Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.FC(F)(F)[C:16](O)=[O:17].C1N2CN3CN(C2)CN1C3.S(=O)(=O)(O)O>C(OCC)(=O)C.CCCCCC>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10]([F:11])([F:12])[F:13])=[CH:5][C:4]=1[CH:16]=[O:17]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(OC(F)(F)F)cc1
Agent: C1N2CN3CN1CN(C2)C3
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(OC(F)(F)F)cc1C=O
Temperature: 60 °C
Reaction time: 24 h

Procedure:
Combine 2-methoxy-5-trifluoromethoxybenzene (1.0 g, 5.2 mmol) and trifluoroacetic acid (200 mL). Add slowly portionwise hexamethylenetetraamine (26 g, 185.7 mmol). Heat at 60° C. After 24 hours, cool to ambient temperature and pour the reaction mixture into a 2 M aqueous solution of sulfuric acid (500 mL). Cool and extract ten times with diethyl ether. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 1/4 ethyl acetate/hexane to give 2-methoxy-5-trifluoromethoxybenzaldehyde.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].C(=O)([O-])[O-].[K+].[K+].[Cl:16][CH:17]1[CH:29]=[C:21]2[CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=32)[C:18]1([C:32]1[N:37]=[C:36](S(C)=O)[N:35]=[C:34]([NH2:41])[N:33]=1)[C:30]#[N:31].O>CN(C)C=O.C(OCC)(=O)C>[Cl:16][CH:17]1[CH:29]=[C:21]2[CH2:22][O:23][CH2:24][C:25]3[CH:26]=[CH:27][CH:28]=[C:19]([C:20]=32)[C:18]1([C:32]1[N:37]=[C:36]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[O:2][CH3:1])[N:35]=[C:34]([NH2:41])[N:33]=1)[C:30]#[N:31]
Reactant: COc1ccccc1S
Reactant: CS(=O)c1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccccc1Sc1nc(N)nc(C2(C#N)c3cccc4c3C(=CC2Cl)COC4)n1
Temperature: 85 °C
Reaction time: 12 h
Yield: 52.7 %

Procedure:
2-Methoxythiophenol (39 mg, 0.278 mmol) was added to a suspension of potassium carbonate (95.7 mg, 0.692 mmol) and 4-(5-chloro-6-cyano-1H,3H benzo[de]isochromen-6-yl)-6-methylsulfinyl-[1,3,5]triazin-2-ylamine (50 mg, 0.139 mmol) in N,N-dimethylformamide (2.5 mL) at room temperature under argon atmosphere. The reaction solution was stirred at 85° C. for 12 hours, and then allowed to return to room temperature. The reaction solution was diluted with ethyl acetate, and then water was added. The organic layer was separated, washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography using methylene chloride-ethyl acetate (mixing ratio=7:1 to 4:1) and dried under reduced pressure to give the title compound (34 mg, 56%).
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C.O=P(Cl)(Cl)Cl.[CH3:21][N:22]([CH:24]=O)[CH3:23]>>[O:6]([C:5](=[CH:21][N:22]([CH3:24])[CH3:23])[CH:4]=[O:3])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C=O
Reactant: CCOC(COc1ccccc1)OCC
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)C=C(C=O)Oc1ccccc1

Procedure:
An appropriate phenol or substituted phenol (i.e., a compound suitable for forming the Y2 substituent of formula I) is reacted with a molar excess of chloroacetaldehyde diethyl acetal (ClCH2CH(OCH2CH3)2) in the presence of potassium hydroxide to form a phenoxyacetaldehyde diethyl acetal. This procedure is taught by Lipinski et al., J. Med. Chem., 23, 1026 (1980) which is incorporated herein by reference. The phenoxyacetaldehyde diethyl acetal is then added to a mixture containing POCl3 and DMF and heated for a period of time sufficient to form 2-(phenoxy)-3-dimethylamino-propenal which is then reacted with malonamide (i.e., CH2 (CONH2)2) in the presence of t-BuOK and DMSO. The desired, 5-(phenoxy-2-hydroxy-3-pyridinecarboxamide may then be collected by conventional techniques. The isolated pyridinecarboxamide is then added to phenylphosphonic dichloride followed by the addition of PCl5. The mixture is heated and the desired 5-(phenoxy)-2-chloro-3-pyridinecarbonitrile is isolated. This product may then be treated with the desired alkylmercaptan in NaOH to form the 5-(phenoxy)-2-(R-thio)- 3-pyridinecarbonitrile which may then be oxidized to the R-sulfinyl or R-sulfonyl form and/or to the 3-pyridinecarboxamide compound if desired.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[C:23]([C:31]([F:34])([F:33])[F:32])[CH:22]=1)[C:13]1[N:18]=[CH:17][C:16]([OH:19])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:35][C:10]=1[CH2:11][N:12]([CH2:20][C:21]1[CH:22]=[C:23]([C:31]([F:33])([F:32])[F:34])[CH:24]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:26]=1)[C:13]1[N:14]=[CH:15][C:16]([O:19][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48])=[CH:17][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2OCc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-[(2-Benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-ol (7.68 g) is dissolved in N,N-dimethylformamide (100 ml) and thereto are added ethyl 4-bromo-butyrate (2.3 ml) and potassium carbonate (2.22 g), and the mixture is stirred at room temperature overnight. To the reaction solution are added ethyl 4-bromo-butyrate (2.3 ml) and potassium carbonate (2.22 g), and the mixture is stirred at room temperature for 3 days. To the reaction solution are added water and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→4:1) to give ethyl 4-{2-[(2-benzyloxy-5-trifluoromethyl-benzyl)-(3,5-bis-trifluoromethyl-benzyl)-amino]-pyrimidin-5-yloxy}-butyrate as crude product (11.3 g). MS (m/z): 716 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][N:17]([C:20]4[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=4)[CH2:16][CH2:15]3)[N:11]=[C:10]([CH2:30]OC)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[BrH:33]>CC(O)=O>[Br:33][CH2:30][C:10]1[N:9]=[C:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH:13]=[C:12]([N:14]2[CH2:19][CH2:18][N:17]([C:20]3[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][N:21]=3)[CH2:16][CH2:15]2)[N:11]=1
Reactant: COCc1nc(-c2cccc(Cl)c2)cc(N2CCN(c3ncccc3C(F)(F)F)CC2)n1
Reactant: Br
Solvent: CC(=O)O
Product: FC(F)(F)c1cccnc1N1CCN(c2cc(-c3cccc(Cl)c3)nc(CBr)n2)CC1

Procedure:
Stir a mixture of 4-(3-chloro-phenyl)-2-methoxymethyl-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine in a solution of 30% HBr in HOAc (25 mL) at 60° C. for 3 hours. Evaporate the mixture, adjust the pH to basic with 1M NaOH, and collect a tan solid. Purify by liquid chromatography (3:1 hexanes/EtOAc) to obtain 2-bromomethyl-4-(3-chloro-phenyl)-6-[4-(3-trifluoromethyl-pyridin-2-yl)-piperazin-1-yl]-pyrimidine as a yellow solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH2:10][OH:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[Cl:19])[C:7]([CH:10]=[O:11])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CO)n1Cc1ccccc1Cl
Solvent: ClCCl
Product: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 17 h
Yield: 77.5 %

Procedure:
A solution of 2-n-butyl-1-(2-chlorophenyl)methyl-5-hydroxymethyl-1H-imidazole (5.4 g, 0.0194 mol) in methylene chloride (25 mL) was added to a suspension of activated maganese dioxide (27 g) in methylene chloride (325 mL). The suspension was stirred at room temperature for 17 hours. The solids were filtered, and the filtrate concentrated and flash chromatographed over silica gel with 6:4 hexane/ethyl acetate to afford 4.16 g (78%) of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24](OC)=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10].[NH2:30][CH2:31][C@@H:32]([OH:34])[CH3:33]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH3:29])[C:9]([C:11]1[S:28][C:14]2[C:15]3[CH:23]=[CH:22][C:21]([C:24]([NH:30][CH2:31][C@@H:32]([OH:34])[CH3:33])=[O:25])=[CH:20][C:16]=3[O:17][CH2:18][CH2:19][C:13]=2[CH:12]=1)=[O:10]
Reactant: C[C@H](O)CN
Reactant: COC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2
Product: C[C@H](O)CNC(=O)c1ccc2c(c1)OCCc1cc(C(=O)N(C)c3ccccc3Cl)sc1-2

Procedure:
Following Example 47 and General Procedure C, methyl 2-((2-chlorophenyl)(methyl)carbamoyl)-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-8-carboxylate 138 and (S)-(+)-1-amino-2-propanol gave 177. MS: (ESI+) 471.0
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:22])[S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[N:11]=1)[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+].Cl>CCOC(C)=O.C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([N:12]([CH3:22])[S:13]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)(=[O:15])=[O:14])[N:11]=1)[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(Cl)nc(N(C)S(=O)(=O)c2cccnc2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CO
Product: CN(c1cc(C(=O)O)cc(Cl)n1)S(=O)(=O)c1cccnc1
Reaction time: 1 h
Yield: 87.9 %

Procedure:
To a solution of methyl 2-chloro-6-[methyl(pyridin-3-ylsulfonyl)amino]isonicotinate (3.12 g, 9.13 mmol) in 1:1 MeOH:THF (60 mL total) was added 1N NaOH solution (27 mL, 27.4 mmol). After 1 h, reaction was concentrated in vacuo. Reaction was diluted with EtOAc (100 mL) and acidified with 1N HCl (50 mL) solution. The aqueous solution was extracted with EtOAc (100 mL×3). The combined organics were washed with brine (100 mL), dried over Mg2SO4, filtered, and concentrated in vacuo to give 2.63 g (88%) of 2-chloro-6-[methyl(pyridin-3-ylsulfonyl)amino]isonicotinic acid as a white solid. LC/MS [M+H]+=328.1.
Reaction SMILES: [CH:1]1[C:6]2[CH2:7][NH:8][C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1.I[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.C(OCC)(=O)C>[CH:1]1[C:6]2[CH2:7][N:8]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[O:11][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)CNc1ccccc1O2
Reactant: CCOC(=O)CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)CCCCCCN1Cc2ccccc2Oc2ccccc21
Temperature: 70 °C
Reaction time: 60 h
Yield: 36.9 %

Procedure:
Title compound 398 (0.304 g, 1.54 mmol) was dissolved in acetonitrile (5.0 mL) and the ethyl 7-iodoheptanoate (0.613 g, 2.16 mmol) and the potassium carbonate (0.639 g, 4.62 mmol) were added. The reaction mixture was stirred at 70° C. for 60 hours. The mixture was cooled down and diluted with ethyl acetate. The organic phase was washed with water and brine, dried over sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography with 10% ethyl acetate in hexanes to afford title compound 399 (201 mg, 37%). MS (m/z): 354.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=[C:4]([CH3:19])[N:3]=1.[NH2:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23]>CS(C)=O>[CH3:19][C:4]1[N:3]=[C:2]([NH:20][C@@H:21]([CH2:24][CH3:25])[CH2:22][OH:23])[C:7]([CH3:8])=[C:6]([O:9][C:10]2[C:15]([CH3:16])=[CH:14][C:13]([CH3:17])=[CH:12][C:11]=2[CH3:18])[N:5]=1
Reactant: Cc1cc(C)c(Oc2nc(C)nc(Cl)c2C)c(C)c1
Reactant: CC[C@H](N)CO
Solvent: CS(C)=O
Product: CC[C@@H](CO)Nc1nc(C)nc(Oc2c(C)cc(C)cc2C)c1C
Temperature: 130 °C

Procedure:
A mixture of 4-chloro-2,5-dimethyl-6-(2,4,6-trimethylphenyoxy)-pyrimidine (30 mg) and 2-(S)-amino-1-butanol (0.5 ml) in 0.5 ml of DMSO was heated at 130° C. for 4 hours. The mixture was quenched with water and extracted with ethyl acetate. The organic layer was separated, dried and concentrated to give a crude material. The crude residue was purified through silica gel column chromatography to give 24 mg of the title compound as white crystals. High MS for (C19H27N3O2) calc. 329.2103, found 329.21249; IR(KBr) 3400, 2940, 1580 cm−1; 1H NMR (CDCl3) δ 6.841 (s, 2H), 5.72 (brs, 1H), 4.45 (d, 1H), 3.82-3.95 (m, 1H), 3.71-3.9 (m, 1H), 3.5-3.6 (m, 1H), 2.27 (s, 3H), 2.21 (s, 3H), 2.08 (s, 3H), 2.02 (s, 6H), 1.4-1.7 (m, 2H), 1.03 (t, 3H) ppm.
Reaction SMILES: [CH3:1][CH:2]([NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([O:22]CC)=[O:21])=[CH:9][C:8]=1[CH3:25])[CH2:3][O:4][CH3:5].Cl>[OH-].[K+]>[CH3:1][CH:2]([NH:6][C:7]1[C:12]([CH2:13][CH3:14])=[CH:11][C:10]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]([OH:22])=[O:21])=[CH:9][C:8]=1[CH3:25])[CH2:3][O:4][CH3:5]
Reactant: CCOC(=O)CCCCOc1cc(C)c(NC(C)COC)c(CC)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: CCc1cc(OCCCCC(=O)O)cc(C)c1NC(C)COC
Temperature: 25 °C
Reaction time: 20 h

Procedure:
19 g (54 mmol) of the N-(1-methyl-2-methoxyethyl)-2-methyl-4-(4'-ethoxycarbonylbutoxy)-6-ethylaniline prepared in stage 4 are mixed at room temperature with 150 ml of 2M potassium hydroxide solution. The resulting emulsion is left to react to completion by stirring at room temperature for about 20 hours. The reaction mixture is then adjusted to pH 7 with hydrochloric acid and extracted twice with diethyl ether. The ether phases are combined, washed several times with saturated brine, dried over sodium sulfate and evaporated. Yield 12.9 g (73.9% of theory)nD23 1.517, viscous oil.
Reaction SMILES: [H-].[Na+].[NH:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:10]3=2)[CH:5]=[CH:4]1.Br[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27]>CN(C=O)C>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12][C:10]3=2)[CH:5]=[CH:4]1)[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc3cc[nH]c3c2CC1
Reactant: CCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1ccc2ccc3c(c21)CCN(C(=O)OC(C)(C)C)CC3
Temperature: 0 °C
Reaction time: 1 h
Yield: 124.7 %

Procedure:
Under N2, a flame-dried, 250-mL, three-necked flask was charged with sodium hydride (0.56 g, 13.9 mmol) and anhydrous DMF (20 mL) and cooled to 0° C. A suspension of tert-butyl 6,7,9,10-tetrahydroazepino[4,5-g]indole-8(1H)-carboxylate (2.66 g, 9.3 mmol) in anhydrous DMF (30 mL) was added and the mixture was stirred at 0° C. for 1 hour and then at room temperature for 30 m. Ethyl bromoacetate (2.06 mL, 18.6 mmol) was added and the mixture was stirred at room temperature for 16 hours. The mixture was partitioned between EtOAc and water and the organic layer was washed with water and the organic layer concentrated to give 4.32 g of a brown oil. Dissolving the oil in CH2Cl2 and filtration of the resulting precipitate removes unreacted starting material. Column chromatography of the filtrate (elution with 20–50% Et2O/hexane) gave 2.11 g (61%) of the title compound as a white solid: mp 111 –115° C.; 1H NMR (300 MHz, CDCl3) δ 7.37 (d, J=8 Hz, 1 H), 6.93–6.90 (m, 2 H), 6.48 (d, J=3 Hz, 1 H), 4.98 (s, 2 H), 4.24 (q, J=7 Hz, 2 H), 3.60–3.57 (m, 4 H) 3.17–3.13 (m, 2 H), 3.04–3.00 (m, 2 H), 1.44 (s, 9 H), 1.29 (t, J=7 Hz, 3 H); MS (EI), m/z 372 (M+); HRMS (FAB) calcd for C20H26N2O4+H 359.1971. found 359.1972. Anal. Calcd for C21H28N2O4: C, 67.72; H, 7.58; N, 7.52. Found: C, 68.06; H, 7.70; N, 7.73.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][N:9]=[CH:10][NH:11][O:12][CH2:13][CH2:14][C@H:15]([NH:22]C(OCC1C=CC=CC=1)=O)[C:16]([N:18]([O:20][CH3:21])[CH3:19])=[O:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)(Cl)Cl>CO.[Pd]>[NH2:22][C@@H:15]([CH2:14][CH2:13][O:12][NH:11][CH:10]=[N:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]([N:18]([O:20][CH3:21])[CH3:19])=[O:17]
Reactant: CON(C)C(=O)[C@H](CCONC=NNC(=O)OC(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CON(C)C(=O)[C@@H](N)CCONC=NNC(=O)OC(C)(C)C
Yield: 92.8 %

Procedure:
A suspension of (2S)-4-({[(tert-butoxy)carbonylamino]iminomethyl}aminooxy)-N-methoxy-N-methyl-2-[(phenylmethoxy)carbonylamino] butanamide (120 mg, 0.27 mmol), as prepared in the preceding step, and 10% Pd/C (18 mg) in methanol (5.0 mL) and chloroform (158 mL, 1.32 mmol) was hydrogenated with a balloon until all starting amine was consumed (in about 6 to 7 h). The mixture was filtered through Celite. The filtrate was concentrated to give the title compound (80 mg, 95% yield) as a colorless oil. Mass spectrum (LCMS, ESI) calcd. for C12H26N5O5 320.4 (M+H); found: 320.0.
Reaction SMILES: ClS([N:5]=[C:6]=[O:7])(=O)=O.[CH2:8]([N:11]([CH3:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]([C:27]2[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=2)=O)=[C:21]([NH:34][CH3:35])[CH:20]=1)[CH:9]=[CH2:10].C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:8]([N:11]([CH3:36])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:20]=[C:21]2[C:22]([C:25]([C:27]3[CH:32]=[CH:31][C:30]([Br:33])=[CH:29][CH:28]=3)=[N:5][C:6](=[O:7])[N:34]2[CH3:35])=[CH:23][CH:24]=1)[CH:9]=[CH2:10]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: C=CCN(C)CCCCCCOc1ccc(C(=O)c2ccc(Br)cc2)c(NC)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CCN(C)CCCCCCOc1ccc2c(-c3ccc(Br)cc3)nc(=O)n(C)c2c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 0.16 ml of chlorosulphonyl isocyanate in 0.8 ml of methylene chloride is added dropwise at 0° C. to a solution of 0.69 g of [4-[6-(allyl-methyl-amino)-hexyloxy]-2-methylamino-phenyl]-(4-bromo-phenyl)-methanone in 4 ml of methylene chloride. After 3 hrs. at room temperature the mixture is again cooled to 0° C. and 0.8 ml of chlorosulphonyl isocyanate in 0.5 ml of methylene chloride is added dropwise. After 1 hr. at room temperature the mixture is worked-up with saturated sodium bicarbonate solution/methylene chloride and purified over silica gel with methylene chloride/methanol/25% aqueous ammonium hydroxide (95:5:0.5). There is obtained 0.26 g of 7-[6-(allyl-methyl-amino)-hexyloxy]-4-(4-bromo-phenyl)-1-methyl-1H-quinazolin-2-one, MS: m/e 484 (M+H+, 1 Br).
Reaction SMILES: [Al].[Li].[O:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([N:12]3[CH2:17][CH2:16][N:15]([C:18]([CH:20]4[CH2:22][CH2:21]4)=O)[CH2:14][CH2:13]3)[C:4]1=2.[OH-].[Na+].[ClH:25]>O1CCCC1.O>[ClH:25].[O:3]1[CH:7]=[CH:6][C:5]2[CH:8]=[CH:9][CH:10]=[C:11]([N:12]3[CH2:13][CH2:14][N:15]([CH2:18][CH:20]4[CH2:21][CH2:22]4)[CH2:16][CH2:17]3)[C:4]1=2
Reactant: O=C(C1CC1)N1CCN(c2cccc3ccoc23)CC1
Agent: Cl
Agent: [Al]
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Product: c1cc(N2CCN(CC3CC3)CC2)c2occc2c1

Procedure:
0.28 g Of lithium aluminum hydide were added in small portions to a solution of 5.8 mmol (1.56 g) of 1-(benzo[b]furan-7-yl)-4-(cyclopropylcarbonyl)piperazine in 30 ml of dry tetrahydrofuran. The mixture was stirred until the formation of gas stopped. After adding of 5 ml of water and 50 ml of 2N sodium hydroxide the reaction mixture was extracted and the organic layers were evaporated. Chromatographic purification on silica gel resulted in 1.0 g of a viscous substance, which was converted into the title compound by treatment with 1 equivalent of HCl. in ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:13])=[C:4]([C:8](=[O:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1.[I-].[Na+].Cl[Si](C)(C)C.O>C(#N)C.CCOC(C)=O>[Cl:1][C:2]1[C:3]([F:13])=[C:4]([CH:8]([OH:12])[CH2:9][CH2:10][I:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCI)c1cccc(Cl)c1F
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: OC(CCI)c1cccc(Cl)c1F
Reaction time: 0.25 h

Procedure:
1-(3-Chloro-2-fluorophenyl)-3-iodopropan-1-one: To a solution of sodium iodide (165 mg, 1.099 mmol) in ACN (1 mL) was added chlorotrimethylsilane (0.139 mL, 1.099 mmol) dropwise. To the mixture was added water (0.016 mL, 0.916 mmol), followed by Intermediate 16B (169 mg, 0.916 mmol) in 1 mL ACN. After 15 min, the reaction mixture was diluted with EtOAc and washed with water followed by 10% Na2S2O3. The organic layer was then washed with brine and dried over MgSO4. The desired product was isolated as a yellow solid (286 mg, 100%). MS (ESI) m/z: 312.9 (M+2+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[C:13]([Si](C)(C)C)[N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C1COCC1>C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([N:10]2[CH:14]=[CH:13][N:12]=[N:11]2)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)c1cn(-c2cccc([N+](=O)[O-])c2)nn1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccc(-n2ccnn2)c1

Procedure:
1-(3-Nitro-phenyl)-4-trimethylsilanyl-1H-[1,2,3]triazole (16.7 g, 64 mmol) tetrabutylammonium fluoride in THF (1M, 100 ml, 100 mmol) were stirred at room temperature for 24 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine. The organic layer was dried with magnesium sulfate, filtered and evaporated. The crude product was purified by chromatography on silica gel (hexane/ethyl acetate 1:1) and the desired product was obtained as a brown solid (9.96 g, 82%), mp 80-83° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[CH2:7]1[O:10][CH:8]1[CH3:9]>CO>[OH:10][CH:8]([CH3:9])[CH2:7][N:3]1[CH:4]=[CH:5][N:6]=[C:2]1[CH3:1]
Reactant: CC1CO1
Reactant: Cc1ncc[nH]1
Solvent: CO
Product: Cc1nccn1CC(C)O

Procedure:
2-Methylimidazole (1 mol) and methanol as a solvent were charged into a stirring-type autoclave, and propylene oxide (1 mol) was reacted therewith at a reaction temperature of 80° C. to 140° C. Thereafter, by purification through distillation, 1-(2-hydroxypropyl)-2-methylimidazole was obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:18][CH:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][N:21]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20]1=[O:36]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:18][CH:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][N:21]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:20]2=[O:36])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Reactant: NC1C(=O)N(Cc2ccccc2)Cc2ccccc21
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)NC1C(=O)N(Cc2ccccc2)Cc2ccccc21

Procedure:
Following General Procedure D above using N-(3,5-difluorophenylacetyl)-L-alanine (Example B) and 4-amino-2-benzyl-1,2,3,4-tetrahydroisoquinoline-3-one (General Procedure 5-D), the title compound was prepared as a solid having a melting point of 144-145° C.