Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2](C=O)C.[Br:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([N:17]2[CH2:28][CH2:27][N:26]3[C:19](=[CH:20][C:21]4[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]=43)[C:18]2=[O:31])[C:8]=1[C:9]([OH:11])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN.Cl>CN(C1C=CN=CC=1)C.C(N(CC)CC)C>[Br:6][C:7]1[CH:15]=[C:14]([F:16])[CH:13]=[C:12]([N:17]2[CH2:28][CH2:27][N:26]3[C:19](=[CH:20][C:21]4[CH2:22][C:23]([CH3:30])([CH3:29])[CH2:24][C:25]=43)[C:18]2=[O:31])[C:8]=1[C:9]([NH:2][CH3:1])=[O:11]
Reactant: CN(C)C=O
Reactant: CC1(C)Cc2cc3n(c2C1)CCN(c1cc(F)cc(Br)c1C(=O)O)C3=O
Agent: CN
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CNC(=O)c1c(Br)cc(F)cc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 70 %

Procedure:
A 25-mL single-neck round-bottomed flask equipped with a magnetic stirrer was charged with DMF (8 mL), 129a (160 mg, 0.38 mmol), HATU (505 mg, 1.33 mmol), DMAP (46 mg, 0.38 mmol), and triethylamine (1.0 mL). The mixture was heated at 25° C. for 0.5 h. Then MeNH2.HCl (266 mg, 3.8 mmol) was added and resulting mixture was stirred at 25° C. for 2.5 h. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by prep-TLC developing with 1:20 methanol/dichloromethane to afford 129b (116 mg, 70%) as a black solid. MS-ESI: [M+H]+ 434.0
Reaction SMILES: CO[CH2:3][CH:4]1[CH2:8][C:7]2[C:9](C3C=CN=CC=3)=[C:10]([CH3:14])[CH:11]=[C:12]([NH2:13])[C:6]=2[O:5]1>CC(O)=O.O=[Pt]=O>[CH3:3][C@H:4]1[CH2:8][C:7]2[CH:9]=[C:10]([CH3:14])[CH:11]=[C:12]([NH2:13])[C:6]=2[O:5]1
Reactant: COCC1Cc2c(c(N)cc(C)c2-c2ccncc2)O1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: Cc1cc(N)c2c(c1)C[C@H](C)O2
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(methoxymethyl)-5-methyl-4-(pyridin-4-yl)-2,3-dihydrobenzofuran-7-amine (8d) (0.57 g, 2.1 mmol), PtO2 (300 mg, 50%) and TEA (0.323 mL, 4.20 mmol) in HOAc (15 mL) was introduced H2 and stirred at ambient temperature for 24 h (88 psi). The mixture was filtered, concentrated, diluted with EtOAc (50 mL), a solution of ammonium hydroxide was added until pH=10. It was extracted with EtOAc (150 mL), washed with water, brine, dried and concentrated to give the title compound (5e) as a yellow oil. MS-ESI (m/z): 277 (M+1)+.
Reaction SMILES: [Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:12][CH3:13].[C:14]1([CH3:26])[CH:19]=[CH:18][C:17]([S:20]([CH2:23][N+:24]#[C-:25])(=[O:22])=[O:21])=[CH:16][CH:15]=1.[C-]#N.[K+]>CCO>[Br:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]2[O:7][CH:25]=[N:24][CH:23]2[S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:26])=[CH:15][CH:16]=2)(=[O:22])=[O:21])=[CH:4][C:3]=1[O:12][CH3:13]
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: COc1cc(C=O)cc(OC)c1Br
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: COc1cc(C2OC=NC2S(=O)(=O)c2ccc(C)cc2)cc(OC)c1Br
Temperature: 25 °C
Reaction time: 19 h

Procedure:
To an oven-dried flask under argon was added 4-bromo-3,5-dimethoxybenzaldehyde (1.0 g, 4.08 mmol), absolute EtOH (34 mL), p-toluenesulfonylmethyl isocyanide (0.78 g, 4.0 mmol) and KCN (0.035 g, 0.54 mmol). The mixture was stirred for 19 hours at room temperature then concentrated in vacuo to give 5-(4-bromo-3,5-dimethoxyphenyl)-4-tosyl-4,5-dihydrooxazole which was used in the next synthetic step without purification.
Reaction SMILES: Cl.[C:2]1([C:8]2[O:12][N:11]=[C:10]([CH:13]3[O:18][CH2:17][CH2:16][NH:15][CH2:14]3)[N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[N:22]=[C:21]1N1CCOC(C2ON=C(C3C=CC=CC=3)N=2)C1.C(N(CC)CC)C>O1CCCC1>[CH3:19][N:20]1[C:25](=[O:26])[CH:24]=[C:23]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][N:28]=2)[N:22]=[C:21]1[N:15]1[CH2:16][CH2:17][O:18][CH:13]([C:10]2[N:9]=[C:8]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[O:12][N:11]=2)[CH2:14]1
Reactant: c1ccc(-c2nc(C3CNCCO3)no2)cc1
Reactant: Cn1c(N2CCOC(c3nc(-c4ccccc4)no3)C2)nc(-c2ccncn2)cc1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cn1c(N2CCOC(c3noc(-c4ccccc4)n3)C2)nc(-c2ccncn2)cc1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 64 %

Procedure:
A solution of the resulting 2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholine hydrochloride (intermediate 28) in tetrahydrofuran (6.0 ml) was added with 2-chloro-3-methyl-6-(pyrimidine-4-yl)pyrimidin-4-one (intermediate 1 260 mg, 2.34 mmol) and triethylamine (1.81 ml, 13.0 mmol), and the reaction mixture was stirred at room temperature for 2 hours. The solution was partitioned between water and chloroform, and the organic layer was washed with water and brine, dried over magnesium sulfate, and concentrated in vacuo. The resulting residue was purified by column chromatography on silica gel (eluent; 5% methanol in chloroform) to afford 1-methyl-2-[2-(5-phenyl-[1,2,4]oxadiazol-3-yl)-morpholin-4-yl]-1H-[4,4′]bipyrimidinyl-6-one (compound 2 in Table 1, 749 mg, 64%, 2 steps) as solid
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:26])[CH2:20][C:21]([O:23]CC)=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1.[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([NH:18][C:19](=[O:26])[CH2:20][C:21]([OH:23])=[O:22])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:14]2=[CH:15][CH:16]=[CH:17][N:13]2[N:12]=[CH:11][N:10]=1
Reactant: CCOC(=O)CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=O)Nc1ccc(Oc2ncnn3cccc23)c(F)c1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
To a solution of the above crude ethyl 3-(3-fluoro-4-(pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)phenylamino)-3-oxopropanoate (180 mg) in ethanol (10 mL) at 0° C. was added 1 N aq NaOH solution (10 mL). After stirring at 0° C. for 3 h, the reaction was washed with 20 mL of EtOAc. The EtOAc layer was back-extracted with 20 mL of 1 N aq NaOH solution. The combined aqueous solution was acidified to pH with 1 N aq HCl solution. The aqueous layer was extracted with EtOAc (3×30 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated in vacuo to give the crude acid which was used without further purification (150 mg). MS(ESI+) m/z 331.1 (M++H)+.
Reaction SMILES: [C:1]([C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:16]([OH:18])=O)[C:12](=[O:14])[CH:13]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1>>[C:1]([C:5]1[CH:28]=[CH:27][CH:26]=[CH:25][C:6]=1[O:7][C:8]1[CH:9]=[N:10][N:11]([CH:15]([CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C:16]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:18])[C:12](=[O:14])[CH:13]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(O)Cn1ccc(N)n1
Reactant: CC(C)(C)c1ccccc1Oc1cnn(C(CC2CCCC2)C(=O)O)c(=O)c1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C(C)(C)C)cc2=O)n1

Procedure:
Using the method described in Example 49, 2-[4-(2-tert-butyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-propionic acid (Intermediate 68) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-tert-butyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-cyclopentyl-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide was obtained as an off-white solid (1.05 g, 77%); ES+-HRMS m/e calcd for C29H39N5O4 [M+H+] 522.3075 found 522.3077. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.03-1.08 (m, 8H), 1.32 (s, 9H), 1.37-1.78 (m, 7H), 1.81-2.02 (m, 1H), 2.17-2.36 (m, 1H), 3.89 (s, 2H), 4.67 (s, 1H), 5.47 (dd, J=10.7, 4.3 Hz, 1H), 5.79 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.16 (d, J=7.9 Hz, 1H), 7.23-7.30 (m, 1H), 7.31-7.38 (m, 1H), 7.50 (dd, J=7.8, 1.4 Hz, 1H), 7.53 (d, J=2.1 Hz, 1H), 8.15 (d, J=2.8 Hz, 1H), 10.81 (s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10](Cl)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1.Cl.Cl.Cl.[NH2:18][CH2:19][C:20]1[O:24][C:23]([C:25]([N:27]2[CH2:32][CH2:31][N:30]([CH2:33][CH:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)[CH2:29][CH2:28]2)=[O:26])=[N:22][N:21]=1.CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[C:6]([S:10]([NH:18][CH2:19][C:20]2[O:24][C:23]([C:25]([N:27]3[CH2:32][CH2:31][N:30]([CH2:33][CH:34]4[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]4)[CH2:29][CH2:28]3)=[O:26])=[N:22][N:21]=2)(=[O:12])=[O:11])=[C:5]([CH3:14])[CH:4]=1
Reactant: COc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Reactant: CN1CCC(CN2CCN(C(=O)c3nnc(CN)o3)CC2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C)c(S(=O)(=O)NCc2nnc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)o2)c(C)c1
Temperature: -30 °C
Reaction time: 0.5 h

Procedure:
4-methoxy-2,6-dimethylbenzenesulfonyl chloride (118 mg, 0.5 mmol) was added to a suspension of (5-Amino methyl-1,3,4-oxadiazol-2-yl)-[4-(1-methyl-piperidin-4-ylmethyl)-piperazin-1-yl]-methanone trihydrochloride (200 mg, 0.43 mmol) in DCM, under N2 and the mixture was cooled to −30° C. DIPEA (376 μL, 2.15 mmol) was added over about 3 min and the resultant pink solution was stirred at −30° C. for 30 min and then at ambient temperature for 16 h. The mixture was diluted with saturated aqueous NaHCO3 and extracted with DCM (×2). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to a brown gum which was purified using FCC, eluting with 5% NH3 (2.0 M in MeOH) in DCM, to give the title compound as a clear gum.
Reaction SMILES: [Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.[NH:10]1[CH:19]2[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]2)[CH2:13][CH2:12][CH2:11]1.CCN(C(C)C)C(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Br:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([N:10]2[CH:19]3[CH:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)[CH2:13][CH2:12][CH2:11]2)=[O:9])[N:6]=1
Reactant: O=C(O)c1csc(Br)n1
Reactant: C1CCC2NCCCC2C1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1csc(Br)n1)N1CCCC2CCCCC21
Yield: 86 %

Procedure:
A solution of 2-bromo-thiazole-4-carboxylic acid (Intermediate 3; 21.2 mmol), decahydroquinoline (3.54 g, 25.4 mmol), DIPEA (7.4 mL, 42.4 mmol), and PyBrop (11.9 g, 25.4 mmol) in dry DCM (70 mL) was stirred overnight at room temperature. The mixture was extracted with DCM and water three times. The combined DCM extracts were evaporated, and the residue was chromatographed on silica, eluting with EtOAc/Hexane (0-10% gradient) to give (2-bromo-thiazol-4-yl)-(octahydro-quinolin-1-yl)-methanone (6.0 g, 86%).
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@@H:2]1[CH2:5][O:6][C:7]1[C:19](Br)=[CH:18][CH:17]=[C:16]([NH:21][C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:25]([O:24][C:22]([NH:21][C:16]1[CH:17]=[CH:18][C:19]2[N:1]3[CH2:4][CH2:3][C@@H:2]3[CH2:5][O:6][C:7]=2[C:8]=1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc(Br)c1OC[C@H]1CCN1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1c(NC(=O)OCc2ccccc2)ccc2c1OC[C@H]1CCN21
Temperature: 100 °C
Yield: 11.6 %

Procedure:
A mixture of tert-butyl 2-((R)-1-azetidin-2-ylmethoxy)-6-benzyloxycarbonylamino-3-bromo-benzoate (Intermediate 46, 1.46 g), palladium acetate (0.167 g), cesium carbonate (1.935 g) and 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.925 g) in toluene (35 mL) was stirred and heated at 100° C. under nitrogen for 4 hours. After cooling, the mixture was diluted with ethyl acetate and water and filtered through celite. The organic layer was separated, dried (Na2SO4) and filtered and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 5-40% to give tert-butyl (R)-6-benzyloxycarbonylamino-1,2,2a,3-tetrahydro-4-oxa-8b-azacyclobuta[a]naphthalene-5-carboxylate (0.141 g) as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[CH2:5][CH2:4]1)[CH3:2]>[Pd].CO>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[C:19]([F:22])([F:20])[F:21])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCN1CCN(Cc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: [Pd]
Solvent: CO
Product: CCN1CCN(Cc2ccc(N)cc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 98.9 %

Procedure:
1-Ethyl-4-(4-nitro-2-(trifluoromethyl)benzyl)piperazine (21.7 g, 68.3 mmol) obtained in Step (2) above was stirred in a solution of methanol. The reaction solution was mixed with Pd/C (1.8 g, 17.08 mmol), followed by stirring under hydrogen conditions for about 12 hours at room temperature. The reaction mixture was filtered through a Celite pad under reduced pressure, and washed with methanol. The filtrate was concentrated under reduced pressure to obtain the title compound (19.4 g, 99%).
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1.[F:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:25]=[CH:26][C:27]([C:30](O)=[O:31])=[N:28][CH:29]=2)=[CH:20][CH:19]=1.[ClH:33].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:33].[CH:1]1([C:4]2[N:5]=[C:6]3[CH:11]=[CH:10][C:9]([NH:12][C:30]([C:27]4[CH:26]=[CH:25][C:24]([C:21]5[CH:22]=[CH:23][C:18]([F:17])=[CH:19][CH:20]=5)=[CH:29][N:28]=4)=[O:31])=[CH:8][N:7]3[C:15]=2[CH3:16])[CH2:3][CH2:2]1
Reactant: Cc1c(C2CC2)nc2ccc([N+](=O)[O-])cn12
Reactant: O=C(O)c1ccc(-c2ccc(F)cc2)cn1
Agent: Cl
Solvent: CCOC(C)=O
Product: Cc1c(C2CC2)nc2ccc(NC(=O)c3ccc(-c4ccc(F)cc4)cn3)cn12

Procedure:
Operations similar to those of Example 1 were conducted using 2-cyclopropyl-3-methyl-6-nitroimidazo[1,2-a]pyridine and 5-(4-fluorophenyl)-2-pyridinecarboxylic acid. The resulting solid was dissolved in ethyl acetate, followed by addition of 4N hydrochloric acid-ethyl acetate solution and concentration under reduced pressure. The title compound was obtained as white solid.
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[CH:5][C:4]([S:7](Cl)(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:12][O:13][C:14](=[O:50])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@@H:21]1[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH:29]([CH3:34])[CH2:30][C:31]#[C:32][CH3:33])[C@H:24]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:23][C@@H:22]1[OH:49].[N+](=C)=[N-].C(=O)(O)[O-].[Na+].S(C1C=CC(C)=CC=1)([O-])(=O)=O>CCOCC.O.N1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:50])[CH2:15][CH2:16][CH2:17]/[CH:18]=[CH:19]\[CH2:20][C@@H:21]1[C@@H:25](/[CH:26]=[CH:27]/[C@@H:28]([O:35][CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)[CH:29]([CH3:34])[CH2:30][C:31]#[C:32][CH3:33])[C@H:24]([O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH2:23][C@@H:22]1[O:49][S:7]([C:4]1[CH:5]=[CH:6][C:1]([CH3:11])=[CH:2][CH:3]=1)(=[O:9])=[O:8]
Reactant: CC#CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: O
Product: CC#CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)OC)[C@@H](OS(=O)(=O)c2ccc(C)cc2)C[C@H]1OC1CCCCO1)OC1CCCCO1
Temperature: 0 °C
Reaction time: 60 h

Procedure:
At 0°, 2.15 g. of p-toluenesulfonyl chloride is addded to a solution of 3.05 g. of (5Z,13E)-(9S,11R,15S,16RS)-11,15-bis(tetrahydropyran-2-yloxy)-9-hydroxy-16-methyl-5,13-prostadien-18-ynoic acid methyl ester (prepared from the corresponding acid with ethereal diazomethane solution) in 6 ml. of pyridine, agitated for 6 hours at room temperature and then allowed to stand for 60 hours at 5°. The mixture is then diluted with ether, shaken in succession once with water, once with ice-cold 3% sulfuric acid, once with water, once with 5% sodium bicarbonate solution, twice with water, and dried over magnesium sulfate and evaporated under vacuum, thus obtaining 3.7 g. of the tosylate as a colorless oil.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:43])[CH2:6][N:7]([CH2:38][C:39]([O:41]C)=[O:40])[C:8](=[O:37])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[C:11]([N+:34]([O-:36])=[O:35])[CH:10]=1>>[C:39]([CH2:38][N:7]([C:8](=[O:37])[C:9]1[CH:14]=[C:13]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH:12]=[C:11]([N+:34]([O-:36])=[O:35])[CH:10]=1)[CH2:6][C:5]([OH:43])=[O:4])([OH:41])=[O:40]
Reactant: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)N(CC(=O)OC)CC(=O)OC)cc([N+](=O)[O-])c1
Agent: [Na+]
Agent: [OH-]
Product: CCCCCCCCCCCCCCCCCCOc1cc(C(=O)N(CC(=O)O)CC(=O)O)cc([N+](=O)[O-])c1
Yield: 92 %

Procedure:
Sodium hydroxide hydrolysis of N-(2-methoxy-2-oxoethyl)-N-[3-nitro-5-(octadecyloxy)benzoyl]glycine methyl ester gave a 92% yield of N-(carboxymethyl)-N-[3-nitro-5-(octadecyloxy)benzoyl]glycine, mp 110°-112°.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:12](I)=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[C:29]([F:36])[CH:28]=1>>[C:1]([O:5][C@@H:6]([C:11]1[C:12]([C:30]2[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][C:29]=2[F:36])=[C:13]2[C:20]3[CH2:21][CH2:22][CH2:23][CH2:24][C:19]=3[S:18][C:14]2=[N:15][C:16]=1[CH3:17])[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1I)CCCC3
Reactant: OB(O)c1ccc(Cl)cc1F
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2sc3c(c2c1-c1ccc(Cl)cc1F)CCCC3

Procedure:
The title compound was prepared from Methyl (2S)-tert-butoxy(4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)acetate (Preparation 16, 100 mg, 212 μmol) and (4-chloro-2-fluorophenyl) boronic acid (74 mg, 424 μmol) using the same method as described in Example 44, Step 1 to yield 57 mg, 56%. Material obtained was a mixture of atropisomers, in a 3:1 ratio. 1H NMR (400 MHz, CDCl3) δ ppm 1.01 (s, 9 H), 1.48-1.55 (m, 1 H), 1.69-1.75 (m, 3 H), 1.95-2.03 (m, 1 H), 2.72 (s, 3 H), 2.80-2.86 (m, 3 H), 3.66 (s, 3 H), 4.98 (s, 1 H), 7.19-7.21 (m, 1 H), 7.25-7.27 (m, 1 H), 7.35-7.37 (m, 1 H).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:23][CH3:24])=[C:7]([O:21][CH3:22])[CH:8]=2)[N:3]=1.Cl.[CH2:26]([NH2:28])[CH3:27]>>[CH3:22][O:21][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:23][CH3:24])[N:3]=[C:2]([NH:28][CH2:26][CH3:27])[N:11]=[C:10]2[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=1
Reactant: CCN
Reactant: COc1cc2nc(Cl)nc(-c3cccc([N+](=O)[O-])c3)c2cc1OC
Agent: Cl
Product: CCNc1nc(-c2cccc([N+](=O)[O-])c2)c2cc(OC)c(OC)cc2n1
Yield: 35.7 %

Procedure:
Starting from 500 mg 2-chloro-6,7-dimethoxy-4-(3-nitrophenyl)quinazoline and 1.18 g ethylamine hydrochloride, 183 mg of the title compound was obtained as yellow crystals in the same manner as in Production Example 4.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH2:14])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:16]([CH3:15])=[CH:17][CH:18]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: Cc1ccc(C(=O)Cl)cc1
Product: Cc1ccc(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1

Procedure:
The 1-benzyl-4-aminopiperidine prepared in Example 30 was treated with p-methylbenzoyl chloride in a similar manner to that described in the sameexample and the product converted to a salt.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[CH:8][C:7]([CH2:10][CH3:11])=[CH:6][C:3]=1[CH:4]=[O:5].C1N2CCN(CC2)C1.[C:20](#[N:23])[CH:21]=[CH2:22]>C(OCC)C>[Cl:1][C:2]1[C:3]([CH:4]([OH:5])[C:21](=[CH2:22])[C:20]#[N:23])=[CH:6][C:7]([CH2:10][CH3:11])=[CH:8][N:9]=1
Reactant: CCc1cnc(Cl)c(C=O)c1
Reactant: C=CC#N
Agent: C1CN2CCN1CC2
Solvent: CCOCC
Product: C=C(C#N)C(O)c1cc(CC)cnc1Cl

Procedure:
To a mixture of 2-Chloro-5-ethylnicotinaldehyde (10 mmol, 1.69 g) and DABCO (10 mmol. 1.12 g) was added an acrylonitrile (60 mmol.) under neat conditions [solvent free conditions] at room temperature and the reaction progress was monitored by TLC. Upon completion of the reaction mixture (˜4-5 min.) was diluted with diethyl ether (300 ml.) and washed with water 3×50 ml. The organic layer was dried over Na2SO4 and concentrated, the residue was subjected to column chromatography over silica gel, eluting with ethyl acetate and hexane (2:8, v/v) to give the desired product in almost quantitative (2.20 g.).
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH:23]([CH3:25])[CH3:24])=[C:18]([Cl:26])[CH:17]=3)[N:12]=2)=[CH:7][CH:6]=1)=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1.O>[Cl:26][C:18]1[CH:17]=[C:16]([C:13]2[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([CH2:4][NH2:1])=[CH:6][CH:7]=3)[O:15][N:14]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH:23]([CH3:25])[CH3:24]
Reactant: CC(C)Oc1ccc(-c2noc(-c3ccc(CN=[N+]=[N-])cc3)n2)cc1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2noc(-c3ccc(CN)cc3)n2)cc1Cl
Temperature: 60 °C
Yield: 65.4 %

Procedure:
To a solution of 5-(4-(azidomethyl)phenyl)-3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazole (0.066 g, 0.178 mmol) in THF (3.40 ml) and water (0.170 ml) was added polymer-supported triphenylphosphine (0.237 g, 0.711 mmol). After about 2 h the reaction mixture was heated to about 60° C. After about 1 h the reaction mixture was cooled to room temperature, filtered, concentrated in vacuo and purified by chromatography on silica gel (eluting with MeOH:DCM) to provide (4-(3-(3-chloro-4-isopropoxyphenyl)-1,2,4-oxadiazol-5-yl)phenyl)methanamine (40 mg, 64%) as a colorless solid.
Reaction SMILES: FC(F)(F)C(O)=O.[Br:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][C:14]2[C:19]([O:20]COC)=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:11]([F:26])[CH:10]=1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(Cl)Cl>[Br:8][C:9]1[CH:25]=[CH:24][C:12]([CH2:13][C:14]2[C:19]([OH:20])=[CH:18][CH:17]=[CH:16][N:15]=2)=[C:11]([F:26])[CH:10]=1
Reactant: COCOc1cccnc1Cc1ccc(Br)cc1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cccnc1Cc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 84.1 %

Procedure:
Trifluoroacetic acid (1 ml) was added to the compound of Example B244 (134 mg, 0.411 mmol) in methylene chloride (4 ml), and this reaction mixture was stirred at room temperature overnight. After neutralizing the mixture with saturated aqueous sodium hydrogencarbonate, ethyl acetate was added. The ethyl acetate layer was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (97.5 mg).