Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:33]=[CH:32][C:25]([O:26][CH2:27][C:28](OC)=[O:29])=[CH:24][CH:23]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1>CO>[CH2:1]([N:8]([CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:29])=[CH:32][CH:33]=1)[CH2:9][CH:10]([OH:19])[CH2:11][O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1
Reactant: C1CCNCC1
Solvent: CO
Product: O=C(COc1ccc(CCN(Cc2ccccc2)CC(O)COc2ccccc2)cc1)N1CCCCC1

Procedure:
A solution of methyl 4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetate (6.0 g) and piperidine (16 ml) in methanol (60 ml) was stored at room temperature for 4 days. The solvent and excess reagent were evaporated under reduced pressure. Toluene was added to the residue and volatile material was evaporated. This procedure was repeated twice more. The crude intermediate (8.0 g) was purified by chromatography on K60 silica (210 g) using a mixture of methanol and dichloromethane of increasing polarity (1% to 2% methanol) to give N-(4-[2-(N-benzyl-N-(2-hydroxy-3-phenoxypropyl)amino)ethyl]phenoxyacetyl)piperidine (6.2 g) as a gum. The purified intermediate (6.2 g) was debenzylated in an analogous manner to that of Example 23, to give a colourless solid (5.1 g) which was recrystallised from propan 2-ol to yield N-(4-[2-(2-hydroxy-3-phenoxypropylamino)ethyl]phenoxyacetyl)piperidine hydrochloride (3.7 g) m.p. 139°-41°; NMR: 1.40-1.70 [m,6H, CH2 (CH2)3CH2 ]; 2.90-3.10[m,2H, CH2C6H4 ]; 3.10-3.35[m,4H, CH2NHCH2 ]; 3.35-3.55[m,4H, CH2NCH2 ]; 4.03[m,2H,PhOCH2 ]; 4.30[m,1H,CHOH]; 4.75[s,2H, OCH2CO]; 6.85-7.05[m,5H, aromatic H]; 7.15-7.38[m,4H, aromatic H]: microanalysis: found: C, 64.2; H, 7.4; N, 5.8; Cl, 7.7%; C24H32N2O4.HC1 requires: C, 64.2; H, 7.4; N, 6.2; Cl 7.9%.
Reaction SMILES: CO[C:3]([CH3:14])(C)[CH:4]([NH:8][C:9]([O:11][CH3:12])=[O:10])[C:5]([OH:7])=[O:6].[NH2:15][CH:16](CCC#N)C(O)=O>>[C:16]([CH2:14][CH2:3][CH:4]([NH:8][C:9]([O:11][CH3:12])=[O:10])[C:5]([OH:7])=[O:6])#[N:15]
Reactant: COC(=O)NC(C(=O)O)C(C)(C)OC
Reactant: N#CCCC(N)C(=O)O
Product: COC(=O)NC(CCC#N)C(=O)O

Procedure:
This compound was prepared using the procedure used to prepare 3-Methoxy-2-methoxycarbonylamino-3-methyl-butyric acid using 2-Amino-4-cyano-butyric acid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][OH:26])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:30]>O1CCCC1>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:17]=[C:16]2[CH2:24][CH2:25][O:26][CH3:30])=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: OCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc2ccccc2n1-c1ccc(OCc2ccccc2)cc1

Procedure:
2-[1-(4-Benzyloxyphenyl)-1H-indol-2-yl]ethanol (0.675 mmol) was dissolved in tetrahydrofuran (5 mL) under N2, and sodium hydride (81 mg, 60% dispersion in mineral oil, 2.03 mmol) was added. The reaction was heated to reflux, at which time iodomethane (0.42 mL, 6.75 mmol) was added. The reaction was stirred at reflux for 3 hours, then carefully quenched with water. The mixture was extracted with ethyl acetate, dried over MgSO4, and concentrated. The residue was purified by SiO2 chromatography (5-20% ethyl acetate/hexanes) to give the desired product, 0.14 g. LC-MS (C24H23NO2 calc'd 357) m/z 358 (M+H).
Reaction SMILES: C([Li])CCC.[CH3:6][C:7]([CH3:21])([CH3:20])[CH2:8][C:9]1[N:10]=[CH:11][N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=1.CN(C)[CH:24]=[O:25]>O1CCCC1>[CH3:6][C:7]([CH3:21])([CH3:20])[CH2:8][C:9]1[N:10]=[C:11]([CH:24]=[O:25])[N:12]([S:14]([N:17]([CH3:19])[CH3:18])(=[O:16])=[O:15])[CH:13]=1
Reactant: CN(C)S(=O)(=O)n1cnc(CC(C)(C)C)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C=O
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-Butyllithium (2.5 M in hexane) (0.83 mL, 2.2 mmol) was added to a −78° C. solution of 4-(2,2-dimethylpropyl)-N,N-dimethyl-1H-imidazole-1-sulfonamide (54 mg, 2.2 mmol) in tetrahydrofuran (5 mL). After stirring at −78° C. for 10 min, N,N-dimethylformamide (0.17 mL, 2.2 mmol) was added and the reaction allowed to warm to ambient temperature. After stirring at ambient temperature for a further 5 min, the reaction mixture was quenched with water and extracted with methylene chloride. The combined aqueous phases were dried (magnesium sulfate) and concentrated. Chromatography over silica eluting with 0-80% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: C[O:2][C:3](=O)[C:4](=[O:30])[N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[CH3:32][C:33]([Mg]Cl)([CH3:36])[CH2:34]C.[Cl-].[NH4+]>C1COCC1>[CH3:32][C:33]([CH3:36])([CH3:34])[C:3](=[O:2])[C:4]([N:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]1[C:11](=[O:29])[CH:12]([CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:30]
Reactant: COC(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Reactant: CCC(C)(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)C(=O)N1CCCCC1C(=O)C(CCc1ccccc1)CCc1ccccc1
Temperature: -78 °C
Reaction time: 3 h
Yield: 77 %

Procedure:
To a solution of 0.38 g (0.90 mmol) of 5 in anhydrous THF (5 mL) was added dropwise at −78° C. a 1.0M solution of 1.9 mL (1.90 mmol) of 1,1-dimethylpropyl magnesium chloride in THF, and the mixture was stirred for 3 hours at −78° C. The solution was poured over saturated ammonium chloride (50 mL) and extracted with EtOAc (2×100 mL). The organic phase was dried (MgSO4) and evaporated to a clear oil which was subject to column chromatography (EtOAc/Hexanes, 1:4) to yield 0.31 g (74.5%) of 6 as a clear oil. TLC Rf=0.8 (EtOAc/Hexanes, 1:4) 1H NMR (CDCl3, 400 MHz): δ 0.94 (t, 3H, J=7.5 Hz); 1.24 (s, 3H); 1.28 (s, 3H); 1.42–2.06 (m, 11H); 2.36 (d, 1H, J=13.0 Hz); 2.61–2.89 (dt, 1H, J=3.2, 12.9 Hz); 3.42 (brt, 1H, J=12.8 Hz); 5.08 (ddd, 1H, J=5.2,7.2,12.3); 5.32 (d, 1H, J=5.4 Hz); 7.16–7.32 (m, 10H); Anal. (C30H39NO3) C, H, N.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([OH:29])=[CH:21][CH:20]=1.O>CN(C=O)C>[CH3:17][O:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]([O:29][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: COc1ccc(O)c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc([N+](=O)[O-])cc2)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of 1-fluoro-4-nitrobenzene (10 mmol) in DMF (20 mL) at rt, solid potassium carbonate (30 mmol) was added followed by addition of 4-methoxy-1-naphthol (10 mmol) to the reaction mixture and heating to 80° C. until the reaction was complete as indicated by TLC or HPLC. After cooling to rt, the reaction mixture was poured into H2O (100 mL), extracted with EtOAc (2×50 mL), washed with H2O (2×50 mL) and brine (50 mL), and dried over sodium sulfate. The solvent was removed in vacuuo to afford the desired 4-(4-methoxynaphthalen-1-yloxy)-1-nitrobenzene. The crude product was used for further transformation .
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>>[S:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:1](=[O:3])[CH2:2][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: CC(=O)c1cccs1
Product: O=C(Cn1ccnc1)c1cccs1

Procedure:
As illustrated in the following diagram, the thienyl compounds of this invention can be prepared by an initial bromination of 2-acetylthiophene 1, and reacting the resulting bromo derivative 2 with imidazole to produce the 1-(2-thienyl)-2-(1H-imidazol-1-yl)ethanone 3. Reaction of compound 3 with N-methylhyroxylamine hydrochloride provides the 1-(2-thienyl)-2-(1H-imidazol-1-yl)-N-methylethanimine N-oxide 4 which is included in the subject matter of our co-pending application Ser. No. 900,856 filed Aug. 27, 1986 entitled "α-Substituted Ketonitrone Derivatives" whose disclosure is incorporated herein by reference. The nitrone compound 4 is then treated with styrene or an appropriate styrene (or allyl phenyl ether or alkyl phenyl thioether) derivative 5 to give a diastereomeric mixture of the desired cis- and trans-5-(phenyl, phenoxymethyl or phenylthiomethyl)-3-(2-thienyl)-3-(1H-imidazol-1-ylmethyl)-2-methylisoxazolidine 6. ##STR3##
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[OH-].[K+].O.NN>C(O)CO>[C:8]1([C:3]2([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:2]2)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)CCC1(c2ccccc2)CCCCC1=O
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: O=C(O)CCC1(c2ccccc2)CCCCC1
Temperature: 130 °C

Procedure:
A mixture of 3-(2-oxo-1-phenylcyclohexyl)propanoic acid (1 g, 4.06 mmol), potassium hydroxide (0.770 g, 13.72 mmol), hydrazine monohydrate (0.348 mL, 6.09 mmol) and ethylene glycol (5 mL) was heated to 130° C. for 1.5 h. The condenser was removed and the mixture was heated to 200° C. for 30 min. The reaction mixture was then heated under reflux with a reflux condenser for additional 1.5 h. The reaction mixture was cooled to room temperature and diluted with 1N HCl to a total reaction volume of 25 mL. The precipitated product was collected by filtration, washed several times with water, and dried in vacuo to obtain 3-(1-phenylcyclohexyl)propanoic acid as a white solid (1C, 923 mg, 93% yield). HPLC: tR=3.7 min, Chromolith SpeedRod 4.6×50 mm, 4 min gradient, Detection Wave length 220 nm, Starting solvent: 10% aq. MeOH—0.2% H3PO4; Final solvent: 90% aq. MeOH—0.2% H3PO4. LC/MS: m/e 215.19 (M+H−H2O)+.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[N:5]([CH2:9][CH2:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[CH:6]=[CH:7][N:8]=1.[H-].[Na+].Cl[CH2:23][C:24]1[N:25]=[C:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=2[F:38])[O:27][CH:28]=1.O>CN(C=O)C>[F:38][C:32]1[CH:33]=[C:34]([F:37])[CH:35]=[CH:36][C:31]=1/[CH:30]=[CH:29]/[C:26]1[O:27][CH:28]=[C:24]([CH2:23][O:19][C:16]2[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][N:5]3[CH:6]=[CH:7][N:8]=[C:4]3[CH2:3][CH2:2][OH:1])=[CH:18][CH:17]=2)[N:25]=1
Reactant: Fc1ccc(/C=C/c2nc(CCl)co2)c(F)c1
Reactant: OCCc1nccn1CCCCc1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: OCCc1nccn1CCCCc1ccc(OCc2coc(/C=C/c3ccc(F)cc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57.4 %

Procedure:
To a solution of 4-[4-[2-(2-hydroxyethyl)-1H-imidazol-1-yl ]butyl]phenol (260 mg) in DMF (4 ml), 60% oily sodium hydride (44 mg) was added under ice cooling. After stirring at room temperature for 30 minutes, (E)-4-chloromethyl-2-[2-(2,4-difluorophenyl) ethenyl]oxazole (281 mg) was added under ice cooling. After stirring at room temperature for 3 days, water was added under ice cooling. The precipitate was collected by filtration and washed with water. The precipitate was dissolved in a mixture of ethyl acetate-THF and dried over magnesium sulfate, after which it was concentrated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to yield the titled compound (275 mg) as pale-yellow crystals.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[NH:4][N:3]=1.CCN(CC)CC.[C:20]([C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1)#[CH:21]>CN(C=O)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>[N:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:20]#[C:21][C:2]2[C:10]3[C:5](=[CH:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=3)[NH:4][N:3]=2)[CH:23]=1
Reactant: O=Cc1ccc2c(I)n[nH]c2c1
Reactant: C#Cc1cccnc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=Cc1ccc2c(C#Cc3cccnc3)n[nH]c2c1
Temperature: 100 °C
Yield: 90.6 %

Procedure:
To a solution of 3-iodo-1H-indazole-6-carbaldehyde (136 mg, 0.5 mmol), Pd(PPh3)2Cl2 (14 mg, 0.02 mmol) and CuI (7.6 mg, 0.04 mmol) in DMF (3 mL) was added Et3N (5 mL), followed by 3-ethynylpyridine (77 mg, 0.75 mmol). The resulting mixture was heated at 100° C. (oil temp.) for 45 min. After removal of Et3N, the residue was loaded directly onto a silical gel column. Flash chromatography (eluent: hex to ethyl acetate), followed by trituration with water and suction filtration gave the title compound (112 mg, 91%) as a light yellow solid. 1H NMR (400 MHz, DMSO-d6) δ 14.16 (s, 1H), 10.16 (s, 1H), 8.90 (s, 1H), 6.64 (d, J=4.0 Hz, 1H), 8.26 (s, 1H), 8.12 (d, J=8.0 Hz, 1H), 8.07 (d, J=8.4 Hz, 1H), 7.74 (d, J=8.4 Hz, 1H), 7.52 (dd, J=8.0 Hz, J=5.2 Hz, 1H); MS ESI 248.0 [M+H]+, calcd for [C15H9N3O+H]+ 248.1.
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:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][CH2:47][CH2:48][CH2:49][OH:50].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44][NH:46][CH2:47][CH2:48][CH2:49][OH:50])=[CH:38][CH:37]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH: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](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: NCCCO
Solvent: NCCO
Product: OCCCNCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(2-hydroxyethoxy)phenyl]ethyl)benzofuran and 3-amino-1-propanol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(3-hydroxypropoxy)phenyl]ethyl)benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: C([S:8][C:9]1(SCC2C=CC=CC=2)[CH2:14][CH2:13][C@H:12]2[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@H:18]([CH2:19][C@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)C1C=CC=CC=1.N>C1COCC1.CCOCC>[OH:28][C@@H:20]1[CH2:21][CH2:22][C@@:23]2([CH3:24])[C@@H:18]([CH2:17][CH2:16][C@@H:15]3[C@@H:25]2[CH2:26][CH2:27][C@@:10]2([CH3:11])[C@H:12]3[CH2:13][CH2:14][C:9]2=[S:8])[CH2:19]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CCC2(SCc1ccccc1)SCc1ccccc1
Agent: N
Solvent: C1CCOC1
Solvent: CCOCC
Product: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=S)CC[C@@H]12
Temperature: -78 °C
Reaction time: 3 h
Yield: 47.9 %

Procedure:
17,17-Bisbenzylthio-5α-androstane-3α-ol (3.76 g, 7.22 mmol) in THF/Et2O (40:100 mL) was added in a dropwise manner to a suspension of Na (3.32 g, 144.4 mmol) in liquid NH3 at −78° C. under N2. The blue suspension was allowed to stir at −78° C. for 3 h. The reaction was then quenched by the addition of saturated NH4Cl (50 mL) and H2O (150 mL). The resulting biphasic mixture was extracted with CH2Cl2 (3×200 mL). The extracts were combined, dried (MgSO4), and concentrated to provide an orange semisolid. The semisolid was purified on silica using medium pressure column chromatography (petroleum ether/acetone, 8:2). The resulting solid was recrystallized from EtOAc/hexane to provide a salmon colored solid (1.06 g, 48%). mp. 172-173° C. 1H-NMR (300 MHz, CDCl3) δ 0.82 (s, 3H), 0.89 (s, 3H), 0.90-1.68 (m, 21H), 1.99-2.03 (m, 2H), 2.59-2.69 (ddd, J=9, 9, 21 Hz, 1H), 2.90-3.00 (dd, J=9, 9 Hz, 1H), 4.06 (m, 1H). Elemental Anal. for C19H30OS Calcd. C, 74.45; H, 9.87; S, 10.46. Found. C, 74.33; H, 10.01; S, 10.47.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][NH2:21])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:24](OC)[N:25]([CH3:27])[CH3:26]>>[C:1]1([S:7]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C:16]([CH2:20][N:21]=[CH:24][N:25]([CH3:27])[CH3:26])=[CH:15][CH:14]=[CH:13]3)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Reactant: COC(OC)N(C)C
Product: CN(C)C=NCc1cccc2cc(S(=O)(=O)c3ccccc3)ccc12
Temperature: 95 °C

Procedure:
C-(6-Benzenesulfonyl-naphthalen-1-yl)-methylamine is added to dimethylformamide dimethyl acetal, and the reaction mixture is heated to 95° C. The reaction mixture is cooled and quenched by addition of water, and the resulting aqueous mixture is extracted with EtOAc. The organic layer is washed with water, brine, dried (MgSO4), and evaporated under reduced pressure to give N′-(6-Benzenesulfonyl-naphthalen-1-ylmethyl)-N,N-dimethyl-formamidine.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]4[CH2:36][CH2:35][CH2:34][CH2:33]4)[CH:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:37])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C(C)(C)C)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([CH:32]4[CH2:33][CH2:34][CH2:35][CH2:36]4)[CH:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:37])[C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1cc(-c2nc(-c3cc(C)c(OCCCC(=O)OC(C)(C)C)c(Cl)c3)no2)cc(C2CCCC2)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2nc(-c3cc(C)c(OCCCC(=O)O)c(Cl)c3)no2)cc(C2CCCC2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 73.5 %

Procedure:
A solution of tert-butyl 4-(2-chloro-4-(5-(2-cyclopentyl-6-methoxypyridin-4-yl)-1,2,4-oxadiazol-3-yl)-6-methylphenoxy)butanoate (90 mg, 170 μmol) in DCM (5 mL) is cooled to 0° C. before TFA (1 mL) is added. The mixture is stirred at 0° C. for 10 min, then at rt for 30 min. The mixture is again cooled to 0° C. before another portion of TFA (1 mL) is added. Stirring is continued at rt for 2 h. The mixture is concentrated and the crude product is purified by prep. HPLC to give the title compound (59 mg) as white solid; LC-MS: tR=1.14 min, [M+H]+=472.29; 1H NMR (CDCl3): δ 8.13 (s br, 1H), 8.02 (d, J=1.4 Hz, 1H), 7.88 (d, J=0.7 Hz, 1H), 7.47 (s, 1H), 7.25 (s, 1H), 4.05 (t, J=5.9 Hz, 2H), 4.00 (s, 3H), 3.17-3.28 (m, 1H), 2.74 (t, J=7.3 Hz, 2H), 2.39 (s, 3H), 2.21 (quint, J=6.5 Hz, 2H), 2.05-2.15 (m, 2H), 1.81-1.95 (m, 4H), 1.68-1.80 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:34][NH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1>>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([N:35]([CH3:34])[CH2:36][CH2:37][N:38]4[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: CNCCN1CCCCC1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(N(C)CCN4CCCCC4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and methyl-(2-piperidin-1-yl-ethyl)-amine. ES-MS m/e (%): 511 (M+H+, 100).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4](S(CC)(=O)=O)[N:3]=1.[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([C:30]2[CH:36]=[CH:35][C:33]([NH2:34])=[CH:32][CH:31]=2)[CH2:26][CH2:25]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:9])=[CH:6][N:5]=[C:4]([NH:34][C:33]2[CH:32]=[CH:31][C:30]([N:27]3[CH2:26][CH2:25][N:24]([CH3:23])[CH2:29][CH2:28]3)=[CH:36][CH:35]=2)[N:3]=1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCS(=O)(=O)c1ncc(C(=O)c2ccccc2OC)c(N)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Solvent: O
Product: COc1ccccc1C(=O)c1cnc(Nc2ccc(N3CCN(C)CC3)cc2)nc1N
Temperature: 100 °C
Yield: 40.9 %

Procedure:
A suspension of (4-amino-2-ethanesulfonylpyrimidin-5-yl)-(2-methoxyphenyl)-methanone (20.0 mg, 0.062 mmol, Example 6), 4-(4-methylpiperazino)aniline (16.6 mg, 0.087 mmol, Appollo Chemical) and p-toluenesulfonic acid hydrate (15 mg, 0.0777 mmol, Aldrich) in isopropanol (2.5 mL) was placed in a sealed tube and heated at 100° C. under microwave conditions for 1 hour. The resulting mixture was concentrated in vacuo and the crude product was purified on silica gel with 95:5 of dichloromethane/methanol to give [4-amino-2-[4-(4-methyl-piperazin-1-yl)-phenylamino]-pyrimidin-5-yl]-(2-methoxyphenyl)-methanone as a light yellow solid (10.6 mg). HRMS, observed: 419.2190; Calcd for (M+H)+: 419.2195.
Reaction SMILES: [F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[CH2:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[CH:12][CH:11]=1)[CH3:6].FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:30]=[CH:29][CH:28]=[CH:27][C:3]=1[CH2:4][N:5]([CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16](=[O:26])[CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:12][CH:11]=1)[CH3:6]
Reactant: CN(CCOc1ccc(C(=O)CCC(=O)OC(C)(C)C)cc1)Cc1ccccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CCOc1ccc(C(=O)CCC(=O)O)cc1)Cc1ccccc1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of tert-Butyl 4-[4-(2-(N-(2-fluorobenzyl)-N-methylamine)ethoxy)phenyl]-4-oxobutyrate (Step E, 2.23 g, 5.3 mol) in dichloromethane (20 ml) was treated with trifluoroacetic acid (10 ml). The reaction mixture was stirred at ambient temperature for 2 hours, and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform: methanol, 92.5:7.5-90:10 spiked with acetic acid) to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9](=[O:12])[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:13](O)[CH2:14][OH:15].CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][C:9]2([O:15][CH2:14][CH2:13][O:12]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC2(CC1)OCCO2
Temperature: 25 °C

Procedure:
The mixture of ethyl-4-oxocyclohexanecarboxylate (10 g, 58.75 mmol), ethylene glycol (4.97 ml, 88.13 mmol) and p-TsOH (cat.) in toluene (80 mL) was refluxed for 16 h in a flask equipped with Dean-Stark adapter. Upon reaction completion, the mixture was cooled to room temperature and solvent was removed under reduced pressure to provide compound D2-1 (9.6 g, crude) as brown oil. The crude product was used in the next step without purification. 1H NMR (CDCl3, 400 MHz): δ 4.15-4.09 (m, 2H), 3.95 (s, 4H), 2.36-2.03 (m, 1H), 1.97-1.91 (m, 2H), 1.85-1.75 (m, 4H), 1.66-1.52 (m, 2H), 1.26-1.27 (m, 3H).