Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11](S(CC)(=O)=O)[S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:22]1[C:23]2[CH:32]=[CH:31][N:30](S(C3C=CC(C)=CC=3)(=O)=O)[C:24]=2[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1.[OH-].[K+]>[Br-].C[N+](C)(C)CCCCCCCCCCCCCCCC.O1CCCC1.O>[F:1][C:2]1[CH:46]=[C:45]([F:47])[CH:44]=[CH:43][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][S:12]([CH2:15][CH3:16])(=[O:14])=[O:13])=[CH:7][C:6]=1[C:22]1[C:23]2[CH:32]=[CH:31][NH:30][C:24]=2[C:25](=[O:29])[N:26]([CH3:28])[CH:27]=1
Reactant: CCS(=O)(=O)N(c1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3c2ccn3S(=O)(=O)c2ccc(C)cc2)c1)S(=O)(=O)CC
Agent: CCCCCCCCCCCCCCCC[N+](C)(C)C
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)Nc1ccc(Oc2ccc(F)cc2F)c(-c2cn(C)c(=O)c3[nH]ccc23)c1
Temperature: 90 °C
Yield: 82 %

Procedure:
A mixture of N-(4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-1-tosyl-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl)-N-(ethylsulfonyl)ethanesulfonamide (5.3 g, 7.5 mmol), potassium hydroxide (8.43 g, 150 mmol), and N,N,N-trimethylhexadecan-1-aminium bromide (0.137 g, 0.375 mmol) in tetrahydrofuran (60 mL) and water (30 mL) was heated at 90° C. for 16 hours. Tetrahydrofuran was removed under reduced pressure, and the residue was partitioned between water and ethyl acetate. The aqueous layer was neutralized to pH=7 using 10% HCl. The aqueous layer was then extracted with ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, ethyl acetate). The desired fractions were combined and concentrated. The residue was triturated with 20 mL of acetonitrile to provide N-[4-(2,4-difluorophenoxy)-3-(6-methyl-7-oxo-6,7-dihydro-1H-pyrrolo[2,3-c]pyridin-4-yl)phenyl]ethanesulfonamide Form I (2.82 g, 82% yield). 1H NMR (300 MHz, DMSO-d6) δ 1.23 (t, J=7.3 Hz, 3H), 3.11 (q, J=7.3 Hz, 2H), 3.53 (s, 3H), 6.27-6.22 (m, 1H), 6.91 (d, J=8.7 Hz, 1H), 7.13-6.93 (m, 2H), 7.19 (dd, J=8.8, 2.7 Hz, 1H), 7.32-7.25 (m, 2H), 7.42-7.31 (m, 2H), 9.77 (s, 1H), 12.04 (bs, 1H). MS (ESI+) m/z 460.1 (M+H)+.
Reaction SMILES: [CH2:1]([C@@:4]1(C)[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@@H:24]([CH2:28][CH3:29])[CH:25]([OH:27])[CH3:26])[C:5]1=[O:30])C=C.CC[O:34][C:35]([CH3:37])=[O:36]>CC#N.O.C(Cl)Cl.O.[Ru](Cl)(Cl)Cl>[Cl:16][C:12]1[CH:11]=[C:10]([C@@H:8]2[C@@H:7]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[N:6]([C@@H:24]([CH2:28][CH3:29])[C:25](=[O:27])[CH3:26])[C:5](=[O:30])[C@:4]([CH2:37][C:35]([OH:34])=[O:36])([CH3:1])[CH2:9]2)[CH:15]=[CH:14][CH:13]=1
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)C(C)O)C1=O
Reactant: CCOC(C)=O
Agent: Cl[Ru](Cl)Cl
Solvent: O
Solvent: CC#N
Solvent: ClCCl
Product: CC[C@@H](C(C)=O)N1C(=O)[C@@](C)(CC(=O)O)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.83 h

Procedure:
Ruthenium(III) chloride hydrate (1.404 g, 6.23 mmol) was added to a solution of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((3S)-2-hydroxypentan-3-yl)-3-methylpiperidin-2-one (Example 151, Step C) (130.30 g, 283 mmol) and NaIO4 (61.5 g) in EtOAc (630 mL), CH3CN (630 mL) and water (935 mL) at 18° C. The remaining NaIO4 (307.5 g) was added in five portions over 2.5 hours while maintaining the temperature below 26° C. 15 minutes after the final addition of NaIO4 the cooling bath was removed and the reaction mixture was stirred at ambient temperature for 50 minutes. The tan reaction mixture was filtered using a Büchner funnel and washed with EtOAc (500 mL) and CH3CN (500 mL). The layers were separated and the aqueous layer was extracted with EtOAc twice. The organics were pooled, washed with 10% aq. NaHSO3 (3×1 L), brine (1 L), dried (Na2SO4), decanted and concentrated in vacuo to provide a green oil. The material was dissolved in a minimum amount of DCM and purified using two 1.5 kg Biotage® Snap™ columns (Biotage, LLC, Charlotte, N.C.) and eluting with 10-50% (15% MeOH/acetone)/hexanes to provide a light pink foam (109.67 g).
Reaction SMILES: [F:1][CH:2]([F:16])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2.Cl[CH2:18][C:19]1[N:23]=[C:22]([C:24]2[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=2)[O:21][N:20]=1>>[F:16][CH:2]([F:1])[C:3]1[N:4]([CH2:18][C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([F:30])[CH:27]=[C:26]([F:31])[CH:25]=3)[O:21][N:20]=2)[C:5]2[C:10]([CH:11]=1)=[C:9]([C:12]#[N:13])[C:8]([C:14]#[N:15])=[CH:7][CH:6]=2
Reactant: N#Cc1ccc2[nH]c(C(F)F)cc2c1C#N
Reactant: Fc1cc(F)cc(-c2nc(CCl)no2)c1
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2noc(-c3cc(F)cc(F)c3)n2)c1C#N

Procedure:
Synthesized as described in Example 23 from 2-(difluoromethyl)-1H-indole-4,5-dicarbonitrile and 3-(chloromethyl)-5-(3,5-difluorophenyl)-1,2,4-oxadiazole: MS (ES) m/z 412 (M+1).
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([O:20]C)=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].[CH3:31]I>O1CCCC1>[CH:1]1([N:7]([CH3:31])[C:8]2[C:9]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)=[N:10][C:11]3[C:16]([N:17]=2)=[CH:15][C:14]([C:18]([OH:20])=[O:19])=[CH:13][CH:12]=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CI
Reactant: COC(=O)c1ccc2nc(-c3ccc(F)cc3)c(NC3CCCCC3)nc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1nc2cc(C(=O)O)ccc2nc1-c1ccc(F)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.7 %

Procedure:
To a solution of methyl 3-(cyclohexylamino)-2-(4-fluorophenyl)quinoxaline-6-carboxylate (200 mg, 0.53 mmol) in tetrahydrofuran (30 mL) was added sodium hydride (105.5 mg, 4.40 mmol) and CH3I (299.9 mg, 2.11 mmol), and the reaction was allowed to proceed with stirring overnight at room temperature. The reaction was then quenched by the addition of water (50 mL), adjusted pH to 5 with HCl (3N). The resulting solution was extracted with ethyl acetate (3×80 mL) and the organic layers combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give the crude product. The crude product was re-crystallized from ethyl acetate:petroleum ether (1:5) to afford 3-(cyclohexyl(methyl)amino)-2-(4-fluorophenyl)quinoxaline-6-carboxylic acid (100 mg, 48%) as a light yellow solid.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:19][CH2:18][C@@H:17]([O:20][Si:21]([CH:28]([CH3:30])[CH3:29])([CH:25]([CH3:27])[CH3:26])[CH:22]([CH3:24])[CH3:23])[C:12]2=[N:13][CH:14]=[CH:15][CH:16]=[C:11]2[C@H:10]1[OH:31].[C:32](OC(=O)C)(=[O:34])[CH3:33].C(N(CC)CC)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:32]([O:31][C@@H:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][CH:16]=2)[C@H:17]([O:20][Si:21]([CH:25]([CH3:27])[CH3:26])([CH:28]([CH3:30])[CH3:29])[CH:22]([CH3:23])[CH3:24])[CH2:18][CH2:19][C@H:9]1[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[F:1])(=[O:34])[CH3:33]
Reactant: CC(C)[Si](O[C@@H]1CC[C@@H](c2cccc(F)c2F)[C@H](O)c2cccnc21)(C(C)C)C(C)C
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)O[C@@H]1c2cccnc2[C@H](O[Si](C(C)C)(C(C)C)C(C)C)CC[C@H]1c1cccc(F)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
In a 250 mL round-bottom flask was dissolved (5S,6S,9R)-6-(2,3-difluorophenyl)-9-(triisopropylsilyloxy)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-ol (1.004 g, 2.243 mmol) in methylene chloride (20 mL) to give a colorless solution. Acetic anhydride (0.423 mL, 4.49 mmol) and triethylamine (0.938 mL, 6.73 mmol) were added, followed by DMAP (0.055 g, 0.449 mmol). The mixture was stirred at room temperature under nitrogen. 2 h: LCMS showed complete conversion. It was quenched with Sodium bicarbonate solution and diluted with ethyl acetate. The layers were separated. The organic layer was washed with brine, dried and concentrated to give a colorless oil (100%), which was directly carried onto next reaction without further purification and characterization. MS(ESI)[M+H+]=490.26.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([OH:20])=O)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Cl.[OH:22][C:23]1[C:32]([O:33][CH3:34])=[CH:31][CH:30]=[C:29]2[C:24]=1[CH2:25][CH2:26][NH:27][CH2:28]2>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:17]=[C:16]([C:18]([N:27]3[CH2:26][CH2:25][C:24]4[C:29](=[CH:30][CH:31]=[C:32]([O:33][CH3:34])[C:23]=4[OH:22])[CH2:28]3)=[O:20])[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1nc(-c2ccc(Cl)cc2)nc2ccccc12
Reactant: COc1ccc2c(c1O)CCNC2
Agent: Cl
Product: COc1ccc2c(c1O)CCN(C(=O)c1nc(-c3ccc(Cl)cc3)nc3ccccc13)C2
Yield: 11 %

Procedure:
Reaction of 2-(4-chlorophenyl)quinazoline-4-carboxylic acid with 5-hydroxy-6-methoxy-1,2,3,4-tetrahydroisoquinoline hydrochloride gave compound 27 (11% yield) as off-white oil. 1H NMR (300 MHz, DMSO-d6) δ 2.62 and 2.90 (2t, 2H), 3.48 and 4.03 (2t, 2H), 3.74-3.80 (2s, 3H), 4.39 and 4.92 (2s, 2H), 6.31 and 6.77 (2d, 1H), 6.71 and 6.91 (2d, 1H), 7.62-7.81 (m, 3H), 7.87-7.98 (2d, 1H), 8.07-8.19 (m, 2H), 8.50-8.56 (m, 2H), 8.67 and 8.72 (2s, 1H); MS (ESI) m/z 446 ([M+H]+).
Reaction SMILES: [C:1]([C:5]1[C:6]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]([CH2:12][CH:13]=[CH2:14])=[C:9]([OH:11])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>ClCCl>[C:1]([C:5]1[C:6]([O:15][C:16](=[O:21])[C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:7][C:8]2[CH2:12][CH:13]([CH3:14])[O:11][C:9]=2[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCc1cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc1O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: ClCCl
Product: CC1Cc2cc(OC(=O)C(C)(C)C)c(C(C)(C)C)cc2O1
Temperature: 25 °C
Yield: 30 %

Procedure:
0.50 g of 5-t-butyl-4-trimethylacetoxy-2-(2-propenyl)phenol was dissolved in 30 ml of dichloromethane, 30 ml of boron trifluoride etherate was added, and the solution was stirred at room temperature under a nitrogen stream. The solution was further refluxed for 30 minutes, and the reaction solution was poured into a saturated aqueous sodium bicarbonate solution and extracted with n-hexane. The organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate and then concentrated. The concentrate was purified by silica gel column chromatography (in n-hexane containing 0.5%-1% ethyl acetate) to give 0.15 g of 6-t-butyl-2-mehtyl-5-trimethylacetoxy-2,3-dihydrobenzofuran as a colorless solid (yield 30%).
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([CH3:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C(N(CC)CC)C.[Cl-].[Cl:18][C:19]1[S:20][S+:21]=[C:22](Cl)[C:23]=1[Cl:24]>C(Cl)Cl>[Cl:24][C:23]1[C:22](=[N:4][C:3]2[CH:5]=[CH:6][C:7]([CH3:9])=[CH:8][C:2]=2[CH3:1])[S:21][S:20][C:19]=1[Cl:18]
Reactant: Cc1ccc(N)c(C)c1
Reactant: Clc1s[s+]c(Cl)c1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(N=c2ssc(Cl)c2Cl)c(C)c1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
14.0 g of 2,4-dimethyl-aniline were dissolved in 300 ml of methylene chloride and 50 ml of triethylamine and 31.0 g of 3,4,5-trichloro-1,2-dithiolium chloride were introduced at 10°-15° C. After stirring for three hours at 20° C., a test for aromatic amine, by diazotizing and coupling, proved negative. The resulting dark solution was then washed three times with 200 ml of water, dried over potassium carbonate and filtered over a column of aluminum oxide, to remove impurities that imparted a color. The filtrate was concentrated and caused to crystallize by adding petroleum ether. Yield, 17.0 g of yellowish crystals; melting point: 72°-74° C. The elementary analysis and NMR spectrum agreed with the assumed structure.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Br:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[F:21].[C:22](=[O:24])=[O:23]>C1COCC1>[Br:13][C:14]1[C:15]([F:21])=[C:16]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[C:22]([OH:24])=[O:23]
Reactant: Fc1ccc(Cl)cc1Br
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)c1cc(Cl)cc(Br)c1F
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a cooled solution of diisopropylamine (2.4 mL, 17.2 mmol) in dry THF (15 mL) under Argon at 0° C. was added n-butyllithium (7.5 mL, 2.0 M in pentane, 15.0 mmol). After 30 minutes the solution was cooled to −78° C. and a solution of 2-bromo-4-chloro-1-fluorobenzene (3 g, 14.3 mmol) in dry THF (15 mL) was added over 15 minutes. After 1 hour, this solution was transferred via cannula over 10 minutes to a mixture of solid carbon dioxide and THF (30 mL) at −78° C. After 45 minutes the cold bath was removed and excess carbon dioxide was allowed to vent while the solution warmed to room temperature. The reaction mixture was then quenched with aqueous 0.5 M HCl solution (60 mL). After concentrating, the remaining aqueous phase was basified with aqueous 0.5 M NaOH solution and was washed with ethyl acetate (100 mL). The aqueous phase was then acidified with aqueous 1.0 M HCl solution and extracted with chloroform (2×75 mL). The combined organic portions were washed with brine, dried (Na2SO4) and concentrated to give 3.34 g of a semi-crystalline solid as a mixture of regioisomers with the desired isomer as the major: LCMS (m/z) not observed (MH+), tR=0.66 minute; 1H NMR (400 MHz, CDCl3) δ 7.80 (dd, J=5.5, 2.7 Hz, 1H), 7.95 (dd, J=5.5, 2.7 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]/[N:9]=[CH:10]/[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][N:9]=[C:10]([Cl:20])[C:11]2[C:16]([F:17])=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:18])=[CH:6][CH:7]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Fc1cccc(Cl)c1/C=N/Nc1ccc(Br)cc1
Solvent: c1ccccc1
Product: Fc1cccc(Cl)c1C(Cl)=NNc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23 %

Procedure:
To a solution of (2E)-1-(4-bromophenyl)-2-(2-chloro-6-fluorobenzylidene)hydrazine (0.300 g, 1.32 mmol) in benzene (10 mL) was added PCl5 (0.330 g, 1.58 mmol). The reaction mixture was stirred at RT for 18 h. The reaction mass was quenched in water, neutralized with NaHCO3 and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulphate and concentrated to afford 0.110 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.17 (d, J=8.7 Hz, 2H), 7.41 (d, J=8.7 Hz, 3H), 7.45-7.61 (m, 2H), 10.26 (s, 1H). MS (m/z): 361.34 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:17]2)[CH2:12]O)[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:43])([CH3:42])[CH3:41])[N:7]=2)[CH:3]=1.C(#N)C.C(N(C(C)C)CC)(C)C.F.F.F.C(N(C(C)C)CC)(C)C.[F:68]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F.C([O-])(O)=O.[Na+]>CCOCC>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([O:14][CH2:15][C:16]2([C:29]3[CH:34]=[CH:33][C:32]([F:35])=[CH:31][CH:30]=3)[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[CH2:18][CH2:17]2)[CH2:12][F:68])[C:8]2[C:4](=[CH:5][N:6]([CH2:36][O:37][CH2:38][CH2:39][Si:40]([CH3:42])([CH3:43])[CH3:41])[N:7]=2)[CH:3]=1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(COC(CO)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Agent: F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(COC(CF)c2cc(Cl)cc3cn(COCC[Si](C)(C)C)nc23)(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.1 %

Procedure:
To a solution of tert-butyl 4-((1-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-hydroxyethoxy)methyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (440 mg, 0.694 mmol) in ACETONITRILE (0.1 mL, 1.915 mmol) at room temperature was added diisopropylethylamine (0.545 mL, 3.12 mmol), Diisopropylethylamine trihydrofluoride (197 mg, 1.041 mmol), and perfluoro-1-butanesulfonyl fluoride (0.249 mL, 1.387 mmol). The reaction was stirred at room temperature overnight. It was then poured into sat'd NaHCO3 and diluted with ether. The ether layer was washed with water and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel column chromatography (15%-20% EtOAc/Hex) to give title compound (420 mg, 0.660 mmol, 95% yield) as a colorless film. LC/MS (HPLC method 3): tR=4.33 min, 636.3(MH)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][C@H:6]([CH3:8])[N:5](CC2C=CC=CC=2)[CH2:4][C@@H:3]1[CH3:16]>CO>[CH3:1][N:2]1[CH2:7][C@H:6]([CH3:8])[NH:5][CH2:4][C@@H:3]1[CH3:16]
Reactant: C[C@H]1CN(Cc2ccccc2)[C@@H](C)CN1C
Solvent: CO
Product: C[C@H]1CN(C)[C@@H](C)CN1
Yield: 155.8 %

Procedure:
(2S,5S)-1,2,5-Trimethyl-4-(phenylmethyl)piperazine (782 mg, 3.58 mmol) was dissolved in 50 mL of MeOH, degassed and placed under argon. 10% Pd/C (200 mg) was added, and the contents were thoroughly degassed and placed under a hydrogen balloon for approximately 3 hrs. The contents were then degassed and filtered through Celite, and the Celite pad was washed with DCM and MeOH. After 7.5 mL 1N HCl was added, the resulting filtrate was concentrated in vacuo to provide the hydrochloride salt of (2S,5S)-1,2,5-trimethylpiperazine (715 mg, 100%). LCMS: (M+H)+: 129.1.
Reaction SMILES: C([O:3][C:4](=[O:20])[C@@H:5]([O:18][CH3:19])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]([OH:17])=O)=[CH:9][CH:8]=1)C.[CH3:21][NH:22][CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1.C(O[C@@H](CC1C=CC(O[C@@H](C(=O)NCCC2C=CC(OC3C=CC=CC=3)=CC=2)C)=CC=1)C(O)=O)C>>[CH3:19][O:18][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:14][C:15](=[O:17])[N:22]([CH3:21])[CH2:23][C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][CH:25]=2)=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:20]
Reactant: CNCc1cccc2ccccc12
Reactant: CCOC(=O)[C@H](Cc1ccc(OCC(=O)O)cc1)OC
Agent: CCO[C@@H](Cc1ccc(O[C@H](C)C(=O)NCCc2ccc(Oc3ccccc3)cc2)cc1)C(=O)O
Product: CO[C@@H](Cc1ccc(OCC(=O)N(C)Cc2cccc3ccccc23)cc1)C(=O)O

Procedure:
The title compound was prepared from (2S)-3-(4-carboxymethoxy-phenyl)-2-methoxy-propionic acid ethyl ester (PREPARATION 3, step 2) and methyl-naphthalen-1-ylmethyl-amine via the same procedure used for the preparation of (2S,1R)-2-ethoxy-3-(4-{1-[2-(4-phenoxy-phenyl)-ethylcarbamoyl]-ethoxy}-phenyl)-propionic acid (Example 1, step 3) to produce a colorless oil. MS (ES) for C24H25NO5 [M+H]+: 408.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][C:12]=1[CH2:13][N:14]1[C:18]2[CH:19]=[C:20]([N+:23]([O-])=O)[CH:21]=[CH:22][C:17]=2[N:16]=[CH:15]1)[C:6]([O:8][CH3:9])=[O:7]>C(O)C.C(OCC)(=O)C>[NH2:23][C:20]1[CH:21]=[CH:22][C:17]2[N:16]=[CH:15][N:14]([CH2:13][C:12]3[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=3[O:2][CH3:1])[C:18]=2[CH:19]=1
Reactant: COC(=O)c1ccc(Cn2cnc3ccc([N+](=O)[O-])cc32)c(OC)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(Cn2cnc3ccc(N)cc32)c(OC)c1
Temperature: 80 °C
Reaction time: 18 h
Yield: 89.7 %

Procedure:
A solution of (K) (0.77 g.) in anhydrous ethanol (23 ml.) was treated with stannous chloride dihydrate (2.6 g.). The mixture was stirred for 18 hours at 80° C. and then diluted with ethyl acetate. This mixture was washed successively with saturated sodium bicarbonate solution, water, and brine, then dried (MgSO4) and evaporated to give methyl 4-(6-aminobenzimidazol-1-ylmethyl)-3-methoxybenzoate (J) (0.63 g., 90%): partial NMR: 3.4(br s, 2H, NH2), 5.2(s,2H, NCH2).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[N:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[CH2:17](OC1N=C(NN)C=CC=1)[CH3:18].[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31](OCC)N=1.IC1C=CC=CC=1C(O)=O>>[CH2:1]([O:3][C:4]1[N:9]=[C:8]([N:10]2[C:14]([NH2:15])=[CH:13][C:12]([CH3:16])=[N:11]2)[CH:7]=[CH:6][CH:5]=1)[CH3:2].[Cl:28][C:29]1[C:34]2[C:33](=[CH:32][CH:31]=[CH:17][CH:18]=2)[N:15]=[C:14]2[N:10]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([O:3][CH2:1][CH3:2])[N:9]=3)[N:11]=[C:12]([CH3:16])[C:13]=12
Reactant: CCOc1cccc(NN)n1
Reactant: CCOc1cccc(Cl)n1
Agent: CCOc1cccc(-n2nc(C)cc2N)n1
Agent: O=C(O)c1ccccc1I
Product: CCOc1cccc(-n2nc(C)c3c(Cl)c4ccccc4nc32)n1

Procedure:
Following the procedure described in Reference Example 2-4, 1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazol-5-ylamine was prepared from 6-ethoxy-2-hydrazinopyridine which was prepared from 2-chloro-6-ethoxypyridine following the method described in Reference Example 2-2. Subsequently, following the methods described in Reference Example 2-5 and Example 2-1, the title compound was prepared from o-iodobenzoic acid and 1-(6-ethoxy-2-pyridinyl)-3-methyl-1H-pyrazol-5-ylamine (36% yield).
Reaction SMILES: [O-:1][C:2]#[N:3].[Na+].[CH3:5][N:6]1[C:10]([NH2:11])=[CH:9][CH:8]=[N:7]1.C(OCC)(=O)C>O.C(O)(=O)C>[CH3:5][N:6]1[C:10]([NH:11][C:2]([NH2:3])=[O:1])=[CH:9][CH:8]=[N:7]1
Reactant: N#C[O-]
Reactant: Cn1nccc1N
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cn1nccc1NC(N)=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 52.2 %

Procedure:
A solution of sodium cyanate (52 g) in water (400 ml) was added dropwise to a solution of 1-methyl-5-aminopyrazole (19.4 g) in acetic acid (96 ml) and water (192 ml), and the mixture was stirred at ambient temperature for 7 hours. The reaction mixture was poured into a mixture of water (400 ml) and ethyl acetate (400 ml). The organic layer was separated, washed with saturated aqueous sodium chloride, dried over magnesium sulfate and evaporated to give 1-methyl-5-ureidopyrazole (14.6 g).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:6][CH2:7][CH2:8][C:9]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(C(OC(C)(C)C)=O)[C:10]([O:12]C(C)(C)C)=[O:11])(=[O:3])[CH3:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[C:10]([CH:9]([CH2:8][CH2:7][CH2:6][CH:5]([O:4][C:1](=[O:3])[CH3:2])[CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])([OH:12])=[O:11]
Reactant: CCCCCC(CCCC(CCCCCCC(=O)OCC)(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCCCC(CCCC(CCCCCCC(=O)OCC)C(=O)O)OC(C)=O

Procedure:
A mixture of di-tert.-butyl 2-(4-acetoxynonyl)-2-(6-ethoxycarbonylhexyl)malonate (104.12 g., 0.187 mole), p-toluenesulfonic acid monohydrate (3.30 g.) and toluene (330 ml.) is heated under reflux for 91/2 hours.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])([O-])=O.[C-:14]#[N:15].[Na+]>[Pd].[OH-].[Na+]>[C:14]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:10][C:11]([OH:13])=[O:12])#[N:15]
Reactant: [C-]#N
Reactant: O=C(O)Cc1ccccc1[N+](=O)[O-]
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1ccccc1CC(=O)O

Procedure:
2-Nitrophenylacetic acid (ex Aldrich) (18.1 g) dissolved in 0.1M.aq.sodium hydroxide (100 ml) was subjected to catalytic hydrogenation (at 30-40 psi) over 10% palladium on charcoal (2 g) until uptake ceased. The resultant solution was subjected first to diazotisation and then reaction with sodium cyanide and cuprous cyanide according to Simchen and Hafner, Ann. Chem., 1974, 1802 to give crude 2-cyanophenylacetic acid (14.9 g). The latter was treated with phosphorous pentachloride (20.6 g) and anhydrous hydrogen chloride in di-n-butyl ether (250 ml) for 2 hours. After a further 18 hours the volatiles were removed, the residue washed with water and recrystallized from ethanol to give 1-chloro-3-hydroxy-isoquinoline (1.48 g).