Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([N:9]=[C:10]=[O:11])=O)=[CH:5][CH:4]=1.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:17][C:16]=1[NH:29][NH:30]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Br:1][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]2[NH:9][C:10](=[O:11])[N:29]([C:16]3[CH:17]=[C:18]([CH:19]=[CH:20][C:15]=3[Cl:14])[CH2:21][NH:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[N:30]=2)=[CH:5][CH:4]=1
Reactant: O=C=NC(=O)c1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(CBr)cc3)[nH]c2=O)c1
Yield: 49.7 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using 4-(bromomethyl)benzoyl isocyanate (0.150 g), tert-Butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g), DCM (20 mL), and trifluoro acetic acid (5.0 mL) to afford 0.100 g of the desired product. 1H NMR (400 MHz, DMSO d6): δ 1.12 (s, 9H), 4.28 (br d, 2H), 4.75 (s, 2H), 7.34 (br d, 2H), 7.43 (br s, 1H), 7.60 (br d, 2H), 7.81 (br d, 2H), 8.17 (br s, 1H), 12.57 (s, 1H).
Reaction SMILES: [O:1]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][C:13]#N)[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].C([Al+]CC(C)C)C(C)C.C[OH:29].Cl>C1(C)C=CC=CC=1.CCOCC>[O:1]([CH2:9][CH:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][CH:13]=[O:29])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: CCCC(CCC#N)CO[Si](C)(C)C(C)(C)C
Reactant: CO
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCC(CCC=O)CO[Si](C)(C)C(C)(C)C
Temperature: -70 °C
Reaction time: 3.25 h
Yield: 81.4 %

Procedure:
To a solution of 12.15 g (47.6 mmol) of 4-(t-butyldimethylsiloxymethyl)heptanenitrile in 120 mL of toluene at -70° C., under argon, was added 35.3 mL (53.0 mmol) of a 1.5 M solution of diisobutylaluminum hydride in toluene. After stirring at -70° C. for 3.25 hr, 36.5 mL of methanol was added and the mixture was poured into a mixture of ca. 200 mL of ether, ca. 100 g of ice and 214 mL of 3N hydrogen chloride solution. The aquenous layer was separated and extracted with 3×200 mL of ether. The combined organic layers were washed with 120 mL of saturated sodium bicarbonate solution and 120 mL of saturated brine (a gelatinous precipitate, which resulted on washing with saturated brine, was removed by filtration through celite prior to separation of the aqueous layer), dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica gel to give 10.01 g (81.4%) of crude 4-(t-butyldimethylsiloxymethyl)heptanal; TLC (SiO2, 1:9 ethyl acetate:hexane) Rf 0.55 (PMA); IR (chloroform): μmax 1719 (adehyde C=O) cm-1.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Cl[CH2:21][C:22]1[CH:43]=[CH:42][C:25]([CH2:26][O:27][C:28]2[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:30]([F:41])[CH:29]=2)=[CH:24][CH:23]=1.Cl>CN(C)C=O>[C:1]([C:5]1[CH:9]=[C:8]([CH2:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:7]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([CH2:26][O:27][C:28]3[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[C:30]([F:41])[CH:29]=3)=[CH:42][CH:43]=2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CCl)cc2)cc1F
Reactant: CC(C)(C)c1cc(CCc2ccccc2)[nH]n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(OCc2ccc(Cn3nc(C(C)(C)C)cc3CCc3ccccc3)cc2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-tert-butyl-5-(2-phenylethyl)-1H-pyrazole (250 mg, 1.1 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (60% in oil, 40 mg, 1.0 mmol) at 0° C., and the mixture was allowed to warm to room temperature and stirred for 30 min. Ethyl 3-(4-{[4-(chloromethyl)benzyl]oxy}-2-fluorophenyl)propanoate (350 mg, 1.0 mmol) was added to the reaction mixture, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried using a Presep Dehydration tube (Manufactured by Wako Pure Chemical Industries, Ltd.), and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1-1:1) to give the title compound as a yellow oil. 1H NMR (CDCl3) δ: 1.22 (3H, t, J=7.2 Hz), 1.33 (9H, s), 2.57 (2H, t, J=7.6 Hz), 2.68-2.76 (2H, m), 2.78-2.83 (2H, m), 2.89 (2H, t, J=7.7 Hz), 4.11 (2H, q, J=7.2 Hz), 4.97 (2H, s), 5.21 (2H, s), 5.98 (1H, s), 6.60-6.69 (2H, m), 6.99-7.12 (5H, m), 7.16-7.30 (3H, m), 7.32 (2H, d, J=8.1 Hz).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])[C:3]=1[CH2:21][CH3:22].[O:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([NH2:35])[CH:32]=[N:33][CH:34]=2)[CH2:25][CH2:24]1>C1(C)C=CC=CC=1>[CH2:21]([C:3]1[C:4]([N:14]2[CH2:19][CH2:18][CH2:17][CH2:16][C:15]2=[O:20])=[N:5][C:6]2[C:11]([C:2]=1[NH:35][C:31]1[CH:32]=[N:33][CH:34]=[C:29]([N:26]3[CH2:27][CH2:28][O:23][CH2:24][CH2:25]3)[CH:30]=1)=[C:10]([F:12])[CH:9]=[C:8]([F:13])[CH:7]=2)[CH3:22]
Reactant: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Cl
Reactant: Nc1cncc(N2CCOCC2)c1
Solvent: Cc1ccccc1
Product: CCc1c(N2CCCCC2=O)nc2cc(F)cc(F)c2c1Nc1cncc(N2CCOCC2)c1

Procedure:
Prepared according to Procedure H using 1-(4-chloro-3-ethyl-5,7-difluoroquinolin-2-yl)piperidin-2-one (40.0 mg, 0.120 mmol) and 5-morpholinopyridin-3-amine in toluene to give 1-(3-ethyl-5,7-difluoro-4-((5-(4-morpholinyl)-3-pyridinyl)amino)-2-quinolinyl)-2-piperidinone. 1H NMR (400 MHz, chloroform-d) δ ppm 7.84 (2H, dd, J=7.2, 2.3 Hz), 7.46 (1H, ddd, J=9.6, 2.5, 1.4 Hz), 7.08 (1H, d, J=11.7 Hz), 6.97 (1H, ddd, J=13.5, 8.6, 2.5 Hz), 6.65 (1H, t, J=2.3 Hz), 4.24-4.39 (1H, m), 3.80 (4H, t, J=4.8 Hz), 3.50-3.60 (1H, m), 3.10-3.30 (4H, m), 2.38-2.64 (4H, m), 1.88-2.17 (4H, m), 1.01 (3H, t, J=7.4 Hz). Mass Spectrum (ESI) m/e=468.2 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[NH:14][N:13]=[N:12][N:11]=1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:18](I)[CH3:19]>C1COCC1.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:15])[NH:7][CH2:8][CH2:9][C:10]1[N:11]=[N:12][N:13]([CH2:18][CH3:19])[N:14]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCI
Reactant: CC(C)(C)OC(=O)NCCc1nnn[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1nnc(CCNC(=O)OC(C)(C)C)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A solution of [2-(1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester (prepared by the protocols outlined in N. A. Delaney, G. C. Rovnyak and M. Loots, European Patent specification EP 449523) (1.0 g, 4.69 mmol) in dry THF (20 ml) is treated with a 60% dispersion of sodium hydride in mineral oil (0.19 g, 4.69 mmol) and stirred at ambient temperature for 10 minutes. Ethyliodide (0.375 ml, 4.69 mmol) is added and the reaction mixture is heated at reflux for 7 hours, then diluted with ethyl acetate and filtered. The filtrate is evaporated and the residue purified by flash silica chromatography (elution 3:2 hexane/ethyl acetate) to afford the titled compound, [2-(2-ethyl-2H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester, eluted first and [2-(1-ethyl-1H-tetrazol-5-yl)-ethyl]-carbamic acid tert-butyl ester, eluted second.
Reaction SMILES: [NH2:1][C:2]([C:4]1([C:7]([OH:9])=O)[CH2:6][CH2:5]1)=[O:3].[F:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.Cl.CN(C)CCCN=C=NCC>ClCCl>[F:10][C:11]1[CH:12]=[C:13]([CH:23]=[CH:24][CH:25]=1)[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:7]([C:4]2([C:2]([NH2:1])=[O:3])[CH2:5][CH2:6]2)=[O:9])=[CH:18][CH:17]=1
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Reactant: NC(=O)C1(C(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: NC(=O)C1(C(=O)Nc2ccc(OCc3cccc(F)c3)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.2 %

Procedure:
A solution of 126 mg (1 mmol) of 1-(aminocarbonyl)-1-cyclopropan-carboxylic acid and of 212 mg (1 mmol) 4-(3-fluoro-benzyloxy)-phenylamine (prepared as in example 1b) in 10 ml dichloromethane is cooled to 0° C. and treated with 206 mg (1.1 mmol) N-(−3-dimethylaminopropyl)-N′-ethyl-carbodiimide-hydrochloride (EDCI). The mixture is stirred for additional 2 h at room temperature, evaporated and acidified with dil. citric acid. Extraction with ethyl acetate and recrystallisation from methanol yields 178 mg (56%) of the title compound. Yellowish solid; MS: m/e=329.3 (M++H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[NH:12][C:13]1[CH:27]=[CH:26][C:16]([CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[CH:15][CH:14]=1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:36](=[O:37])[O:35][C:33](=[O:34])[C:32]2=[CH:38][C:39]=1[Cl:40]>C(Cl)(Cl)Cl>[C:21]([O:20][C:19]([NH:18][CH2:17][C:16]1[CH:26]=[CH:27][C:13]([NH:12][C:3]2[CH:4]=[CH:5][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:7][C:2]=2[NH:1][C:33]([C:32]2[CH:38]=[C:39]([Cl:40])[C:29]([Cl:28])=[CH:30][C:31]=2[C:36]([OH:37])=[O:35])=[O:34])=[CH:14][CH:15]=1)=[O:25])([CH3:23])([CH3:24])[CH3:22]
Reactant: CC(C)(C)OC(=O)NCc1ccc(Nc2ccc(C(F)(F)F)cc2N)cc1
Reactant: O=C1OC(=O)c2cc(Cl)c(Cl)cc21
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCc1ccc(Nc2ccc(C(F)(F)F)cc2NC(=O)c2cc(Cl)c(Cl)cc2C(=O)O)cc1
Reaction time: 18 h

Procedure:
Tert-butyl 4-{[2-amino-4-(trifluoromethyl)phenyl]amino}benzylcarbamate (216 mg, 0.56 mmol), and 4,5-dichlorophthalic anhydride (110 mg, 0.51 mmol) are added to a 7 ml vial. After diluting with chloroform (4 mL), the reaction vial is placed on an orbit shaker at 40° C. After 18 hr, the reaction mixture is concentrated. Recrystallization gives 2-({[2-[(4-{[(tert-butoxycarbonyl)amino]methyl}phenyl)amino]-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid, which is dissolved in ethyl acetate (10 mL). After cooling to 0° C., ethyl acetate saturated with HCl (10 mL) is added. After 2 hr the reaction mixture is concentrated and purified by recrystallization to give 2-({[2-{[4-(aminomethyl)phenyl]amino}-5-(trifluoromethyl)phenyl]amino}carbonyl)-4,5-dichlorobenzoic acid hydrochloride. The yield is 92 mg (34%). 1H NMR (400 MHz, DMSO-d6) 13.91 (s, 1H), 10.24 (s, 1H), 8.25 (s, 3H), 8.09 (s, 1H), 8.02 (s, 1H), 7.95, (s, 1H), 7.83 (m, 1H), 7.49 (m, 1 H), 7.43 (d, 2H), 7.36 (m, 1H), 7.21 (d, 2H), 3.97 (m, 2H); HRMS for C22H16Cl2F3N3O3 498.0584 (M+H)+.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH:7]=[C:8]([C:14]([OH:16])=O)[NH:9]2)([CH3:3])[CH3:2].Cl.Cl.Cl.[N:20]1([CH2:27][CH2:28][N:29]2[CH2:34][CH2:33][CH:32]([NH2:35])[CH2:31][CH2:30]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:27][CH2:28][N:29]2[CH2:30][CH2:31][CH:32]([NH:35][C:14]([C:8]3[NH:9][C:10]4[C:6]([CH:7]=3)=[C:5]([O:4][CH:1]([CH3:2])[CH3:3])[CH:13]=[CH:12][CH:11]=4)=[O:16])[CH2:33][CH2:34]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: CC(C)Oc1cccc2[nH]c(C(=O)O)cc12
Reactant: NC1CCN(CCN2CCCCCC2)CC1
Agent: Cl
Product: CC(C)Oc1cccc2[nH]c(C(=O)NC3CCN(CCN4CCCCCC4)CC3)cc12

Procedure:
This compound is synthesized analogously to Example 1 from 4-Isopropoxy-1H-indole-2-carboxylic acid 74 (preparation see below) and amine 5.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([O:32]CC)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[NH2:37][NH2:38].[C-]#N.[Na+].NN>CCO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:24][CH2:25][CH2:26][CH2:27]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:35])[CH2:29][C:30]([NH:37][NH2:38])=[O:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)CC(=O)N1CCN(c2ccc(OC)c(OC3CCCC3)c2)C[C@@H]1Cc1ccccc1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc(N2CCN(C(=O)CC(=O)NN)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Temperature: 60 °C
Yield: 72 %

Procedure:
A solution of (S)-Ethyl 3-(2-benzyl-4-(3-(cyclopentyloxy)-4-methoxyphenyl)piperazin-1-yl)-3-oxopropanoate (120 mg, 0.25 mmol) in EtOH (4 mL) was treated with hydrazine hydrate (24 μL, 0.50 mmol), a catalytic amount of sodium cyanide, and heated in a sealed tube at 50° C. for 24 hr after which time and additional amount of hydrazine was added (48 μL, 1.0 mmol) and the reaction mixture heated at 60° C. for 48 h. After this time the reaction mixture was evaporated, triturated with water and dissolved in EtOAc (2 mL), which was dried over MgSO4, filtered, and evaporated to afford the title compound as a foam (84 mg, 72%). LC/MS (Method B) 3.04 min, [M+1]+ 467.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10](Br)(Br)([Br:12])[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:11][C:10]([Br:12])=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Fc1ccc(C=C(Br)Br)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 39.5 %

Procedure:
4-Fluoro benzaldehyde (1.23 g, 0.00995 mol) was dissolved in DCM (120 mL). Carbon tetrabromide (6.6 g, 0.0199 mol) and triphenylphosphine (10.42 g, 0.0398 mol) were added. The mixture was stirred at RT for 3 h. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified through column chromatography (100% pentane in silica 100-200 mesh, Diameter of column—5.0 cm, height of silica—approx. 5 inch) to provide the desired compound as a yellow colored oil (1.1 g, 44% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C@@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([N:30](C)[C:31](=O)OC(C)(C)C)[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10]([C@@H:12]1[N:20]([C:21](=[O:40])[C@@H:22]([NH:26][C:27](=[O:39])[C@@H:28]([NH:30][CH3:31])[CH3:29])[CH:23]([CH3:25])[CH3:24])[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: COc1ccccc1NC(=O)[C@H]1Cc2cccnc2N1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN[C@@H](C)C(=O)N[C@H](C(=O)N1c2ncccc2C[C@@H]1C(=O)Nc1ccccc1OC)C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.6 %

Procedure:
For Example 9: To a solution of tert-butyl (R)-(2S)-1-((2S)-1-(2-(2-methoxyphenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-1-yl)-3-methyl-1-oxobutan-2-ylamino)-1-oxopropan-2-yl(methyl)carbamate (36 mg, 65.0 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (1 mL, 13.0 mmol, Eq: 200) and the resulting solution was stirred at rt. After 2 h, the reaction mixture was concentrated in vacuo, the residue was treated with saturated aqueous NaHCO3 (5 mL) and the resulting mixture was extracted with DCM (2×5 mL). The combined organic layers were concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM) to give (R)-1-[(S)-3-methyl-2-((S)-2-methylamino-propionylamino)-butyryl]-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid (2-methoxyphenyl)-amide (22 mg), m/z=454 (M+H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1.[CH3:22][NH:23][CH3:24].O>C(O)C>[CH3:22][N:23]([CH3:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:21]=[CH:20][C:11]([C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(OCCCCCBr)cc1
Reactant: CNC
Solvent: O
Solvent: CCO
Product: CN(C)CCCCCOc1ccc(C(=O)c2ccccc2)cc1
Yield: 97 %

Procedure:
A solution of 3.0 g of 4-[(5-bromopentyl)oxy]benzophenone in 30 ml of ethanol was heated to 90° in a pressure tube for 1.5 hours with 16 ml of a 33 percent solution of dimethylamine in ethanol. After cooling the mixture was poured into water and extracted three times with ethyl acetate. The organic phases, dried over sodium sulphate, were evaporated and the residue was chromatographed on neutral aluminium oxide (activity grade III) with hexane:ethyl acetate (7:3). There were obtained 2.69 g (97%) of 4-[(5-(dimethylamino)pentyl)oxy]benzophenone as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]([C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][NH:18][C@H:17]([CH3:21])[CH2:16]2)=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30].C(N(CC)CC)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:23][C:2]([F:1])([F:22])[C:3]([C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[C@H:17]([CH3:21])[CH2:16]2)=[CH:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5]
Reactant: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Reactant: O=S(=O)(Cl)c1cccs1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1S(=O)(=O)c1cccs1
Reaction time: 1 h
Yield: 31.3 %

Procedure:
A 100 mL round-bottomed flask was charged with 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-1-piperazinyl)phenyl)-2-propanol (0.950 g, 2.78 mmol), 5 mL of CH2Cl2, 2-thiophenesulfonyl chloride (0.583 g, 3.19 mmol, Sigma-Aldrich, St. Louis, Mo.), and triethylamine (0.580 mL, 4.16 mmol). After 1 h at room temperature, 0.010 g of DMAP was added. After an additional 30 min, the mixture was concentrated and purified via column chromatography (80 g of silica, 0 to 40% EtOAc in hexanes) to give 1,1,1,3,3,3-hexafluoro-2-(4-((3R)-3-methyl-4-(2-thiophenylsulfonyl)-1-piperazinyl)phenyl)-2-propanol (0.425 g) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ=7.70-7.46 (m, 4H), 7.12 (dd, J=3.7, 4.9 Hz, 1H), 6.94 (d, J=9.0 Hz, 2H), 4.30 (m, 1H), 3.83 (td, J=3.0, 13.1 Hz, 1H), 3.66-3.57 (m, 1H), 3.54-3.38 (m, 2H), 3.31 (s, 1H), 3.07 (dd, J=3.5, 12.3 Hz, 1H), 2.95 (dt, J=3.6, 11.6 Hz, 1H), 1.30 (d, J=6.7 Hz, 3H). m/z (ESI, +ve ion) 488.7 (M+H)+. GK-GKRP EC50 (NADPH-coupled)=2.36 μM; GK-GKRP EC50 (LC MS/MS)=2.57 μM.
Reaction SMILES: [CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11](I)[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][CH2:26][C:27]#[CH:28]>CN(C)C=O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[CH2:1]([C:5]1[NH:6][C:7](=[O:15])[C:8]2[NH:13][N:12]=[C:11]([C:28]#[C:27][CH2:26][CH2:25][CH2:24][Cl:23])[C:9]=2[N:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(I)n[nH]c2c(=O)[nH]1
Reactant: C#CCCCCl
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCCc1nc2c(C#CCCCCl)n[nH]c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 74.7 %

Procedure:
To a nitrogen degassed solution of 5-butyl-3-iodo-1H-pyrazolo[4,3-d]pyrimidin-7(6H)-one (250 mg, 0.786 mmol) in anhydrous N,N-dimethylformamide (6 mL) under nitrogen atmosphere at room temperature was added copper(I) iodide (30 mg, 0.158 mmol), bis(triphenylphosphine)palladium(II)dichloride (62 mg, 0.088 mmol) and finally triethylamine (0.219 mL, 1.572 mmol). The mixture was stirred at room temperature under nitrogen atmosphere for 10 minutes and then a solution of 5-chloro-1-pentyne (161 mg, 1.572 mmol) in anhydrous N,N-dimethylformamide (1.5 mL) was added. The reaction mixture was stirred at 60° C. for 80 minutes. The reaction was evaporated in-vacuo to yield a brown oil. The oil was partitioned between water/brine (1:1) and ethyl acetate. The organic layer was separated, passed through a hydrophobic frit and evaporated in-vacuo to yield a brown solid. The solid was absorbed onto Florisil, loaded onto a 50 g silica cartridge and purified by chromatography using a 0-100% ethyl acetate in cyclohexane gradient over 60 minutes. Appropriate fractions were combined and evaporated in-vacuo to yield the title compound as a pale yellow solid (172 mg).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:38])[CH:12]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)[CH:21]=[N:20]2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:6][CH:5]=1.[OH-].[Li+].CO>O1CCCC1>[CH:14]1([CH2:13][CH:12]([N:19]2[C:24](=[O:25])[CH:23]=[C:22]([O:26][C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=3[CH:33]3[CH2:34][CH2:35][CH2:36][CH2:37]3)[CH:21]=[N:20]2)[C:11]([NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][N:6]=2)=[O:38])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: COC(=O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCC3)cc2=O)nc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(NC(=O)C(CC2CCCC2)n2ncc(Oc3ccccc3C3CCCC3)cc2=O)nc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 30.6 %

Procedure:
A solution of 6-{3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid methyl ester (Example 66, 130 mg, 0.24 mmol) in tetrahydrofuran (5.0 mL) at 25° C. was treated with a 0.5N aqueous lithium hydroxide solution (1.0 mL) and methanol (1.0 mL). The resulting solution was stirred at 25° C. for 5 h. After this time, the solution was concentrated in vacuo. The residue was treated with a 1N aqueous hydrochloric acid solution (0.6 mL). The mixture was extracted with ethyl acetate. The organics were then washed with a saturated aqueous sodium chloride solution and then concentrated in vacuo. The resulting solids were triturated with hexanes and diethyl ether. The resulting solids were collected by filtration and dried in vacuo to afford 6-{3-cyclopentyl-2-[4-(2-cyclopentyl-phenoxy)-6-oxo-6H-pyridazin-1-yl]-propionylamino}-nicotinic acid (38 mg) as a solid; ES+-HRMS m/e calcd for C29H32N4O5 [M+H+] 517.2446 found 517.2443. 1H-NMR (300 MHz, DMSO-d6) δ ppm 1.03-2.05 (m, 18H), 2.31 (m, 1H), 3.04 (m, 1H), 5.57 (dd, J=4.2, J=10.6 Hz, 1H), 5.61 (d, J=2.7 Hz, 1H), 7.20 (m, 1H), 7.27-7.38 (m, 2H), 7.49 (m, 1H), 8.08 (d, Jo=8.8 Hz, 1H), 8.20 (d, J=2.7 Hz, 1H), 8.24 (dd, Jo=8.8 Hz, Jm=2.2 Hz, 1H), 8.84 (d, Jm=2.2 Hz, 1H), 11.33 (s, 1H), 13.18 (br.s., 1H).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:26]([O:32][CH2:33]Cl)(=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[N:14]([CH2:33][O:32][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:13](=[O:18])[N:12]([CH3:19])[C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Reactant: CC(C)(C)C(=O)OCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1c(=O)n(COC(=O)C(C)(C)C)c(=O)c2c1ncn2Cc1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
7-Benzyl-3-methyl-3,7-dihydropurine-2,6-dione (3.18 g) was suspended in N,N-dimethylformamide (40 ml), and potassium carbonate (2.6 g) and chloromethyl pivalate (2.15 ml) were added thereto. The reaction solution was stirred at 40° C. overnight, then diluted with ethyl acetate, and washed with 1 N hydrochloric acid. The organic layer was dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain 4.26 g of the title compound from a fraction eluted with hexane-ethyl acetate (1:3).