Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=O)=[C:4]([Cl:11])[N:3]=1.C(O)(=O)C.Cl.[NH2:17][OH:18]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([CH:9]=[N:17][OH:18])=[C:4]([Cl:11])[N:3]=1
Reactant: Nc1nc(Cl)c(C=O)c(Cl)n1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1nc(Cl)c(C=NO)c(Cl)n1
Yield: 84.1 %

Procedure:
Following the method of Bell et al. (J. Heterocyclic Chem. 1983, 20, 41), to a solution of 29.6 g (154 mmol) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde in 31 acetic acid in a 2-necked flask at room temperature was added dropwise with stirring a solution of 11.8 g (170 mmol) hydroxylamine hydrochloride in 2.31 ethanol. Stirring was continued for 3 h at room temperature during which time crystallisation occurred. The crystals were collected by filtration to afford 26.8 g (84%) 2-amino-4,6-dichloro-pyrimidine-5-carbaldehyde oxime as a light yellow crystalline solid. ES-MS m/e (%): 209 ([M{37Cl, 37Cl}-H]−, 20), 207 ([M{37Cl, 35Cl}-H]−, 55), 205 ([M{35Cl, 35Cl}-H]−, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.ClC[C:11]([N:13](C(C)C)C(C)C)=[O:12].C(N(C(C)C)CC)(C)C.C(COC)[O:30]C>>[N:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[C:3]=1[C:2]([NH2:1])=[O:30]
Reactant: CC(C)N(C(=O)CCl)C(C)C
Reactant: NCc1ccccn1
Reactant: COCCOC
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1cccnc1C(N)=O

Procedure:
Pyridine diamide 7 was prepared according to the general procedure described in Example 8 using 2-(aminomethyl)pyridine (0.013 mol), 2-chloro-N,N-diisopropylacetamide (0.038 mol), diisopropylethylamine (0.038 mol) and dimethoxyethane (25 mL). The product was isolated from both the methylene chloride extraction of the acidic aqueous layer and the heptane extraction of the basic layer in about equal amounts. Mass spectral analysis of the two layers showed the material in the heptane layer to be of greater purity. The residue from the heptane layer was distilled (150° C., 0.05 mm) to afford 2.2 g of product.
Reaction SMILES: C(S[CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=2)[C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1)C=C.[Cl:39]Cl>ClCCl.C(Cl)(Cl)(Cl)Cl>[Cl:39][CH:5]1[N:8]([C:9](=[C:23]([O:30][C:31]2[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=2)[C:24](=[O:29])[C:25]([CH3:27])([CH3:28])[CH3:26])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[S:11])[C:7](=[O:38])[CH2:6]1
Reactant: C=CCSC1CC(=O)N1C(C(=S)OCc1ccc([N+](=O)[O-])cc1)=C(Oc1ccc(Cl)cc1)C(=O)C(C)(C)C
Reactant: ClCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)C(=O)C(Oc1ccc(Cl)cc1)=C(C(=S)OCc1ccc([N+](=O)[O-])cc1)N1C(=O)CC1Cl
Temperature: 25 °C
Yield: 64.2 %

Procedure:
To a solution of 0.5 g of 4-nitrobenzyl 2-(4-allylthioazetidin-2-on-1-yl)-3-(4-chlorophenoxy)-3-trimethylacetylthio-propenate in dichloromethane at -20° C. was added a solution of 1.7 mmol chlorine in carbon tetrachloride. After 30 minutes the mixture was warmed to room temperature, evaporated in vacuo, and the residual oil was chromatographed over silica gel. Elution with hexane-ethyl acetate mixtures afforded 0.3 g of the title compound as a pale yellow foam (65% of the theoretical yield).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]([N:11]3[CH2:15][CH2:14][N:13]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][C:21]=4[CH3:22])[C:12]3=[O:23])[S:10][C:6]=2[CH:5]=[CH:4][N:3]=1>CO.C(Cl)(Cl)Cl.[Pd]>[CH3:22][C:21]1[CH:20]=[CH:19][N:18]=[CH:17][C:16]=1[N:13]1[CH2:14][CH2:15][N:11]([C:9]2[S:10][C:6]3[CH:5]=[CH:4][N:3]=[CH:2][C:7]=3[CH:8]=2)[C:12]1=[O:23]
Reactant: Cc1ccncc1N1CCN(c2cc3c(Cl)nccc3s2)C1=O
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccncc1N1CCN(c2cc3cnccc3s2)C1=O
Reaction time: 12 h
Yield: 13.9 %

Procedure:
10% Pd-C (10 mg) was added to a solution of 1-(4-chloro-thieno[3,2-c]pyridin-2-yl)-3-(4-methyl-pyridin-3-yl)-imidazolidin-2-one (98A: 80 mg, 0.232 mmol) in methanol (10 mL) under nitrogen atmosphere. The resulting mixture was hydrogenated at 30 PSI (2.04 atm) for 12 hours at room temperature. The reaction was monitored by TLC (10% MeOH in CHCl3). The reaction mixture was filtered through celite bed, washed with methanol and the filtrate was concentrated under reduced pressure to afford the crude product. Purification by preparative TLC afforded 10 mg of the product (14% yield).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[N:9]=1)(=[O:3])[CH3:2].[Cl-].[NH4+].C(O)C.O>O1CCCC1.[Fe]>[C:1]([NH:4][C:5]1[S:6][CH:7]=[C:8]([CH2:10][S:11][C:12]2[CH:13]=[CH:14][C:15]([NH2:18])=[CH:16][CH:17]=2)[N:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1nc(CSc2ccc([N+](=O)[O-])cc2)cs1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CC(=O)Nc1nc(CSc2ccc(N)cc2)cs1
Yield: 93.6 %

Procedure:
To a mixture of 2-acetylamino-4-(4-nitrophenylthiomethyl)thiazole (11 g) and ammonium chloride (2 g) in a mixture of tetrahydrofuran (200 ml), ethanol (200 ml) and water (100 ml) was added portionwise the iron powder (17 g) at 80° C. with stirring. The mixture was refluxed for 3 hours with stirring. The reaction mixture was filtered by suction and the filtrate was concentrated under reduced pressure and then the residue was triturated with water. The precipitates were collected by filtration, washed with water and dried in vacuo to give 2-acetylamino-4-(4-aminophenylthiomethyl)thiazole (9.3 g, yield: 93.6%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][NH:10][C:9](=[O:13])[CH2:8][C:7]=2[C:14]=1[O:15][CH3:16].Br[CH2:18][CH2:19][CH2:20][Cl:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[CH:12]=[CH:11][N:10]([CH2:18][CH2:19][CH2:20][Cl:21])[C:9](=[O:13])[CH2:8][C:7]=2[C:14]=1[O:15][CH3:16]
Reactant: ClCCCBr
Reactant: COc1ccc2c(c1OC)CC(=O)NC=C2
Product: COc1ccc2c(c1OC)CC(=O)N(CCCCl)C=C2

Procedure:
This compound was prepared analogous to Example 1(a) by reacting 8,9-dimethoxy-1,3-dihydro-2H-3-benzazepin-2-one (m.p.: 165°-168° C.) with 1-bromo-3-chloro-propane.
Reaction SMILES: CCCCCC.[H-].[Na+].[F:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16]C)=O)=[C:12]([CH3:20])[CH:11]=1.[C:21](#[N:23])[CH3:22]>C(OCC)(=O)C.Cl.C1COCC1>[F:9][C:10]1[CH:19]=[CH:18][C:13]([C:14](=[O:16])[CH2:22][C:21]#[N:23])=[C:12]([CH3:20])[CH:11]=1
Reactant: COC(=O)c1ccc(F)cc1C
Reactant: CC#N
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1cc(F)ccc1C(=O)CC#N
Temperature: 70 °C
Reaction time: 16 h
Yield: 99.9 %

Procedure:
To a suspension of hexane-washed sodium hydride (60% oil dispersion, 995 mg, 24.9 mmol) was added dropwise a THF solution (20 mL) of methyl 4-fluoro-2-methylbenzoate (3.8 g, 22.6 mmol) and anhydrous acetonitrile (2.4 mL, 45.2 mmol). The mixture was stirred at 70° C. for 16 h, and then cooled to rt. The resulting mixture was diluted with ethyl acetate (20 mL) and 1 N HCl (10 mL) and the layers were partitioned. The organic phase was washed with water (3×20 mL) and brine (20 mL), dried (Na2SO4), and concentrated under reduced pressure to afford 4.0 g of yellow oil, which was taken to the next step without further purification. ES-MS m/z 178.2 (MH+); HPLC RT (min) 2.22.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([CH2:8][OH:9])[CH:3]=1.[CH3:10][NH:11][CH2:12][CH2:13][OH:14]>>[OH:9][CH2:8][C:4]1[CH:3]=[C:2]([N:11]([CH3:10])[CH2:12][CH2:13][OH:14])[CH:7]=[CH:6][N:5]=1
Reactant: CNCCO
Reactant: OCc1cc(Cl)ccn1
Product: CN(CCO)c1ccnc(CO)c1
Temperature: 140 °C
Reaction time: 1 h

Procedure:
A mixture of (4-chloro-pyridin-2-yl)-methanol (20.0 g, 139 mmol) and 2-methylaminoethanol (11.7 ml, 146 mmol) is stirred for 1 h at 140° C. After cooling to room temperature the viscous oil is employed without additional purification for the synthesis described in step b).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[CH:19]=[C:18]([C:20]#[N:21])[CH:17]=[CH:16][C:15]=2[CH:22]2[C:27]([C:28](=[O:30])[CH3:29])=[C:26]([CH3:31])[N:25]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=3)[C:24](=[O:42])[N:23]2[CH3:43])[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>>[C:28]([C:27]1[CH:22]([C:15]2[CH:16]=[CH:17][C:18]([C:20]#[N:21])=[CH:19][C:14]=2[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH:10]=2)[N:23]([CH3:43])[C:24](=[O:42])[N:25]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([F:41])([F:40])[F:39])[CH:33]=2)[C:26]=1[CH3:31])(=[O:30])[CH3:29]
Reactant: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(C)C1c1ccc(C#N)cc1C1=CCNCC1
Reaction time: 0.25 h

Procedure:
4-{2-[5-Acetyl-3,6-dimethyl-2-oxo-1-(3-trifluoromethyl-phenyl)-1,2,3,4-tetrahydro-pyrimidin-4-yl]-5-cyano-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (example 5.6) (35 mg, 0.06 mmol) is suspended with aqueous trifluoroacetic acid (95%, 2 mL). The reaction mixture is shaken for 15 min, evaporated and the product is purified by reversed phase HPLC. Yield: 25 mg; ESI mass spectrum [M+H]+=495; Retention time HPLC: 1.20 min (HPLC method Z018_S04).
Reaction SMILES: C[O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][CH2:12][CH2:13]Br)=[CH:6][C:5]=1[OH:15].[F:17][C:18]([F:33])([F:32])[C:19]1[CH:20]=[C:21]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH:22]=[N:23][OH:24]>>[F:17][C:18]([F:32])([F:33])[C:19]1[CH:20]=[C:21](/[CH:22]=[N:23]/[O:24][CH2:13][CH2:12][CH2:11][O:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:2])=[O:16])=[C:5]([OH:15])[CH:6]=2)[CH:25]=[C:26]([C:28]([F:30])([F:31])[F:29])[CH:27]=1
Reactant: ON=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC(=O)c1ccc(OCCCBr)cc1O
Product: O=C(O)c1ccc(OCCCO/N=C/c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1O
Yield: 12 %

Procedure:
The title compound (0.115 g, 12%) was prepared as a white solid from 4-(3-bromo-propoxy)-2-hydroxy-benzoic acid methyl ester and 3,5-bis-trifluoromethyl-benzaldehyde oxime using a procedure similar to step 1 of example 12. mp=181.9-183.4° C.; mass spectrum −ESI, (M−H) m/z 450. 1H NMR (400 MHz, DMSO-d6); 613.60 (bs, 1H), 11.50 (bs, 1H), 8.48 (s, 1H), 8.23 (s, 2H), 8.13 (s, 1H), 7.66 (d, 1H), 6.47 (m, 2H), 4.33 (t, 2H), 4.12 (t, 2H), 2.12 (m, 2H). Elemental analysis: Calcd. for C19H15F6NO5: C, 50.56; H, 3.35; N, 3.1, Found: C, 50.25; H, 3.32; N, 2.93.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](O)=[O:46])([CH3:44])[CH3:43])=[CH:33][CH:32]=2)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=1)(=O)C.[CH3:52][N:53]([CH3:58])[CH2:54][CH2:55][CH2:56][NH2:57].OCCN1CCNCC1>>[C@@H:6]1([O:24][C:25]2[C:29]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][CH2:39][C:40](=[O:48])[NH:41][C:42]([C:45](=[O:46])[NH:57][CH2:56][CH2:55][CH2:54][N:53]([CH3:58])[CH3:52])([CH3:44])[CH3:43])=[CH:35][CH:36]=3)=[C:28]([CH:49]([CH3:51])[CH3:50])[NH:27][N:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(CCCC(=O)NC(C)(C)C(=O)O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)CCCN
Agent: OCCN1CCNCC1
Product: CC(C)c1[nH]nc(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)c1Cc1ccc(CCCC(=O)NC(C)(C)C(=O)NCCCN(C)C)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 48 using 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethyl-carbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and N,N-dimethyl-1,3-propanediamine instead of 3-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyloxy)-4-[(4-{3-[1-carboxy-1-(methyl)ethylcarbamoyl]propyl}phenyl)methyl]-5-isopropyl-1H-pyrazole and 1-(2-hydroxyethyl)piperazine, respectively.
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]=12.[Br:20]Br>C(O)(=O)C>[BrH:20].[Br:20][C:3]1[N:4]2[CH:9]=[C:8]([C:10]3[CH:11]=[C:12]([C:18]#[N:19])[C:13](=[O:17])[NH:14][C:15]=3[CH3:16])[CH:7]=[CH:6][C:5]2=[N:1][CH:2]=1
Reactant: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2nccn2c1
Reactant: BrBr
Solvent: CC(=O)O
Product: Br
Product: Cc1[nH]c(=O)c(C#N)cc1-c1ccc2ncc(Br)n2c1
Temperature: 30 °C
Yield: 155.9 %

Procedure:
In 10 ml of acetic acid was dissolved 0.3 g of 1,2-dihydro-5-(imidazo[1,2-a]pyridin-6-yl)-6-methyl-2-oxo-3-pyridinecarbonitrile. To the solution 0.2 g of bromine was added and the mixture was warmed to 30° C. After cooling, precipitated white crystals were taken by filtration. After washing with ether, the crystals were recrystallized from methanol to obtain 0.4 g of 5-(3-bromoimidazo[1,2-a]pyridin-6-yl)-1,2-dihydro-6-methyl-2-oxo-3-pyridinecarbonitrile hydrobromide.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:32])([F:31])[F:30])=[N:19][N:18]=2)[CH2:16][CH2:15]1)[C:7](N)=[O:8].C(O)C[OH:35]>O>[Br:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][C:14]1([C:17]2[N:21]([CH3:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]([F:30])([F:31])[F:32])=[N:19][N:18]=2)[CH2:15][CH2:16]1)[C:7]([OH:8])=[O:35]
Reactant: OCCO
Reactant: Cn1c(-c2ccccc2C(F)(F)F)nnc1C1(Oc2ccc(C(N)=O)cc2Br)CC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1c(-c2ccccc2C(F)(F)F)nnc1C1(Oc2ccc(C(=O)O)cc2Br)CC1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
Potassium hydroxide (87 mg) was added to a mixture of 3-bromo-4-[(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}cyclopropyl)oxy]benzamide (250 mg) and ethyleneglycol (6 ml), followed by stirring at 130° C. for 3 hours. The reaction solution was cooled to room temperature, and water was added thereto, followed by washing with ethyl acetate. The aqueous layer was acidified with 1M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting product was solidified with diisopropylether and washed to obtain, as a colorless solid, 3-bromo-4-[(1-{4-methyl-5-[2-(trifluoromethyl)phenyl]-4H-1,2,4-triazol-3-yl}cyclopropyl)oxy]benzoic acid (71 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5]Cl.[Br:13][C:14]1[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16][NH:17][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][N:17]1[CH:18]=[C:14]([Br:13])[C:15]([C:19]([F:22])([F:21])[F:20])=[N:16]1
Reactant: FC(F)(F)c1n[nH]cc1Br
Reactant: Cc1cc(CCl)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(Cn2cc(Br)c(C(F)(F)F)n2)ccc1[N+](=O)[O-]
Yield: 59.6 %

Procedure:
3-Methyl-4-nitrobenzyl chloride (0.77 g), 4-bromo-3-trifluoromethyl-1H-pyrazole (0.90 g) and potassium carbonate (0.57 g) were stirred in DMF (10 ml) at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and washed with water and saturated aqueous solution of sodium chloride. After drying the organic layer with magnesium sulfate, the solvent was distilled off under the reduced pressure and the obtained residue was purified by silica gel column chromatography to obtain 1-(3-methyl-4-nitrobenzyl)-4-bromo-3-trifluoromethyl-1H-pyrazole (0.9 g).
Reaction SMILES: [CH2:1]([C@H:8]([NH:11][C:12]1[N:20]=[C:19](Cl)[N:18]=[C:17]2[C:13]=1[N:14]=[CH:15][N:16]2[C@@H:22]1[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]1[OH:33])[CH2:9][OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][C:42]#[CH:43])([CH3:37])([CH3:36])[CH3:35].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(NCC)C.CN(C=O)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:34]([O:38][C:39](=[O:44])[NH:40][CH2:41][C:42]#[C:43][C:19]1[N:18]=[C:17]2[C:13]([N:14]=[CH:15][N:16]2[C@@H:22]2[CH2:26][C@H:25]([NH:27][C:28](=[O:31])[CH2:29][OH:30])[C@@H:24]([OH:32])[C@H:23]2[OH:33])=[C:12]([NH:11][C@H:8]([CH2:9][OH:10])[CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:20]=1)([CH3:37])([CH3:36])[CH3:35]
Reactant: O=C(CO)N[C@H]1C[C@@H](n2cnc3c(N[C@H](CO)Cc4ccccc4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCC#Cc1nc(N[C@H](CO)Cc2ccccc2)c2ncn([C@@H]3C[C@H](NC(=O)CO)[C@@H](O)[C@H]3O)c2n1
Temperature: 120 °C

Procedure:
N-{(1S,2R,3S,4R)-4-[6-((S)-1-Benzyl-2-hydroxy-ethylamino)-2-chloro-purin-9-yl]-2,3-dihydroxy-cyclopentyl}-2-hydroxy-acetamide (Intermediate GC) (1 eq.), prop-2-ynyl-carbamic acid tert-butyl ester (10 eq.), CuI (0.25 eq.), bis(triphenylphosphine)-palladium(II) chloride (0.25 eq.) and triphenylphosphine (0.5 eq.) are dissolved in diethylamine and DMF. The reaction mixture is heated in a microwave for 1 hour at 120° C. The title compound is obtained by column chromatography.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12](Cl)=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9].[N-:15]=[N+:16]=[N-:17].[Na+]>CC(C)=O.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]([N:15]=[N+:16]=[N-:17])=[O:13])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C=CC(=O)Cl)ccc1C
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(C=CC(=O)N=[N+]=[N-])ccc1C

Procedure:
The 3-(3-methoxy-4-methylphenyl)acryloyl chloride was dissolved in acetone (800 ml). The resulting solution was added slowly (15 min) at 0° C. to a mixture of sodium azide (13 g) in water (100 ml) and acetone (100 ml) while vigorously stirring and cooling with an ice-bath. After addition was complete the reaction mixture was stirred at 0° C. for 90 minutes while vigorously stirring. The reaction mixture was then poured out on ice-water (300ml). After stirring for 15 minutes the mixture was filtered and the solid residue washed with excess water. The remaining solid residue was dissolved in dichloromethane (45 ml). The liberated water was removed with a separatory funnel. The dichloromethane layer was dried with Na2SO4 and filtered to give a dichloromethane solution of 3-(3-methoxy-4-methylphenyl)acryloyl azide for immediate use in the next step.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]=[CH:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2].[F:19][C:20]([F:29])([F:28])[C:21]1[CH:22]=[CH:23][C:24](Cl)=[N:25][CH:26]=1.[H-].[Na+].O>CN(C)C=O>[CH:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N:10]=[C:11]1[N:16]([C:24]2[CH:23]=[CH:22][C:21]([C:20]([F:29])([F:28])[F:19])=[CH:26][N:25]=2)[CH2:15][C:14]([CH3:18])([CH3:17])[CH2:13][S:12]1)([CH3:3])[CH3:2]
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: CC(C)c1ccccc1N=C1N=CC(C)(C)CS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)c1ccccc1N=C1SCC(C)(C)CN1c1ccc(C(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32 %

Procedure:
To a solution of 2-(2-isopropylphenyl)imino-5,5-dimethyl-1,3-thiazine (0.26 g), 5-trifluoromethyl-2-chloropyridine (0.24 g) in N,N-dimethylformamide (3 ml) was added 60% sodium hydride (0.05 g) under ice-cooling. The mixture was stirred at room temperature for 2 h. To a reaction mixture was added water (80 ml), extracted with diethylether (100 ml), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 2-(2-isopropylphenyl)imino-3-(5-trifluoromethyl-2-pyridyl)-5,5-dimethyl-1,3-thiazine (0.13 g, yield: 32%) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:12][CH2:11][CH2:10][C@@:9]2([CH3:16])[C:13]([OH:15])=O)=[CH:4][CH:3]=1.C(N(CC)CC)C.O1CCCC1.[NH2:29][C:30]1[CH:34]=[C:33]([C:35]([CH3:38])([CH3:37])[CH3:36])[O:32][N:31]=1>C(OCC)(=O)C>[C:35]([C:33]1[O:32][N:31]=[C:30]([NH:29][C:13]([C@:9]2([CH3:16])[CH2:10][CH2:11][CH2:12][N:8]2[C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[O:15])[CH:34]=1)([CH3:38])([CH3:37])[CH3:36]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: C[C@@]1(C(=O)O)CCCN1c1ccc(Cl)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(NC(=O)[C@]2(C)CCCN2c2ccc(Cl)cc2)no1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A round bottomed flask is charged with (S)-1-(4-chloro-phenyl)-2-methyl-pyrrolidine-2-carboxylic acid (0.260 g; 1.085 mmol), triethylamine (0.529 mL; 3.798 mmol), and tetrahydrofuran (3 mL). Propylphorsphoric anhydride (50% in ethyl acetate) (0.678 mL; 1.139 mmol) is added dropwise and stirred for 30 minutes. 3-Amino-5-tertbutylisoxazole (0.152 g; 1.085 mmol) is added and the reaction is heated at 80° C. for 40 minutes in a microwave reactor. After this time, the reaction mixture is cooled to room temperature, diluted with ethyl acetate and washed with aqueous sodium bicarbonate solution. The aqueous is back extracted with ethyl acetate and the organics are combined and washed with brine, dried (Na2SO4), filtered and concentrated. Purification by preparative HPLC affords title compound. ESI m/z 362 [M+H]+
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.[CH2:15]1[O:18][CH:16]1[CH3:17].[ClH:19]>CCOCC>[ClH:19].[OH:18][CH:16]([CH3:17])[CH2:15][N:10]1[CH2:11][CH2:12][N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: CC1CO1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CC(O)CN1CCN(c2ccccc2)CC1

Procedure:
N-Phenylpiperazine (130 g.) was dissolved in 200 ml. methanol and the solution cooled to 0°-10° C. Propylene oxide (62 ml) was added over 5 minutes at a temperature under 10° . After the addition the cooling bath was removed. The reaction was allowed to warm to a maximum of 30° . When the reaction temperature stopped rising the solution was refluxed for 11/2 hours and then cooled. A solution of 1 mole HCl gas in 100 ml. methanol was added gradually followed by 300 ml. ether. The solid was filtered, washed with methanol-ether, then with ether to give 170 g., m. 201-5° .
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([CH:18]([C:20]3[NH:29][C:28](=[O:30])[C:27]4[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=4)[N:21]=3)[CH3:19])[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH2:26]([N:29]1[C:28](=[O:30])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]1[CH:18]([N:15]1[CH2:14][CH2:13][N:12]([S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:10])=[O:11])[CH2:17][CH2:16]1)[CH3:19])[CH:27]([CH3:28])[CH3:22]
Reactant: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccccc4c(=O)[nH]3)CC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)N2CCN(C(C)c3nc4ccccc4c(=O)n3CC(C)C)CC2)cc1
Temperature: 90 °C
Yield: 72.2 %

Procedure:
In a flask containing of 2-{1-[4-(4-Methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-quinazolin-4-one (50.0 mg, 0.12 mmol) in DMF was added I-Iodo-2-methylpropane (42.0 mg, 0.24 mmol), K2CO3 (80.0 mg, 0.6 mmol). The mixture was heated at 90° C. for 2 hours with stirring. After cooling down to room temperature, the excess K2CO3 was filtrated; the solution was treated with TFA (0.5 ml) and water (0.1 ml) with stirring at 90° C. for 2 hrs. Purification by HPLC (Gilson-215, 0.035% TFA in acetonitrile and 0.05% water as mobile phase) yielded 3-Isobutyl-2-{1-[4-(4-methoxy-benzenesulfonyl)-piperazin-1-yl]-ethyl}-3H-quinazolin-4-one (Yield 21.0 mg, 37.0%) that was dried under reduced pressure. 1H NMR (400 MHz, DMSO-6): δ 0.98 (d, 3H, J=6.82 Hz), 1.01 (d, 3H, J=6.82 Hz), 1.76 (d, 3H, J=6.82 Hz), 2.08-1.99 (m, 1H), 3.51-3.19 (m, 6H), 3.86-3.75 (m, 2H), 3.93 (s. 3H), 4.16-3.93 (m, 2H), 4.84 (q, 1H, J=12.88, 7.07 Hz), 7.03 (dd, 2H, J=6.82, 2.27 Hz), 7.57 (dt, 1H, J=8.08, 1.01 Hz), 7.67 (dd, 2H, J=6.82, 2.27 Hz), 7.71 (d, 1H, J=8.08, Hz), 7.82 (dt, 1H, 8.59, 1.52 Hz), 8.39 (dd, 1H, J=8.08, 1.52 Hz). MS m/z calc. 484.21, found (ESI); 485.3 (M+1)+. Retention time 2.83 minutes.