Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].O.[C:4]([CH2:6][C:7]([NH2:9])=[O:8])#[N:5].[CH2:10]([N:17]=[N+:18]=[N-:19])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>CS(C)=O>[NH2:5][C:4]1[N:17]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:18]=[N:19][C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: [N-]=[N+]=NCc1ccccc1
Reactant: N#CCC(N)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: NC(=O)c1nnn(Cc2ccccc2)c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a separate reactor, DMSO (17.6 g, 16.0 ml) was charged followed by, 32% aqueous NaOH (7.86 g, 5.82 ml, 62.9 mmol, Eq: 1.0) and water (5.00 g, 5.00 ml). A solution of 2-cyanoacetamide (7.93 g, 94.3 mmol, Eq: 1.50) in DMSO (17.6 g, 16.0 ml) was added dropwise over 15 min at 25° C. The previously prepared benzyl azide solution was added dropwise over 4 h at 25° C. The reaction was stirred overnight at 25° C. and water (120 g, 120 ml) was added dropwise over 30 min at 25° C. (exothermic). The resulting suspension was cooled over 30 min to 0° C., stirred at 0° C. for 30 min and filtered. The filter cake was washed with water (40.0 g, 40.0 ml) and was dried at 50° C./5 mbar to give 12.6 g of the title compound.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24](C(=O)C(F)(F)F)[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([C:49]([F:52])([F:51])[F:50])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[BH4-].[Na+].O>C(O)C>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([CH:40]([OH:48])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:47])=[C:36]([C:49]([F:52])([F:50])[F:51])[CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:53]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3C(=O)C(F)(F)F)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(C(O)c4cccc[n+]4[O-])c(C(F)(F)F)c2)CCN3)cc1
Reaction time: 7 h
Yield: 81.5 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]1-(2,2,2-trifluoroacetyl)-2,3-dihydro-1-benzazepine-4-carboxamide (155 mg) in ethanol (10 ml) was added sodium borohydride (79 mg) and the mixture was stirred for 7 hours. To the mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and recrystallized from diisopropyl ether-ethyl acetate, to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[hydroxy(1-oxidopyridin-2-yl)methyl]-3-trifluoromethylphenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (110 mg) as yellow crystals.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C:20](=[NH:23])OC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>CCO.CO>[ClH:1].[NH2:25][C:20](=[NH:23])[CH2:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:14][CH:15]=1
Reactant: COC(=N)Cc1ccc(CCc2csc(NC(C)=O)n2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(CC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 58.9 %

Procedure:
Methyl 2-(4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}phenyl)ethanimidoate hydrochloride (600 mg) was dissolved in EtOH (12 ml). Then ammonium chloride (136 mg) and ammonia in methanol (2 ml) were added to the solution. The reaction mixture was refluxed for 4 hours under N2 atmosphere. After cooled to r.t., the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with EtOH/diethyl ether to give N-(4-{2-[4-(2-amino-2-iminoethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide hydrochloride (338.6 mg) as an off-white solid.
Reaction SMILES: [CH3:1][CH:2]([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:3].[Br:9]Br.Br>C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+]>[Br:9][C:2]([CH3:3])([C:4](=[O:8])[CH:5]([CH3:7])[CH3:6])[CH3:1]
Reactant: CC(C)C(=O)C(C)C
Reactant: BrBr
Agent: Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)C(=O)C(C)(C)Br
Yield: 85.7 %

Procedure:
2,4-dimethyl-3-pentanone (330 g, 2.89M) in chloroform (800 ml) was cooled in an ice water bath to 10° C. and bromine (462 g, 2.89M) was added slowly over 3 hours. After the addition, a slow stream of nitrogen was introduced to the mixture and HBr gas was slowly evolved from the flask. The nitrogen was left bubbling over a weekend to remove all of the HBr produced and then sodium carbonate (5 g) was added. The reaction mixture was then filtered through Celite and the chloroform removed using a rotary evaporator. Distillation of the crude product using a 1′ (2.54 cm) vigreux gave essentially pure 2-bromo-2,4-dimethyl-3-pentanone (478 g, 2.47M) b.pt. 50-52° C./10 mb (1000 Nm−2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][NH:12][C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:32]=[C:33]([O:37][CH3:38])[C:34]=1[O:35][CH3:36])[CH2:30]Br>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([CH2:15][CH2:16][CH2:17][O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][O:20]3)[CH2:13][N:12]([CH2:30][C:29]3[CH:32]=[C:33]([O:37][CH3:38])[C:34]([O:35][CH3:36])=[C:27]([O:26][CH3:25])[CH:28]=3)[C:11](=[O:14])[CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1cc(CBr)cc(OC)c1OC
Reactant: O=C1CC(CCCOC2CCCCO2)(c2ccc(Cl)c(Cl)c2)CN1
Product: COc1cc(CN2CC(CCCOC3CCCCO3)(c3ccc(Cl)c(Cl)c3)CC2=O)cc(OC)c1OC

Procedure:
Prepare according to the procedure of example 11.4 using 4-(3,4-dichloro-phenyl)-4-[3-(tetrahydro-pyran-2-yloxy)-propyl]-pyrrolidin-2-one (2.79 mmol) and 3,4,5-trimethoxy-benzyl bromide (5.9 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4]O)#[N:2].N1C=CC=CC=1.P(Br)(Br)[Br:20]>C(Cl)Cl>[C:1]([CH:3]([C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[CH:8][CH:7]=1)[CH2:4][Br:20])#[N:2]
Reactant: N#CC(CO)c1ccc(Br)cc1
Reactant: BrP(Br)Br
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#CC(CBr)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 24 g (0.11 mol) 2-cyano-2-(4-bromophenyl)-ethanol and 4.5 g (0.055 mol) pyridine in 100 ml CH2Cl2 are slowly added, at -5° to 0°, 12 g (0.044 mol) PBr3. The mixture is stirred for 3 hours at room temperature, thereafter for 2 hours at 40°, allowed to cool off, then poured into 500 ml ice water and extracted with CH2Cl2. The extract is washed with water, dried and evaporated. The resulting residue is chromatographed over a silica gel column with hexane/diethylether 6:4. The glassy residue obtained after evaporation is worked up in toluene and thereafter ether to give the title compound in the form of a yellow powder, m.p. 171° (decomposing).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C(C)=CC=CC=1C.[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>O1CCCC1>[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)=[O:27])(=[O:22])[CH3:21]
Reactant: Cc1nc2cc(N)ccc2o1
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Solvent: Cc1cccc(C)n1
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc2oc(C)nc2c1
Temperature: 3 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
5-Amino-2-methylbenzoxazole (18.6 g, 0.126 mol) and 2,6-lutidine (14.8 g, 0.138 mol) were combined with 125 mL of tetrahydrofuran and the solution was cooled to 3° C. in an ice-bath under nitrogen. 2-Acetoxybenzoyl chloride (25.0 g, 0.126 mol) was added as a solid, portionwise, so as to keep the temperature below 10° C. An additional 150 mL of tetrahydrofuran was added. After addition of all the 2-acetoxybenzoyl chloride, the ice-bath was removed and after stirring for 2 hr the mixture was poured into 300 mL of water and then combined with an additional 300 mL of water. The solid was collected and washed with water and dried. This afforded 33.6 g (86% yield) of product; m.p. 169°-171° C.
Reaction SMILES: [S:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH2:33][CH3:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1O)[CH3:17].C(N(CC)CC)C>ClCCl.C(=O)([O-])O.[Na+]>[CH2:16]([O:18][C:19]1[CH:20]=[C:21](/[CH:26]=[C:27](\[CH2:33][CH3:34])/[C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH:22]=[CH:23][C:24]=1[O:8][S:1]([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2])[CH3:17]
Reactant: CCOC(=O)/C(=C/c1ccc(O)c(OCC)c1)CC
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(OS(=O)(=O)C(F)(F)F)c(OCC)c1)CC
Temperature: 25 °C
Reaction time: 1 h
Yield: 107.2 %

Procedure:
808 μL (4.8 mmol) of triflic anhydride are added to a solution of 1.5 g (4 mmol) of ethyl 2-[1-(3-ethoxy-4-hydroxyphenyl)meth-(E)-ylidene]butyrate and 1.6 mL (12 mmol) of triethylamine in 20 mL of dichloromethane at 0° C. The reaction mixture is stirred at room temperature for 1 hour. The reaction medium is hydrolyzed in sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic phases are combined, washed with water and dried over magnesium sulfate. The solvent is evaporated off and 1.7 g (100%) of ethyl 2-[1-(3-ethoxy-4-trifluoromethanesulfonyloxyphenyl)meth-(E)-ylidene]butyrate are obtained in the form of a brown oil.
Reaction SMILES: C([O:5][C:6](=[O:59])[CH2:7][N:8]([CH2:51][C:52](=[O:58])[O:53]C(C)(C)C)[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]([O:26]C(C)(C)C)=[O:25])[CH2:19][CH2:18][N:17]([CH2:31][C:32]([O-:34])=[O:33])[CH2:16][CH2:15][N:14]([CH2:35][C:36]([O-:38])=[O:37])[CH2:13][CH2:12]1)(C)(C)C.Cl.CCOCC>O1CCOCC1>[C:52]([CH2:51][N:8]([CH2:7][C:6]([OH:59])=[O:5])[CH:9]([CH2:39][CH2:40][CH2:41][C:42]1[CH:47]=[CH:46][C:45]([N+:48]([O-:50])=[O:49])=[CH:44][CH:43]=1)[CH2:10][N:11]1[CH2:12][CH2:13][N:14]([CH2:35][C:36]([OH:38])=[O:37])[CH2:15][CH2:16][N:17]([CH2:31][C:32]([OH:34])=[O:33])[CH2:18][CH2:19][N:20]([CH2:23][C:24]([OH:26])=[O:25])[CH2:21][CH2:22]1)([OH:58])=[O:53]
Reactant: CC(C)(C)OC(=O)CN1CCN(CC(=O)[O-])CCN(CC(=O)[O-])CCN(CC(CCCc2ccc([N+](=O)[O-])cc2)N(CC(=O)OC(C)(C)C)CC(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(CCCc2ccc([N+](=O)[O-])cc2)N(CC(=O)O)CC(=O)O)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 22 h

Procedure:
Compound 10 (77.0 mg, 0.081 mmol) at 0-5° C. was treated dropwise with 4M HCl(g) in 1,4-dioxane (15 mL) over 20 min. The resulting mixture was allowed to warm to room temperature. After 22 h, ether (˜20 mL) was added and continued to stir for 10 min. The resulting mixture was capped and placed in the freezer for 1 h. The solid formed was filtered, washed with ether, and quickly dissolved in DI water. Evaporation of the aqueous solution gave an off-white solid 3p-2C-DEPA (68.0 mg, 97%). 1H NMR (D2O, 300 MHz) δ 1.26-1.40 (m, 1H), 1.48-1.70 (m, 3H), 2.52-2.78 (m, 2H), 2.90-3.70 (m, 27H), 3.75-3.98 (m, 2H), 7.35 (d, J=8.3 Hz, 2H), 8.06 (d, J=8.2 Hz, 2H); 13C NMR (D2O, 300 MHz) δ 27.08 (t), 27.12 (t), 34.64 (t), 48.45 (t), 48.82 (t), 50.22 (t), 51.09 (t), 52.40 (t), 53.58 (t), 54.28 (t), 55.46 (t), 59.43 (d), 123.55 (d), 129.40 (d), 145.71 (s), 150.54 (s), 169.54 (s), 172.97 (s), 173.93 (s); HRMS (Positive ion FAB) Calcd for C29H45N6O12 [M+H]+ m/z 669.3095. Found: [M+]+ m/z 669.3086.
Reaction SMILES: O1CCOCC1.[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14](Cl)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8].[Cl:20][C:21]1[CH:40]=[CH:39][C:24]([C:25]([C:27]2[CH:38]=[CH:37][C:30]([CH2:31][NH:32][CH2:33][CH2:34][CH2:35][OH:36])=[CH:29][CH:28]=2)=[O:26])=[CH:23][CH:22]=1>O>[C:7]([N:11]1[C:16](=[O:17])[C:15]([Cl:18])=[C:14]([N:32]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:31][C:30]2[CH:29]=[CH:28][C:27]([C:25](=[O:26])[C:24]3[CH:39]=[CH:40][C:21]([Cl:20])=[CH:22][CH:23]=3)=[CH:38][CH:37]=2)[CH:13]=[N:12]1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CNCCCO)cc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)n1ncc(N(CCCO)Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)c(Cl)c1=O
Temperature: 100 °C
Reaction time: 64 h
Yield: 11.5 %

Procedure:
In a solvent mixture of dioxane (5 ml) and water (5 ml) were dissolved 2-tert-butyl-4,5-dichloro-3(2H)-pyridazinone (473 mg) and 3-[4-(4-chlorobenzoyl)benzyl-amino]-1-propanol (1.30 g) and the mixture was stirred at 100° C. for 64 hours. After cooling to room temperature, the reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=4:1-2:1) to provide the title compound as white powder (120 mg; yield 12%). 1H-NMR (CDCl3) δ: 1.63(9H,s), 1.83-1.98(3H,m), 3.51(2H,t,J=7.2Hz), 3.70(2H,m), 4.71(2H,m), 7.40(2H,d,J=8.4Hz), 7.46(2H,d,J=8.4Hz), 7.60(1H,s), 7.75(2H,d,J=8.4Hz), 7.77(2H,d,J=8.4Hz).
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:5]=2[N:6]=1.[CH2:13](Br)[CH2:14][CH3:15].[OH-].[Na+].C(OC(=O)C)C>CCCCCC>[CH2:13]([S:1][C:2]1[NH:6][C:5]2[CH:7]=[C:8]([CH3:12])[C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCBr
Reactant: Cc1cc2nc(S)[nH]c2cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCSc1nc2cc(C)c(C)cc2[nH]1

Procedure:
2-Propylthio-5,6-dimethylbenzimidazole (II) was prepared by the same procedure for I from 0,89 g (0,005 mol) 2-mercapto-5,6-dimethyl-benzimidazole, 0,8 g (0,006 mol) propylbromide in the presence 0,24 g (0,006 mol) sodium hydroxide in a yield of 0,72 g (60%), m.p. 122-123° C. (from mixture ethylacetate with hexane).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8].C(N(CC)CC)C.[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27](Cl)=[O:28])[CH3:25]>C(Cl)(Cl)Cl>[CH2:24]([CH:26]([CH2:30][CH2:31][CH2:32][CH3:33])[C:27]([N:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])=[O:28])[CH3:25]
Reactant: O=C1CC[C@@H](C(=O)OCc2ccccc2)N1
Reactant: CCCCC(CC)C(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCCCC(CC)C(=O)N1C(=O)CC[C@H]1C(=O)OCc1ccccc1

Procedure:
39.4 g (180 mmol) of benzyl (L)-pyroglutamate, prepared according to Example II(1), are dissolved in 160 ml of chloroform and 28.4 g (28 mmol) of triethylamine at ordinary temperature. A solution of 29.3 g (180 mmol) of 2-ethylhexanoyl chloride in 40 ml of chloroform is run in and the mixture is heated under reflux for 5 hours.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22](Cl)[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[N:32]1[CH2:36][CH:35]=[CH:34][N:33]1[CH3:37])CCC>>[CH2:1]([O:8][C:9]1[CH:26]=[CH:25][C:12]([NH:13][C:14]2[C:15]3[CH:23]=[C:22]([N:32]4[CH2:36][CH:35]=[CH:34][N:33]4[CH3:37])[N:21]=[CH:20][C:16]=3[N:17]=[CH:18][N:19]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)N1CC=CN1C
Reactant: Clc1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1
Product: CN1C=CCN1c1cc2c(Nc3ccc(OCc4ccccc4)cc3)ncnc2cn1

Procedure:
Prepared according to Procedure B from 4-(4-benzyloxyanilino)6-chloropyrido[3,4-d]pyrimidine and 2-(tri-n-butylstannyl)-N-methylpyrazole (prepared according to the published method: WO 94/00825); δH [2H6]-DMSO 9.30 (1H,s), 8.80 (2H,m), 7.80 (2H,d), 7.65 (1H,d), 7.50 (6H,m), 7.20 (2H,d), 6.90 (1H,d), 5.20 (2H,s), 4.25 (3H,s); m/z (M+1)+409.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([CH3:21])[CH2:6][C:7]1[N:11]([CH:12]2[CH2:14][CH2:13]2)[C:10]([C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[N:9][N:8]=1)C.O.[NH2:24][NH2:25]>C(O)C>[CH:12]1([N:11]2[C:10]([C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)=[N:9][N:8]=[C:7]2[CH2:6][CH:5]([CH3:21])[C:4]([NH:24][NH2:25])=[O:3])[CH2:14][CH2:13]1
Reactant: CCOC(=O)C(C)Cc1nnc(-c2ccncc2)n1C1CC1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CC(Cc1nnc(-c2ccncc2)n1C1CC1)C(=O)NN

Procedure:
3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid ethyl ester (2.14 g, 7.1 mmol) was mixed with hydrazine monohydrate in ethanol at 120° C. in a sealed flask for 2 hours. The reaction mixture was concentrated and triturated with ether to give 3-(4-cyclopropyl-5-pyridin-4-yl-4H-[1,2,4]triazol-3-yl)-2-methyl-propionic acid hydrazide. This compound was mixed with 3-Chloro-benzimidic acid ethyl ester hydrochloride (0.722 g, 7.8 mmol) in ethanol at 130° C. o.n. The reaction mixture was concentrated, quenched with saturated sodium carbonate, extracted with DCM. The organic layer was dried and purified by column chromatograph with 5% methanol (2M NH3) in DCM to racemic 4-(5-{2-[3-(3-chloro-phenyl)-[1,2,4]oxadiazol-5-yl]-propyl}-4-cyclopropyl-4H[1,2,4] triazol-3-yl)-pyridine 1.19 g (41.1%). This material (70 mg) was separated on Chiralpak AD using ethanol as eluent to give the title compound. 1H-NMR: 8.77(d, 2H), 8.02 (s, 1H), 7.92 (d, 1H), 7.72 (d, 2H), 7.51 (d, 1H), 7.47(t, 1H), 4.12 (m, 1H), 3.69 (dd, 1H), 3.44 (m, 1H), 3.26 (dd, 1H), 1.66 (d, 3H), 1.24 (m, 2H) and 0.79 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:11])=[O:10])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1.[CH3:24][O:25][CH2:26]Cl.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[Br:1][C:2]1[C:7]([N:8]([CH2:24][O:25][CH3:26])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19]([F:22])([F:21])[F:20])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][C:5]([CH3:23])=[CH:4][N:3]=1
Reactant: COCCl
Reactant: Cc1cnc(Br)c(NS(=O)(=O)c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COCN(c1cc(C)cnc1Br)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.9 %

Procedure:
A mixture of N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-3-trifluoromethyl-benzenesulfonamide (1.4 g, 3.27 mmol), chloromethyl methyl ether (0.4 mL, 5.23 mmol) and K2CO3 (1.35 g, 9.81 mmol) in THF (20 mL) was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was concentrated and purified by flash chromatography (SiO2, 20% EtOAc-hexanes) to afford N-(2-bromo-5-methyl-pyridin-3-yl)-4-chloro-N-methoxymethyl-3-trifluoromethyl-benz-enesulfonamide (1.3 g) as a white solid in 84% yield. ESMS m/z (relative intensity): 473 (M+H)+ (100).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36](O)[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C1CCC(N=C=NC2CCCCC2)CC1>>[CH2:23]([O:30][C:31]([N:33]1[CH2:38][CH2:37][CH:36]([O:19][C:18](=[O:20])[CH2:17][O:16][C:15]2[CH:14]=[CH:13][C:12]([C:10](=[O:11])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:22][CH:21]=2)[CH2:35][CH2:34]1)=[O:32])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C(OCc1ccccc1)N1CCC(O)CC1
Reactant: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Product: CC(C)(C)OC(=O)NCC(=O)c1ccc(OCC(=O)OC2CCN(C(=O)OCc3ccccc3)CC2)cc1

Procedure:
The compound of example 1f was treated with 4-hydroxy-piperidine-1-carboxylic acid benzyl ester in the presence of DCC as described in the procedure of example 5a to obtain the title compound. The crude material was purified using flash chromatography (silica gel, 5% CH3CN in chloroform). Yield, 73%; analysis: C28H34N2O8 requires: C, 63.87; H, 6.51; N, 5.32; found: C, 64.13; H, 6.78; N, 5.02%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.[I:16]N1C(=O)CCC1=O>FC(F)(F)C(O)=O>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][C:7]=1[I:16]
Reactant: O=C1CCC(=O)N1I
Reactant: O=C1OC(CO)CN1c1cccc(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C1O[C@@H](CO)CN1c1ccc(I)c(F)c1
Reaction time: 2 h
Yield: 5.8 %

Procedure:
A solution of alcohol 92 (10.74 g, 50.9 mmol) in trifluoroacetic acid (TFA, 50 mL) was treated with N-iodosuccinimide (12.03 g, 53.45 mmol, 1.05 equiv) at 25° C. and stirred for 2 h. When TLC and HPLC/MS showed the reaction was complete, the reaction mixture was concentrated in vacuo. The residue was then treated with H2O (100 mL) and 20% EtOAc/hexane (100 mL) at 25° C., and the resulting mixture was stirred at 25° C. for 30 min before being cooled to 0–5° C. for 2 h. The white solids were collected by filtration, washed with H2O (2×25 mL) and 20% EtOAc/hexane (2×25 mL), and dried in vacuo to afford the desired (5R)-3-(3-fluoro-4-iodo-phenyl)-5-hydroxymethyl-oxazolidin-2-one (iodo-alcohol 93, 15; 1 g, 88% yield) as an off-white powder. This product was directly used in subsequent reactions without further purification. 1H NMR (300 MHz, DMSO-d6) δ 3.58 (dd, 1H, J=4.2, 12.6 Hz), 3.67 (dd, 1H, J=3.0, 12.6 Hz), 3.67 (dd, 1H, J=6.3, 9.0 Hz), 4.07(t, 1H, J=9.0 Hz), 4.72 (m, 1H), 5.21 (br. s, 1H, OH), 7.22 (dd, 1H, J=2.4, 8.4 Hz), 7.58 (dd, 1H, J=2.4, 11.1 Hz), 7.81 (dd, 11H, J=7.8, 8.7 Hz). C10H9FINO3, LCMS (EI) m/e 338 (M++H).
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:37](Cl)=[O:38])[CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:37]([CH:33]3[CH2:36][CH2:35][CH2:34]3)=[O:38])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclobutanecarbonyl chloride (23 mg, 193 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (21.9 mg, 68% of theory).