Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[CH3:23][O:24][C:25]1[C:33]2[N:32]=[C:31]3[N:34]([C:38]4[C:39]([CH3:47])=[N:40][C:41]([O:45][CH3:46])=[N:42][C:43]=4[CH3:44])[CH2:35][CH2:36][CH2:37][N:30]3[C:29]=2[C:28]([CH2:48][OH:49])=[CH:27][CH:26]=1>CS(C)=O.C(#N)C.C(=O)([O-])O.[Na+]>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([CH:48]=[O:49])=[C:29]2[C:33]=1[N:32]=[C:31]1[N:34]([C:38]3[C:39]([CH3:47])=[N:40][C:41]([O:45][CH3:46])=[N:42][C:43]=3[CH3:44])[CH2:35][CH2:36][CH2:37][N:30]21
Reactant: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(CO)c23)c(C)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC#N
Product: COc1nc(C)c(N2CCCn3c2nc2c(OC)ccc(C=O)c23)c(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.7 %

Procedure:
Dess-Martin reagent (1.31 g, 3.09 mmol) was added to a stirred solution of [9-methoxy-1-(2-methoxy-4,6-dimethylpyrimidin-5-yl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]methanol (761 mg, 2.06 mmol) in dimethyl sulfoxide (0.50 mL) and acetonitrile (8.2 mL) at 0 ° C., and the mixture was stirred at room temperature for 3 hr. The mixture was diluted with saturated aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-5% methanol/ethyl acetate gradient mixture. The eluate was concentrated in vacuo to give the title compound as a brown solid (467 mg).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[Cl:1][CH2:2][C:3]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CCl)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1.7 ml of chloroacetyl chloride was dropwise added to a solution of 3.0 g of aniline hydrochloride and 7 ml of triethylamine in 30 ml of dichloromethane. The mixture was stirred at room temperature for 3 hours, then washed with water and a saturated aqueous sodium hydrogencarbonate solution in this order, and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was crystallized from ethyl acetate-n-hexane to obtain 2.45 g of N-(2-chloroacetyl)aniline as a light brown solid. A suspension of 2.45 g of the N-(2-chloroacetyl)-aniline, 2.8 g of 4-methoxymethoxypiperidine, 2.45 g of sodium iodide and 2.3 ml of triethylamine dissolved in 30 ml of acetonitrile was refluxed for 1.5 hours. The reaction mixture was diluted with ethyl acetate. The dilution was washed with water and dried with magnesium sulfate. The solvent was removed by distillation. The resulting residue was purified by a silica gel column chromatography (eluant: ethyl acetate: n-hexane=1:1) to obtain 3.64 g of 1-(anilinocarbonylmethyl)-4-methoxymethoxypiperidine as a light yellow oil.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:8][CH2:7][CH:6]1[C:17]([OH:19])=[O:18])=[O:4].[NH2:20][CH:21]([CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:22]([OH:24])=[O:23].Cl>[OH-].[Na+]>[C:22]([CH:21]([NH:20][CH2:2][C:3]([N:5]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[OH:16])[CH2:8][CH2:7][CH:6]1[C:17]([OH:19])=[O:18])=[O:4])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([OH:24])=[O:23]
Reactant: NC(CCc1ccccc1)C(=O)O
Reactant: O=C(O)C1CCC(c2ccccc2O)N1C(=O)CCl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)C(CCc1ccccc1)NCC(=O)N1C(C(=O)O)CCC1c1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
1-(Chloroacetyl)-5-(2-hydroxyphenyl)-2-pyrrolidinecarboxylic acid [mp 204°-206° C.(dec.), [α]D24 +24.5° (c=1.2, MeOH)] (2.8 g) was added to a stirred solution of 2-amino-4-phenylbutanoic acid (1.8 g) in N sodium hydroxide (40 ml). The reaction mixture was stirred overnight at room temperature. The solution was adjusted to pH 1.5 by 20% hydrochloric acid, and washed with ethyl acetate. The aqueous layer was adjusted to pH 3.0, and the separated solid was collected by filtration to give 1.0 g (24%) of the titled compound. IR (nujol, cm-1): 3425, 1735, 1625, 1588.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:12][N:13]3C(=O)C4C(=CC=CC=4)C3=O)=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>Cl>[C:1]1([C:7]2[O:8][C:9]([CH2:12][NH2:13])=[CH:10][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(-c2ccccc2)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCc1cnc(-c2ccccc2)o1
Yield: 46.5 %

Procedure:
Heat a suspension of 2-(2-phenyloxazol-5-ylmethyl)isoindole-1,3-dione (1.5 g, 4.94 mmol) in 6N HCl (75 mL) at reflux for 5 days. Cool, basify with 3 N sodium hydroxide, and extract with methylene chloride (2×150 mL). Dry the organic phase (Na2SO4), filter, and concentrate to afford 400 mg of the title compound as a yellow oil. MS: m/e=175 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:12][CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=3)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.[H-].[CH2:21]([O:23][C:24](=[O:30])[CH2:25][CH:26]([CH3:29])[CH2:27]Br)[CH3:22]>CN(C=O)C>[CH3:27][CH:26]([CH2:29][O:19][C:16]1[CH:17]=[CH:18][C:13]([N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=3)[CH2:12][CH2:11]2)=[CH:14][CH:15]=1)[CH2:25][C:24]([O:23][CH2:21][CH3:22])=[O:30]
Reactant: Oc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: CCOC(=O)CC(C)CBr
Agent: [H-]
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)COc1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (1.02 g) in dry DMF (10 ml) was added solution hydride (60% dispersion in mineral oil, 0.16 g) and the mixture stirred for 1 hour at room temperature. To the resulting solution was added ethyl-4-bromo-3-methylbutyrate and the mixture stirred for 16 hours. Solvent was evaporated and the residue partitioned between water and dichloromethane. Insoluble material was removed by centrifugation. The organic layer was filtered through phase separating paper (Whatman IPS) and the residue was purified by flash chromatography on silica gel by elution with methanol/dichloromethane/concentrated ammonia (50/950/5) to give ethyl 3-methyl-4-[4-[4-(4-pyridyl)piperazin-1-yl]phenoxy]butyrate (0.27 g) which was hydrolysed in methanol (3 ml) and aqueous sodium hydroxide (1N, 2 ml) for 2 hours at room temperature. The solution was evaporated and the residue purified by reverse phase h.p.l.c (water/acetonitrile/0.1% TFA gradient) to give a glass which crystallised on trituration with ether to give the title compound (0.08 g): m.p. 169°-171° C.; NMR (d6DMSO) δ 13.45(1H,br), 12.07 (1H,br), 8.27(2H,d), 7.28(2H,d), 6.9(4H,m), 3.80(6H,m), 3.16(4H,t), 2.45(1H,m), 2.37(1H,m), 2.12(1H,m), 1.0(3H,d); m/e 356(M+H)+ ; calculated for C22 H25N3O4F3. 0.5 H2O: C, 55.2; H, 5.6; N, 8.9 Found: C, 55.3; H, 5.6; N, 8.7%.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][C:21]([F:24])([F:23])[F:22])[N:3]=1.CC[N:27]([CH:31]([CH3:33])[CH3:32])C(C)C>CN(C=O)C.CCOC(C)=O>[NH2:27][C@H:31]1[CH2:32][CH2:8][C@H:7]([CH2:2][NH:3][C:2]2[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][C:21]([F:24])([F:23])[F:22])[N:3]=2)[CH2:6][CH2:33]1
Reactant: CCN(C(C)C)C(C)C
Reactant: FC(F)(F)Oc1ccccc1CNc1ncc(C(F)(F)F)c(Cl)n1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: N[C@H]1CC[C@H](CNc2nc(NCc3ccccc3OC(F)(F)F)ncc2C(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h
Yield: 109.9 %

Procedure:
To a solution of the above (4-chloro-5-trifluoromethyl-pyrimidin-2-yl)-(2-trifluoromethoxy-benzyl)-amine (80 mg, 0.22 mmol) in DMF (2 mL) was added the Boc-protected cyclohexyl amine (74 mg, 0.33 mmol) followed by DIPEA (37 μL, 0.22 mmol). The reaction mixture was stirred at 70° C. for 3 h. When the reaction was complete, the reaction mixture was diluted with EtOAc and washed with water (×4). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel preparative TLC using 95:5 CH2Cl2:MeOH as an eluent. The resulting residue was then re-dissolved in CH2Cl2 (10 mL) and TFA (1 mL) was added. The reaction mixture was stirred at room temperature for 2 h and treated with saturated NaHCO3. The product was extracted with CH2Cl2 and dried over anhydrous Na2SO4. Silica gel preparative TLC using CH2Cl2:MeOH:NH4OH 10:1:0.2 as an eluent afforded 56 mg (56%) of the title compound as a white solid, m/z 462.4 [M−1]+.
Reaction SMILES: [C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6](O)=[O:7])(=[O:3])[CH3:2].[O:27]=[C:28]1[O:32][N:31]=[C:30]([C:33]2[CH:38]=[CH:37][C:36]([NH-:39])=[CH:35][CH:34]=2)[NH:29]1.CCN=C=NCCCN(C)C>CC#N>[C:1]([O:4][C@H:5]([C@H:9]1[O:14][CH2:13][CH2:12][N:11]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[CH2:20][N:19]([CH3:24])[C:18]3=[O:25])[C:10]1=[O:26])[C:6](=[O:7])[NH:39][C:36]1[CH:35]=[CH:34][C:33]([C:30]2[NH:29][C:28](=[O:27])[O:32][N:31]=2)=[CH:38][CH:37]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H](C(=O)O)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Reactant: [NH-]c1ccc(-c2noc(=O)[nH]2)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: CC#N
Product: CC(=O)O[C@@H](C(=O)Nc1ccc(-c2noc(=O)[nH]2)cc1)[C@H]1OCCN(c2ccc3c(c2)C(=O)N(C)C3)C1=O
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.1 %

Procedure:
To a solution of compound 70-4 (40 mg) in CH3CN (1 mL) at 0° C. was added 4-(5-oxo-4,5-dihydro-[1,2,4]oxadiazol-3-yl)-phenyl amide (21 mg) followed by EDCI (25 mg). The reaction mixture was warmed to rt and stirred for 72 h. The mixture was concentrated under reduced pressure and placed under high vacuum. The crude material was purified by reverse phase HPLC using a C18 column and a gradient of (89.95:9.95:0.1 H2O:MeCN:HCO2H to 9.95:89.95:0.1 H2O:MeCN:HCO2H) to afford compound 70-5 (30 mg) as a white solid. LC-MS: M+H=522.
Reaction SMILES: [C:1]([C:5]([CH3:7])=[O:6])([CH3:4])([CH3:3])[CH3:2].[NH2-].[Na+].[C:10](OCC)(=[O:12])[CH3:11]>>[CH3:2][C:1]([CH3:4])([CH3:3])[C:5](=[O:6])[CH2:7][C:10](=[O:12])[CH3:11]
Reactant: CCOC(C)=O
Reactant: CC(=O)C(C)(C)C
Agent: [NH2-]
Agent: [Na+]
Product: CC(=O)CC(=O)C(C)(C)C

Procedure:
Methyl t-butyl ketone was condensed with ethyl acetate in the presence of sodamide to yield 5,5-dimethyl-2,4-hexanedione. This material was reacted with phosphorus pentachloride to yield the divinyl chloride, which was in turn dehydrohalogenated with sodamide to give 5,5-dimethyl-1,3-hexadiyne. This alkyne was then dimerized using the procedure of Hay (see e.g. Hay, A. S., J. Org. Chem. 27, 3320 (1962) ), using copper(I) chloride-tetramethylethylenediamine (TMEDA) complex as the catalyst, to yield the desired t-butyl endcapped tetrayne. The tetrayne melted at 99° C. and decomposed between 130° C. and 140° C. It is also stable to moderate pressures; exposure to 40 kbar pressure for one hour caused no changes in the IR spectrum, and at 60 kbar only about 2% graphitization was seen.
Reaction SMILES: O[CH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][CH2:5][N:4]1[CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=1.C(N(CC)CC)C.CS([Cl:31])(=O)=O.C(=O)([O-])O.[Na+]>ClCCl>[Cl:31][C@@H:6]1[CH2:7][CH2:8][CH2:2][CH2:3][N:4]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=2)[CH2:5]1
Reactant: CN(C)c1ccc(CCN2CCCC[C@@H]2CO)cc1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(C)c1ccc(CCN2CCCC[C@@H](Cl)C2)cc1
Reaction time: 14 h

Procedure:
(R)-2-Hydroxymethyl-1-(4-dimethylaminophenethyl)piperidine (452 mg, 1.72 mmol) was dissolved in 10 ml of dichloromethane. Triethylamine (226 mg, 2.26 mmol) and methanesulfonyl chloride (260 mg, 2.26 mmol) were added to the obtained solution under stirring under cooling on ice. They were stirred under cooling on ice for 1 hour and then at room temperature for 14 hours. The reaction liquid was distributed in dichloromethane and saturated aqueous sodium hydrogencarbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to obtain (R)-3-chloro-1-(4-dimethylaminophenethyl) homo-piperidine in the form of a light yellow oil (470 mg, 97%).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C([O-])([O-])=O.[Na+].[Na+]>CC(O)C.O.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>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Nc1ccc(Cl)nn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: Nc1ccc(-c2ccccc2F)nn1
Temperature: 80 °C
Yield: 87.4 %

Procedure:
To a mixture of 6-chloropyridazin-3-amine (3.00 g, 23.1 mmol), 4-fluorophenylboronic acid (34.7 mmol), Na2CO3 (69.3 mmol) in 2-propanol (150 mL) and water (50 mL) that has been degassed with N2 (5 minutes) is added PdCl2(PPh3)2(1.15 mmol). The mixture is heated at 80° C. for 12 hours, concentrated under reduced pressure, added sat. aqueous NaHCO3 (100 mL) and extracted with EtOAc (3×100 mL). Organic layer is collected, dried over Na2SO4, filtered and concentrated to dryness. The crude product is purified via chromatography using a gradient of CH2Cl2 to 70% CH2Cl2:EtOAc:methanol (1:1:0.1) to afford the title compound (3.82 g, 87%) as a white solid: Rf 0.37 (1:1:0.1 CH2Cl2:EtOAc:methanol); LCMS (m/z)=190.2 [M+H]+, tR=0.44 min.
Reaction SMILES: [N+:1]([C:4]1[C:10]([CH2:11][P:12]([O:17]CC)([O:14]CC)=[O:13])=[CH:9][CH:8]=[CH:7][C:5]=1[NH2:6])([O-])=O.Cl.[CH2:21]([OH:23])[CH3:22]>[Pd]>[OH:23][CH2:21][C:22]1[NH:1][C:4]2[C:10]([CH2:11][P:12]([OH:14])([OH:17])=[O:13])=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1
Reactant: CCOP(=O)(Cc1cccc(N)c1[N+](=O)[O-])OCC
Reactant: CCO
Agent: [Pd]
Agent: Cl
Product: O=P(O)(O)Cc1cccc2nc(CO)[nH]c12

Procedure:
2-Nitro-3-(diethylphosphonomethyl)aniline (3.2 gm) in ethanol (60 mL) was combined with 10% Pd on carbon and concentrated HCl (ca. 1 mL) and hydrogenated at 55 psi for 3 hours. Additional ethanol was added and the mixture filtered through diatomaceous earth and concentrated to a solid. The solid was combined with 6N HCl and heated to reflux for 16 hours. The reaction was concentrated to a reddish solid combined with water and reconcentrated. The solid was then combined with glyoxalic acid (1.4 gm) and water (30 mL) and heated to reflux for 16 hours. The reaction mixture was concentrated to a solid. H NMR data: D2O (HDO at 4.81 ppm) 3.26 (d,2H), 4.92 (s, 2H), 7.26 (m, 3H).
Reaction SMILES: C([O:8][CH2:9][CH2:10][S:11][C:12]([F:30])([F:29])[C:13]([C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=1[F:28])([OH:20])[CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)C1C=CC=CC=1.[H][H].O>C(O)C.[Pd]>[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[C:13]([OH:20])([CH2:14][N:15]1[CH:19]=[N:18][CH:17]=[N:16]1)[C:12]([F:30])([F:29])[S:11][CH2:10][CH2:9][OH:8]
Reactant: [H][H]
Reactant: OC(Cn1cncn1)(c1ccc(F)cc1F)C(F)(F)SCCOCc1ccccc1
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: OCCSC(F)(F)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Yield: 59.5 %

Procedure:
To a solution of 1-(2-benzyloxyethyl)thio-2-(2,4-difluorophenyl)-1,1-difluoro-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (1.0 g, 2.2 mmol) in ethanol (20 ml), palladium black (20 mg, catalytic) was added, followed by stirring at room temperature and 1 atmospheric pressure in a hydrogen gas for 12 hours. After the completion of the reaction, an insoluble matter was filtered off. The solvent was then distilled off under reduced pressure. To the residue so obtained, water was added, followed by extraction with chloroform. The chloroform solution was washed with water, dried over magnesium sulfate and then distilled off under reduced pressure. To the residue, isopropyl ether was added for crystallization, whereby 2-(2,4-difluorphenyl)-1,1-difluoro-1-(2-hydroxyethyl)thio-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.46 g, yield: 55.0%) was obtained as colorless crystals.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[CH3:12][NH:13][C:14]([N:16]1[CH:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=2[S:34][CH3:35])[C:24]2[C:23](=[O:36])[CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:46])([F:45])[F:44])[CH:38]=2)[C:17]1=[O:47])=[O:15]>ClCCl>[CH3:12][NH:13][C:14]([N:16]1[CH:25]([C:26]2[CH:31]=[CH:30][C:29]([C:32]#[N:33])=[CH:28][C:27]=2[S:34]([CH3:35])=[O:6])[C:24]2[C:23](=[O:36])[CH2:22][CH2:21][CH2:20][C:19]=2[N:18]([C:37]2[CH:42]=[CH:41][CH:40]=[C:39]([C:43]([F:45])([F:44])[F:46])[CH:38]=2)[C:17]1=[O:47])=[O:15]
Reactant: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1SC
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CNC(=O)N1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CCC2)C1c1ccc(C#N)cc1S(C)=O
Reaction time: 1.5 h

Procedure:
3-Chloroperoxybenzoic acid (77%, 24 mg, 0.107 mmol) is added at room temperature to a solution of 4-(4-cyano-2-methylsulfanyl-phenyl)-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-1,4,5,6,7,8-hexahydro-2H-quinazoline-3-carboxylic acid methylamide (INTERMEDIATE 8, 63 mg, 0.122 mmol) in dichloromethane (2 mL), and the mixture is stirred for 90 min. The reaction mixture is concentrated under reduced pressure and purified by reversed phase HPLC (X-Bridge C18, gradient of acetonitrile in water, 0.1% NH4OH) yielding the two diastereomers of the title compound.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]2[CH:8]=[C:9]([Cl:12])[CH:10]=[CH:11][C:6]=2[S:5][CH:4]=1.[N:13]1([C:19]2[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=2[C:21]#[N:22])[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[Cl:12][C:9]1[CH:10]=[CH:11][C:6]2[S:5][CH:4]=[C:3]([CH2:2][N:16]3[CH2:15][CH2:14][N:13]([C:19]4[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=4[C:21]#[N:22])[CH2:18][CH2:17]3)[C:7]=2[CH:8]=1
Reactant: N#Cc1ccccc1N1CCNCC1
Reactant: Clc1ccc2scc(CBr)c2c1
Product: N#Cc1ccccc1N1CCN(Cc2csc3ccc(Cl)cc23)CC1

Procedure:
3-(Bromomethyl)-5-chloro-1-benzothiophene and 2-(1-piperazinyl)benzonitrile were processed as described in Example 2 to provide the title compound. 1H NMR (d6-DMSO, 300 MHz) δ 3.2–3.65 (m, 10H), 7.21 (m, 1H), 7.28 (d, 1H, J=7.8 Hz), 7.51 (dd, 1H, J=7.8,1.5 Hz), 7.66 (m, 1H), 7.79 (dd, 1H, J=7.5,1.5 Hz), 8.14 (d, 1H, J=7.8 Hz), 8.25 (s, 1H), 8.40 (s, 1H). MS (DCI/NH3) m/z 368.1 (M+H)+.
Reaction SMILES: [CH2:1]([NH:4][S:5]([C:8]1[C:13]([Cl:14])=[CH:12][CH:11]=[C:10]([NH2:15])[C:9]=1[OH:16])(=[O:7])=[O:6])[CH:2]=[CH2:3].[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([NH:4][S:5]([C:8]1[C:9]([OH:16])=[C:10]([NH:15][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])[CH:11]=[CH:12][C:13]=1[Cl:14])(=[O:7])=[O:6])[CH:2]=[CH2:3]
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: C=CCNS(=O)(=O)c1c(Cl)ccc(N)c1O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCNS(=O)(=O)c1c(Cl)ccc(NC(=O)Nc2cccc(Cl)c2Cl)c1O
Yield: 29.1 %

Procedure:
A solution of crude N-allyl-3-amino-6-chloro-2-hydroxybenzenesulfonamide (20 mg) and 2,3-dichlorophenylisocyanate (12 μL, 0.09 mmol) in 1 mL of N,N-dimethylformamide was stirred at room temperature for 20 hours. The mixture was diluted with ethyl acetate and washed with water to give the crude material. Purification by column chromatography on silica gel, eluting with ethyl acetate/hexane (30/70, v/v), gave the desired product (10 mg, 29% for two steps). EI-MS (m/z) 450.2, 452.2, 454.1 (M−).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][C:20]([N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[C:21]([F:24])[CH:22]=3)[N:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)=[O:7])(C)(C)C.Cl.[N+](C1C=CC(OC(=O)[NH:43][C:44]2[CH:49]=[CH:48][C:47]([N:50]3[CH2:54][CH2:53][CH2:52][CH2:51]3)=[CH:46][CH:45]=2)=CC=1)([O-])=O>>[N:50]1([C:47]2[CH:48]=[CH:49][C:44]([NH:43][C:6]([N:8]3[CH2:9][CH2:10][CH:11]([C:14]4[C:23]5[C:18](=[CH:19][C:20]([N:25]6[CH2:30][CH2:29][O:28][CH2:27][CH2:26]6)=[C:21]([F:24])[CH:22]=5)[N:17]=[CH:16][N:15]=4)[CH2:12][CH2:13]3)=[O:7])=[CH:45][CH:46]=2)[CH2:51][CH2:52][CH2:53][CH2:54]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1
Reactant: O=C(Nc1ccc(N2CCCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Product: O=C(Nc1ccc(N2CCCC2)cc1)N1CCC(c2ncnc3cc(N4CCOCC4)c(F)cc23)CC1

Procedure:
The title compound was prepared from 4-(6-Fluoro-7-morpholin-4-yl-quinazolin-4-yl)-piperidine-1-carboxylic acid tert-butyl ester, prepared as described in Example 210a, and (4-pyrrolidin-1-yl-phenyl)-carbamic acid 4-nitro-phenyl ester hydrochloride, prepared as described in Example 74a, using essentially the protocol given for Example 170c. 1H-NMR (400 MHz, CDCl3) δ 9.12 (s, 1H), 7.70 (d, 1H), 7.38 (d, 1H), 7.18 (m, 2H), 6.52 (m, 2H), 6.24 (s, 1H), 4.26 (m, 2H), 3.93 (m, 4H), 3.51 (tt, 1H), 3.31 (m, 4H), 3.26 (m, 4H), 3.11 (td, 2H), 2.17-2.05 (m, 2H), 2.03-1.90 (m, 6H). LC/MS (ESI): calcd mass 504.3, found 505.3.
Reaction SMILES: [CH:1]1([O:7][CH2:8][CH2:9][CH2:10][OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>ClCCl.CCOCC>[CH:1]1([O:7][CH2:8][CH2:9][CH:10]=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OCCCOC1CCCCC1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=CCCOC1CCCCC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 75.5 %

Procedure:
The obtained 3-cyclohexyloxypropan-1-ol (11.5 g, 72.9 mmol) was dissolved in dichloromethane (240 ml), and then molecular sieve 4 Å (58 g) and pyridinium chlorochromate (23.8 g, 0.11 mol) were added thereto in the ice bath followed by stirring under a nitrogen atmosphere for 1 hour and 40 minutes. The reaction solution was diluted with ether, and then the solution was filtered through Celite. The Celite was washed with diethyl ether, and this filtrate was added to the previous filtrate. The total filtrate was evaporated in vacuo, and the residue was purified roughly by chromatography on a silica gel column (elution solvent; n-hexane:ethyl acetate=20:1-10:1) to give a crude 3-cyclohexyloxypropionaldehyde (8.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:15](#[N:18])[CH:16]=[CH2:17]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([CH2:17][CH2:16][C:15]#[N:18])[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: C=CC#N
Reactant: COc1ccc(N2CCNCC2)cc1
Product: COc1ccc(N2CCN(CCC#N)CC2)cc1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
4-Methoxyphenypiperazine (0.92 g, 4.68 mmol) and acrylonitrile (0.31 mL, 4.68 mmol) were mixed in a 10 mL reaction tube and stirred for 16 hours. The product was purified by silica gel flash chromatography (EtOAc/hexanes=1:8, Rf=0.3) to give 0.8 g (74%) white solid. 1H NMR (400 MHz, CDCl3) δ 6.98-6.90 (m, 2H), 6.90-6.82 (m, 2H), 3.79 (s, 3H), 3.17-3.07 (m, 4H), 2.78 (t, J=7.0 Hz, 2H), 2.74-2.64 (m, 4H), 2.57 (t, J=7.0 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 154.0, 145.5, 118.8, 118.4, 114.5, 55.6, 53.4, 52.8, 50.6, 15.9. Upadhayaya, et al. (2004) Bioorg. Med. Chem. 12:2225-2238.