Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:43])([F:42])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([O:37]CC)=[O:36])[CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21].C1COCC1.[OH-].[Na+].Cl>C(O)C>[F:43][C:2]([F:1])([F:42])[CH2:3][CH2:4][CH:5]([NH:22][C:23]1[CH:41]=[CH:40][C:26]([C:27]([N:29]2[CH2:34][CH2:33][CH2:32][C@@H:31]([C:35]([OH:37])=[O:36])[CH2:30]2)=[O:28])=[CH:25][CH:24]=1)[C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][CH2:17][CH2:18]3)=[N:13]2)=[CH:8][C:7]=1[CH3:21]
Reactant: CCOC(=O)[C@@H]1CCCN(C(=O)c2ccc(NC(CCC(F)(F)F)c3ccc(-n4cc5c(n4)CCCC5)cc3C)cc2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(-n2cc3c(n2)CCCC3)ccc1C(CCC(F)(F)F)Nc1ccc(C(=O)N2CCC[C@@H](C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.9 %

Procedure:
To a mixture of ethyl (3R)-1-(4-((4,4,4-trifluoro-1-(2-methyl-4-(4,5,6,7-tetrahydro-2H-indazol-2-yl)phenyl)butyl)amino)benzoyl)piperidine-3-carboxylate (155.4 mg), THF (0.5 mL) and ethanol (0.5 mL) was added 1M aqueous sodium hydroxide solution (0.521 mL), and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added 1M hydrochloric acid (0.6 and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give the title compound (131.6 mg).
Reaction SMILES: [C:1]([O:9][CH2:10]C)(=[O:8])[CH2:2][C:3]([O:5][CH2:6]C)=[O:4]>CCC(=O)CC>[C:1]([O:9][CH3:10])(=[O:8])[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: CCOC(=O)CC(=O)OCC
Solvent: CCC(=O)CC
Product: COC(=O)CC(=O)OC
Yield: 29 %

Procedure:
The target product was obtained in the same manner as in Production Example 1, except that 3-pentanone was used instead of benzaldehyde, and diethyl malonate was used instead of dimethyl malonate (yield: 29%). The 1H-NMR spectrum of the reaction product obtained using a nuclear magnetic resonance spectrometer was analyzed, and it was found that the chemical shift values were 1.09 (t, 6H), 2.27 (t, 6H), 2.36 (q, 4H), 4.20 (q, 4H). It was thus confirmed that the product was diethyl(1-ethylpropylidene)malonate. The purity of the resulting diethyl(1-ethylpropylidene)malonate determined by liquid chromatography was 100%.
Reaction SMILES: [C:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)(=[O:3])[CH3:2].[BH4-].[Na+].[Cl-].[NH4+]>O1CCCC1.C(O)(C)C>[OH:3][CH:1]([C:4]1[CH:15]=[CH:14][C:7]2[O:8][C:9]3([C:12](=[O:13])[C:6]=2[CH:5]=1)[CH2:11][CH2:10]3)[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)C(=O)C1(CC1)O2
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CC(O)c1ccc2c(c1)C(=O)C1(CC1)O2
Temperature: -50 °C
Reaction time: 0.5 h

Procedure:
To a well stirred solution of 5-acetylspiro[benzo-[b]furan-2(3H), 1'-cyclopropane]-3-one (1 g) in tetrahydrofuran (25 ml) and isopropanol (3 ml) was added portionwise NaBH4 (0.9 g) cooling at -50° C. The reaction mixture was then stirred at room temperature for 30 minutes, followed by dilution with ice-water, which was neutralized with aqueous ammonium chloride. The aqueous solution was extracted with ethyl acetate. The extract was washed with water and dried. The residue obtained by removal of the solvent was chromatographed on silica gel, eluting with CHCl3. The product was distilled under reduced pressure to give 5-(1-hydroxyethyl)spiro[benzo[b]furan-2(3H), 1'-cyclopropane]-3-one as colorless oil. b.p. 0.05 mmHg: 110° C. (bath temperature). IRνmaxfilm cm-1 : 3350(OH), 1710 (CO). NMR (CDCl3)δ: 1.45 (3H, d, J=6 Hz, CH3), 1.62 (4H, q, J=3 Hz, CH2), 3.33 (1H, b, OH), 4.83 (1H, q, J=6 Hz, CH), 6.97 (1H, d, J=9 Hz, aromat.H), 7.55 (2H, m, aromat.H).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]#[N:16])=[CH:6][CH:5]=1)([O-:3])=[O:2].[OH-:17].[NH4+]>S(=O)(=O)(O)O>[N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][NH:10][CH:11]2[CH2:14][C:15]([NH2:16])=[O:17])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: [OH-]
Reactant: N#CCC1NCCc2ccc([N+](=O)[O-])cc21
Agent: O=S(=O)(O)O
Agent: [NH4+]
Product: NC(=O)CC1NCCc2ccc([N+](=O)[O-])cc21
Reaction time: 6 h
Yield: 89 %

Procedure:
To cold concentrated sulfuric acid (100 ml) was added, in a single portion, 7-nitro-1,2,3,4-tetrahydroisoquinoline-1-acetonitrile (12.6 g, 58.0 mmol). The reaction mixture was stirred for 6 h at that temperature after which time all the starting material had dissolved. The reaction mixture was poured on ice and the solution made basic with concentrated ammonium hydroxide at such a rate as to control the exotherm. The precipitated product was collected, washed with copious amounts of water, and air-dried to give the title compound as a red solid (12.1 g, 89%), m.p. 246-7° C. (dec.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)=[N:9][S@@:10]([C:12]([CH3:15])([CH3:14])[CH3:13])=[O:11])=[CH:4][C:3]=1[O:30][CH3:31].B(F)(F)F.CCOCC.[CH2:41]([Mg]Cl)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([NH:9][S@@:10]([C:12]([CH3:13])([CH3:14])[CH3:15])=[O:11])([C:16]2[CH:21]=[C:20]([O:22][C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])[CH:19]=[C:18]([F:29])[CH:17]=2)[CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[CH:4][C:3]=1[O:30][CH3:31]
Reactant: Cl[Mg]Cc1ccccc1
Reactant: COc1cc(C(=N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Agent: FB(F)F
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc(C(Cc2ccccc2)(N[S@](=O)C(C)(C)C)c2cc(F)cc(OC(F)(F)C(F)F)c2)ccc1F
Reaction time: 0.17 h

Procedure:
To a solution of (R)-N-((4-fluoro-3-methoxyphenyl)(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)methylene)-2-methylpropane-2-sulfinamide (4.4 g, 9.42 mmol) in CH2Cl2 (190 mL, 0.05 M) at −71° C. was added BF3.Et2O (2.37 mL, 18.8 mmol). The reaction mixture was stirred for 10 min and BnMgCl (25 mL, 1N in Et2O, 26 mmol) was added. The reaction mixture was stirred at −75° C. for an additional 5 min, and quenched by the addition of saturated NH4Cl. The organic portion was separated, washed by H2O, dried over Na2SO4 and filtered. The solvent was then removed under reduced pressure and the residue was purified by ISCO chromatography using hexanes/EtOAc (0-80%) to give (R)-N-(1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide as a mixture of two diastereomers. The mixture (1 to 4 ratio) was then separated by chiral AD column using 20% IPA/hep/0.15 DEA as mobile phase to afford (R)-N-((S)-1-(4-fluoro-3-methoxyphenyl)-1-(3-fluoro-5-(1,1,2,2-tetrafluoroethoxy)phenyl)-2-phenylethyl)-2-methylpropane-2-sulfinamide (0.79 g, 15% yield). LCMS: RT=2.09 min, [M+H] 560.2 (Phenomenex Luna C18 column, 4.6×30 mm eluting with 10-90% MeOH/H2O over 2 minutes containing 0.1% TFA; 5 mL/min, monitoring at 220 nm).
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.O=C1C=CC=CN1OC(N(C)C)=[N+](C)C.F[B-](F)(F)F.[NH2:41][CH2:42][C:43]1[CH:48]=[CH:47][C:46]([C:49]2[NH:66][C:52]3[N:53]=[CH:54][N:55]=[C:56]([NH:57][C@@H:58]([C:60]4[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=4)[CH3:59])[C:51]=3[CH:50]=2)=[CH:45][CH:44]=1>CN(C=O)C>[C:60]1([C@H:58]([NH:57][C:56]2[C:51]3[CH:50]=[C:49]([C:46]4[CH:45]=[CH:44][C:43]([CH2:42][NH:41][C:9](=[O:11])[CH2:8][CH2:7][N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[CH:48][CH:47]=4)[NH:66][C:52]=3[N:53]=[CH:54][N:55]=2)[CH3:59])[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=1
Reactant: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CN)cc3)cc12)c1ccccc1
Reactant: O=C(O)CCN1CCCCC1
Agent: CN(C)C(On1ccccc1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Nc1ncnc2[nH]c(-c3ccc(CNC(=O)CCN4CCCCC4)cc3)cc12)c1ccccc1
Reaction time: 0.08 h

Procedure:
Under an atmosphere of nitrogen a mixture of 0.0865 g (0.55 mmol) 3-piperidin-1-yl-propionic acid and 0.117 ml (0.68 mmol) N,N-diisopropylethylamine in DMF (5 ml) is treated at RT and over a period of 5 min with a solution of 0.163 g (0.55 mmol) O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N′,N′-tetramethyluronium-tetrafluoroborate (TPTU, Fluka, Buchs, Switzerland) in 2 ml DMF. After stirring for 5 min the resulting solution is added slowly (1.5 h) at RT to 0.172 g (0.5 mmol) [6-(4-aminomethyl-phenyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-((R)-1-phenyl-ethyl)-amine (step 40.5) in 3 ml DMF. The reaction mixture is allowed to stand over night after which the DMF is evaporated under reduced pressure. The residue is purified by flash chromatography using gradients of first dichloromethane/methanol 100:2.5 to 10:1 and then mixtures of dichloromethane/methanol/conc. ammonia 90:10:0.5 to 40:10:1. The title compound is obtained as yellowish solid; m.p. 140° C.; MS-ES+: (M+H)+=483.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][C:5]([C:9]([F:12])([F:11])[F:10])=[CH:4][N:3]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])O.[Na+].Cl>O1CCCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:8][C:7]1[C:2]([C:18]2[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)=[N:3][CH:4]=[C:5]([C:9]([F:12])([F:11])[F:10])[CH:6]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(-c2ncc(C(F)(F)F)cc2Cl)cc1
Yield: 71.8 %

Procedure:
20.4 g of 2,3-dichloro-5-trifluoromethylpyridine, 18.9 g of p-methoxyphenylboronic acid, 0.4 g of tetrakis(triphenylphosphine)palladium(0) and 23.8 g of sodium hydrogencarbonate were refluxed for 2 hours in a mixture of 300 ml of tetrahydrofuran and 300 ml of water. After colling, the mixture was acidified by means of 10% strength hydrochloric acid. The tetrahydrofuran was removed by distillation under reduced pressure, and the product was then extracted three times with 100 m of methylene chloride in each case. The combined organic phases were sucked through silica gel and then evaporated. Recrystallization of the crude product from n-hexane gave 19.5 g (72%) of colorless crystals; m.p. 71-72° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH2:15])[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:18][C:19]([F:35])([F:34])[C:20]1[O:24][N:23]=[C:22]([C:25]2[CH:26]=[C:27]([CH:31]=[CH:32][N:33]=2)[C:28](O)=[O:29])[N:21]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:13]([CH3:17])([CH3:16])[CH2:14][NH:15][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][N:33]=[C:25]([C:22]4[N:21]=[C:20]([C:19]([F:35])([F:34])[F:18])[O:24][N:23]=4)[CH:26]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccnc(-c2noc(C(F)(F)F)n2)c1
Reactant: CC(C)(CN)c1nc(-c2ccc(Cl)cc2)cs1
Product: CC(C)(CNC(=O)c1ccnc(-c2noc(C(F)(F)F)n2)c1)c1nc(-c2ccc(Cl)cc2)cs1
Yield: 33 %

Procedure:
This compound was synthesized from 2-(4-(4-chlorophenyl)thiazol-2-yl)-2-methylpropan-1-amine and 2-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)isonicotinic acid as described in example 8 step 6 (65 mg, yield 33%). 1H NMR (400 MHz, CDCl3) δ 8.94-8.92 (dd, J=5.0 Hz, 0.8 Hz, 1H), 8.50 (m, 1H), 8.39-8.36 (t, J=5.6 Hz, 1H), 7.88-7.86 (dd, J=5.0 Hz, 1.5 Hz, 1H), 7.79-7.77 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.35-7.33 (d, J=8.5 Hz, 2H), 3.83-3.82 (d, J=5.8 Hz, 2H), 1.57 (s, 6H). MS (ESI) m/z: Calculated for C22H17ClF3N6O2S: 507.07. found: 508.0 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([O:13]C)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([C:8]1[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=1)[C:11]([OH:13])=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cccc(Cc2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cccc(Cc2ccccc2)c1
Yield: 92 %

Procedure:
To a solution of methyl 3-benzylbenzoate (0.610 g; 2.70 mmol) in THF (14 mL) was added a solution of lithium hydroxide hydrate (0.403 g; 5.39 mmol) in water (12 mL). The mixture was refluxed for 2 hours and concentrated under reduced pressure to remove the THF. The aqueous solution was acidified with 6N hydrochloric acid. The white precipitate formed was collected by filtration, washed with water and dried to afford 0.527 g (92%) of 3-benzylbenzoic acid which was directly used in the next step.
Reaction SMILES: [CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([OH:17])=O)=[CH:10][C:9]=1[F:19])(=[O:5])=[O:4])[CH3:2].[C:20]1([CH3:38])[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[C:31]([CH2:32][NH2:33])=[CH:30][CH:29]=[C:28]([C:34]([F:37])([F:36])[F:35])[N:27]=2)[CH:21]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.C(N(CC)CC)C>O1CCOCC1>[CH2:1]([S:3]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH3:18])[C:15]([NH:33][CH2:32][C:31]2[C:26]([C:22]3[CH:21]=[C:20]([CH3:38])[CH:25]=[CH:24][CH:23]=3)=[N:27][C:28]([C:34]([F:37])([F:35])[F:36])=[CH:29][CH:30]=2)=[O:17])=[CH:10][C:9]=1[F:19])(=[O:4])=[O:5])[CH3:2]
Reactant: CCS(=O)(=O)NCc1ccc(C(C)C(=O)O)cc1F
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCc1ccc(C(C)C(=O)NCc2ccc(C(F)(F)F)nc2-c2cccc(C)c2)cc1F
Reaction time: 8 h

Procedure:
2-(4-(Ethylsulfonamidomethyl)-3-fluorophenyl)propanoic acid (60 mg, 0.207 mmol) and (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (61 mg, 0.228 mmol) was dissolved and mixed in 1,4-dioxane, followed by addition of N-hydroxybenzotriazole (42 mg, 0.311 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (60 mg, 0.311 mmol) and triethylamine (0.07 mL, 0.518 mmol). The reaction mixture was stirred for overnight and then quenched by water and extracted with ethyl acetate. Drying over magnesium sulfate, evaporation of the ethyl acetate and purification by column chromatography gave 2-(4-(ethylsulfonamidomethyl)-3-fluorophenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (example 83) in pure form (52 mg, 47%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:21])[C:10]([C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15])=[N:11][N:12]=1.[H-].C([Al+]CC(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]([CH3:21])[C:10]([C:13]([CH3:19])([CH3:20])[CH:14]=[O:15])=[N:11][N:12]=1
Reactant: CCOC(=O)C(C)(C)c1nnc(-c2ccccc2Cl)n1C
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: Cn1c(-c2ccccc2Cl)nnc1C(C)(C)C=O

Procedure:
Ethyl 2-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropanoate was reacted with diisobutylaluminum hydride in toluene at −78° C. to obtain 2-[5-(2-chlorophenyl)-4-methyl-1,2,4-triazol-3-yl]-2-methylpropanal.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].C(N=C=[Se:43])C1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][N:11]=[C:12]=[Se:43])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Se]=C=NCc1ccccc1
Reactant: O=CNCCCCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: [Se]=C=NCCCCc1ccccc1
Yield: 95 %

Procedure:
A mixture of phenylbutyl formamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2c as an oil. 1H NMR (CDCl3) δ 1.74-1.76 (m, 4H), 2.66 (t, 2H, J=6.6 Hz), 3.60 (t, 2H, J=5.6 Hz), 7.15-7.32 (m, 5H); HRMS (EI) calcd for C11H13NSe, 239.0208. found, 239.0211.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]([CH3:31])[O:4][C:5]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:6]=1[C:7]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[C:18]([Cl:30])[CH:17]=1)=[N:8][CH:9]=[N:10]2.[OH:32][C@H:33]1[CH2:38][CH2:37][O:36][C:34]1=[O:35]>>[Cl:30][C:18]1[CH:17]=[C:16]([NH:15][C:7]2[C:6]3[C:11](=[CH:12][CH:13]=[CH:14][C:5]=3[O:4][C@@H:3]([CH3:31])[CH2:2][NH:1][C:34](=[O:35])[C@@H:33]([OH:32])[CH2:38][CH2:37][OH:36])[N:10]=[CH:9][N:8]=2)[CH:21]=[CH:20][C:19]=1[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: O=C1OCC[C@@H]1O
Reactant: C[C@@H](CN)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: C[C@@H](CNC(=O)[C@@H](O)CCO)Oc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Yield: 60 %

Procedure:
The procedure described in Example 63 was repeated using 5-[(1S)-2-amino-1-methylethoxy]-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]quinazolin-4-amine (obtained as described in Example 36, preparation of starting materials) and (S)-(−)-α-hydroxy-γ-butyrolactone to give the title compound in 60% yield; NMR spectrum (DMSO-d6) 1.39 (d, 3H), 1.43-1.57 (m, 3H), 1.71-1.86 (m, 1H), 3.33-3.53 (m, 3H), 3.65-3.79 (m, 1H), 3.88-4.00 (m, 1H), 4.36 (t, 1H), 4.85-4.96 (m, 1H), 5.29 (s, 2H), 5.45 (d, 1H), 7.24 (d, 2H), 7.28-7.41 (m, 2H), 7.59 (t, 2H), 7.71 (t, 1H), 7.87 (t, 1H), 8.10-8.21 (m, 2H), 8.48 (s, 1H), 8.59 (d, 1H), 9.99 (s, 1H); Mass spectrum MH+ 537.9.
Reaction SMILES: N12CCCN=C1CCCCC2.[F:12][C:13]([F:27])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[NH:21][O:22][C:23](=[O:25])[N:24]=2)[CH:15]=1.[CH3:28][O:29][N:30]([CH3:34])[C:31](Cl)=[O:32]>N1C=CC=CC=1>[F:27][C:13]([F:12])([F:26])[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([C:20]2[N:24]([C:31]([N:30]([O:29][CH3:28])[CH3:34])=[O:32])[C:23](=[O:25])[O:22][N:21]=2)[CH:15]=1
Reactant: CON(C)C(=O)Cl
Reactant: O=c1nc(-c2cc(C(F)(F)F)ccn2)[nH]o1
Solvent: c1ccncc1
Solvent: C1CCC2=NCCCN2CC1
Product: CON(C)C(=O)n1c(-c2cc(C(F)(F)F)ccn2)noc1=O
Temperature: 50 °C
Reaction time: 4 h
Yield: 69 %

Procedure:
To 1 ml of pyridine were added 0.18 g of 1,8-diazabicyclo[5,4,0]undec-7-ene, and 0.2 g of 3-(4-trifluoromethylpyridin-2-yl)-1,2,4-oxadiazol-5-one, and 0.15 g of N-methoxy-N-methylcarbamoyl chloride was added at room temperature. After stirring at 50° C. for 4 hours, the resultant solution was concentrated, and the residue was subjected to silica gel column chromatography to obtain 0.19 g of 3-(4-trifluoromethylpyridin-2-yl)-N-methoxy-N-methyl-1,2,4-oxadiazol-5-one-4-carboxamide (present compound (21))
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]2[CH2:14][NH:13][C:12](=[O:15])[CH2:11]2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].[C:16]1([CH2:22][CH2:23][CH2:24]Br)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:16]1([CH2:22][CH2:23][CH2:24][O:1][C:2]2[CH:3]=[C:4]([CH:10]3[CH2:14][NH:13][C:12](=[O:15])[CH2:11]3)[CH:5]=[CH:6][C:7]=2[O:8][CH3:9])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: BrCCCc1ccccc1
Reactant: COc1ccc(C2CNC(=O)C2)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C2CNC(=O)C2)cc1OCCCc1ccccc1
Temperature: 100 °C
Reaction time: 18 h
Yield: 72.2 %

Procedure:
A mixture of 4-(3-hydroxy-4-methoxyphenyl)-2-pyrrolidone (42 mg, 0.2 mmol), 3-phenylpropyl bromide (44 mg, 0.22 mmol), potassium carbonate (83 mg, 0.6 mmol) and N,N-dimethylformamide (3 mL) was allowed stirred at 100° C. for 18 hours, then cooled to 25° C. The solid was removed by filtration, and the filtrate was concentrated in vacuo. The same work up procedure as described in Example 1 gave 47 mg (72%) of 4-(3-(3-phenylpropoxy)-4-methoxyphenyl)-2-pyrrolidone: 1H NMR (300 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 6.82 (d, J=8.4 Hz, 1H), 6.78 (d, J=12 Hz, 1H), 6.70 (s, 1H), 6.02 (b, 1H), 4.03 (t, J=7.2 Hz, 2H), 3.84 (s, 3H), 3.75 (t, J=8.8 Hz, 1H), 3.63-3.55 (m, 1H), 3.36 (t, J=8.8 Hz, 1H), 2.82 (t, J=8.0 Hz, 2H), 2.71 (dd, J=16.8, 8.8 Hz, 2H), 2.47 (dd, J=16.6, 8.8 Hz), 2.20-2.13 (m, 2H).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.Cl[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14]>[OH-].[Na+]>[CH2:16]([O:15][C:13]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)=[O:14])[CH:17]=[CH2:18]
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: C=CCOC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Product: C=CCOC(=O)NCc1ccc(C(=O)O)cc1
Reaction time: 0.5 h
Yield: 64.8 %

Procedure:
To a solution of 7.55 g of 4-(aminomethyl)-benzoic acid in 50 ml of 1N sodium hydroxide solution were added at 6°-8° C. over 1.5 h 6.55 g of allyl chloroformate. Stirring was continued at 0° C. for 0.5 h and the mixture was then extracted with 60 ml of diethyl ether. The organic phase was extracted with 20 ml of saturated sodium carbonate solution and the combined aqueous layers were then acidified to pH 1.8 by the addition of12N sulfuric acid and subsequently extracted with ethyl acetate. The ethyl acetate extract was washed with brine, dried over sodium sulfate, and the solvent was evaporated in vacuo. The solid residue was crystallized from ethyl acetate/hexane to yield 7.61 g of 4-(allyloxycarbonylaminomethyl)-benzoic acid as a white solid, m.p. 175°-177° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:17]=2[O:23][CH3:24])([O:14][CH3:15])[CH2:10][CH2:9]1)=O)(C)(C)C>CO.Cl>[Cl:22][C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([C:11]2([O:14][CH3:15])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:21]=1.[ClH:22]
Reactant: COc1ccc(Cl)cc1C1(OC)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Product: COc1ccc(Cl)cc1C1(OC)CCNCC1

Procedure:
A solution of 4-(5-chloro-2-methoxy-phenyl)-4-methoxy-piperidine-1-carboxylic acid tert-butyl ester 5c (3.8 g, crude from last step) in methanol/HCl (2 M, 50 mL) was stirred at room temperature for 4 h, then the mixture was concentrated to half of volume under 40° C. and then ether was added. The precipitated was filtered and washed with ether to obtain 4-(5-chloro-2-methoxyphenyl)-4-methoxypiperidine 5d as its HCl salt. 1H NMR (DMSO-d6): δ 8.95 (b, 2H), 7.37-7.34 (q, J1=8.8 Hz, J2=8.8 Hz, 1H), 7.21-7.20 (d, J=2.8 Hz, 1H), 7.09-7.07 (d, J=8.8 Hz, 1H), 3.78 (s, 3H), 3.16-3.13 (m, 2H), 3.13-2.98 (m, 5H), 2.35-2.28 (m, 2H), 2.19-2.16 (m, 2H). ESI-MS m/z 256.8.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[F:23][C:24]1[C:32]([OH:33])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH3:34])[NH:28]2.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[C:12]([C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1)[N:5]=[CH:4][CH:3]=[C:2]2[O:33][C:32]1[C:24]([F:23])=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:34])=[CH:26]2)#[N:13]
Reactant: N#Cc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc2c(F)c(Oc3ccnc4cc(OCCCN5CCCC5)c(C#N)cc34)ccc2[nH]1
Temperature: 95 °C
Yield: 79.5 %

Procedure:
A suspension of 4-chloro-6-cyano-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (500 mg, 1.58 mmol), 4-fluoro-5-hydroxy-2-methylindole (314 mg, 1.9 mmol) and cesium carbonate (775 mg, 2.38 mmol) in DMF (15 ml) was heated at 95° C. for 2 hours. After removal of the volatiles by evaporation under vacuum, the residue was dissolved in methylene chloride and poured onto a column of silica and eluted with a mixture of methylene chloride/methanol (90/10) followed by methylene chloride/methanol/methanol saturated with ammonia (88/10/2). The fractions containing the expected product were combined and evaporated to give 6-cyano-4-(4-fluoro-2-methylindol-5-yloxy)-7-(3-(pyrrolidin-1-yl)propoxy)quinoline (558 mg, 79%).