Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:10]2[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]([NH:23][C:24]3[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=3)=[N:6][C:5]=2[N:4](COCC[Si](C)(C)C)[CH:3]=1.C(O)(C(F)(F)F)=O.CCO.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.O>[F:1][C:2]1[C:10]2[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:22])[CH:20]=[CH2:21])[CH:15]=[CH:16][CH:17]=3)=[N:8][C:7]([NH:23][C:24]3[CH:28]=[CH:27][N:26]([CH3:29])[N:25]=3)=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccn(C)n3)nc3c2c(F)cn3COCC[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(Oc2nc(Nc3ccn(C)n3)nc3[nH]cc(F)c23)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 55.5 %

Procedure:
To a solution N-{3-[(5-fluoro-2-[(1-methyl-1H-pyrazol-3-yl)amino]-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)oxy]phenyl}prop-2-enamide (120 mg, 0.23 mmol) in DCM (10 mL) was added TFA (0.7 mL, 6.7 mmol). The reaction solution was stirred at rt for 4 hrs. The reaction was evaporated to dryness and EtOH (5 mL), water (1 mL), and K2CO3 (158 mg, 1.1 mmol) were added. The reaction mixture was stirred at rt for 2 hrs and concentrated to dryness, suspended in EtOAc and filtered. The filtrate was concentrated to dryness and then suspended in EtOAc (20 mL) and heated to 70° C. with stirring for 30 min. The mixture was then cooled to rt with stirring overnight. A light yellow solid precipitated over this time and was collected by filtration, washed with EtOAc (5 mL) and dried to afford the title compound (50.2 mg, 56% yield) as a pale yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.25 (br. s., 1H) 10.27 (s, 1H) 9.25 (s, 1H) 7.64 (s, 1H) 7.53-7.60 (m, 1H) 7.41 (t, J=8.06 Hz, 1H) 7.28 (d, J=1.26 Hz, 1H) 7.02 (dd, J=7.93, 1.89 Hz, 1H) 6.99 (s, 1H) 6.38-6.48 (m, 1H) 6.05 (br. s., 1H) 5.77 (dd, J=10.07, 1.51 Hz, 1H) 3.65 (s, 4H). m/z (APCI+) for C19H16FN7O2 394.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.CCN(CC)CC.Cl.[O:35]1[CH2:39][CH2:38][C@H:37]([NH2:40])[CH2:36]1>CN(C=O)C>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:40][C@H:37]2[CH2:38][CH2:39][O:35][CH2:36]2)[CH2:13][CH2:14]1
Reactant: N[C@H]1CCOC1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Fc1ccc(CN2CCN(c3nc4ccncc4nc3N[C@H]3CCOC3)CC2)c(F)c1
Temperature: 60 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
To a solution of 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (3.0 g, 7.98 mmol) and Et3N (10 mL, 71.7 mmol) in DMF (30 mL) was added (S)-tetrahydrofuran-3-amine hydrochloride (2.96 g, 23.95 mmol) at room temperature. The mixture was stirred at 60° C. for 16 h then separated between water and EtOAc. The organic layer was washed with brine and water, then dried and concentrated to yield the crude residue, which was purified by column to give the title compound (800 mg) as a yellow oil. ESI-MS m/z [M+H]+ 427.1.
Reaction SMILES: C([O:3][C:4](=[O:38])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)=[CH:9][C:8]=1[CH3:37])C.[OH-].[Na+].Cl>C(O)C>[CH3:37][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([C:20]#[C:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:17]=[C:16]([O:28][CH2:29][CH2:30][N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:38])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#Cc3ccccc3)cc(OCCN3CCOCC3)c2)cc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(Sc2cc(C#Cc3ccccc3)cc(OCCN3CCOCC3)c2)ccc1OCC(=O)O
Reaction time: 1 h

Procedure:
{2-Methyl-4-[3-(2-morpholin-4-yl-ethoxy)-5-phenylethynyl-phenylsulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (15 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried and evaporated to dryness. Yield: 140 mg. HPLC-MS: m/z: 504.1 (M+); Rt: 1.80 min.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]1[CH2:13][C@@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([CH2:22][C:23]([NH2:25])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:11][O:10][C@@H:9]1[C:26]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=1[F:33])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[C@@H:9]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:27]=2[F:33])[O:10][CH2:11][C@H:12]([N:14]2[CH2:21][C:20]3[C:16](=[N:17][N:18]([CH2:22][C:23]([NH2:25])=[O:24])[CH:19]=3)[CH2:15]2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@@H](N2Cc3cn(CC(N)=O)nc3C2)CO[C@@H]1c1cc(F)ccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Cn1cc2c(n1)CN([C@H]1CO[C@H](c3cc(F)ccc3F)[C@@H](N)C1)C2

Procedure:
The product from Step A (433 mg, 0.907 mmol) in CH2Cl2 (60 mL) was treated with TFA (60 mL) at RT for 2 h. After removing the TFA/CH2Cl2, the residue was purified on a silica gel column and eluting with 2.5-5% MeOH (containing 10% NH4OH)/CH2Cl2 to give the title compound. LC-MS=378.04 [M+1].
Reaction SMILES: C(OC([NH:11][C:12]([CH3:35])([CH3:34])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH2:30][CH:31]([CH3:33])[CH3:32])[CH:21]=2)=[CH:16][CH:15]=1)=O)C1C=CC=CC=1.C([O-])=O.[NH4+]>[Pd].CO.O>[NH2:11][C:12]([CH3:34])([CH3:35])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([O:28][CH3:29])=[O:27])=[C:22]([CH2:30][CH:31]([CH3:32])[CH3:33])[CH:21]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(CC(C)(C)NC(=O)OCc3ccccc3)cc2)cc1CC(C)C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(CC(C)(C)N)cc2)cc1CC(C)C
Yield: 91 %

Procedure:
The mixture of methyl 4′-[2-[[(benzyloxy)carbonyl]-amino]-2-methylpropyl]-3-isobutyl-4-biphenylcarboxylate (570 mg), ammonium formate (351 mg) and palladium on carbon powder (400 mg) in methanol (10 ml) and water (1.0 ml) was refluxed for 3 hours. The catalyst was filtered off, and the filtrate was diluted with chloroform-methanol (19:1). The organic layer was washed with saturated aqueous sodium bicarbonate solution and brine, dried over magnesium sulfate, and evaporated to give methyl 4′-(2-amino-2-methylpropyl)-3-isobutyl-4-biphenylcarboxylate (372 mg).
Reaction SMILES: [Br:1][C:2]1[CH:22]=[CH:21][C:5]2[CH:6]=[C:7]([C:9]([C:11]3[O:12][C:13]4[CH:19]=[C:18]([Br:20])[CH:17]=[CH:16][C:14]=4[CH:15]=3)=O)[O:8][C:4]=2[CH:3]=1>C(OCC)C>[Br:20][C:18]1[CH:17]=[CH:16][C:14]2[CH:15]=[C:11]([CH2:9][C:7]3[O:8][C:4]4[CH:3]=[C:2]([Br:1])[CH:22]=[CH:21][C:5]=4[CH:6]=3)[O:12][C:13]=2[CH:19]=1
Reactant: O=C(c1cc2ccc(Br)cc2o1)c1cc2ccc(Br)cc2o1
Solvent: CCOCC
Product: Brc1ccc2cc(Cc3cc4ccc(Br)cc4o3)oc2c1

Procedure:
Following the procedure described above for 84, 85 was prepared from 83 as white crystals (1.43 g, 99%): mp 146-147° C. (diethyl ether). 1H NMR (DMSO-d6) δ7.85 (br s, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.39 (dd, J=8.2, 1.6 Hz, 2H), 6.82 (s, 2H), 4.44 (s, 2H). HPLC (method B) tR 10.43 min (100.00 area %). Anal. (C17H10Br2O3) C, H, Br.
Reaction SMILES: [O:1]=[C:2]1[N:6]([C@@H:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][C@H:8]2[F:20])[C:5](=[O:21])[CH2:4][S:3]1.[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33]([CH:37]=O)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:44])([F:43])[F:42])[CH:24]=1>>[Cl:22][C:23]1[CH:40]=[CH:39][C:26]([CH2:27][N:28]2[C:36]3[C:31](=[CH:32][C:33](/[CH:37]=[C:4]4/[C:5](=[O:21])[N:6]([C@@H:7]5[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][C@H:8]5[F:20])[C:2](=[O:1])[S:3]/4)=[CH:34][CH:35]=3)[CH:30]=[N:29]2)=[C:25]([C:41]([F:42])([F:44])[F:43])[CH:24]=1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)CSC2=O)[C@H](F)C1
Product: CC(C)(C)OC(=O)N1CC[C@@H](N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)C2=O)[C@H](F)C1

Procedure:
1,1-Dimethylethyl trans-4-{(5Z)-5-[(1-{[4-chloro-2-(trifluoromethyl)phenyl]methyl}-1H-indazol-5-yl)methylidene]-2,4-dioxo-1,3-thiazolidin-3-yl}-3-fluoropiperidine-1-carboxylate was prepared either from 1,1-dimethylethyl trans-4-(2,4-dioxo-1,3-thiazolidin-3-yl)-3-fluoropiperidine-1-carboxylate (from Example 273) and [4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 1) following General Procedure F1, or as described in Example 273, Preparation 2.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:25][N:24]([CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][CH:35]=2)[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][C@@H:22]1[C@@H:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:25][N:24]([CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][CH:35]=2)[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1ccc(CN2C[C@H](CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)[C@@H](c3ccccc3)C2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C[C@H](c1cccc2ccccc12)N(C[C@H]1CN(Cc2ccc(C(=O)O)cc2)C[C@@H]1c1ccccc1)C(=O)OC(C)(C)C

Procedure:
A 170 mg portion of methyl 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]methyl}benzoate was dissolved in 4 ml of methanol, mixed with 2 ml of 1 M sodium hydroxide aqueous solution at room temperature and stirred for 41Hours. The reaction solution was concentrated under a reduced pressure, and 1 M hydrochloric acid was added to the residue until its pH became 3. This was extracted with chloroform and washed with saturated brine, and then the organic layer was dried with anhydrous sodium sulfate and concentrated under a reduced pressure to obtain 4-{[(3R,4S)-3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]methyl}benzoic acid as a crude product. The thus obtained crude product was dissolved in 3.0 ml of 4 M hydrogen chloride/1,4-dioxane solution and 30 ml of dioxane at room temperature and stirred for 1Hour. The thus obtained residue was purified by a silica gel column chromatography (chloroform-methanol), and then dissolved in 2.0 ml of dioxane, mixed with 2.0 ml of 4 M hydrogen chloride/1,4-dioxane solution and concentrated under a reduced pressure. The residue was dissolved in chloroform and mixed with diisopropyl ether, and the resulting precipitate was collected by filtration and dried under a reduced pressure to obtain 76 mg of 4-{[(3S,4S)-3-({[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpyrrolidin-1-yl]methyl}benzoic acid dihydrochloride as a colorless solid.
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([F:23])[C:5]([CH2:6][N:7]2[C:11]([CH:12]3[CH2:14][CH2:13]3)=[C:10]([CH3:15])[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:8]2)=[C:4]([F:24])[CH:3]=1.[CH:25]1(B(O)O)[CH2:27][CH2:26]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH:12]1([C:11]2[N:7]([CH2:6][C:5]3[C:21]([F:23])=[CH:22][C:2]([CH:25]4[CH2:27][CH2:26]4)=[CH:3][C:4]=3[F:24])[N:8]=[C:9]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:10]=2[CH3:15])[CH2:14][CH2:13]1
Reactant: OB(O)C1CC1
Reactant: CCOC(=O)c1nn(Cc2c(F)cc(Br)cc2F)c(C2CC2)c1C
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1nn(Cc2c(F)cc(C3CC3)cc2F)c(C2CC2)c1C
Temperature: 100 °C

Procedure:
1.0 g ethyl 1-(4-bromo-2,6-difluorobenzyl)-5-cyclopropyl-4-methyl-1H-pyrazole-3-carboxylate (2.51 mmol, 1.0 eq.) were dissolved in 40 mL toluene and 0.280 g cyclopropylboronic acid (3.26 mmol, 1.3 eq.), 1.86 g potassium phosphate (8.77 mmol, 3.5 eq.), 70 mg tricyclohexylphosphine (0.25 mmol, 0.10 eq.) and 0.66 mL water were added. The reaction mixture was flushed with nitrogen and 28 mg palladium acetate (0.125 mmol, 0.050 eq.) were added. The reaction mixture was stirred at 100° C. over night. Again 0.280 g cyclopropylboronic acid (3.26 mmol, 1.3 eq.), 1.86 g potassium phosphate (8.77 mmol, 3.5 eq.), 70 mg tricyclohexylphosphine (0.25 mmol, 0.10 eq.) and 0.66 mL water were added. The reaction mixture was flushed with nitrogen and 28 mg palladium acetate (0.125 mmol, 0.050 eq.) were added. The reaction mixture was stirred at 100° C. over night. Water was added and the aqueous phase was washed with ethyl acetate twice. The combined organic layers were dried over a silicon filter and concentrated in vacuo. The crude product was purified by flash chromatography to provide 652 mg (1.63 mmol, 65%) of the analytically pure target compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][C:21]=1[N+:22]([O-])=O)[NH:7][C:8](=[O:18])[C:9]1[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=1)([O-])=O.[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[CH:33][C:28]=2[CH:27]=[CH:26]1>>[O:25]1[C:29]2[CH:30]=[CH:31][C:32]([C:34]3[NH:22][C:21]4[CH:20]=[CH:19][C:6]([NH:7][C:8](=[O:18])[C:9]5[CH:14]=[CH:13][C:12]([N:15]([CH3:17])[CH3:16])=[CH:11][CH:10]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:33][C:28]=2[CH:27]=[CH:26]1
Reactant: O=Cc1ccc2occc2c1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4ccc5occc5c4)nc3c2)cc1

Procedure:
Compound 188 was prepared according to the procedure similar to that described in Scheme III from 3,4-dinitro-N-(4-dimethylaminobenzoyl)aniline and benzofuran-5-carboxaldehyde. [M+H]+ calcd for C24H20N4O2: 397.16; found: 397.52.
Reaction SMILES: [NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([O:14]C)=O.O.[NH2:17][NH2:18]>CCO>[NH2:1][C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[CH:4][C:3]=1[C:12]([NH:17][NH2:18])=[O:14]
Reactant: COC(=O)c1cnc2cc(C)nn2c1N
Reactant: NN
Solvent: O
Solvent: CCO
Product: Cc1cc2ncc(C(=O)NN)c(N)n2n1
Temperature: 25 °C

Procedure:
A 250 mL flask containing the Methyl 7-amino-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxylate (2.1 g, 20 mmol), EtOH (55 mL), and hydrazine hydrate (20 mL) was heated to reflux for 6 hours. The mixture was allowed to cool to room temperature. The precipitated solid was filtered and washed with water (2×10 mL) to provide Compound (10-1) as a white solid.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]1[C@H:14]2[C@@H:9]([CH2:10][CH2:11][CH2:12][CH2:13]2)[CH2:8][C:7]1=[O:15])C.[NH3:17]>CO>[O:15]=[C:7]1[N:6]([CH2:5][C:4]([NH2:17])=[O:3])[C@@H:14]2[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:8]1
Reactant: CCOC(=O)CN1C(=O)C[C@@H]2CCCC[C@H]21
Reactant: N
Solvent: CO
Product: NC(=O)CN1C(=O)C[C@@H]2CCCC[C@H]21
Reaction time: 24 h

Procedure:
A solution of trans-octahydro-2-oxo-1H-indole-1-acetic acid ethyl ester; (7.7 g, 0.032 mole) in methanol (200 ml) in methanol (200 ml) is saturated with ammonia and stirred at ambient temperatures 24 hours. The solution is concentrated at reduced pressure to yield a solid, trans-hexahydro-2-oxocyclohexa[b]pyrrol-1-(2H)-acetamide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([S:8]([N:11]([CH2:19][C:20]([OH:22])=O)[C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)(=[O:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH3:24]>>[CH2:23]([N:25]([CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[C:20](=[O:22])[CH2:19][N:11]([S:8]([C:3]1[C:2]([CH3:1])=[CH:7][CH:6]=[CH:5][N:4]=1)(=[O:9])=[O:10])[C:12]1[CH:13]=[CH:14][C:15]([CH3:18])=[CH:16][CH:17]=1)[CH3:24]
Reactant: CCNCc1ccccn1
Reactant: Cc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cc1
Product: CCN(Cc1ccccn1)C(=O)CN(c1ccc(C)cc1)S(=O)(=O)c1ncccc1C

Procedure:
prepared by reaction of [(3-methyl-pyridine-2-sulfonyl)-p-tolyl-amino]-acetic acid with ethyl-pyridin-2-ylmethyl-amine
Reaction SMILES: [CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]([N:14]2[C@H:29]([C:30]([O:32]C(C)(C)C)=[O:31])[CH2:28][C@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:7][C:8]([NH:10][C@@H:11]([C:37]([CH3:40])([CH3:39])[CH3:38])[C:12]([N:14]2[C@H:29]([C:30]([OH:32])=[O:31])[CH2:28][C@:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[CH2:17]3)[CH2:15]2)=[O:13])=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN(c3ccccc3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)N1C[C@@]2(C[C@H]1C(=O)O)CN(c1ccccc1)C(=O)O2

Procedure:
(5S,8S)-tert-butyl 7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (G1) (70 mg, 126 μmol, 1 eq.) was diluted in 1:1 DCM:TFA (2 mL) and stirred overnight at room temp. then concentrated to give (5S,8S)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-3-phenyl-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylic acid (H1) in quantitative yield. LC MS+/−: 500.41/498.55 at 3.09 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:14])([F:13])[F:12])[CH:6]=1)[CH2:3][NH2:4].[CH3:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][C:22](=O)[CH3:23])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:26]=[CH:25][C:19]([O:20][CH2:21][CH:22]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([C:11]([F:12])([F:13])[F:14])[CH:6]=2)[CH3:23])=[CH:18][CH:17]=1
Reactant: NCC(O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)COc1ccc(C)cc1
Product: Cc1ccc(OCC(C)NCC(O)c2cccc(C(F)(F)F)c2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 using 2-hydroxy-2-(3-trifluoromethylphenyl)ethanamine and (4-methylphenoxy)propan-2-one. The residual oil was chromatographed on Kieselgel 60. Elution with 5% methanol-chloroform gave the title compound m.p. 86-96 (heptane). τ(CDCl3) 8.9 (3H, d, J=6 Hz), 7.7 (3H, s), 6.7-7.6 (5H, m, 2H disappears with D2O) 6.0-6.5 (2H, m), 5.3 (1H, m), 3.25 (2H, d, J=9 Hz), 2.95 (2H, d, J=9 Hz), 2.3-2.65 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:5][N:4](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:3]=1.Cl.[OH-].[Na+].C(=O)(O)[O-].[Na+]>O.C(OCC)(=O)C.CO.O1CCCC1>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:14](=[CH:15][CH:16]=2)[N:13]=[CH:12][CH:11]=[C:10]3[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:5][NH:4][N:3]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc2nccc(-c3ccc(O)cc3)c2c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: Cc1n[nH]cc1-c1ccc2nccc(-c3ccc(O)cc3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
A mixture of 9.5 mg 4-[6-(3-methyl-1-trityl-1H-4-pyrazolyl)-4-quinolyl]phenol obtained in Example 153, 0.13 mL of 5 N hydrochloric acid, 1 mL tetrahydrofuran, and 1 mL methanol was stirred overnight at room temperature. The reaction solution was cooled and then neutralized with 2 N aqueous sodium hydroxide and an aqueous saturated sodium bicarbonate solution. Then, ethyl acetate and water were added thereto, the organic layer was separated, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give 4 mg of the title compound as a colorless amorphous.
Reaction SMILES: C([Li])CCC.[CH3:6][N:7]1[CH:11]=[CH:10][N:9]=[CH:8]1.Br[C:13]1[C:22]2[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([CH3:24])[CH:14]=1.CO>C1COCC1.O1CCOCC1.[Cl-].[Cl-].[Zn+2]>[CH3:24][C:15]1[CH:14]=[C:13]([C:8]2[N:7]([CH3:6])[CH:11]=[CH:10][N:9]=2)[C:22]2[C:17](=[C:18]([OH:23])[CH:19]=[CH:20][CH:21]=2)[N:16]=1
Reactant: Cn1ccnc1
Reactant: Cc1cc(Br)c2cccc(O)c2n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: C1COCCO1
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cc(-c2nccn2C)c2cccc(O)c2n1
Temperature: -40 °C
Reaction time: 1.5 h

Procedure:
n-Butyllithium (1.6 M in hexane, 6.0 mL, 9.7 mmol) was added dropwise to a stirred solution of 1-methyl-1H-imidazole (0.83 mL, 11 mmol) in anhydrous THF (60 mL) at −78° C. The reaction mixture was allowed to warm to −40° C. A solution of ZnCl2 (3.9 g, 28 mmol) in anhydrous THF (28 mL) was than added dropwise at −40° C. The reaction mixture was allowed to reach room temperature and was then transferred to a suspension of Pd(PPh4)4 (340 mg, 0.29 mmol) and 4-bromo-2-methyl-quinolin-8-ol (1.0 g, 4.2 mmol) in anhydrous dioxane (20 mL). After stirring for 90 min at 80° C., the reaction mixture was cooled to room temperature, MeOH (5 mL) was added and the solvent was removed in vacuo. The residue was partitioned between DCM (150 mL) and water (50 mL). The pH of the aqueous layer was adjusted to 11 by addition of concentrated aqueous NH3 solution and the aqueous layer was extracted with DCM (2×100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with DCM/MeOH 20:1) to give the title compound. MS (m/z): 240.2 [M+H+].
Reaction SMILES: Br.[N+:2]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[N:9]([CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[C:8]2=[O:22])([O-:4])=[O:3].Cl[C:24]1[C:33]2[C:28](=[CH:29][C:30]([O:36][CH3:37])=[C:31]([O:34][CH3:35])[CH:32]=2)[N:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:35][O:34][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][C:30]=1[O:36][CH3:37])[N:27]=[CH:26][N:25]=[C:24]2[N:19]1[CH2:18][CH2:17][CH:16]([N:9]2[C:8](=[O:22])[C:7]3[C:12](=[CH:13][CH:14]=[C:5]([N+:2]([O-:4])=[O:3])[CH:6]=3)[NH:11][C:10]2=[O:15])[CH2:21][CH2:20]1
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1C1CCNCC1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCC(n4c(=O)[nH]c5ccc([N+](=O)[O-])cc5c4=O)CC3)c2cc1OC
Temperature: 80 °C
Yield: 84.7 %

Procedure:
In 150 ml of DMF was dissolved 3.0 g (8.09 mmol) of 1,2,3,4-tetrahydro-6-nitro-2,4-dioxo-3-(4-piperidinyl)-quinazoline hydrobromide, and 1.7 g (8.09 mmol) of 4-chloro-6,7-dimethoxyquinazoline and 1.1 g (24 mmol) of potassium carbonate were added to the solution, followed by heating at 80° C. for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was washed with an aqueous solution of sodium chloride and dried. After the solvent was distilled off, ethanol and ether were added to the residue. The precipitated crystals were collected by filtration and washed with ether to give 3.28 g (yield: 85%) of Compound 24 as white crystals.