Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:6](=[O:38])[NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)=[CH:16]2)=[O:12])(C)(C)C.[F:39][C:40]([F:45])([F:44])C(O)=O.C(N(CC)CC)C.FC(F)(F)C(OCC)=O>C(Cl)Cl.C1COCC1>[F:39][C:40]([F:45])([F:44])[C:6]([NH:7][CH2:8][CH2:9][NH:10][C:11]([C:13]1[C:14]([OH:37])=[C:15]2[C:20](=[CH:21][N:22]=1)[N:19]([CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:18](=[O:30])[C:17]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)=[CH:16]2)=[O:12])=[O:38]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NCCNC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Agent: CCOC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(NCCNC(=O)C(F)(F)F)c1ncc2c(cc(-c3ccccc3)c(=O)n2Cc2ccccc2)c1O
Reaction time: 2 h

Procedure:
{2-[(1-Benzyl-5-hydroxy-2-oxo-3-phenyl-1,2-dihydro-[1,7]naphthyridine-6-carbonyl)-amino]ethyl}-carbamic acid tert-butyl ester (25 mg, 0.049 mmol) was dissolved in CH2Cl2 (2 mL). Trifluoroacetic acid (1 mL) was added, and the mixture was stirred for 2 h. Solvent and excess TFA was removed by evaporation, and to the residue were added THF (3 mL), triethylamine (0.034 mL, 0.24 mmol), and ethyl trifluoroacetate (2 mL). The resulting mixture was refluxed overnight, then concentrated to dryness. The residue was dissolved in EtOAc and washed with 0.1 M HCl. The organic layer was dried over MgSO4 and concentrated, and the crude product was purified by silica gel chromatography (0-5% MeOH/CH2Cl2) to give 12.7 mg of the title compound as a light yellow solid. MS: (+) m/z 511.33 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N+:9]([O-:11])=[O:10])[CH:5]=[CH:6][C:7]=1[CH3:8].[Br:12]Br>[Fe]>[Br:12][C:6]1[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=[C:2]([F:1])[C:7]=1[CH3:8]
Reactant: BrBr
Reactant: Cc1ccc([N+](=O)[O-])cc1F
Agent: [Fe]
Product: Cc1c(F)cc([N+](=O)[O-])cc1Br
Temperature: 100 °C
Yield: 23.2 %

Procedure:
To 3-fluoro-4-methylnitrobenzene (4.0 gm, 25.8 mmol) was added bromine (5.2 gm, 32 mmol) and iron powder (100 mg). The mixture was heated under a condenser at 100° C. for 40 hr and then poured into ice water containing enough sodium sulfite to quench the excess bromine. The aqueous layer was extracted twice with ether and the ether layers were washed with brine, dried over sodium sulfate, combined and evaporated. The residue was purified by FC (10-20% ethyl acetate/hexanes) to afford 1.4 gm of the title compound as a white solid (the major and highest Rf isomer). NMR (CDCl3): δ 2.41 (d, 3H, J=3 Hz), 7.85 (dd, 1H, J=2.1 and 9 Hz), 8.24 (dd, 1H, J=1.8 and 2.1 Hz).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][N:27]2[CH:31]=[C:30]([C:32]([O:34]CC)=[O:33])[N:29]=[CH:28]2)[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.[OH-].[Li+]>C1COCC1.O>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2)[CH2:26][N:27]1[CH:31]=[C:30]([C:32]([OH:34])=[O:33])[N:29]=[CH:28]1
Reactant: CCOC(=O)c1cn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)cn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(Cc2ccc(-c3nc4ccc(C5(c6ccccc6)CC5)nc4s3)c(F)c2)cn1
Temperature: 100 °C

Procedure:
To a solution of ethyl 1-((3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)methyl)-1H-imidazole-4-carboxylate (0.034 g, 0.068 mmol) in THF was added a solution of lithium hydroxide (0.0082 g, 0.34 mmol) in 1.0 mL of water. The reaction mixture was heated to 100° C. for 18 h. The crude reaction mixture was concentrated in vacuo. The residue was diluted with water and the pH was adjusted to 1 with aq. HCl. The solid was collected by filtration, rinsed with water and Et2O, and dried in vacuo at 50° C. for 2 h to afford 1-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)benzyl)-1H-imidazole-4-carboxylic acid. MS (ESI) m/z: calculated: 470.1; Observed: 471.0 (M++1).
Reaction SMILES: [CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][NH:6]1)[CH:2]([CH3:4])[CH3:3].[F:15][C:16]([F:21])([F:20])[C:17](O)=[O:18]>>[CH2:1]([CH:5]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][N:6]1[C:17](=[O:18])[C:16]([F:21])([F:20])[F:15])[CH:2]([CH3:4])[CH3:3]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)CC1Cc2ccccc2CN1
Product: CC(C)CC1Cc2ccccc2CN1C(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
To 206 mg of 3-isobutyl-1,2,3,4-tetrahydroisoquinoline obtained in Example 20 was added 458 mg of anhydrous trifluoroacetic acid, followed by stirring at room temperature for 2 hours. Further, 200 mg of anhydrous trifluoroacetic acid was added thereto, followed by stirring at 40° C. for 1 hour. After completion of the reaction, the reaction liquid was concentrated under reduced pressure, added with ethyl acetate, and washed with an aqueous sodium bicarbonate solution and then with brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by evaporation to obtain 283 mg (yield 91%) of a title compound as a pale yellow oily substance.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][S:37]([CH2:40][C:41]1[CH:47]=[CH:46][C:44]([NH2:45])=[CH:43][CH:42]=1)(=[O:39])=[O:38].Cl.C([O-])(O)=O.[Na+]>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:45][C:44]4[CH:46]=[CH:47][C:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])=[CH:42][CH:43]=4)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Reactant: CS(=O)(=O)Cc1ccc(N)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Nc5ccc(CS(C)(=O)=O)cc5)n4)ccc3n2C)cc1

Procedure:
To a solution of {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-(4-methoxy-phenyl)-carbamic acid tert-butyl ester (100 mg, 0.20 mmol) and 4-[(methylsulfonyl)methyl]aniline (37 mg, 0.20 mmol) was added cat HCl and the reaction was heated to 70 C overnight. The reaction was neutralized with solid NaHCO3, filtered and concentrated. The crude material as purified through silica gel to give the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.24 (s, 1H), 7.82 (d, J=6.0 Hz, 1H), 7.65-7.74 (m, 3H), 7.54 (d, J=1.5 Hz, 1H), 7.35 (d, J=8.7 Hz, 2H), 7.24 (dd, J=8.7 and 1.5 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 6.94 (d, J=9.0 Hz, 2H), 5.72 (d, J=5.7 Hz, 1H), 4.32 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.46 (s, 3H), 2.84 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=644 [M+H]+.
Reaction SMILES: Br[C:2]1[C:3]([O:13]C)=[C:4]([CH3:12])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>C(OCC)(=O)C>[C:15]([O:19][C:20]([N:22]1[CH2:28][CH2:27][CH2:26][N:25]([C:2]2[C:3]([OH:13])=[C:4]([CH3:12])[CH:5]=[C:6]3[C:11]=2[N:10]=[CH:9][CH:8]=[CH:7]3)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Reactant: COc1c(C)cc2cccnc2c1Br
Solvent: CCOC(C)=O
Product: Cc1cc2cccnc2c(N2CCCN(C(=O)OC(C)(C)C)CC2)c1O
Temperature: 140 °C
Yield: 34 %

Procedure:
A mixture of product from step 2 (1.66 g, 6.58 mmol) and [1,4]Diazepane-1-carboxylic acid tert-butyl ester (4 g, 20 mmol) was heated via microwave to 140° C. for 1 h. After being cooled to rt, it was diluted with ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4 and then purified by flash column chromatography on silica gel to give the desired product (0.8 g, 35%). MS (ES) m/z 358 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][C:24](OC)=[C:23]([O:29]C)[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([C:31]([F:34])([F:33])[F:32])[NH:11]1.B(Br)(Br)Br>C(Cl)Cl>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14]2=[N:15][C:16]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([OH:29])[CH:22]=3)=[N:17][C:18](=[O:19])[C:13]2=[C:12]([C:31]([F:33])([F:32])[F:34])[NH:11]1
Reactant: COc1ccc(Cc2nc3n(-c4c(Cl)cc(Cl)cc4Cl)[nH]c(C(F)(F)F)c-3c(=O)n2)cc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=c1nc(Cc2cccc(O)c2)nc2n(-c3c(Cl)cc(Cl)cc3Cl)[nH]c(C(F)(F)F)c1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a stirred solution of 60 mg (0.12 mmol) of 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-methoxy-4-methoxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one in 2 mL of CH2Cl2 was added 2 mL of a 1M solution of BBr3 in CH2Cl2. The solution was stirred 2.5 h at RT and quenched with 1 N aq. HCl. The mixture was diluted with water and extracted with EtOAc. The organic extract was washed with brine, dried (MgSO4), and concentrated under reduced pressure. The crude product was chromatographed on silica gel (elution with 1:1 hexanes-THF, then THF) to afford 1-(2,4,6-trichlorophenyl)-3-trifluoromethyl-6-(3-hydroxybenzyl)pyrazolo[3,4-d]pyrimidin-4-one, as an off-white solid. Mass spec.: 487 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH3:17])=[C:6]([CH:9]=1)[CH:7]=[O:8].[BH4-].[Na+]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]2[CH2:16][CH3:17])=[C:6]([CH2:7][OH:8])[CH:9]=1
Reactant: CCC1CCCCN1c1ccc(Br)cc1C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCC1CCCCN1c1ccc(Br)cc1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 5-bromo-2-(2-ethylpiperidin-1-yl)benzaldehyde (10 g, 48.4 mmol) in methanol (100 mL) under nitrogen was added sodium borohydride (1.28 g, 48.4 mmol) at 0° C. in portions. The reaction mixture was stirred at RT for 1 hour, then evaporated to remove methanol. The resulting crude was taken up with water (100 mL) and extracted with EtOAc. The organic layer was washed with water, then dried (Na2SO4) and concentrated under reduced pressure to afford the title compound as a yellow oil (8.8 g, 88%). 1H NMR (DMSO-d6, 400 MHz) δ 7.55 (1H, s), 7.34-7.54 (1H, m), 7.08 (1H, d), 5.19 (1H, t), 4.62 (1H, d), 4.46 (1H, d), 2.77-2.84 (2H, m), 2.45 (1H, m), 1.74 (2H, t), 1.55 (2H, t), 1.33 (2H, m), 1.17 (2H, m), 0.62 (3H, t).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:27])[C:22]([O:24]CC)=[O:23])[CH2:17][CH2:16]1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+].Cl>C1COCC1>[C:1]([C:5]1[CH:10]=[C:9]([C:11]([OH:14])([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=1[N:15]1[CH2:16][CH2:17][N:18]([C:21](=[O:27])[C:22]([OH:24])=[O:23])[CH2:19][CH2:20]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(=O)N1CCN(c2ccc(C(C)(C)O)cc2C(C)(C)C)CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(C)(C)O)ccc1N1CCN(C(=O)C(=O)O)CC1
Yield: 94.6 %

Procedure:
To a stirred solution of ethyl {4-[2-tert-butyl-4-(1-hydroxy-1-methylethyl)phenyl]piperazin-1-yl}(oxo)acetate (Example 167, 0.38 g, 1.01 mmol) in THF (5 mL) stirring at 0° C. was added 1 M lithium hydroxide solution (5 mL, 5 mmol). After 2 h the reaction mixture was acidified with 1 M hydrochloric acid solution and extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure to provide {4-[2-tert-butyl-4-(1-hydroxy-1-methylethyl)phenyl]piperazin-1-yl}(oxo)acetic acid (0.333 g, 95%) as a pale yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])/[C:5]/2=[CH:12]\[C:13]1[NH:17][C:16]([CH3:18])=[C:15]([C:19]([OH:21])=O)[C:14]=1[CH3:22].Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.[NH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:74])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][NH2:73])=[N:64][CH:63]=1>[Cl-].[Na+].O.CN(C=O)C>[NH2:52][C:53]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:54]=1[NH:60][C:61](=[O:74])[C:62]1[CH:67]=[CH:66][C:65]([NH:68][CH2:69][CH2:70][CH2:71][CH2:72][NH:73][C:19]([C:15]2[C:14]([CH3:22])=[C:13](/[CH:12]=[C:5]3\[C:6](=[O:11])[NH:7][C:8]4[C:4]\3=[CH:3][C:2]([F:1])=[CH:10][CH:9]=4)[NH:17][C:16]=2[CH3:18])=[O:21])=[N:64][CH:63]=1
Reactant: NCCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c(C)c1C(=O)NCCCCNc1ccc(C(=O)Nc2ccc(F)cc2N)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 80.9 %

Procedure:
5-(5-Fluoro-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl)-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (300 mg, 1 mmol) and 8 ml of DMF were stirred at room temperature while 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (384 mg, 2 mmol), hydroxybenzotriazole (162 mg, 1.2 mmol), triethylamine (404 mg, 4 mmol) and N-(2-amino-4-fluorophenyl)-6-(4-aminobutylamino)nicotinamide (333 mg, 1.05 mmol) were added. The mixture was stirred for 20 hours at room temperature. The mixture was diluted with 400 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (485 mg, 81%) as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH2:12][S:13]([C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[CH:18][CH:17]=2)(=[O:15])=[O:14])=[CH:10][C:5]([O:6][CH2:7][CH2:8][OH:9])=[CH:4][C:3]=1[O:26][CH2:27][CH2:28][Cl:29].[N:30]([O-])=O.[Na+].C(=O)(O)[O-].[Na+]>C1COCC1.Cl.O>[Cl:29][CH2:28][CH2:27][O:26][C:3]1[CH:4]=[C:5]([O:6][CH2:7][CH2:8][OH:9])[CH:10]=[C:11]2[C:2]=1[NH:1][N:30]=[C:12]2[S:13]([C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][CH:17]=1)(=[O:14])=[O:15]
Reactant: O=N[O-]
Reactant: Nc1c(CS(=O)(=O)c2cccc3ccccc23)cc(OCCO)cc1OCCCl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)c1n[nH]c2c(OCCCl)cc(OCCO)cc12
Temperature: 3 °C
Yield: 94.6 %

Procedure:
A mixture of 2-[4-amino-3- (2-chloroethoxy)-5-(naphthalene-1-sulfonylmethyl)phenoxy]ethanol (1.22 g, 2.8 mmoles) in THF and 4M HCl was stirred, under nitrogen, at 3° C., treated dropwise with a solution of sodium nitrite (0.20 g, 2.94 mmoles) in H2O, poured into a cold solution of saturated sodium bicarbonate and extracted with EtOAc. The extracts were combined, dried over Na2SO4 and concentrated under vacuum to afford the title compound (1.18 g, 2.65 mmoles), identified by HNMR and mass spectral analyses.
Reaction SMILES: [C:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]#[C:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)[CH:20]=3)[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][CH2:13]2)[CH:9]=1)([O:3]C)=[O:2].[OH-].[K+].O.Cl>O1CCCC1.CO>[C:1]([C:5]1[S:6][CH:7]=[C:8]([C:10]#[C:11][C:12]2([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[CH:20]=3)[CH2:13][CH2:14][C:15](=[O:18])[CH2:16][CH2:17]2)[CH:9]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1cc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC(=O)CC2)cs1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: COc1ccc(C2(C#Cc3csc(C(=O)O)c3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 95.5 %

Procedure:
A solution of 4-(2-carbomethoxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.19 g, 0.43 mmol) and coarsely ground potassium hydroxide (0.036 g, 0.64 mmol) in tetrahydrofuran (2 mL), methanol (2 mL), and water (0.4 mL) was stirred at room temperature under an argon atmosphere for 24 h. The reaction was acidified (10% HCl), was extracted three times with 5:95 methanol:dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 0.1:3:97 acetic acid:methanol:dichloromethane, provided 4-(2-carboxythien-4-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as an off-white solid (0.18 g, 95%), mp 80°-82° C. Anal. (C25H26O5S.0.25 H2O) calcd: C, 67.78; H, 6.03; found: C, 67.72; H, 6.02.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6](=[O:35])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:15]4[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]5[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:28]=5[F:34])[C:16]=4[N:17]=[C:18](SC)[N:19]=3)[CH:8]=2)[CH2:3][CH2:2]1.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[CH:1]1([CH2:4][NH:5][C:6](=[O:35])[C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[C:9]([C:14]3[C:15]4[CH:25]=[CH:24][C:23](=[O:26])[N:22]([C:27]5[C:28]([F:34])=[CH:29][CH:30]=[CH:31][C:32]=5[F:33])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH:8]=2)[CH2:3][CH2:2]1
Reactant: CSc1nc(-c2cc(C(=O)NCC3CC3)ccc2C)c2ccc(=O)n(-c3c(F)cccc3F)c2n1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1ccc(C(=O)NCC2CC2)cc1-c1ncnc2c1ccc(=O)n2-c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 8.3 %

Procedure:
N-(cyclopropylmethyl)-3-[8-(2,6-difluorophenyl)-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzamide (13.5 mg, 0.027 mmol), was dissolved in anhydrous methanol (2 mL) and was added to a tube containing nickel chloride hexahydrate (2 mg). The tube was placed under an atmosphere of nitrogen and cooled using a dry-ice/acetone bath to about −15° C. Sodium borohydride (2 mg) was then added (nitrogen removed during addition and then replaced) and the solution turned black. The solution was stirred in the dry ice/acetone bath for 1.5 h. 1 N HCl (4 mL) was added and the solution was allowed to warm to room temperature and stirred under an air atmosphere for about 2 hours. Dichloromethane (2 mL) was added to the solution and it was stirred vigorously for 10 min. The solution was filtered through a hydrophobic frit packed with celite and was washed with further dichloromethane (2 mL×2). The filtrate was concentrated and purified by HPLC to give the title product (1 mg, 8.2%). LC-MS m/z 447 (M+H)+, 2.98 min (ret time). 1H-NMR (d6-DMSO) δ 0.22 (m, 2H), 0.42 (m, 2H), 1.01 (br s, 1H), 2.23 (s, 3H), 3.14 (br s, 2H), 6.87 (m, 1H), 7.43 (m, 2H), 7.65 (m, 2H), 7.95 (m, 2H), 8.60 (m, 1H), 9.07 (s, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[C:12]([O:14][CH3:15])[C:11]([O:16][CH3:17])=[C:10]([O:18][CH3:19])[CH:9]=2)[O:5][N:4]=1.[NH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[CH3:19][O:18][C:10]1[CH:9]=[C:8]([C:6]2[O:5][N:4]=[C:3]([CH2:2][N:20]3[CH2:25][CH2:24][N:23]([CH2:2][C:3]4[CH:7]=[C:6]([C:8]5[CH:9]=[C:10]([O:18][CH3:19])[C:11]([O:16][CH3:17])=[C:12]([O:14][CH3:15])[CH:13]=5)[O:5][N:4]=4)[CH2:22][CH2:21]3)[CH:7]=2)[CH:13]=[C:12]([O:14][CH3:15])[C:11]=1[O:16][CH3:17]
Reactant: C1CNCCN1
Reactant: COc1cc(-c2cc(CCl)no2)cc(OC)c1OC
Product: COc1cc(-c2cc(CN3CCN(Cc4cc(-c5cc(OC)c(OC)c(OC)c5)on4)CC3)no2)cc(OC)c1OC

Procedure:
3-Chloromethyl-5-(3,4,5-trimethoxyphenyl)isoxazole (170 mg) and piperazine (26 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: C(O[C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5])C.[CH3:15][C@H:16]1[CH2:21][CH2:20][CH2:19][C@H:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH:18]([CH3:22])[N:17]1[CH2:23][CH2:24][CH2:25][NH:26][C:4]([CH:6]1[N:13]2[CH:9]([CH2:10][CH2:11][C:12]2=[O:14])[CH2:8][CH2:7]1)=[O:5]
Reactant: CCOC(=O)C1CCC2CCC(=O)N21
Reactant: C[C@H]1CCC[C@H](C)N1CCCN
Product: CC1CCCC(C)N1CCCNC(=O)C1CCC2CCC(=O)N21

Procedure:
A solution of hexahydro-5-oxo-1H-pyrrolizine-3-carboxylic acid ethyl ester (5.0 g, 0.0254 mol) in trans-3-[2,6-dimethylpiperidinyl]propylamine (34 g, 0.2 mol) is stirred at room temperature 24 hours. The solution is concentrated at reduced pressure and distilled to yield N-[3-[2,6-dimethyl-1-piperidinyl]propyl]-hexahydro-5-oxo-1H-pyrrolizine-3-carboxamide, trans-isomer.
Reaction SMILES: CCN(C(C)C)C(C)C.[C:10]([NH:18][CH2:19][C:20]([OH:22])=O)(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[N:46]1([C:52]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]([F:63])([F:62])[F:61])=[O:53])[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CN(C=O)C.O>[O:22]=[C:20]([N:49]1[CH2:50][CH2:51][N:46]([C:52](=[O:53])[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][C:55]=2[C:60]([F:63])([F:61])[F:62])[CH2:47][CH2:48]1)[CH2:19][NH:18][C:10](=[O:17])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(c1ccccc1C(F)(F)F)N1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30 %

Procedure:
DIPEA (0.169 mL, 0.98 mmol) was added to a stirred solution of benzoylamino-acetic acid (50 mg, 0.28 mmol) in DMF (1 mL). HOBT (45 mg, 0.34 mmol) and EDCI.HCl (64 mg, 0.34 mmol) were added followed by the addition of piperazine-1-yl-(2-trifluoromethyl-phenyl)-methanone hydrochloride (0.31 mmol) at room temperature. The resulting mixture was stirred at room temperature overnight. Water was then added, and the product was extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude product. Purification using column chromatography (using silica gel, 60-120 A° and 10% methanol in chloroform as the eluent) afforded N-{2-Oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazine-1-yl]-ethyl}benzamide in 30% yield, LC-MS purity: 95%, 1H NMR (CDCl3): δ 7.84 (d, 2H), 7.76 (d, 1H), 7.66-7.56 (m, 2H), 7.54-7.42 (m, 3H), 7.34 (d, 2H), 7.24 (t, 1H), 4.36-4.20 (m, 2H), 4.02-3.84 (m, 2H), 3.78-3.50 (m, 4H), 3.26 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:10]2[C:5](=[CH:6][C:7]([C:11]([O:13][CH3:14])=[O:12])=[CH:8][CH:9]=2)[C:4](=O)[CH2:3]1.Cl.[NH2:18][OH:19].C([O-])(=O)C.[Na+]>CO>[OH:19][N:18]=[C:4]1[C:5]2[C:10](=[CH:9][CH:8]=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:6]=2)[C:2]([CH3:16])([CH3:1])[CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)C(=O)CC2(C)C
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc2c(c1)C(=NO)CC2(C)C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 1,1-dimethyl-3-oxo-2,3-dihydro-1H-indene-5-carboxylate (430 mg, 1.97 mmol, 1.0 eq.) in methanol (7.5 ml) was added hydroxylamine hydrochloride (340 mg, 4.93 mmol, 2.5 eq.) followed by sodium acetate (807 mg, 9.85 mmol, 5.0 eq.) and the reaction mixture was heated at reflux for 2 h at 80° C. The reaction mixture was concentrated and then extracted with ethyl acetate (3×40 ml). The organic part was separated, washed with water (20 ml) and brine (20 ml) and dried over sodium sulfate. After concentrating the filtrate the crude product thus obtained was directly taken through to the next step without purification.