Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([CH:17]=1)[CH:15]=[CH:14][CH:13]=[CH:12]2.[N+:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25](Cl)=[O:26])=[CH:23][CH:22]=1)([O-:20])=[O:19].C(=O)([O-])O.[Na+]>ClC(Cl)C>[CH3:8][C:9]1[CH:10]=[C:11]2[N:16]([C:17]=1[C:25]([C:24]1[CH:23]=[CH:22][C:21]([N+:18]([O-:20])=[O:19])=[CH:29][CH:28]=1)=[O:26])[CH:15]=[CH:14][CH:13]=[CH:12]2
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc2ccccn2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: Cc1cc2ccccn2c1C(=O)c1ccc([N+](=O)[O-])cc1
Yield: 74.8 %

Procedure:
4.54 ml (32.52 mmol) of triethylamine are added, at ambient temperature under an inert atmosphere, to 3.56 g (27.14 mmoles) of 2-methylindolizine in 15 ml of dichloroethane, followed, dropwise, by 5.53 g (29.85 mmol) of 4-nitrobenzoic acid chloride. The reaction medium is stirred for 18 h at ambient temperature, hydrolysed with a saturated aqueous solution of sodium hydrogen carbonate and then extracted with dichloromethane. The organic phase is washed with a saturated aqueous solution of sodium chloride, dried over sodium sulphate, and then concentrated under reduced pressure. The residue obtained is washed with diethyl ether. 5.69 g of a yellow solid are obtained.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.C(N(C(C)C)CC)(C)C.FC(F)(F)S(O[Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])(=O)=O>C(Cl)Cl>[CH:27]([Si:26]([CH:33]([CH3:35])[CH3:34])([CH:30]([CH3:32])[CH3:31])[O:1][CH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:29])[CH3:28]
Reactant: CC(C)[Si](OS(=O)(=O)C(F)(F)F)(C(C)C)C(C)C
Reactant: O=C1CCC(CCO)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)[Si](OCCC1CCC(=O)CC1)(C(C)C)C(C)C

Procedure:
A solution of 4-(2-hydroxy-ethyl)-cyclohexanone (Intermediate R10, 6.8 g, 52.6 mmol, (obtainable as described in the publication by Ciufolini et. al. J. Amer. Chem. Soc. 1991, 113, 8016) was dissolved in CH2Cl2 (75 mL) and treated with diisopropylethylamine (9.2 mL, 52.6 mmol) followed by tri-isopropylsilyl trifluoromethane sulfonate (TIPSTf) (15.3 g, 50.2 mmol) at −30 EC. The reaction mixture was warmed to 0 EC for 1 h. The mixture was subjected to an aqueous work-up and purified by chromatography on SiO2 to give 4-(2-triisopropylsilanyloxy-ethyl)-cyclohexanone (Intermediate R11, 11.8 g (82%). Intermediate R11 was converted via Intermediate R12 to the unsaturated aldehyde, 5-(2-triisopropylsilanyloxy-ethyl)-cyclohex-1-enecarbaldehyde (Intermediate R13)
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:34])/[CH:6]=[CH:7]/[C:8]1[CH:9]=[C:10]2[C:30](=[CH:31][CH:32]=1)[O:29][C:13]1([CH2:18][CH2:17][N:16]([CH2:19][C:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[NH:22][CH:21]=3)[CH2:15][CH2:14]1)[CH2:12][C:11]2=[O:33].Cl>O1CCOCC1.O>[NH:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:20]([CH2:19][N:16]2[CH2:17][CH2:18][C:13]3([CH2:12][C:11](=[O:33])[C:10]4[C:30](=[CH:31][CH:32]=[C:8](/[CH:7]=[CH:6]/[C:5]([OH:34])=[O:4])[CH:9]=4)[O:29]3)[CH2:14][CH2:15]2)=[CH:21]1
Reactant: COC(=O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4ccccc34)CC1)O2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)/C=C/c1ccc2c(c1)C(=O)CC1(CCN(Cc3c[nH]c4ccccc34)CC1)O2
Temperature: 25 °C
Reaction time: 10 h

Procedure:
4 M NaOH (0.081 ml, 0.325 mmol) was added to a solution of (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid methyl ester (140 mg, 0.325 mmol) in dioxane (2 ml) and water (1 ml) and the mixture was stirred at RT for 10 h. The pH was brought to 4 with 2 M HCl and the solvent was removed under vacuum to give (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-acrylic acid. The crude compound (135 mg) was dissolved in THF (12 ml). TEA (0.092 ml, 0.66 mmol), EDC (126 mg, 0.66 mmol) HOBT (44 mg, 0.33 mmol) and NH2OTHP (48 mg, 0.41 mmol) were added and the mixture was stirred at RT overnight. The solvent was removed and the residue was partitioned between DCM and water. The organic phase was dried over Na2SO4, evaporated and the crude product was purified by column chromatography (eluent:DCM/MeOH/NH4OH 96:4:0.4). The resulting (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide was dissolved in DCM and treated with HCl/Et2O for 3 h. The precipitate was filtered and washed with DCM to give (E)-3-{1′-(1H-indol-3-ylmethyl)-4-oxo-spiro[chromane-2,4′-piperidine]-6-yl}-N-hydroxy-acrylamide hydrochloride as a white solid (40 mg).
Reaction SMILES: N[C:2]1[C:11]2[N:12]=[C:13]([CH2:22][O:23][CH2:24][CH3:25])[N:14]([CH2:15][C:16]3([OH:21])[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].I[CH3:29].O>C1COCC1>[CH2:24]([O:23][CH2:22][C:13]1[N:14]([CH2:15][C:16]2([O:21][CH3:29])[CH2:17][CH2:18][CH2:19][CH2:20]2)[C:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=3[N:3]=[CH:2][C:11]=2[N:12]=1)[CH3:25]
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC1(O)CCCC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOCc1nc2cnc3ccccc3c2n1CC1(OC)CCCC1
Temperature: 50 °C
Reaction time: 1 h
Yield: 24.1 %

Procedure:
To a solution of 1-{[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]methyl}cyclopentanol (1.19 g, 3.66 mmol, prepared as described in Example 3) in THF (18 mL) at rt was added sodium hydride (60% dispersion in oil, 161 mg, 4.03 mmol). The mixture was stirred for 1 h and iodomethane (0.25 mL, 4.03 mmol) was added. The mixture was heated to 50° C. for 3 h and then was left to stand at rt overnight. More sodium hydride (60% dispersion in oil, 80 mg) and iodomethane (0.13 mL) were added. The mixture was heated for 2 h, then water was added and the mixture was extracted three times with ethyl acetate. The combined organic extracts were washed with brine and dried over Na2SO4, filtered and concentrated to an oil. The crude product was purified by flash chromatography (silica gel, eluted with ethyl acetate) to yield 2-(ethoxymethyl)-1-[(1-methoxycyclopentyl)methyl]-1H-imidazo[4,5-c]quinoline as a yellow oil (0.30 g, 24%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]([C:8]2[CH:9]=[CH:10][C:11]3[N:15]=[C:14]([CH:16]4[CH2:18][CH:17]4[C:19]([OH:22])([CH3:21])[CH3:20])[N:13]([CH3:23])[C:12]=3[CH:24]=2)[C:4](=[O:25])[CH:3]=1.[Cl:26][C:27]1[S:31][CH:30]=[C:29]([CH2:32]O)[CH:28]=1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1>[Cl:26][C:27]1[S:31][CH:30]=[C:29]([CH2:32][O:1][C:2]2[CH:7]=[CH:6][N:5]([C:8]3[CH:9]=[CH:10][C:11]4[N:15]=[C:14]([CH:16]5[CH2:18][CH:17]5[C:19]([OH:22])([CH3:20])[CH3:21])[N:13]([CH3:23])[C:12]=4[CH:24]=3)[C:4](=[O:25])[CH:3]=2)[CH:28]=1
Reactant: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(O)cc3=O)cc21
Reactant: OCc1csc(Cl)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: Cn1c(C2CC2C(C)(C)O)nc2ccc(-n3ccc(OCc4csc(Cl)c4)cc3=O)cc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 8.7 %

Procedure:
To a mixture of 4-hydroxy-1-(2-((1RS,2SR)-2-(2-hydroxypropan-2-yl)cyclopropyl)-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (100 mg), (5-chloro-3-thienyl)methanol (77 mg), tributylphosphine (0.219 ml) and THF (10 ml) was added 1,1′-(azodicarbonyl)dipiperidine (223 mg), and the mixture was stirred at 60° C. for 2 h. The solvent was evaporated, and the residue was purified by column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was suspended in toluene, and the insoluble material was collected by filtration to give the title compound (12 mg) as an off-white solid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH:5]1([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[CH:17]([C:19]([CH3:21])=[O:20])=[CH2:18]>>[CH:11]1([C:5]2[CH:6]=[CH:7][C:8]([CH2:18][CH2:17][C:19](=[O:20])[CH3:21])=[CH:9][CH:10]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: C=CC(C)=O
Reactant: c1ccc(C2CCCCC2)cc1
Agent: [Al+3]
Agent: [Cl-]
Product: CC(=O)CCc1ccc(C2CCCCC2)cc1
Reaction time: 8 h

Procedure:
To a stirred solution of aluminium chloride (0.15 mole) in cyclohexylbenzene (0.5 mole) at 10° - 15° C was added dropwise methyl vinyl ketone. The resulting mixture was left overnight at room temperature and worked up as above The crude ketone was purified by distillation, b.p. 150 - 60 (2 mm), followed by column chromatography using silica as support and petrol/ethyl acetate as eluants.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([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)[S:8][CH:9]=1)([O:3]C)=[O:2].[OH-].[K+].O.Cl>O1CCCC1.CO>[C:1]([C:5]1[CH:6]=[C:7]([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)[S:8][CH:9]=1)([OH:3])=[O:2]
Reactant: COC(=O)c1csc(C#CC2(c3ccc(OC)c(OC4CCCC4)c3)CCC(=O)CC2)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(C2(C#Cc3cc(C(=O)O)cs3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 58.7 %

Procedure:
A solution of 4-(4-carbomethoxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one (0.12 g, 0.427 mmol) and coarsely ground potassium hydroxide (0.045 g, 0.81 mmol) in tetrahydrofuran (2.5 mL), methanol (2.5 mL), and water (0.5 mL) was stirre at room temperature under an argon atmosphere for three days. 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 0.25:2.5:97.5 acetic acid:methanol:dichloromethane, provided 4-(4-carboxythien-2-ylethynyl)-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-one as an off- white foam (0.11 g, 94%), mp 75°-76° C. Anal. (C25H26O5S.0.25 H2O) calcd: C, 67.78; H, 6.03; found: C, 67.73; H, 5.80.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[O-]CC.[Na+].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[Cl:33][C:34]1[CH:35]=[CH:36][C:37]([NH:40][C:41](=[O:49])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=2[NH2:48])=[N:38][CH:39]=1>C1COCC1>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]([CH:14]([CH3:16])[CH3:15])[CH:11]=[CH:10][C:6]=1[C:7]([NH:48][C:43]1[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=1[C:41]([NH:40][C:37]1[CH:36]=[CH:35][C:34]([Cl:33])=[CH:39][N:38]=1)=[O:49])=[O:9]
Reactant: Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reactant: COCOc1cc(C(C)C)ccc1C(=O)O
Agent: CC[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COCOc1cc(C(C)C)ccc1C(=O)Nc1ccccc1C(=O)Nc1ccc(Cl)cn1
Reaction time: 0.25 h

Procedure:
To a stirring solution of 2-methoxymethyloxy-4-isopropylbenzoic acid (3.0 g, 13.4 mmol) in THF (50 mL) was added sodium ethoxide (0.91 g, 13.4 mmol). After 15 min, the solvent was removed in vacuo and the residue was suspended in dichloromethane (50 mL). To this mixture was added a couple drops of DMF followed by oxalyl chloride (1.7 g, 13.4 mmol). After another 30 min, the solvent was removed in vacuo and the residue was again suspended in dichloromethane (150 mL). To this mixture was added pyridine (2.9 g, 36.5 mmol), followed by N-(5-chloropyridin-2-yl)-2-aminobenzamide (3.02 g, 12.2 mmol). After stirring for 2 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (400 mL) and water (200 mL). The organic phase was washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate and once with brine. The organic phase was then dried with MgSO4 and filtered. To this solution was added silica gel (about 10 g) and the solvent was removed in vacuo. The resulting dry pack was loaded onto the top of a silica gel column loaded with 10% ethyl acetate in hexanes and eluted with a gradient of 10% ethyl acetate in hexanes through 30% ethyl acetate in hexanes. The clean product containing fractions were combined and concentrated in vacuo to give 2.18 g (39%) of off white solid. Another set of fractions which contained a small amount of impurity were combined and concentrated in vacuo to give 2.09 g (about 38%) of an off white solid.
Reaction SMILES: [C:1]([C:4]1[CH2:8][O:7][CH2:6][C:5]=1[C:9]1[CH:10]=[C:11]([C:15]2[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=2)[CH:12]=[CH:13][CH:14]=1)(=O)[NH2:2].O>ClCCl>[C:1]([C:4]1[CH2:8][O:7][CH2:6][C:5]=1[C:9]1[CH:10]=[C:11]([C:15]2[O:16][CH2:17][C:18]([CH3:21])([CH3:20])[N:19]=2)[CH:12]=[CH:13][CH:14]=1)#[N:2]
Reactant: CC1(C)COC(c2cccc(C3=C(C(N)=O)COC3)c2)=N1
Solvent: ClCCl
Solvent: O
Product: CC1(C)COC(c2cccc(C3=C(C#N)COC3)c2)=N1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-[3-(4-carbamoyl-2,5-dihydrofuran-3-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (0.1 g) in dichloromethane (1 ml) was added dropwise bis(trifluoromethanesulfonic)anhydride (0.0588 ml) at 0° C. and the mixture was stirred at room temperature for two hours. Then water was added to the reaction mixture and the stirring was continued for thirty minutes. The product was extracted with ethyl acetate and the organic layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform. The fractions containing the desired product were collected and evaporated in vacuo to give 2-[3-(4-cyano-2,5-dihydrofuran-3-yl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole.
Reaction SMILES: [N:1]([CH:4]([CH3:21])[CH2:5][N:6]1[C:10]2=[CH:11][C:12]3[C:17]([CH2:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])=[C:9]2[C:8](C)=[N:7]1)=[N+]=[N-].[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26]>C(O)C.C(OCC)C.CO.[Pt]=O>[C:22]([OH:29])(=[O:28])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]([CH3:22])[C:17]2[C:12]=1[CH:11]=[C:10]1[C:9]=2[CH:8]=[N:7][N:6]1[CH2:5][CH:4]([NH2:1])[CH3:21]
Reactant: COC1=C2C=c3c(c(C)nn3CC(C)N=[N+]=[N-])=C2CC=C1
Agent: O=[Pt]
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Solvent: CCOCC
Solvent: CO
Product: COC1=C2C=c3c(cnn3CC(C)N)=C2C(C)C=C1
Temperature: 25 °C
Reaction time: 15 h
Yield: 165.7 %

Procedure:
1.1 g (3.88 mmol) of (RS)-1-(2-azido-propyl)-7-methoxy-3-methyl-1,4-dihydro-indeno[2,1-c]pyrazole dissolved in 60 ml of anhydrous ethanol were hydrogenated over 110 mg of platinum oxide for 2 hours. The catalyst was subsequently filtered off, rinsed with ethanol and the solvent was removed in a vacuum. The colorless oil obtained was dissolved in 120 ml of anhydrous diethyl ether, filtered and treated while stirring with a solution of 450 mg (3.88 mmol) of fumaric acid in 5 ml of methanol. The mixture was stirred at room temperature for 15 hours and the white crystals were subsequently filtered off. 1.2 g (83%) of (RS)-2-(7-methoxy-4-methyl-1,4-dihydroindeno[2,1-c]pyrazol-1-yl)-1-methyl-ethylamine fumarate (1:1) with m.p. 184° were obtained.
Reaction SMILES: ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[F:13][C:14]([F:22])([F:21])[CH:15]([OH:20])[C:16]([F:19])([F:18])[F:17].CCN(C(C)C)C(C)C.ClC([O-])=O.C(OC([NH:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:50]=2[CH2:51][N:52]2[CH2:57][CH2:56][N:55]([C:58](OC(C)(C)C)=[O:59])[CH2:54][CH2:53]2)[CH2:45]1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:43][C@@H:44]1[CH2:48][CH2:47][N:46]([C:49]2[CH:68]=[C:67]([Cl:69])[CH:66]=[CH:65][C:50]=2[CH2:51][N:52]2[CH2:57][CH2:56][N:55]([C:58]([O:20][CH:15]([C:16]([F:19])([F:18])[F:17])[C:14]([F:22])([F:21])[F:13])=[O:59])[CH2:54][CH2:53]2)[CH2:45]1
Reactant: OC(C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: N[C@@H]1CCN(c2cc(Cl)ccc2CN2CCN(C(=O)OC(C(F)(F)F)C(F)(F)F)CC2)C1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 28.4 %

Procedure:
A round bottom flask was charged with triphosgene (18 mg, 0.061 mmol), CH2Cl2 (1 mL), and 1,1,1,3,3,3-hexafluoropropan-2-ol (30 mg, 0.202 mmol). DIPEA (104 μL, 0.606 mmol) was added to this solution dropwise and the chloroformate was allowed to form at room temperature for 2 h. A separate flask was charged with (R)-tert-butyl 4-(2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (100 mg, 0.202 mmol) and CH2Cl2 (3 mL) and cooled to 0° C. Trifluoroacetic acid (1 mL) was added dropwise over 1 minute. The reaction was stirred at 0° C. for 15 min. The reaction was allowed to warm to room temperature. After 60 min, the reaction was concentrated under reduced pressure. Methanol was added and the solution was concentrated yielding crude diamine. The crude diamine was dissolved in CH2Cl2 (3 mL) and cooled to 4° C. DIPEA (150 μL, 0.876 mmol) was added followed by the chloroformate solution over 5 minutes. After stirring for 2 h at 0° C. the reaction was quenched by addition of sat Na2CO3 and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 10% 2M NH3 in MeOH) and yielded (R)-1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(3-aminopyrrolidin-1-yl)-4-chlorobenzyl)piperazine-1-carboxylate (28 mg, 28%): 1H NMR 400 MHz (CDCl3) δ 7.29-7.22 (m, 1H), 6.92-6.76 (m, 2H), 5.82-5.66 (m, J=6.4 Hz, 1H), 3.54 (tddd, J=37.8, 22.2, 11.8, 6.2 Hz, 9H), 3.21 (ddd, J=15.3, 10.0, 5.8 Hz, 1H), 3.11-3.04 (m, 1H), 2.49-2.34 (m, 4H), 2.22 (ddd, J=19.5, 13.0, 6.6 Hz, 1H), 1.80 (dt, J=12.7, 6.4 Hz, 1H). LCMS (ESI, m/z): 489 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14](=[O:29])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:30][O:31][CH2:32][CH2:33][CH2:34][CH2:35][Mg]Cl>C1COCC1>[F:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[C@:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)([OH:29])[CH2:35][CH2:34][CH2:33][CH2:32][O:31][CH3:30]
Reactant: COCCCC[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2ccccc2Oc2cccc(F)c2)C1
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1ccccc1Oc1cccc(F)c1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Yield: 43 %

Procedure:
To a solution of (3R)-1-(tert-butoxycarbonyl)-3-((3-fluorophenoxy)benzoyl)piperidine (0.95 g, 2.37 mmol) in THF (3 mL) at −20° C. was added 1.45 M 4-methoxybutyl magnesium chloride in THF (3.3 mL, 4.76 mmol) dropwise. The resulting solution was warmed to rt slowly, and the completion of reaction was confirmed by LC-MS (˜20 min). The reaction was quenched with sat'd aq NH4Cl (4 mL) and extracted with Et2O (4×5 mL). The combined organic layers were washed with water and brine, and the solvent was removed in vacuo to give a crude product which was purified by flash column chromatography to afford (R)-tert-butyl 3-((S)-1-(2-(3-fluorophenoxy)phenyl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (0.50 g, 43%).
Reaction SMILES: [CH:1]1([NH:6][C:7]2[C:8]([CH3:21])=[C:9]([CH:14]=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:22](=O)([O-])[O-].[Cs+].[Cs+].CI>C(#N)C>[CH:1]1([N:6]([CH3:22])[C:7]2[C:8]([CH3:21])=[C:9]([CH:14]=[C:15]([C:17]([F:18])([F:19])[F:20])[CH:16]=2)[C:10]([O:12][CH3:13])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(C(F)(F)F)cc(NC2CCCC2)c1C
Agent: [Cs+]
Solvent: CC#N
Solvent: CI
Product: COC(=O)c1cc(C(F)(F)F)cc(N(C)C2CCCC2)c1C
Temperature: 80 °C

Procedure:
To a stirred solution of methyl 3-(cyclopentylamino)-2-methyl-5-(trifluoromethyl)benzoate (1.6 g, 5.38 mmol) in acetonitrile (25 mL) was added cesium carbonate (3.5 g, 10.7 mmol) and methyl iodide (3.8 g, 26.8 mmol). The mixture was heated at 80° C. for 8 h. On completion, the reaction was cooled to room temperature and filtered. The residue was washed with ethyl acetate and the filtrate was concentrated to give methyl 3-(cyclopentyl(methyl)amino)-2-methyl-5-(trifluoromethyl)benzoate.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C@H:5]1[CH2:9][CH2:8][CH2:7][N:6]1[CH2:10]CC(N(OC)C)=O)[CH3:2].C([N:20]([CH2:31][CH3:32])[C:21](=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[CH3:29])C>>[ClH:28].[Cl:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]2[C:23]=1[CH:29]=[C:31]([CH2:32][CH2:10][N:6]1[CH2:7][CH2:8][CH2:9][C@@H:5]1[CH2:4][O:3][CH2:1][CH3:2])[NH:20][C:21]2=[O:30]
Reactant: CCOC[C@H]1CCCN1CCC(=O)N(C)OC
Reactant: CCN(CC)C(=O)c1cccc(Cl)c1C
Product: CCOC[C@H]1CCCN1CCc1cc2c(Cl)cccc2c(=O)[nH]1
Product: Cl
Yield: 55.9 %

Procedure:
In the same manner as: in Example 20b (b) and (c) and using (R)-3-(2-ethoxymethylpyrrolidin-1-yl)-N-methoxy-N-methylpropanamide (1.22 g) and N,N-diethyl-3-chloro-2-methylbenzamide (1.13 g), (R)-5-chloro-3-[2-(2-ethoxymethylpyrrolidin-1-yl)ethyl]-2H-isoquinolin-1-one hydrochloride (0.52 g) was obtained.
Reaction SMILES: C([O:5][C:6]([C@@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])=[O:7])(C)(C)C.Br>C(O)(=O)C.C(Cl)Cl>[C:6]([C@H:8]([C@@H:20]([CH2:29][CH:30]1[CH2:34][CH2:33][CH2:32][CH2:31]1)[C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22])[CH2:9][N:10]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[N:12]([CH3:18])[C:11]1=[O:19])([OH:7])=[O:5]
Reactant: CN1C(=O)N(C[C@@H](C(=O)OC(C)(C)C)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Agent: Br
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN1C(=O)N(C[C@H](C(=O)O)[C@@H](CC2CCCC2)C(=O)N2CCCCC2)C(=O)C1(C)C
Reaction time: 4 h

Procedure:
A solution of 15.11 g of the 9:1 mixture from Example 4 in 15 ml of acetic acid was treated at 0° with 15 ml of 33% hydrogen bromide in acetic acid and stirred at 0° for 4 hrs. The solution was diluted with methylene chloride, washed with water and the organic phase was dried, filtered and evaporated. The residue was crystallized from 26 ml of tert-butyl methyl ether and 26 ml of hexane, after which 6.90 g (70%) of diastereomer-pure (de >98%) 1-[2(R)-[1(R)-carboxy-2-(3,4,4,-trimethyl-2,5-dioxo-1-imidazolidinyl)ethyl]-3-cyclopentylpropionyl]piperidine (IX), m.p. 111-114°, was obtained. IR (KBr): 1770m and 1715s (C═O).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[CH:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=1.[CH:17]([C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)=[O:18].C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]1([C:10]2[CH:9]=[N:8][N:6]3[CH:7]=[C:2]([C:22]4[CH:23]=[CH:24][C:19]([CH:17]=[O:18])=[CH:20][CH:21]=4)[CH:3]=[N:4][C:5]=23)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Brc1cnc2c(-c3ccccc3)cnn2c1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: O=Cc1ccc(-c2cnc3c(-c4ccccc4)cnn3c2)cc1

Procedure:
A deoxygenated solution of 6-bromo-3-phenylpyrazolo[1,5-a]pyrimidine (1-3, 2.00 g, 7.30 mmol, 1 equiv), 4-formylphenylboronic acid (1-4, 1.65 g, 11.0 mmol, 1.51 equiv), aqueous sodium carbonate solution (6.00 mL, 12.0 mmol, 1.64 equiv), and tetrakis(triphenylphosphine)palladium (0.420 g, 0.363 mmol, 0.0500 equiv) in dioxane (100 mL) was heated at reflux for 20 hours. The reaction mixture was partitioned between aqueous sodium bicarbonate solution (200 mL) and ethyl acetate (200 mL). The organic layer was dried over sodium sulfate and concentrated. The residue was suspended in methanol (100 mL) and filtered to give 4-(3-phenylpyrazolo[1,5-a]pyrimidin-6-yl)benzaldehyde (1-5) as a yellow solid. 1H NMR (400 MHz, CDCl3) δ10.11 (s, 1H), 8.93 (d, 1H, J=2.4 Hz), 8.87 (d, 1H, J=2.2 Hz), 8.51 (s, 1H), 8.07 (m, 2H), 7.81 (br d, 2H, J=7.8 Hz), 7.49 (br t, 2H, J=7.7 Hz), 7.32 (t, 1H, J=7.5 Hz).