Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13]Cl.O>C1(C)C=CC=CC=1>[CH3:10][N:11]([CH3:15])[CH2:12][CH2:13][CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:8]#[N:9]
Reactant: N#CCc1ccccc1
Reactant: CN(C)CCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CN(C)CCC(C#N)c1ccccc1
Yield: 21.9 %

Procedure:
To a refluxing suspension of 35 g (0.90 mol) of NaNH2 in 750 ml of toluene was added, dropwise with mechanical stirring under N2, 100 g (0.85 mol) of phenylacetonitrile in 100 ml of toluene. The resulting suspension was stirred at reflux for a further 3 hr. Then, 92.5 g (0.86 mol) of 2-dimethylaminoethyl chloride in 50 ml of toluene was added dropwise, and the resulting dark suspension was first heated at reflux for 41/2 hr and then stirred at RT for 16 hr. Water (1.5 liters) was added to the mixture, and the organic layer was separated and extracted with 1N HCl. The acid extract was cooled in ice and then basified with 2.5N NaOH. The product was extracted from the basified solution with Et2O. The ethereal extract was dried (Na2SO4) and concentrated by evaporation. Distillation of the resulting crude oil afforded 35 g (52.5%) of the desired 4-dimethylamino-2-phenylbutanenitrile as a colorless oil; bp 95°-98°/0.1 mm.
Reaction SMILES: Cl.Cl.Cl.[F:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[N:14]([CH2:16][CH2:17][N:18]([CH3:20])[CH3:19])[CH:15]=2)=[CH:7][C:6]=1[C:27]([F:30])([F:29])[F:28].CS(C)=O.Cl[C:36]1[C:37]2[CH2:44][C:43](=[O:45])[N:42]([CH2:46][C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=3[O:55][CH3:56])[C:38]=2[N:39]=[CH:40][N:41]=1>O>[CH3:19][N:18]([CH3:20])[CH2:17][CH2:16][N:14]1[CH:15]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]([F:4])=[C:6]([C:27]([F:28])([F:29])[F:30])[CH:7]=2)[N:12]=[C:13]1[CH:21]1[CH2:26][CH2:25][N:24]([C:36]2[C:37]3[CH2:44][C:43](=[O:45])[N:42]([CH2:46][C:47]4[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][C:48]=4[O:55][CH3:56])[C:38]=3[N:39]=[CH:40][N:41]=2)[CH2:23][CH2:22]1
Reactant: CN(C)CCn1cc(-c2ccc(F)c(C(F)(F)F)c2)nc1C1CCNCC1
Reactant: COc1ccc(CN2C(=O)Cc3c(Cl)ncnc32)c(OC)c1
Agent: Cl
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(CN2C(=O)Cc3c(N4CCC(c5nc(-c6ccc(F)c(C(F)(F)F)c6)cn5CCN(C)C)CC4)ncnc32)c(OC)c1
Temperature: 62.5 °C
Reaction time: 6 h
Yield: 79.75 %

Procedure:
Combine 2-(4-(4-fluoro-3-(trifluoromethyl)phenyl)-2-(piperidin-4-yl)-1H-imidazol-1-yl)-N,N-dimethylethanamine trihydrochloride (98.76 g, 1 eq), DMSO (395 mL) and 4-chloro-7-(2,4-dimethoxybenzyl)-5H-pyrrolo[2,3-d]pyrimidin-6(7H)-one (1.1 eq). Heat the resulting suspension to 60-65° C. then add TEA (6 eq). Stir for 6 hours. Add DMSO (395 mL) and water (150 mL) as a stream and stir the resulting suspension for 1 hour at 45-38° C. Filter the slurry and wash the solids with a mixture of DMSO (1 vol) and water (1 vol) two times. Further wash the solids with water (3×200 mL), methanol (3×200 mL) and heptane (3×200 mL). Dry the cake on the filter to afford the target compound (106.5 g, 79.75% yield) as a tan solid. 1H NMR (400 MHz, DMSO): 8.18 (s, 1H), 7.99-7.95 (m, 2H), 7.71 (s, 1H), 7.43-7.39 (m, 2H), 6.76 (d, J=7.1 Hz, 1H), 6.54 (d, J=2 Hz 1H), 6.38-6.35 (m, 1H), 4.67 (s, 2H), 4.49 (d, J=13.1 Hz, 2H), 4.03 (t, J=6.52, 2H), 3.89 (s, 2H), 3.78 (s, 3H), 3.69 (s, 3H), 3.15-3.09 (m, 3H), 2.57 (t, J=6.6 Hz, 2H), 2.18 (s, 6H), 1.89-1.74 (m, 4H).
Reaction SMILES: Br[CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1.[CH3:15][S-:16].[Na+]>CO.CN(C=O)C>[CH3:15][S:16][CH2:2][CH2:3][CH:4]1[C:9](=[O:10])[NH:8][C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]=2[O:5]1
Reactant: C[S-]
Reactant: O=C1Nc2ccccc2OC1CCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSCCC1Oc2ccccc2NC1=O
Reaction time: 4 h
Yield: 53 %

Procedure:
586 mg of 2-(2-bromoethyl)-1,4-benzoxazin-3-one is mixed in a methanol-DMF mixture with 245 mg of sodium thiomethylate while being stirred. After 4 hours, it is concentrated by evaporation. After column chromatography, the title compound is obtained in a yield of 53%.
Reaction SMILES: [CH3:1][C:2]1[N:13]=[C:12]2[N:4]([C:5](=[O:19])[N:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]3[N:8]=[CH:9][NH:10][C:11]=32)[N:3]=1.[Br:20]N1C(=O)CCC1=O.C1(O)C=CC=CC=1>C1COCC1>[Br:20][C:9]1[NH:10][C:11]2[C:12]3=[N:13][C:2]([CH3:1])=[N:3][N:4]3[C:5](=[O:19])[N:6]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C:7]=2[N:8]=1
Reactant: CCCCCn1c(=O)n2nc(C)nc2c2[nH]cnc21
Reactant: O=C1CCC(=O)N1Br
Solvent: Oc1ccccc1
Solvent: C1CCOC1
Product: CCCCCn1c(=O)n2nc(C)nc2c2[nH]c(Br)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the mixture of 8-methyl-4-pentyl-1,4-dihydro-5H-[1,2,4]triazolo[5,1-i]purin-5-one (20 mg, 0.078 mmol) in THF (5 mL) was added N-Bromosuccinimide (19 mg, 0.11 mmol). After stirring at room temperature for 1 hour, phenol was added to quench the reaction. The reaction mixture was concentrated at reduced pressure, and the residue was purified by preparative LCMS (method B) to yield the desired product as white powder. LCMS calculated for C12H16BrN6O (M+H): 339.1. found: 339.0, 341.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:10](N3C(OC(C)(C)C)=O)[CH2:9]2)=[CH:4][CH:3]=1.C12CC([O:27]1)CNC2>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH:12]3[CH2:14][CH:10]([O:27]3)[CH2:9]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CC1CN(c1ccc(Br)cc1)C2
Reactant: C1NCC2CC1O2
Product: Brc1ccc(N2CC3CC(C2)O3)cc1
Yield: 61 %

Procedure:
Prepared by the procedure, previously described for the synthesis of tert-butyl 3-(4-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate, using instead 6-oxa-3-azabicyclo[3.1.1]heptane as a starting material to afford 570.0 mg (61%) of 3-(4-bromophenyl)-6-oxa-3-azabicyclo[3.1.1]heptane.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(=O)(O)[O-].[Na+].[CH3:15][CH:16]1[CH2:20][CH2:19][CH2:18][NH:17]1>CO>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[N:7]=[C:2]([N:17]2[CH2:18][CH2:19][CH2:20][CH:16]2[CH3:15])[N:3]=1
Reactant: CC1CCCN1
Reactant: Clc1cc(Cl)nc(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC1CCCN1c1nc(Cl)cc(Cl)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
Dissolve 2,4,6-trichloropyrimidine (23.5 g, 0.13 mol) in anhydrous MeOH (220 mL), and add solid sodium bicarbonate (28.3 g, 0.33 mol). Cool to 0° C. and add 2-methylpyrrolidine (12 g, 0.14 mol) dropwise. Let stir at room temperature for 16 h. Filter off the excess sodium bicarbonate, and evaporate under reduced pressure. Purify by SiO2 liquid chromatography, using 50:1 hexanes:EtOAc, increasing to 30:1 hexanes:EtOAc, to provide the title compound as a white solid.
Reaction SMILES: [O:1]([CH2:8][CH:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[OH:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:17](C(C1C=CC=CC=1)CO)[C:18]1C=CC=CC=1>>[OH:17][CH2:18][C:7]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:1][CH2:8][CH:9]([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[OH:10]
Reactant: OC(COc1ccccc1)c1ccccc1
Reactant: OCC(Oc1ccccc1)c1ccccc1
Product: OCc1ccccc1OCC(O)c1ccccc1

Procedure:
2-phenoxy-1-phenylethanol or 2-phenoxy-2-phenyl ethanol
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.Cl[C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13]>>[C:12]([C:11]1[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=1[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[CH:3]=1)#[N:13]
Reactant: Cc1cccc(Br)c1
Reactant: N#Cc1ccccc1Cl
Product: Cc1cccc(-c2ccccc2C#N)c1

Procedure:
In the same manner as in Example 2, 3-bromotoluene and 2-chlorobenzonitrile were reacted at 85° C. for 3 hours, and the reaction solution was analyzed by gas chromatography. The results are shown in Table 1.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]1[C:8](=[O:14])[NH:9][C:10](=[O:13])[NH:11][CH:12]=1.[H-].[Na+].I[CH2:18][CH2:19][CH2:20][CH2:21][O:22][Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].O>CN(C=O)C>[C:26]([Si:23]([CH3:24])([CH3:25])[O:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[C:7]([C:3]2[S:4][CH:5]=[CH:6][C:2]=2[CH3:1])[C:8](=[O:14])[NH:9][C:10]1=[O:13])([CH3:29])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)OCCCCI
Reactant: Cc1ccsc1-c1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccsc1-c1cn(CCCCO[Si](C)(C)C(C)(C)C)c(=O)[nH]c1=O
Temperature: 70 °C
Reaction time: 24 h
Yield: 23.2 %

Procedure:
To a solution of 5-(3-methyl-thiophen-2-yl)-1H-pyrimidine-2,4-dione (Prep 26, 250 mg, 1.2 mmol) in DMF (10 mL), 60% NaH (58 mg, 1.44 mmol) was added portionwise. The reaction was then heated to 70° C. and this temperature was maintained for 1.5 hour. After cooling to room temperature, (4-iodo-butoxy)-tert-butyl-dimethyl-silane (452 mg, 1.44 mmol) was then added dropwise and the reaction was stirred for 24 hours. Water (30 mL) was added and the product was extracted with Et2O. The organic phase was dried (Na2SO4) and evaporated. The crude was purified by flash chromatography with ethyl acetate-petroleum ether (15-85) followed by DCM/MeOH (70:30) to give the title compound as a yellow oil (110 mg, 23% yield).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[N:17]=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][C:20]=2[CH3:21])=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[F:32][C:33]([F:47])([F:46])[C:34]1[CH:39]=[CH:38][C:37]([C:40](=[O:45])[CH2:41][C:42](=O)[CH3:43])=[CH:36][CH:35]=1>>[CH:29]([O:28][C:25]1[CH:24]=[CH:23][C:22]([C:18]2[O:19][C:20]([CH3:21])=[C:16]([CH2:15][CH2:14][O:13][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C@H:2]([NH:1]/[C:42](/[CH3:43])=[CH:41]\[C:40](=[O:45])[C:37]4[CH:38]=[CH:39][C:34]([C:33]([F:32])([F:46])[F:47])=[CH:35][CH:36]=4)[C:3]([OH:5])=[O:4])=[CH:12][CH:11]=3)[N:17]=2)=[CH:27][CH:26]=1)([CH3:31])[CH3:30]
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCOc1ccc(C[C@H](N)C(=O)O)cc1
Reactant: CC(=O)CC(=O)c1ccc(C(F)(F)F)cc1
Product: C/C(=C/C(=O)c1ccc(C(F)(F)F)cc1)N[C@@H](Cc1ccc(OCCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared (as described above for the preparation of Example 2) from 75 mg (0.18 mmol) of Intermediate 51 and 41 mg (0.18 mmol) of Intermediate 24 to yield 48 mg (43% yield) of Example 3: TLC (DCM/MeOH, 4/1): Rf=0.42; 1H NMR (DMSO-d6, 400 MHz) δ11.5 (d, 1H, J=8.9), 7.95 (d, 2H, J=7.2), 7.77 (d, 2H, J=8.7), 7.72 (d, 2H, J=8.2), 7.1 (d, 2H, J=8.4), 6.97 (d, 2H, J=8.9), 6.79 (d, 2H, J=8.5), 5.58 (s, 1H), 4.65 (m, 1H), 4.11 (t, 2H, J=6.5), 4.1 (m, 1H), 3.16 (dd, 1H, J=13.7, 3.6), 2.84 (t, 2H, J=6.5), 2.74 (dd, 1H, 13.7, 9.0), 2.28 (s, 3H), 1.67 (s, 3H), 1.25 (d, 6H, J=6.0); low resolution MS (ES+)m/e 637.1 (MH+);
Reaction SMILES: [F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH2:15])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7].[CH:16](O)=[O:17]>>[F:1][CH2:2][O:3][N:4]=[C:5]([C:10]1[N:14]=[C:13]([NH:15][CH:16]=[O:17])[S:12][N:11]=1)[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(=NOCF)c1nsc(N)n1
Reactant: O=CO
Product: COC(=O)C(=NOCF)c1nsc(NC=O)n1
Yield: 33.1 %

Procedure:
A solution of methyl 2-fluoromethoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl)-acetate (anti-isomer) (1.17 g, 5 mmol) in 99% formic acid (2.34 g, 51 mmol) was reacted at 35° C. for 90 hrs. The reaction mixture was cooled to below 10° C. to separate crystals, which were collected by filtration, washed with methanol and dried to give methyl 2-fluoromethoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (434 mg). The crystals thereof (100 mg) were further obtained from the mother liquor. (Yield: 39.6%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.C[O:21][C:22](=O)[C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29]>>[C:31]([O:30][C:28]([N:24]1[CH2:25][CH2:26][CH2:27][C@H:23]1[C:22]([C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1)=[O:21])=[O:29])([CH3:34])([CH3:33])[CH3:32]
Reactant: FC(F)(F)c1cc(Br)c2cccc(C(F)(F)F)c2n1
Reactant: COC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Yield: 29 %

Procedure:
This was prepared from 4-bromo-2,8-bis(trifluoromethyl)quinoline by the method of example 31 using (S)-N-tert-butoxycarbonylproline methyl ester in place of N-diphenylmethyl-3-azetidinone and the product (1.32 g, 29%) isolated as a cream solid: IR νmax (Nujol)/cm−1 2979, 2883, 1748, 1698, 1401, 1368, 1312, 1160 and 1110; NMR δH (400 CDCl3) (mixture of 2 rotamers) 1.41 and 1.45 (9H, 2×s), 1.79-2.13 (3H, m), 2.11-2.31 (1H, m), 3.32-3.70 (2H, m), 5.09 and 5.16 (1H, 2×dd, J 8.8, 4.3 and J 9.0, 5.5 Hz), 7.78-7.83 (1H, m), 8.03 and 8.04 (1H, 2×s), 8.18-8.29 (1H, m), 8.41 and 8.51 (1H, 2×d, J 8.5 and J 8.5 Hz).
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[N:8]=[C:9]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH2:22][CH2:23][CH3:24])[NH:10][C:11](=[O:14])[C:12]=1[NH2:13].O.[CH:26]([CH:28]=O)=O.O>C(O)CCC>[CH2:22]([O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C:9]1[NH:10][C:11](=[O:14])[C:12]2[C:7](=[N:6][CH:26]=[CH:28][N:13]=2)[N:8]=1)[CH2:23][CH3:24]
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Reactant: O=CC=O
Agent: O=S(=O)(O)O
Solvent: CCCCO
Solvent: O
Product: CCCOc1ccccc1-c1nc2nccnc2c(=O)[nH]1
Yield: 97.5 %

Procedure:
A stirred mixture of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.25 g), glyoxal hydrate (0.4 g), water (62.5 ml) and n-butanol (1 ml) was heated under reflux for one hour to afford a crude product (0.97 g) which was collected and washed with water. The crude product together with another sample (0.12 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.96 g) which was recrystallized from ethanol-water to afford the title compound, 0.8 g, m.p. 177.5-178.5° C.
Reaction SMILES: [C:1]([O:11]N1C(=O)CCC1=O)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[CH3:19][C:20]([NH2:27])([CH2:22][CH2:23][N:24]([CH3:26])[CH3:25])[CH3:21]>C1COCC1>[CH3:25][N:24]([CH3:26])[CH2:23][CH2:22][C:20]([NH:27][C:1](=[O:11])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)([CH3:21])[CH3:19]
Reactant: CN(C)CCC(C)(C)N
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Solvent: C1CCOC1
Product: CN(C)CCC(C)(C)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 89.1 %

Procedure:
Solid CbzOSu (15.6 g, 1 equiv, 48.8 mmol) was added in one portion to a solution of N1,N1-3-trimethylbutane-1,3-diamine (8.15 g, 62.6 mmol) in THF (100 mL). The reaction was left to stir at room temperature for 17 h. The solvent was removed and the residue was taken up in a mixture of ethyl acetate (500 mL) and water (100 mL). The layers were separated and the organic layer washed with saturated sodium bicarbonate (2×100 mL), water (100 mL) and brine (100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated to a pale yellow oil. The crude oil was purified on an ISCO purification system with gradient elution from 1-5% methanol in DCM. The desired fractions were collected and concentrated to give a colorless oil (11.49 g, yield: 69.6%). 1H NMR (CDCl3, 400 MHz): δ 1.35 (s, 6H), 1.67-1.72 (t, J=6.6, 2H), 2.23 (s, 6H), 2.36-2.40 (t, J=7.2, 2H), 6.46 (s, 1H), 7.27-7.36 (m, 5H), LRMS (ESI+) for C15H24N2O2 (264.2); Found: 265 (MH+).
Reaction SMILES: [CH3:1][N:2]1[CH2:22][CH2:21][C:5]2[N:6]([CH2:14][CH2:15][C:16](OCC)=[O:17])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.[CH2:23]([NH2:25])[CH3:24]>>[CH2:23]([NH:25][C:16](=[O:17])[CH2:15][CH2:14][N:6]1[C:7]2[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=2[C:4]2[CH2:3][N:2]([CH3:1])[CH2:22][CH2:21][C:5]1=2)[CH3:24]
Reactant: CCN
Reactant: CCOC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Product: CCNC(=O)CCn1c2c(c3cc(C)ccc31)CN(C)CC2
Temperature: 110 °C

Procedure:
A mixture of ethyl 3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanoate (100 mg, 0.33 mmol) and ethyl amine (40% aq, 2.5 ml) was heated at 100-120° C. for 3-4 h to obtain 19 mg of N-ethyl-3-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)propanamide after purification on neutral alumina chromatography eluting with methanol-dichloromethane gradient.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1.[CH:20]([C:23]1[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=1)([CH3:22])[CH3:21]>N1C=CC=CC=1>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:29][C:26]3[CH:25]=[CH:24][C:23]([CH:20]([CH3:22])[CH3:21])=[CH:28][N:27]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:19])[O:4][N:3]=1
Reactant: Cc1noc(C)c1COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)c1ccc(N)nc1
Solvent: c1ccncc1
Product: Cc1noc(C)c1COc1ccc(S(=O)(=O)Nc2ccc(C(C)C)cn2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.1 %

Procedure:
To a stirred solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)benzene-1-sulfonyl chloride (500 mg, 1.66 mmol) in pyridine (5 mL) at 25° C. was added 5-isopropylpyridin-2-amine (226 mg, 1.66 mmol). The reaction mixture was stirred at 25° C. for 2 hours, then left to stand at this temperature overnight. The crude reaction mixture was then purified by flash silica (Si) chromatography (0-50% ethyl acetate-cyclohexane gradient). The appropriate fractions were combined and concentrated in vacuo to give the title compound (454 mg) as an orange solid. LCMS (2 min, formic) Rt 1.00 min, m/z (ES+) 402 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:7][CH2:6][C:5]2=[C:8]([CH3:15])[N:9]=[C:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[N:4]2[N:3]=1.[CH:16]1[C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=[C:18]([Cl:25])[CH:17]=1>>[CH3:15][C:8]1[N:9]=[C:10]([CH2:11][CH:12]([CH3:13])[CH3:14])[N:4]2[C:5]=1[CH2:6][NH:7][C:2]([NH:1][C:22](=[O:23])[C:21]1[CH:20]=[CH:19][C:18]([Cl:25])=[CH:17][CH:16]=1)=[N:3]2
Reactant: O=C(O)c1ccc(Cl)cc1
Reactant: Cc1nc(CC(C)C)n2c1CNC(N)=N2
Product: Cc1nc(CC(C)C)n2c1CNC(NC(=O)c1ccc(Cl)cc1)=N2

Procedure:
N-(3,4-Dihydro-5-methyl-7-isobutylimidazo[ 5,1-f]-as-triazin-2-yl)-p-chlorobenzamide, m.p. 236°-239° was prepared from 2-amino-3,4-dihydro-5-methyl-7-isobutylimidazo[5,1-f]-as-triazine (Example 1d) and P-chlorobenzoic acid. It was converted into its hydrochloride salt m.p. 240°-247°.
Reaction SMILES: [C:1]([Si:5]([CH3:22])([CH3:21])[O:6][CH2:7][CH2:8][NH:9][CH2:10][CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:23]([O:27][C:28](=[O:47])/[CH:29]=[CH:30]/[C:31]1[CH:35]=[CH:34][N:33]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45]Br)=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]>C(O)C>[C:23]([O:27][C:28](=[O:47])/[CH:29]=[CH:30]/[C:31]1[CH:35]=[CH:34][N:33]([S:36]([C:39]2[CH:44]=[CH:43][C:42]([CH2:45][N:9]([CH2:8][CH2:7][O:6][Si:5]([C:1]([CH3:2])([CH3:4])[CH3:3])([CH3:22])[CH3:21])[CH2:10][CH2:11][C:12]3[C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[NH:14][CH:13]=3)=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:32]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)OCCNCCc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CBr)cc2)c1
Solvent: CCO
Product: CC(C)(C)OC(=O)/C=C/c1ccn(S(=O)(=O)c2ccc(CN(CCO[Si](C)(C)C(C)(C)C)CCc3c[nH]c4ccccc34)cc2)c1
Reaction time: 43 h

Procedure:
[2-(tert-Butyl-dimethyl-silanyloxy)-ethyl]-[2-(1H-Indol-3yl)-ethyl]-amine (compound E2) (830 mg, 2.60 mmol) is dissolved in ethanol (200 ml). (E)-3-[1-(4-bromomethyl-benzenesulfonyl)-1H-pyrrol-3yl]-acrylic acid tert-butyl ester (compound D4) (1.01 g, 2.37 mmol) is added and the mixture is stirred for 43 hours and evaporated. The residue is purified by a silica gel flash chromatograph using petrol ether-ether eluent.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][C:3]=1[CH3:10].Cl.[NH2:12][OH:13]>CO>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[N:12][OH:13])=[CH:4][C:3]=1[CH3:10]
Reactant: Cc1cc(C=O)ccc1Br
Reactant: NO
Agent: Cl
Solvent: CO
Product: Cc1cc(C=NO)ccc1Br
Yield: 64.7 %

Procedure:
A solution of 4-bromo-3-methylbenzaldehyde (D80) (1 g; 0.005 mol) in methanol (20 ml) was treated with hydroxylamine hydrochloride (700 mg, 0.01 mol) and the mixture stood at room temperature over a weekend. The solvent was evaporated under reduced pressure and the residual solid was partitioned between saturated K2CO3 solution and ethyl acetate. The organic phase was dried (Na2SO4), concentrated in vacuo and the residue purified by chromatography on silica gel eluting with 60-80 petroleum-ether and ethyl acetate, to afford the title compound as a pale pink powder (693 mg, 20%).
Reaction SMILES: COP([CH2:7][C:8](=[O:22])[CH:9]([O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:10][CH2:11][CH2:12][CH3:13])(=O)OC.[Si](OC(CCC)CC(=O)/C=[CH:35]/[C@H:36]1[C@H:40]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:39][C@@H:38]([Cl:48])[C@@H:37]1[CH2:49][CH2:50][CH2:51][C:52]1[S:56][C:55]([C:57]([O:59][CH3:60])=[O:58])=[CH:54][CH:53]=1)(C(C)(C)C)(C)C>>[Si:15]([O:14][CH:9]([CH2:10][CH2:11][CH2:12][CH3:13])[C:8](=[O:22])/[CH:7]=[CH:35]/[C@H:36]1[C@H:40]([O:41][CH:42]2[CH2:47][CH2:46][CH2:45][CH2:44][O:43]2)[CH2:39][C@@H:38]([Cl:48])[C@@H:37]1[CH2:49][CH2:50][CH2:51][C:52]1[S:56][C:55]([C:57]([O:59][CH3:60])=[O:58])=[CH:54][CH:53]=1)([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)CP(=O)(OC)OC
Reactant: CCCC(CC(=O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1OC1CCCCO1)O[Si](C)(C)C(C)(C)C
Product: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)/C=C/[C@@H]1[C@@H](CCCc2ccc(C(=O)OC)s2)[C@H](Cl)C[C@H]1OC1CCCCO1
Yield: 86 %

Procedure:
Compound 15 (1.32 g) was prepared in 86% yield by employing dimethyl (3-((tert-butyldimethylsilyl)oxy)-2-oxoheptyl)phosphonate 6 and aldehyde 10 according to the procedures described for compound 11 (see Schemes 1 and 2).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:6](I)=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2].[CH3:18][C:19]([CH3:23])([CH3:22])[C:20]#[CH:21].C(N(CC)CC)C>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.[Cu]I.O1CCOCC1>[C:1]([NH:4][C:5]1[C:6]([C:21]#[C:20][C:19]([CH3:23])([CH3:22])[CH3:18])=[C:7]([OH:16])[C:8](=[CH:13][C:14]=1[Br:15])[C:9]([O:11][CH3:12])=[O:10])(=[O:3])[CH3:2]
Reactant: C#CC(C)(C)C
Reactant: COC(=O)c1cc(Br)c(NC(C)=O)c(I)c1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: COC(=O)c1cc(Br)c(NC(C)=O)c(C#CC(C)(C)C)c1O
Temperature: 30 °C
Reaction time: 2 h

Procedure:
Under nitrogen atmosphere, methyl 4-acetylamino-5-bromo-3-iodosalicylate (I-250) (414 mg, 1.0 mmol), bis(triphenylphosphine)palladium(II) chloride (49 mg, 0.07 mmol), copper(I) iodide (19 mg, 0.1 mmol) and 3,3-dimethyl-1-butyne (0.13 ml, 1.1 mmol) were added to a mixed liquid of triethylamine (4 ml) and dioxane (6 ml), followed by stirring at 30° C. for 2 hours. The reaction liquid was concentrated under reduced pressure, then saturated ammonium chloride water was added to the residue, followed by extraction twice with chloroform, the organic layer was washed with saturated brine, then dried over anhydrous magnesium sulfate. After filtration and concentration under reduced pressure, the resulting residue was subjected to column, chromatography, and the eluate with n-hexane/ethyl acetate (2:1) gave the entitled compound (243 mg, 66.5) as a white solid.