Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23](#[N:25])[CH3:24]>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]1[CH:16]=[C:17]([CH:18]([OH:19])[CH2:24][C:23]#[N:25])[CH:20]=[CH:21][CH:22]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1cccc(OCCCCCOCc2ccccc2)c1
Reactant: CC#N
Product: N#CCC(O)c1cccc(OCCCCCOCc2ccccc2)c1

Procedure:
Addition of acetonitrile to 3-(5-(benzyloxy)pentyloxy)benzaldehyde gave 3-(3-(5-(benzyloxy)pentyloxy)phenyl)-3-hydroxypropanenitrile as a yellow oil. Yield (0.74 g, 51%): 1H NMR (400 MHz, CDCl3) δ 7.27-7.37 (m, 6H), 6.93-6.96 (m, 2H), 6.86 (d, J=8.0 Hz, 1H), 5.0-5.05 (m, 1H), 4.51 (s, 2H), 3.97 (t, J=6.4 Hz, 2H), 3.51 (t, J=6.4 Hz, 2H), 2.76 (d, J=6.0 Hz, 2H), 2.30 (s, 1H), 1.78-1.85 (m, 2H), 1.58-1.64 (m, 2H), 1.52-1.58 (m, 2H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][C:8]([O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)=O>C1(C)C=CC=CC=1>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][CH2:7][CH2:8][O:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1
Reactant: COC(=O)c1ccc(OC(=O)CNc2nccs2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OCCNc2nccs2)cc1
Reaction time: 0.25 h

Procedure:
Amide 24-3 (1.0 g, 3.4 mmol) was dissolved in 7 mL toluene at 0°, and BH3 ·DMS (341 μL, 3.6 mmol) was added. After 15 min, the reaction was heated to reflux for 16 h, cooled to 0°, and quenched with 10% Na2CO3. The mixture was extracted with EtOAc, the organic phase was washed with water and brine, dried (MgSO4), concentrated, and purified by flash chromatography (silica, 70% EtOAc/hexane) providing 24-4 as a white solid. Rf 0.64 (silica, EtOAc).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.C([N:17](C(C)C)CC)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.[NH4+].[Cl-]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:17])=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Br)ccc2[nH]1
Reactant: CCN(C(C)C)C(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)c1cc2cc(Br)ccc2[nH]1
Reaction time: 0.5 h
Yield: 53.1 %

Procedure:
To a solution of 5-bromo-1H-indole-2-carboxylic acid (4 g, 16.7 mmol) in DMF (50 ml) at room temperature was added diisopropylethylamine (DIPEA) (5.71 ml, 32.8 mmol), PyBOP (13 g, 25.0 mmol) and HOBT (3.39 g, 25.0 mmol). After stirring the mixture for 30 minutes, NH4Cl (1.75 g, 32.8 mmol) was added and the resulting yellow suspension was stirred at room temperature for 6 hours. The reaction was quenched by addition of H2O. The yellow foamy precipitate was discarded and the mother liquor was extracted with EtOAc. The organic layers were combined, washed with NaOH (1M) and brine, dried over Na2SO4, filtered and concentrated. The residue was then dissolved in EtOAc and washed with HCl (1 M) and brine, dried over Na2SO4, filtered and concentrated. The oily residue was triturated with DCM affording, after filtration, 5-Bromo-1H-indole-2-carboxylic acid amideC as a light yellow solid (2.12 g, 53% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][CH:12]2[CH2:14][CH2:13]2)=[O:10])=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C.[C:22](O)(=[O:27])[CH2:23][C:24](O)=[O:25]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:24](=[O:25])[CH2:23][C:22](=[O:27])[N:11]([CH:12]3[CH2:13][CH2:14]3)[C:9]2=[O:10])=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccc(Br)cc1)NC1CC1
Reactant: O=C(O)CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(=O)N(C2CC2)C(=O)N1c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 3 h
Yield: 72.8 %

Procedure:
To 1-(4-bromo-phenyl)-3-cyclopropyl-urea 31 (12.9 g) obtained in Step 1 was added acetic anhydride (25.8 ml), malonic acid 4 (5.79 g) was added under a nitrogen atmosphere, and the mixture was stirred at 100° C. for 3 hrs. After allowing to cool to room temperature, the reaction mixture was concentrated under reduced pressure. Diethyl ether-ethanol [4:1 (volume ratio), 100 ml] was added to the residue and, after stirring, the crystals were collected by filtration and dried to give 1-(4-bromo-phenyl)-3-cyclopropyl-pyrimidine-2,4,6-trione 32 (11.9 g, yield 73%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[O:17][C:18]=1[CH3:19])[CH:7]=[O:8])[CH3:2].C(O)C.[BH4-].[Na+].O>O1CCCC1>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH2:7][OH:8])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][C:14]1[N:15]=[C:16]([C:20]2[O:21][CH:22]=[CH:23][CH:24]=2)[O:17][C:18]=1[CH3:19])[CH3:2]
Reactant: CCOc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: CCOc1cc(CO)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.4 %

Procedure:
To a solution of 3-ethoxy-4-[[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy]benzaldehyde (20.00 g) in tetrahydrofuran (250 mL)-ethanol (100 mL) was gradually added sodium borohydride (2.31 g) at 0° C. After stirring at room temperature for 1 hr, water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (3-ethoxy-4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}phenyl)methanol as pale-yellow crystals (18.80 g, yield 93%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 141-142° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)[O:10][C:3]=12.[CH3:19][C:20]1[C:28]([NH2:29])=[CH:27][CH:26]=[C:25]2[C:21]=1[CH:22]=[CH:23][NH:24]2>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[O:10][C:3]3[C:4](=[N:5][CH:6]=[CH:7][C:2]=3[NH:29][C:28]3[C:20]([CH3:19])=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[CH:22]4)[CH:8]=2)=[CH:12][CH:13]=1
Reactant: Cc1c(N)ccc2[nH]ccc12
Reactant: COc1ccc(-c2cc3nccc(Cl)c3o2)cc1
Product: COc1ccc(-c2cc3nccc(Nc4ccc5[nH]ccc5c4C)c3o2)cc1

Procedure:
The title compound was prepared by procedure E using 7-chloro-2-(4-methoxyphenyl)furo[3,2-b]pyridine (30.10 mg; 0.12 mmol; 1.00 eq.) instead of 7-chloro-2-(3,4,5-trimethoxyphenyl)furo[3,2-b]pyridine, and 4-methyl-1H-indol-5-ylamine (17.79 mg; 0.12 mmol; 1.05 eq.) instead of 6-amino-2,2-difluoro-4H-benzo[1,4]oxazin-3-one, and was obtained as a beige solid (27 mg, 64%). (HPLC (method F): 93%, RT: 4.07 min); 1H NMR (500 MHz, DMSO-d6) δ[ppm] 11.14 (s, 1H), 8.49 (s, 1H), 7.92 (d, J=5.5, 1H), 7.90 (d, J=8.8, 2H), 7.38 (t, J=2.7, 1H), 7.30 (d, J=8.4, 1H), 7.27 (s, 1H), 7.06 (d, J=8.9, 2H), 7.00 (d, J=8.5, 1H), 6.52 (s, 1H), 6.06 (d, J=5.5, 1H), 3.83 (s, 3H), 2.36 (s, 3H); MS (m/z) 370 [M+H]+, RT: 3.9 min.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11](OS(C)(=O)=O)[CH2:10][CH2:9]1)=O)(C)(C)C.[C:19]([C:23]1[CH:28]=[C:27]([SH:29])[CH:26]=[C:25]([C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]=1[OH:34])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[OH-].[Na+]>CC(=O)CC.O.C(OCC)(=O)C>[C:30]([C:25]1[CH:26]=[C:27]([S:29][CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:28]=[C:23]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:24]=1[OH:34])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CCC(C)=O
Solvent: O
Product: CC(C)(C)c1cc(SC2CCNCC2)cc(C(C)(C)C)c1O
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of 4-methanesulfonyloxy-piperidine-1-carboxylic acid tert-butyl ester (Ex. 3a, 35.5 g, 0.13 moles) in degassed 2-butanone (400 mL) were added 2,6-di-tert-butyl-4-mercapto-phenol (37.9 g, 0.16 moles) and cesium carbonate (62.7 g, 0.19 moles). The resulting solution was heated to 60° C. and stirred for 8 hours. Upon completion, as determined by HPLC, the reaction was diluted with 400 mL water and 500 mL ethyl acetate. The layers were cut and the organic layer was washed with saturated ammonium chloride solution (400 mL) and brine (400 mL). The volume was then concentrated under reduced pressure to 250 mL. 1,4-Dioxane (300 mL) was added, and then concentrated under reduced pressure to 100 mL. 1,4-Dioxane (300 mL) was added again. HCl (4.0 M in dioxane, 195 mL, 0.7 moles) was added slowly over 30 minutes, and the reaction was stirred at room temperature for 16 hours. The solution was concentrated under reduced pressure to 100 mL, and 1:3 solution of ethyl acetate:hexanes (250 mL) was added while stirring. After 3 hours, the solid was filtered and rinsed with a 1:9 solution of Ethyl acetate:hexanes (80 mL). The wet cake was allowed to air dry, and the solid were added to 120 mL of ethyl acetate and 120 mL of water. A 5.0 N solution of NaOH (28 mL, 0.14 moles) was added to the solution and the reaction was stirred for 30 minutes. The layers were cut. The organic layer was washed with a 6% brine solution (2×100 mL). The solution was concentrated under reduced pressure, and hexanes (70 mL) was added. The mixture was stirred for 16 hours at room temperature, then cooled to −5° C. and stirred for another hour. The solution was filtered and the solid was rinsed with cold hexanes (15 mL) and dried in a vacuum oven for 16 hours, affording 29.5 g (72.2%) of 2,6-di-tert-butyl-4-(piperidin-4-ylsulfanyl)-phenol as a white solid, mp 113-114° C. 1H-NMR (400 MHz, CDCl3): δ7.28 (s, 2H), 5.27 (s, 1H), 3.14-3.09 (m, 2H), 2.98-2.91 (m, 1H), 2.66-2.59 (m, 2H), 1.96-1.92 (m, 2H), 1.51-1.47 (m, 2H), 1.44 (s, 18H). HRMS (ESI) Calcd. for C19H31NOS: 322.2204 ([M+H]+). Found: 322.2196. Anal. Calcd. for C19H31NOS, C, 70.98; H, 9.72; N, 4.36; S, 9.97. Found: C, 70.87; H, 9.76; N, 4.30; S, 9.93.
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.[C:11]([OH:19])(=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(Cl)CCl.Cl.[NH2:25][CH:26]([CH2:42][CH2:43][CH3:44])[C:27]([N:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1)=[O:28]>CN(C=O)C.CCN(C(C)C)C(C)C.CO>[Cl:41][C:38]1[CH:39]=[CH:40][C:35]([CH:32]2[CH2:31][CH2:30][N:29]([C:27](=[O:28])[CH:26]([NH:25][C:11](=[O:19])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:42][CH2:43][CH3:44])[CH2:34][CH2:33]2)=[CH:36][CH:37]=1
Reactant: CCCC(N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: O=C(O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC(NC(=O)c1ccccc1)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A reaction tube was charged with HOBt (13 mg), benzoic acid (9 mg) and EDC (18 mg) in DMF (0.75 mL) and then agitated at rt. for 15 min. A solution of 2-amino-1-(4-(4-chlorophenyl)piperidin-1-yl)pentan-1-one hydrochloride (20 mg) in DIEA (65 μL) and DMF (185 μL) was added to the reaction tube, and the resulting mixture was shaken overnight at rt. After this time, the resulting solution was diluted with MeOH and purified by preparative LC-MS to provide Example 180. MS found: (M+H)+=400.
Reaction SMILES: O[N:2]=[C:3]([C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=O)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[N+:19]([C:22]1[CH:29]=[CH:28][C:25]([CH2:26][NH2:27])=[CH:24][CH:23]=1)([O-:21])=[O:20]>>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[NH:27][C:26]([C:25]3[CH:24]=[CH:23][C:22]([N+:19]([O-:21])=[O:20])=[CH:29][CH:28]=3)=[N:2][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:12][CH:13]=1
Reactant: NCc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)C(=NO)C(=O)c1ccc(OC)cc1
Product: CCOC(=O)c1nc(-c2ccc([N+](=O)[O-])cc2)[nH]c1-c1ccc(OC)cc1
Yield: 35.8 %

Procedure:
Ethyl 2-hydroxyimino-3-(4-methoxyphenyl)-3-oxopropionate (105.2 g) and 4-nitrobenzylamine (76.4 g) were reacted and treated in the same manner as in Starting Material Synthetic Example 1 to give ethyl 5-(4-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylate (55.1 g), which was dissolved in ethyl alcohol. 1 M Sodium hydroxide solution was added and the mixture was reacted and treated in the same manner as in Starting Material Synthetic Example 2 to give 5-(4-methoxyphenyl)-2-(4-nitrophenyl)imidazole-4-carboxylic acid (40.3 g), melting point 205-208° C. (decomposition).
Reaction SMILES: Cl.[N:2]12[CH2:9][CH2:8][C:5]([C:10](O)=[O:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2.CO>O1CCCC1>[N:2]12[CH2:9][CH2:8][C:5]([CH2:10][OH:11])([CH2:6][CH2:7]1)[CH2:4][CH2:3]2
Reactant: O=C(O)C12CCN(CC1)CC2
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: OCC12CCN(CC1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of quinuclidine-4-carboxylic acid hydrochloride (100 mg, 0.523 mmol) in 3 mL of anhydrous tetrahydrofuran at 0° C. was added borane methylsulfide complex (42 mg, 0.553 mmol). The mixture was stirred at room temperature for 1 hr and heated to reflux overnight. The reaction was cooled to 0° C. and carefully treated with 1 mL of methanol. The solvent was then removed under reduced pressure to leave the desired alcohol. Yield 36 mg. MS (m/e): 141.
Reaction SMILES: [O:1]=[C:2]([CH2:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[Br:9]Br>C(Cl)Cl.CCOC(C)=O>[Br:9][CH:7]([CH3:8])[C:2](=[O:1])[C:3]([O:5][CH3:6])=[O:4]
Reactant: CCC(=O)C(=O)OC
Reactant: BrBr
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)C(=O)C(C)Br
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.1 %

Procedure:
To a solution of methyl 2-oxobutanoate (6.92 g, 59.6 mmol) in DCM (60 mL) at 0° C. was added bromine (3.10 mL, 60.3 mmol). The reaction mixture was warmed to room temperature and stirred for 2 h, diluted with EtOAc, washed with saturated NaHCO3 (2×), water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. The product, methyl 3-bromo-2-oxobutanoate, (8.26 g, 42.4 mmol, 71% yield) was used in the next step without further purification.
Reaction SMILES: O.[OH-].[Li+].[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:19]([CH2:37][CH2:38][C:39]([O:41]C)=[O:40])[C:20]2[C:25]([C:26]=1[CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[CH:24][CH:23]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:21]=2)=[O:10])([CH3:7])([CH3:6])[CH3:5]>C1COCC1.O>[C:4]([O:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]1[N:19]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])[C:20]2[C:25]([C:26]=1[CH:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]1)=[CH:24][CH:23]=[C:22]([C:33]([O:35][CH3:36])=[O:34])[CH:21]=2)=[O:10])([CH3:7])([CH3:5])[CH3:6]
Reactant: COC(=O)CCn1c(-c2ccccc2NC(=O)OC(C)(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3NC(=O)OC(C)(C)C)n(CCC(=O)O)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 81 %

Procedure:
1.1 eq of lithium hydroxide monohydrate was added to a solution of methyl 2-{2-[(tert-butoxycarbonyl) amino]phenyl}-3-cyclohexyl-1-(3-methoxy-3-oxopropyl)-1H-indole-6-carboxylate in a mixture THF:H2O (4:1; 0.1 M). The mixture was stirred at RT for 1.5 h. The reaction was quenched with 1 N HCl and the solvent evaporated in vacuo. The residue was washed with the minimum amount of Et2O and the resultant precipitate filtered to obtain the title compound as a white solid (81%); MS (ES+) m/z 521 (M+H)+.
Reaction SMILES: [CH2:1]([N:3]=C=O)[CH3:2].[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:21][CH2:20][N:19]([C:22](OC(C)(C)C)=[O:23])[CH2:18][CH2:17]1)[CH2:15][C:14]2=[O:33]>C(Cl)Cl>[CH3:6][O:7][C:8](=[O:34])/[CH:9]=[CH:10]/[C:11]1[CH:12]=[C:13]2[C:30](=[CH:31][CH:32]=1)[O:29][C:16]1([CH2:17][CH2:18][N:19]([C:22](=[O:23])[NH:3][CH2:1][CH3:2])[CH2:20][CH2:21]1)[CH2:15][C:14]2=[O:33]
Reactant: CCN=C=O
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(C(=O)OC(C)(C)C)CC1)O2
Solvent: ClCCl
Product: CCNC(=O)N1CCC2(CC1)CC(=O)c1cc(/C=C/C(=O)OC)ccc1O2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 91.5 %

Procedure:
TEA (0.185 ml, 1.33 mmol) and ethylisocyanate (38 mg, 0.53 mmol) were added to a suspension of (E)-3-{4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester hydrochloride (150 mg, 0.44 mmol, Intermediate 1) in DCM (4 ml), and the mixture was stirred at RT for 1.5 h. The mixture was partitioned between aqueous NaHCO3 (saturated solution) and DCM and the organic phase was dried over Na2SO4 and evaporated. The crude product was purified by column chromatography (eluent: DCM/MeOH/NH4OH 97:3:0.3) to give (E)-3-{1′-ethylcarbamoyl-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (150 mg).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]1[CH:10]=[C:9]([CH3:11])[NH:8][C:7]=1[CH:12]=[O:13].[Cl:14][CH2:15][C:16](Cl)=[O:17]>ClCCCl>[Cl:14][CH2:15][C:16]([C:10]1[C:6]([CH3:5])=[C:7]([CH:12]=[O:13])[NH:8][C:9]=1[CH3:11])=[O:17]
Reactant: O=C(Cl)CCl
Reactant: Cc1cc(C)c(C=O)[nH]1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: Cc1[nH]c(C=O)c(C)c1C(=O)CCl
Reaction time: 0.25 h
Yield: 57 %

Procedure:
Anhydrous aluminum chloride (42 g, 315 mmol) was added portionwise over 30 min to a room temperature solution of 3,5-dimethylpyrrol-2-carboxaldehyde (5 g, 40 mmol) in 1,2-dichloroethane (50 ml) under nitrogen. After stirring for 15 min, chloroacetyl chloride (17 g, 150 mmol) was added dropwise over 1 h. After addition was complete, the mixture was stirred at room temperature for 16 h. The mixture was poured onto crushed ice and the organic layer separated, dried over anhydrous sodium sulfate, and the solvent removed under reduced pressure. Yield 57%, m.p. 205–09° C. (toluene).
Reaction SMILES: C[O:2][C:3](=[O:36])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([F:11])=[C:7]([NH:12][C:13](=[O:35])[C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:27][N:26]([CH3:28])[C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[O:23]3)=[C:16]([CH3:33])[C:15]=2[CH3:34])[CH:6]=1.COCCOC.[OH-].[Na+].C(COC)(C)(C)C>CO>[CH3:34][C:15]1[C:16]([CH3:33])=[C:17]([O:20][CH2:21][C@@H:22]2[CH2:27][N:26]([CH3:28])[C:25]3[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=3[O:23]2)[CH:18]=[CH:19][C:14]=1[C:13]([NH:12][C:7]1[CH:6]=[C:5]([CH2:4][C:3]([OH:36])=[O:2])[CH:10]=[CH:9][C:8]=1[F:11])=[O:35]
Reactant: COC(=O)Cc1ccc(F)c(NC(=O)c2ccc(OC[C@@H]3CN(C)c4ccccc4O3)c(C)c2C)c1
Agent: COCC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: COCCOC
Product: Cc1c(OC[C@@H]2CN(C)c3ccccc3O2)ccc(C(=O)Nc2cc(CC(=O)O)ccc2F)c1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the compound (240 mg) prepared in Example 12, 1,2-dimethoxyethane (5.0 mL), and methanol (5.0 mL), 1N sodium hydroxide solution (3.0 mL) was added, and the mixture was stirred for 1 hour at room temperature. Methyl tert-butylmethyl ether was added to the reaction mixture, which was extracted by 1N sodium hydroxide solution. The water layer was neutralized by adding 5N hydrochloric acid and was extracted with ethyl acetate. The organic layer was washed with water and saturated brine solution, and was dried by anhydrous magnesium sulphate. The compound (208 mg) of the present invention having the following physical data was obtained by allowing the residue obtained by removing the solvent to recrystallize from a mixed solvent of n-hexane, ethyl acetate, and tetrahydrofuran.
Reaction SMILES: [OH:1][NH:2]/[C:3](=[N:14]\[H])/[C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=1.[O:16]=[C:17]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][N:18]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClC(Cl)C>[C:28]1([C:21]2([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:20][CH2:19][N:18]([CH2:34][C:35]3[O:1][N:2]=[C:3]([C:4]4[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:6][CH:5]=4)[N:14]=3)[C:17]2=[O:16])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: O=C(O)CN1CCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(\NO)c1ccc(C(F)(F)F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(Cl)Cl
Product: O=C1N(Cc2nc(-c3ccc(C(F)(F)F)cc3)no2)CCC1(c1ccccc1)c1ccccc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of (Z)—N-hydroxy-4-(trifluoromethyl)benzimidamide (0.579 g, 2.84 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.762 g, 2.58 mmol) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.594 g, 3.10 mmol) were stirred together in dichloroethane (0.5 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 5% to 30% ethyl acetate/hexanes over 30 minutes (flow=40 mL/minute). 1H NMR (300 MHz, CDCl3) δ ppm 8.09-8.15 (m, 2H), 7.71-7.76 (m, 2H), 7.23-7.43 (m, 10H), 4.91 (s, 2H), 3.58 (t, J=6.5 Hz, 2H), 2.90 (t, J=6.4 Hz, 2H); MS (ESI−) m/z 462 (M−H)−.
Reaction SMILES: Cl.Br[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[N:8][C:7]([C:15]([NH2:17])=[O:16])=[C:6]2[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26].CC1(C)C(C)(C)OB([C:35]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1>C(O)CCC.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:17][C:15]([C:7]1[N:8]=[N:9][C:10]2[C:5]([C:6]=1[NH:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1[F:26])=[CH:4][C:3]([C:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37][CH:36]=1)=[C:12]([O:13][CH3:14])[CH:11]=2)=[O:16]
Reactant: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1Br
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: [Pd]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: Cl
Solvent: O
Solvent: CCCCO
Product: COc1cc2nnc(C(N)=O)c(Nc3ccc(C)cc3F)c2cc1C1=CCN(C(=O)OC(C)(C)C)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.7 %

Procedure:
A mixture of 6-bromo-4-(2-fluoro-4-methylphenylamino)-7-methoxycinnoline-3-carboxamide hydrochloride (Example 54, 1.40 g, 3.169 mmol), tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (1.47 g, 4.75 mmol), tripotassium phosphate (2.018 g, 9.51 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (0.260 g, 0.63 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.29 g, 0.32 mmol) in n-butanol (4.53 ml) and water (1.81 ml) was stirred under N2 (g) at 100° C. overnight. The reaction mixture was cooled, concentrated under reduced pressure and the residue purified with silica chromatography (CH2Cl2/MeOH) to give 1.54 g (96%) of a light brown solid. 1H NMR: 11.54 (s, 1H), 8.79 (s, 1H), 7.94 (s, 1H), 7.62 (s, 1H), 7.25 (m, 2H), 7.08 (m, 2H), 5.56 (s, 1H), 3.97 (s, 3H), 3.82 (m, 2H), 3.37 (m, 2H), 2.35 (s, 3H), 2.14 (m, 2H), 1.41 (s, 6H), 1.06 (s, 9H); m/z 508.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[C:10]([CH:14]([F:20])[C:15](OCC)=[O:16])[CH:11]=[CH:12][CH:13]=1>C1COCC1>[Br:7][C:8]1[CH:9]=[C:10]([CH:14]([F:20])[CH2:15][OH:16])[CH:11]=[CH:12][CH:13]=1
Reactant: CCOC(=O)C(F)c1cccc(Br)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCC(F)c1cccc(Br)c1
Temperature: 0 °C

Procedure:
Lithium aluminum hydride (1M in THF, 13.0 mL) was added portionwise over 7 minutes to a solution of ethyl 2-(3-bromophenyl)-2-fluoroacetate (example 39, step a) (2.94 g) in THF (35 mL), pre-cooled in ice-water. The resulting mixture was stirred in ice-water for 30 minutes, then quenched by the careful addition of methanol (5 mL), added portionwise over 30 minutes. The mixture was poured into 2 molar aqueous HCl and extracted three times with ethyl, acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulphate and purified by flash chromatography on silica eluted with 25% diethyl ether in isohexane to afford the subtitled compound as colourless oil. Yield 1.39 g.