1S-2R-4R)-4-(2-amino-6-chloro-9H-purin-9-yl)-2-(hydroxymethyl)cyclopentanol (400 mg, 1.4 mmol). The solution was maintained at 85° for 40 minutes, cooled to room temperature, and neutralized with 1N hydrochloric acid. Volatiles were removed and the residue chromatographed on silica gel. Title compound was eluted with methanol:chloroform/15:85 as a white solid foam which solidified form acetonitrile:methanol/20:1 as a white powder (223 mg, 48%), m.p. 181-182°; mass spectrum (Cl, CH4): 334(M+1); 1H-NMR (DMSO-d6)δ: 7.97 (s, 1, H8), 6.32 (br s, 2, NH2), 5.60 (m, 1, CHO of cyclopentyl) 5.0-4.8 (m, 1, CHN), 4.78 (d, J=4.1 Hz, 1, OH), 4.66 (t, J=5.1 Hz, 1, CH2OH), 4.1 (m, 1, CHOH), 3.6-3.4 (m, 2, CH2O), 2.4-1.9 (m, 6 methylene), 1.9-1.5 (m, 7, methylene); [α]20589 +9.34°, [α]20578 +9.85°, [α]20546 +11.1°, [α]20430 +18.2°, [α]20365 +26.6° (c=0.782, methanol).
Reaction SMILES: [N:1]1([C:7]([NH:9][CH:10]([C:16]([CH3:24])([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([O:13]CC)=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.O>[N:1]1([C:7]([NH:9][CH:10]([C:16]([CH3:24])([CH3:23])[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]([OH:13])=[O:12])=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(NC(=O)N1CCOCC1)C(C)(C)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(c1ccccc1)C(NC(=O)N1CCOCC1)C(=O)O
Temperature: 35 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
A solution of the product from Example 115 (2 g, 5.99 mmol) in dioxane (10 ml) was treated with 0.26 g (6.5 mmol) of sodium hydroxide in 5 ml of water. After stirring for 16 h at 35° C., the reaction was worked up as described in Example 114 to give a 93% yield of product.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:12]([N:17]([CH3:25])[C:18](=[O:24])[C@H:19]([CH:21]([CH3:23])[CH3:22])[NH2:20])[C@@H:13]([CH3:16])[CH2:14][CH3:15])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@:28]1([CH3:35])[C:29](O)=[O:30].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>ClCCl>[CH3:26][N:27]1[CH2:34][CH2:33][CH2:32][C@:28]1([CH3:35])[C:29]([NH:20][C@H:19]([C:18]([N:17]([C@@H:12]([C@@H:13]([CH3:16])[CH2:14][CH3:15])[C@H:3]([O:2][CH3:1])[CH2:4][C:5]([O:7][C:8]([CH3:11])([CH3:9])[CH3:10])=[O:6])[CH3:25])=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:30]
Reactant: CN1CCC[C@]1(C)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](N)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)OC(C)(C)C)OC)N(C)C(=O)[C@@H](NC(=O)[C@@]1(C)CCCN1C)C(C)C
Yield: 106.2 %

Procedure:
According to the general procedure D, from #6 (7.75 g, 21.6 mmol, 1 eq.), #152 (3.88 g, 21.6 mmol, 1 eq.), dichloromethane (100 mL), HATU (9.8 g, 25.9 mmol, 1.2 eq.), and diisopropylethylamine (11.1 g, 86.4 mmol, 4 eq.) was synthesized the crude desired material, which was purified by silica gel chromatography (Gradient: 20 to 55% ethyl acetate in petroleum ether) to afford #195 (11.1 g, quantitative yield) as a yellow oil.
Reaction SMILES: [CH2:1]([OH:4])[CH:2]=[CH2:3].[H-].[Na+].[F:7][C:8]1[CH:9]=[C:10]([Br:15])[CH:11]=[C:12](F)[CH:13]=1>CC(N(C)C)=O>[CH2:1]([O:4][C:12]1[CH:13]=[C:8]([F:7])[CH:9]=[C:10]([Br:15])[CH:11]=1)[CH:2]=[CH2:3]
Reactant: Fc1cc(F)cc(Br)c1
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C=CCOc1cc(F)cc(Br)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 69.1 %

Procedure:
To a DMA (400 ml) solution of allyl alcohol (8.9 g, 0.154 mol), at room temperature (r.t.) is added NaH (60% oil dispersion) (6.4 g, 0.160 mol) in portions. The mixture is stirred at r.t. for 1.5 h followed by the slow addition of 3,5-difluoro bromobenzene (17.9 ml, 30 g, 0.155 mol). The reaction mixture is stirred at r.t. overnight. The reaction is quenched by the addition of 1500 ml of water and extracted with ether (4×300 ml). The organic layer is dried over MgSO4 and concentrated at reduced pressure to yield 24.6 g (69%) of a colorless oil after flash chromatography (pentane, rf.=0.3). Anal. Calc. for C9H8BrFO: C, 46.78; H, 3.49. Found: C. 46.18, H, 3.45. Calculated mass for C9H8OFBr: 229.97. Mass found for C9H8OFBr: (OAMS) ES−: 189.0 (M-allyl)
Reaction SMILES: [CH2:1]([C:3]1[C:4](=[O:28])[NH:5][C:6](=[O:27])[N:7]([CH:26]=1)[C@@H:8]1[O:25][C@H:12]([CH2:13]OS(C2C=CC(C)=CC=2)(=O)=O)[C@@H:10]([OH:11])[CH2:9]1)[CH3:2].[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>CN(C=O)C.O.CO>[Br:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH:33][CH2:13][C@H:12]1[O:25][C@@H:8]([N:7]2[CH:26]=[C:3]([CH2:1][CH3:2])[C:4](=[O:28])[NH:5][C:6]2=[O:27])[CH2:9][C@@H:10]1[OH:11]
Reactant: NCc1ccccc1Br
Reactant: CCc1cn([C@H]2C[C@H](O)[C@@H](COS(=O)(=O)c3ccc(C)cc3)O2)c(=O)[nH]c1=O
Solvent: O
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1cn([C@H]2C[C@H](O)[C@@H](CNCc3ccccc3Br)O2)c(=O)[nH]c1=O
Temperature: 80 °C
Reaction time: 1.5 h

Procedure:
2.5 g of 2'-deoxy-5-ethyl-5'-O-(p-toluenesulphonyl)-uridine were dissolved in 15 ml of DMF and added to 2-bromobenzylamine. The mixture was heated at 80° C. under nitrogen for 5 hours. The solvent was removed by evaporation and the residue was re-evaporated with toluene to give an oil. This was taken up in 20 ml of water/methanol (1:3) and stored in a refrigerator for 1.5 hours. A solid crystallized out and this was filtered off and washed with water/methanol (1:3) to give 0.99 g of 5'-(2-bromobenzylamino)-2',5'-dideoxy-5-ethyluridine, mp 144°-146° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[OH-].[K+].[CH:13](=[O:16])[CH2:14][CH3:15]>C1(C)C=CC=CC=1.O>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[C:14]([CH3:15])[CH:13]=[O:16]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CCC=O
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C=O)=Cc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
2,4-dichlorobenzaldehyde (26.26 g, 0.15 mol) was dissolved in toluene (200 mL), and then KOH (8.4 g, 1 eq) in water (183 mL) was added followed by BnEt3NCl. The mixture was cooled to 0° C. and n-propanal (26.15 g, 0.45 mol, 3 eq) in toluene (50 mL) was added dropwise. The mixture was allowed to warm to room temperature and stirred overnight. The organic layer was separated and washed successively with water, brine, dried (MgSO4), and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (0-1-2-3% EtOAc in hexanes) to give 17.56 g of 3-(2,4-dichlorophenyl)-2-methylpropenal.
Reaction SMILES: S(=O)(=O)(O)O.[OH2:6].[NH2:7][C:8]1[NH:9][CH:10]=[CH:11][N:12]=1.[C:13]1(OC2C=CC=CC=2)[CH:18]=CC=C[CH:14]=1>O1CCOCC1.CO.C(O)C>[N:9]1[C:10](=[O:6])[CH2:11][N:12]2[CH:14]=[CH:13][CH:18]=[N:7][C:8]=12
Reactant: O
Reactant: c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: CO
Solvent: CCO
Product: O=C1CN2C=CC=NC2=N1

Procedure:
As shown in Reaction Scheme A, imidazolo[1,2-a]pyrimidone (iva) can be prepared from alpha-bromoheteroaryl ketone (R═alkyl). Thus, cyclization of bromoketone (ia) with acetyl guanidine in an appropriate solvent such as dimethylformamide at a temperature of 25-120° C. for a period of 1-72 hours to give 2-acetamidoimidazole (iia), which can be hydrolyzed with an acid such as sulfuric acid in an appropriate solvent such as water or ethanol at a temperature of 60-120° C. for a period of 2-24 hours to give 2-aminioimidazole (iiia). 2-Aminoimidazole (iiia) can be modified by cyclization with substituted acrylate in an inert solvent such as methanol, dioxane or phenylether at a temperature of 60-260° C. for a period of 0.5-16 hours to give imidazolo[1,2-a]pyrimidone (iva).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]([CH:13]=[CH:14][C:15]=1[O:16][C:17](=[O:19])[CH3:18])[CH:8]=[CH:9][C:10](Cl)=[O:11])(=[O:3])[CH3:2].[CH2:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH:21]1[NH:29][S:30]([C:33]1[CH:38]=[CH:37][C:36]([NH:39][CH3:40])=[CH:35][CH:34]=1)(=[O:32])=[O:31].O>ClCCl.N1C=CC=CC=1>[CH2:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH:21]1[NH:29][S:30]([C:33]1[CH:34]=[CH:35][C:36]([N:39]([CH3:40])[C:10](=[O:11])/[CH:9]=[CH:8]/[C:7]2[CH:13]=[CH:14][C:15]([O:16][C:17](=[O:19])[CH3:18])=[C:5]([O:4][C:1](=[O:3])[CH3:2])[CH:6]=2)=[CH:37][CH:38]=1)(=[O:32])=[O:31]
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1OC(C)=O
Reactant: CNc1ccc(S(=O)(=O)NC2Cc3ccccc3C2)cc1
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(/C=C/C(=O)N(C)c2ccc(S(=O)(=O)NC3Cc4ccccc4C3)cc2)cc1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
A solution of 3,4-diacetoxycinnamoyl chloride (5.61 g, 19.9 mmol) in dichloromethane (50 ml) was dropped into a solution of the N-(2-indanyl)-4-(methylamino)benzenesulfonamide (5.00 g, 16.6 mmol) prepared in Preparative Example 14 in pyridine (50 ml) at 0° C. The obtained mixture was stirred at room temperature for 2 hours, followed by the addition of water. The obtained mixture was extracted with ethyl acetate. The organic layer was washed with 1N aqueous hydrochloric acid and a saturated aqueous solution of common salt, dried over magnesium sulfate, and concentrated to give a solid residue. This residue was recrystallized from ethyl acetate/ether/isopropyl ether to give the title compound as a white crystal (8.90 g, 100%). m.p. (°C.): 152~153 (iso-Pr2O)
Reaction SMILES: O[C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[C:11]([OH:19])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(C)N=C=NC(C)C>CN(C1C=CN=CC=1)C.CN(C=O)C.C(Cl)Cl>[N:9]1([O:19][C:11](=[O:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:10]2[CH:2]=[CH:3][CH:4]=[CH:5][C:6]=2[N:7]=[N:8]1
Reactant: O=C(O)c1ccccc1
Reactant: Oc1cccc2[nH]nnc12
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(On1nnc2ccccc21)c1ccccc1
Reaction time: 5 h

Procedure:
Hydroxybenzotriazole resin (0.107 g, 0.196 mmol) was treated with benzoic acid (0.12 g, 0.982 mmol, 5 eq), DIC (0.152 mL, 0.982 mmol, 5 eq) and DMAP (0.024 g, 0.196 mmol, 1 eq) in DMF-CH2Cl2 (1:1) and shaken for 5 h. The mixture was filtered and the resin was washed with DMF (10×5 mL) and CH2Cl2 (10×5 mL) to give resin-supported benzoic acid benzotriazol-1-yl ester. To a suspension of the resin-ester (0.196 mmol, 1.5 eq) in CH2Cl2 (2 mL) were added i-Pr2NEt (0.033 mL, 0.196 mmol, 1.5 eq) and 2-amino-2-methyl-pentan-3-one (0.03 g, 0.131 mmol, 1 eq). The mixture was agitated for 16 h and filtered. The filtrate was shaken with a weakly basic ion exchange resin Amberlite IRA-95 (1 g, 4.7 mmol g−1, 25 eq) for 16 h to remove benzoic acid present in the solution and filtered. The filtrate was eluted through a short column of silica gel (hexane/ethyl acetate 50:50) to remove the unreacted amine. The organic solvent was evaporated to leave N-(1,1-dimethyl-2-oxo-butyl)-benzamide (0.03 g, 87%) as a white solid. 1H NMR (200 MHz, CDCl3) δ(ppm): 1.14 (t, J=7.2 Hz, 3H), 1.57 (s, 6H), 2.63 (q, J=7 Hz, 2H), 7.21 (bs, 1H), 7.38-7.56 (aromatic H's, 3H), 7.79 (dd, J=8, 1.8 Hz, 2H). MS (ESI, positive ion): mz/z 220.2 (M+1)+.
Reaction SMILES: [Cl:1][CH2:2][S:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1.CO.C1C(=O)N(Br)C(=[O:16])C1>O>[Cl:1][CH2:2][S:3]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][CH:5]=1)=[O:16]
Reactant: Cc1ccc(SCCl)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CO
Product: Cc1ccc(S(=O)CCl)cc1
Yield: 89.5 %

Procedure:
(Choromethyl)(p-tolyl)sulfane (10 g, 57.91 mmol) was added to a mixture of methanol (50 mL) and water (10 mL). The resulting mixture was cooled to a temperature between 0° C. and 5° C. NBS (12.37 g, 1.2 eq) was added in small portions, maintaining the same temperature range. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, the reaction mixture was quenched by the addition of Na2SO3 (10%, 30 mL). The pH of the reaction mixture was adjusted to a value between 7 and 8, with saturated NaHCO3 solution. The mixture was concentrated under vacuum at a temperature between 20° C. and 25° C. and then extracted with dichloromethane (40 mL, 30 mL). The combined organic layer was washed with water (2×60 ml) and concentrated to ⅓ of the volume. Heptane (10 mL) was added and then removed by distillation. The crude product was purified by flash chromatography (Ethyl Acetate/Hexane 30:70) to give 9.78 g (89.51%) of the desired product as a white solid.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][C@@H:3]([CH2:11][N:12]2[C:16]([CH2:17][C:18]3[CH:25]=[CH:24][C:21]([C:22]#[N:23])=[CH:20][CH:19]=3)=[CH:15][N:14]=[CH:13]2)[NH:2]1.[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32].ON1C2C=CC=CC=2N=N1.C(Cl)CCl.CN1CCOCC1>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31]([N:2]1[C@H:3]([CH2:11][N:12]2[C:16]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([C:22]#[N:23])=[CH:24][CH:25]=3)=[CH:15][N:14]=[CH:13]2)[CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH2:1]1)=[O:32]
Reactant: N#Cc1ccc(Cc2cncn2C[C@@H]2Cc3ccccc3CN2)cc1
Reactant: COc1cccc(C(=O)O)c1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: CN1CCOCC1
Product: COc1cccc(C(=O)N2Cc3ccccc3C[C@H]2Cn2cncc2Cc2ccc(C#N)cc2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 4-{3-[(S)-1,2,3,4-tetrahydro-isoquinolin-3-yl-methyl]-3H-imidazol-4-yl-methyl}-benzonitrile (0.16 g, 0.487 mmol), 3-methoxybenzoic acid (0.074 g, 0.487 mmol), 1-hydroxybenzotriazole (0.075 g, 0.487 mmol), EDC (0.093 g, 0.487 mmol) and N-methylmorpholine (0.2 ml, 1.95 mmol) in 5 ml DMF was stirred for 18 hr at 25° C. The solvent was removed in vacuo. The residue was partitioned between ethyl acetate and saturated sodium bicarbonate. The ethyl acetate layer was dried with saturated sodium chloride and magnesium sulfate. Evaporation in vacuo of the ethyl acetate layer yielded the crude product. Purification was done on silica gel using methylene chloride:methanol:amonia hydroxide 98:2:0.2 and yielded the title compound.
Reaction SMILES: Cl.Cl.[N:3]1([CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:22]=[C:21]3[C:16]([CH2:17][CH2:18][NH:19][CH2:20]3)=[CH:15][CH:14]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CCN(CC)CC.[CH:30]([N:33]=[C:34]=[O:35])([CH3:32])[CH3:31]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH:30]([NH:33][C:34]([N:19]1[CH2:18][CH2:17][C:16]2[C:21](=[CH:22][C:13]([O:12][CH2:11][CH2:10][CH2:9][N:3]3[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]3)=[CH:14][CH:15]=2)[CH2:20]1)=[O:35])([CH3:32])[CH3:31]
Reactant: c1cc2c(cc1OCCCN1CCCCC1)CNCC2
Reactant: CC(C)N=C=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)N1CCc2ccc(OCCCN3CCCCC3)cc2C1

Procedure:
A 10 mL CH2Cl2 solution of 7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline dihydrochloride (254 mg, 0.73 mmol), NEt3 (0.20 mL, 1.4 mmol), isopropyl isocyanate (192 mg, 2.2 mmol), and 4-dimethylaminopyridine (12 mg, 0.1 mmol) is stirred under N2, at room temperature for 18 hours. The reaction mixture is concentrated and the residue is purified by chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO2; 0-10% MeOH/CH2Cl2/1% NH4OH gradient) to give pure product (110 mg, 42% yld). MS(ES+) 360.2(M+H)+.
Reaction SMILES: [NH2:1][CH:2]1[CH:7]2[CH:3]1[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]2.[OH:15][CH2:16][C:17]1[O:21][N:20]=[C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:18]=1.C(N(CC)C(C)C)(C)C.Cl[C:37](OC1C=CC([N+]([O-])=O)=CC=1)=[O:38]>>[CH2:25]([O:24][C:22]([C:19]1[CH:18]=[C:17]([CH2:16][O:15][C:37]([NH:1][CH:2]2[CH:7]3[CH:3]2[CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6]3)=[O:38])[O:21][N:20]=1)=[O:23])[CH3:26]
Reactant: CC(C)(C)OC(=O)N1CC2C(N)C2C1
Reactant: CCOC(=O)c1cc(CO)on1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(COC(=O)NC2C3CN(C(=O)OC(C)(C)C)CC32)on1
Yield: 75 %

Procedure:
The procedure described in Example 3, step 3.4. is followed. Starting from 3.00 g (15.13 mmol) of tert-butyl 6-amino-3-azabicyclo[3.1.0]hexane-3-carboxylate, 2.58 g (15.13 mmol) of ethyl 5-hydroxymethyl-isoxazole-3-carboxylate, 5.27 ml (30.26 mmol) of N,N-diisopropylethylamine and 3.05 g (15.13 mmol) of para-nitrophenyl chloroformate, 4.50 g of product are obtained in the form of a colourless oil (75%).
Reaction SMILES: [F:1][CH:2]([F:11])[C:3]1[C:7]([C:8](O)=[O:9])=[CH:6][NH:5][N:4]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]1([C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH2:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>C1COCC1>[CH:24]1([C:30]2[CH:36]=[CH:35][CH:34]=[CH:33][C:31]=2[NH:32][C:8]([C:7]2[C:3]([CH:2]([F:11])[F:1])=[N:4][NH:5][CH:6]=2)=[O:9])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]1
Reactant: O=C(O)c1c[nH]nc1C(F)F
Reactant: Nc1ccccc1C1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: O=C(Nc1ccccc1C1CCCCC1)c1c[nH]nc1C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
3-(difluoromethyl)-1H-pyrazole-4-carboxylic acid (2.0 g) and 1,1'-carbonyldiimidazole (2.0 g) were mixed in THF (20mL, anhydrous) and stirred for 1 h. 2-Cyclohexylaniline (2.2 g) was added, and the contents were heated at reflux for 2 h. After cooling to RT, the contents were concentrated in vacuo leaving a foam (3.7 g). The foam was chromatographed on silica gel (Waters Prep 500) eluting with EtOAc and hexanes to give the desired amide as a white foam (750 mg). The foam was crystallized from EtOAc /pentane to give the product as a white solid (510 mg).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[CH2:16][C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][CH:18]=1.[Br:25]Br>ClCCl>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][O:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([Br:25])[N:6]2[CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]#[N:22])=[CH:23][CH:24]=1
Reactant: BrBr
Reactant: COCCOc1nc(N)c2ncn(Cc3ccc(C#N)cc3)c2n1
Solvent: ClCCl
Product: COCCOc1nc(N)c2nc(Br)n(Cc3ccc(C#N)cc3)c2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The product of example 3 (700 mg) is dissolved in dichloromethane (400 mL) and bromine (7 mL) is added dropwise. The mixture is stirred overnight at room temperature and extracted with aqueous sodium thiosulfate (2 L of 0.1 M) solution and then with aqueous sodium bicarbonate (500 mL, saturated). The residue from the organic layer is chromatographed on silica gel using 3% methanol in dichloromethane) to yield 460 mg of bromo product. NMR, UV and MS are consistent with structure assignment.