Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]#[C:11][C:12]([O:14][C:15]2[CH:20]=[C:19]([CH3:21])[C:18]([Br:22])=[C:17]([CH3:23])[CH:16]=2)=[O:13])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(O)(C(F)(F)F)=O.ClCCCl>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[Br:22][C:18]1[C:19]([CH3:21])=[C:20]2[C:15](=[CH:16][C:17]=1[CH3:23])[O:14][C:12](=[O:13])[CH:11]=[C:10]2[C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: Cc1cc(OC(=O)C#Cc2cccc([N+](=O)[O-])c2)cc(C)c1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc2oc(=O)cc(-c3cccc([N+](=O)[O-])c3)c2c(C)c1Br
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 97.2 %

Procedure:
To a stirred solution of 4-bromo-3,5-dimethylphenyl 3-(3-nitrophenyl)propiolate (6-2) (15.96 g, 42.65 mmol) in CH2Cl2 (100 mL) was added TFA (10 mL) and Pd(OAc)2 (480 mg, 2.14 mmol) at 0° C. The mixture was warmed to room temperature and stirred for 4.5 h. To the mixture was added 1,2-dichloroethane and concentrated. Then toluene was added and concentrated. To the concentrate added toluene, dichloromethane and hexane, and the precipitated solid was collected by filtration. The solid was washed with hexane and dried to give the title compound 6-3 (15.51 g, 97% yield) as a brown solid.
Reaction SMILES: [F:1][C:2]([F:44])([C:40]([F:43])([F:42])[F:41])[CH2:3][CH2:4][CH2:5][S:6]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([C@H:20]2[CH2:37][C@@:35]3([CH3:36])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[OH:38])[C@H:30]3[C@H:21]2[C:22]2[CH:23]=[CH:24][C:25]([OH:39])=[CH:26][C:27]=2[CH2:28][CH2:29]3)=[CH:16][CH:15]=1)=[O:7].[H-].[Na+].CC1C=CC(S(O[CH:58]2[CH2:62][CH2:61][CH2:60][CH2:59]2)(=O)=O)=CC=1.[Cl-].[NH4+]>CN(C)C=O>[CH:58]1([O:39][C:25]2[CH:24]=[CH:23][C:22]3[C@@H:21]4[C@H:30]([C@H:31]5[C@@:35]([CH2:37][C@@H:20]4[C:17]4[CH:16]=[CH:15][C:14]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][S:6]([CH2:5][CH2:4][CH2:3][C:2]([F:1])([F:44])[C:40]([F:41])([F:42])[F:43])=[O:7])=[CH:19][CH:18]=4)([CH3:36])[C@@H:34]([OH:38])[CH2:33][CH2:32]5)[CH2:29][CH2:28][C:27]=3[CH:26]=2)[CH2:62][CH2:61][CH2:60][CH2:59]1
Reactant: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reactant: Cc1ccc(S(=O)(=O)OC2CCCC2)cc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: C[C@]12C[C@H](c3ccc(OCCCCCS(=O)CCCC(F)(F)C(F)(F)F)cc3)[C@@H]3c4ccc(OC5CCCC5)cc4CC[C@H]3[C@@H]1CC[C@@H]2O
Reaction time: 5 h
Yield: 77.8 %

Procedure:
1 g of the product prepared in Example 31, 8.7 cm3 of dimethylformamide and 82 mg of sodium hydride are agitated for 30 minutes. Then 486 mg of cyclopentyl 4-methylbenzenesulphonate is added, agitation is carried out for 5 hours, the whole is poured into an aqueous solution of ammonium chloride, extracted with ethyl acetate, washed with salt water, dried and the solvent is evaporated off. The residue is chromatographed on silica (eluant: methylene chloride-isopropanol 95-5) and 861 mg of product is obtained which is crystallized from a methylene chloride/ethyl ether mixture and 777 mg of expected product is collected.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][C:3]=1[C:13]#[C:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH:32]C(=O)OCC3C=CC=CC=3)[C:22]=2[N:21]=[CH:20]1>[Pt].CO>[CH3:12][NH:11][S:8]([C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]2[C:31]3[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[N:24]=[C:23]([NH2:32])[C:22]=3[N:21]=[CH:20]2)[CH:4]=1)(=[O:10])=[O:9]
Reactant: CNS(=O)(=O)c1ccc(C)c(C#CCOCCn2cnc3c(NC(=O)OCc4ccccc4)nc4ccccc4c32)c1
Agent: [Pt]
Solvent: CO
Product: CNS(=O)(=O)c1ccc(C)c(CCCOCCn2cnc3c(N)nc4ccccc4c32)c1
Reaction time: 16 h
Yield: 47.6 %

Procedure:
Platinum on carbon (0.08 g of 10%) was added to a mixture of benzyl N-(1-{2-[(3-{2-methyl-5-[(methylamino)sulfonyl]phenyl}-2-propynyl)oxy]ethyl}-1H-imidazo[4,5-c]quinolin-4-yl)carbamate (0.3 g, 0.51 mmol) and methanol (10 mL). The mixture was hydrogenated on a Parr apparatus at 40 psi (2.8 Kg/cm2) for 16 hours. Analysis by LC-MS indicated alkyne reduction but no phenoxycarbonyl removal. Palladium on carbon (0.1 g of 10%) was added and the reaction mixture was hydrogenated at 40 psi (2.8 Kg/cm2) for 8 hours. Analysis by LC-MS indicated only a small amount of phenoxycarbonyl removal. Palladium black (0.1 g) was added and the reaction mixture was hydrogenated at 40 psi (2.8 Kg/cm2) for 16 hours. Analysis by LC-MS indicated one major product with a mass consistent with the desired product. The reaction mixture was filtered and the filtrate was washed with methanol and dichloromethane. The solvents were removed under reduced pressure to provide an off-white powder. This material was recrystallized from acetonitrile to provide 0.11 g of N1,4-dimethyl-3-{3-[2-(4-amino-1H-imidazo[4,5-c]quinolin-1-yl)ethoxy]propyl}-1-benzensulfonamide as a light yellow crystalline solid, m.p. 207-209° C.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][S:22][C:21](=[S:24])[CH:20]=2)=[CH:15][CH:14]=1>CC(C)=O>[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[S:23][S:22][C:21](=[S:24]=[O:9])[CH:20]=2)=[CH:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Oc1ccc(-c2cc(=S)ss2)cc1
Solvent: CC(C)=O
Product: O=S=c1cc(-c2ccc(O)cc2)ss1

Procedure:
A solution of 9.4 g 80-90% pure 3-chloroperbenzoic acid (=approximately 0.046 Mol) in 200 ml acetone was added dropwise with vigorous stirring to a solution of 10 g (=0.004 Mol) 5-(4-hydroxyphenyl)-1,2-dithiol-3-thione in 300 ml acetone within one hour at room temperature. Thereafter, the reaction mixture was kept at the same temperature for a further hour. The 5-(4-hydroxyphenyl)-1,2-dithiol-3-thion-S-oxide which resulted as a red precipitate was filtered-off under suction and dried over phosphorus pentoxide. 9.4 g of the S-oxide with a melting point of 118-124° C. were obtained.
Reaction SMILES: [CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([O:24][B:25](OC(C)C)[O:26]C(C)C)(C)C.[Li+].CC([N-]C(C)C)C>C1COCC1>[CH:1]1([N:6]2[C:14]3[C:9](=[CH:10][C:11]([F:16])=[C:12]([CH3:15])[CH:13]=3)[C:8]([C:17]([O:19][CH3:20])=[O:18])=[C:7]2[B:25]([OH:26])[OH:24])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cn(C2CCCC2)c2cc(C)c(F)cc12
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)c1c(B(O)O)n(C2CCCC2)c2cc(C)c(F)cc12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
Into a solution of methyl 1-cyclopentyl-5-fluoro-6-methyl-1H-indole-3-carboxylate (2.64 g, 9.6 mmol) and triisopropylborate (4.0 mL, 17.28 mmol) in THF (40 mL) at −78° C. was added LDA (1.5 M, 8.3 mL, 12.48 mmol) dropwise. The mixture was stirred for 45 min, and then treated with ice water and extracted with dichloromethane. The organic layer was dried over sodium sulfate and evaporated to give 1-cyclopentyl-5-fluoro-3-(methoxycarbonyl)-6-methyl-1H-indol-2-ylboronic acid as a semi-solid (3.1 g, ˜50% pure), which was used in next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:14])[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1.Cl[C:23]1[N:31]=[CH:30][N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][N:27]2C1CCCCO1.CCN(C(C)C)C(C)C>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:14][C:23]3[N:31]=[CH:30][N:29]=[C:28]4[C:24]=3[N:25]=[CH:26][NH:27]4)[CH2:11][O:12][CH3:13])[N:7]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=3)[C:6]=2[CH:21]=1
Reactant: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccn1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 90 °C
Yield: 49.5 %

Procedure:
A mixture of (R)-1-(6-fluoro-1-pyridin-2-yl-1H-benzoimidazol-2-yl)-2-methoxyethylamine (69 mg, 0.24 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (56 mg, 0.24 mmol) and DIPEA (0.21 mL, 1.2 mmol) in IPA (1 mL) was heated for 16 h at 90° C. After cooling to RT, the volatiles were removed under reduced pressure and the resulting residue loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH followed by 2M NH3/MeOH. The basic fractions were combined, concentrated in vacuo and the resulting residue was purified by column chromatography (Si—PCC, gradient 0-7.5% 2M NH3/MeOH in DCM) to afford 270 as a white solid (48 mg, 49%). LCMS (Method K): RT 3.07 min [M+H]+ 405.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.80 (1H, br s), 8.65 (1H, s), 8.16-8.04 (2H, m), 7.98 (1H, s), 7.87-7.81 (1H, m), 7.79 (1H, d, J=8.01 Hz), 7.72 (1H, dd, J=8.82, 4.90 Hz), 7.56-7.49 (1H, m), 7.21-7.10 (2H, m), 6.05 (1H, s), 3.90 (2H, d, J=6.25 Hz), 3.20 (3H, s)
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]3[N:13]([N:17]=[C:18]([NH2:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].Br[C:22]1[CH:23]=[C:24]([CH:34]=[CH:35][CH:36]=1)[CH2:25][N:26]1[CH2:31][CH2:30][S:29](=[O:33])(=[O:32])[CH2:28][CH2:27]1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)CCCCC1>>[O:33]=[S:29]1(=[O:32])[CH2:30][CH2:31][N:26]([CH2:25][C:24]2[CH:23]=[C:22]([NH:20][C:18]3[N:19]=[C:12]4[C:11]([C:8]5[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=5)=[CH:16][CH:15]=[CH:14][N:13]4[N:17]=3)[CH:36]=[CH:35][CH:34]=2)[CH2:27][CH2:28]1
Reactant: O=S1(=O)CCN(Cc2cccc(Br)c2)CC1
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(N)nc23)cc1
Agent: c1ccc(P(C2CCCCC2)C2CCCCC2)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c1
Product: CS(=O)(=O)c1ccc(-c2cccn3nc(Nc4cccc(CN5CCS(=O)(=O)CC5)c4)nc23)cc1

Procedure:
To a suspension of thiomorpholine 1,1-dioxide (0.72 g, 5.4 mmol) and potassium carbonate (0.74 g, 5.4 mmol) in acetone (10 mL) was added bromo-3-chloromethyl-benzene (0.62 mL, 4.9 mmol). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with dichloromethane (50 mL), filtered through a plug of diatomaceous earth and evaporated to a waxy solid. The material was purified via chromatography utilizing an ISCO automated purification apparatus (24 g silica gel column 10%→100% ethyl acetate in hexane). 4-(3-Bromo-benzyl)-thiomorpholine 1,1-dioxide was isolated as a clear viscous oil that solidified to a white solid (1.0 g, 67%). 1H NMR (400 MHz, CDCl3, δ, ppm): 7.49 (s, 1H), 7.41 (ddd, J=6.9, 1.9, 1.9 Hz, 1H), 7.25-7.19 (m, 2H), 3.62 (s, 2H), 3.10-2.96 (m, 8H). MS=304, 306 (MH)+. 120b) N-{3-[(1,1-dioxidothiomorpholin-4-yl)methyl]phenyl}-8-[4-(methylsulfonyl)phenyl][1,2,4]triazolo[1,5-a]pyridin-2-amine was prepared from 8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (75.0 mg, 0.260 mmol) and 4-(3-bromo-benzyl)-thiomorpholine 1,1-dioxide (90.0 mg, 0.296 mmol) with 2,2′-bis-dicyclohexylphosphanyl-biphenyl (29.0 mg, 0.0530 mmol) as the ligand in a manner analogous to Example 2d. Product isolated as a pale yellow foam (0.046 g, 34%). 1H NMR (400 MHz, CDCl3, δ, ppm): 8.52 (dd, J=6.7, 1.0 Hz, 1H), 8.23 (d, J=8.H Hz, 2H), 8.09 (d, J=8.4 Hz, 2H), 7.68 (dd, J=7.4, 0.9 Hz, 1H), 7.62-7.60 (m, 1H), 7.48 (dd, J=8.1, 1.8 Hz, 1H), 7.32 (t, J=7.7 Hz, 1H), 7.05 (t, J=7.1 Hz, 1H), 6.97-6.93 (m, 2H), 3.70 (s, 2H), 3.13-3.01 (m, 11H). MS=512 (MH)+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]=[C:12]([CH:15]=P(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[S:13][CH:14]=2)=[CH:6][CH:5]=1.O=[C:36]1[CH2:39][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:37]1>C1COCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:11]=[C:12]([CH:15]=[C:36]3[CH2:37][N:38]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[CH2:39]3)[S:13][CH:14]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(-c2csc(C=P(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CC(=O)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=Cc2nc(-c3ccc(F)cc3)cs2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 54.4 %

Procedure:
Sodium hydride (0.818 g, 20.4 mmol) was added to a solution of 4-(4-fluorophenyl)-2-((triphenylphosphoranylidene)methyl)thiazole (3.1 g, 5.84 mmol) in THF (15.0 mL) at 0° C. and the reaction mixture was stirred for 30 min. tert-Butyl 3-oxoazetidine-1-carboxylate (1.0 g, 5.84 mmol) was then added portionwise and the reaction mixture was allowed to warm up to room temperature and stirred overnight. The reaction mixture was then poured over crushed ice and then filtered through Celite. The filtrate was extracted with CH2Cl2. The combined extracts were dried over sodium sulphate and concentrated under reduced pressure to provide tert-butyl 3-((4-(4-fluorophenyl)thiazol-2-yl)methylene)azetidine-1-carboxylate (1.1 g, 10.89%). 1H NMR (400 MHz, CDCl3) δ 7.78-7.82 (m, 2H), 7.30 (s, 1H), 7.02-7.06 (m, 2H), 6.54-6.55 (t, 1H), 4.83-4.85 (t, 2H), 4.61-4.64 (q, 2H), 1.54 (s, 9H). MS (ESI) m/z: Calculated for C18H19FN2O2S: 346.12. found: 347.0 (M+H)+
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[CH2:7]([O:11][C:12]1[CH:17]=[CH:16][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O-:29])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:14][CH:13]=1)[CH2:8][CH2:9][CH3:10].CI>CC(CC)=O>[CH2:7]([O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][NH:20][C:21]2[C:26]([C:27]([O:29][CH3:1])=[O:28])=[C:25]([CH2:30][CH3:31])[N:24]=[CH:23][N:22]=2)=[CH:16][CH:17]=1)[CH2:8][CH2:9][CH3:10]
Reactant: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)[O-])cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CI
Product: CCCCOc1ccc(CCNc2ncnc(CC)c2C(=O)OC)cc1
Temperature: 65 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
Potassium carbonate (0.27 g, 1.95 mmol) was added to a solution of 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate acid (0.34 g, 0.99 mmol) in ethyl methyl ketone (20 ml), and methyl iodide (0.42 g, 2.96 mmol) was added. After stirring at 65° C. for 3 hours, the mixture was cooled to room temperature. The resulting solid was filtered off and the solvent was evaporated. The reside was purified by column chromatography on silica gel eluting with n-hexane/ethyl acetate (=8/2) to give the desired methyl 4-(2-(4-butoxyphenyl)ethylamino)-6-ethylpyrimidine-5-carboxylate (0.26 g, 73%).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[CH:11][CH:10]=3)[CH2:8][C@H:4]2[CH2:3]1.[H-].[Na+].Br[CH2:26][CH2:27][CH:28]([CH3:30])[CH3:29]>C1COCC1>[CH3:29][CH:28]([CH3:30])[CH2:27][CH2:26][O:1][C@@H:2]1[CH2:22][N:5]2[C:6](=[O:21])[N:7]([C:9]3[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]([F:20])([F:18])[F:19])=[CH:13][CH:14]=3)[CH2:8][C@H:4]2[CH2:3]1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)C[C@H]2C[C@H](O)CN12
Reactant: CC(C)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCO[C@H]1C[C@@H]2CN(c3ccc(OCC(F)(F)F)cc3)C(=O)N2C1
Reaction time: 0.5 h
Yield: 49.1 %

Procedure:
To a solution of (6S,7aR)-6-Hydroxy-2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-hexahydro-pyrrolo[1,2-c]imidazol-3-one (100 mg, 0.316 mmol) in THF (3 mL) was added NaH (60% dispersion, 18.96 mg, 0.474 mmol) at room temperature and stirred for 30 min and then added 1-Bromo-3-methyl-butane (57.3 mg, 0.379 mmol) and left stirring for 12 h. The reaction mixture was quenched with NH4Cl aq., DCM was added. The organic layer was separated, washed with water and brine, dried over Na2SO4 and concentrated. The residue was purified through column chromatography (elution with ethyl acetate in hexane) to afford 60 mg (49%) of the title compound. LC-MS: 386 [M+1]+.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>ClCCl>[CH3:43][S:44]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35])(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(-c2cc3cc(CN4CCCCC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 85.3 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-methyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.5 mg, 0.170 mmol) was dissolved in dichloromethane (3 mL), and the solution was treated with triethylamine (0.095 mL, 0.68 mmol) and methanesulfonyl chloride (0.026 mL, 0.34 mmol), followed by purification by slurry using hexane to obtain 4-methanesulfonyloxy-5-methyl-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (80.3 mg, yield 85%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH2:14]([NH2:18])[CH2:15][CH2:16][CH3:17].C(O)(=O)C.C([BH3-])#N.[Na+]>CO.O>[CH2:14]([NH:18][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([C:10]([F:13])([F:12])[F:11])=[CH:9][C:2]=1[F:1])[CH2:15][CH2:16][CH3:17]
Reactant: O=Cc1ccc(C(F)(F)F)cc1F
Reactant: CCCCN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CCCCNCc1ccc(C(F)(F)F)cc1F
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.7 %

Procedure:
To a solution of 2-fluoro-4-(trifluoromethyl)benzaldehyde (3.84 g, 20.0 mmol) and n-butylamine (1.46 g, 20.0 mmol) in methanol (100 mL) were added acetic acid (4.6 mL, 80 mmol) and sodium cyanoborohydride (1.51 g, 24.0 mmol) and the solution was stirred at room temperature for 3 days. Water (10 mL) was added and the mixture was concentrated in vacuo. The residue was taken, up in aqueous 1 M KOH (125 mL) and ethyl acetate (100 mL) and the phases were separated. The aqueous phase was extracted with ethyl acetate (2×100 mL) and the combined organic phase was dried over Na2SO4 and concentrated in vacuo. Purification on a prepacked column of silica gel (Isolute® SPE Column, 70 g/150 mL) with ethyl acetate (33-100% gradient) in heptane as the eluent and collection of pure fractions yielded 1.28 g (26%) of a colourless oil of low viscosity.
Reaction SMILES: Br[C:2]1[C:3]2[N:4]([N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[O:18][CH3:19])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:19][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[N:10]=[C:3]2[C:2]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)=[CH:7][CH:6]=[CH:5][N:4]2[N:8]=1
Reactant: OB(O)c1ccccc1
Reactant: COc1ccccc1Nc1nc2c(Br)cccn2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: COc1ccccc1Nc1nc2c(-c3ccccc3)cccn2n1

Procedure:
(2-Methoxy-phenyl)-(8-phenyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amine was prepared from (8-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-(2-methoxy-phenyl)-amine (50.0 mg, 0.157 mmol) and phenylboronic acid (21.0 mg, 0.172 mmol) with Pd(dppf)Cl2 (0.012 g) as the catalyst in a manner analogous to Step 2c and was isolated as a white solid (0.012 g, 24%). MP=155-157° C. 1H NMR (400 MHz, CDCl3, δ, ppm): 8.44 (dd, J=6.6, 0.9 Hz, 1H), 8.40 (dd, J=8.0, 1.4 Hz, 1H), 8.02-7.97 (m, 2H), 7.61 (s, 1H), 7.56 (dd, J=7.4, 0.9 Hz, 1H), 7.55-7.50 (m, 2H), 7.45-7.40 (m, 1H), 7.07-7.02 (m, 1H), 6.98-6.88 (m, 3H), 3.91 (s, 3H). MS=317 (MH)+.
Reaction SMILES: CC1C=CC(S(O[CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>C(Cl)Cl>[O:35]1[CH2:36][CH2:37][N:32]([CH2:12][C@H:13]2[CH2:17][CH2:16][C@@H:15]([NH:18][C:19](=[O:20])[O:21][C:22]([CH3:23])([CH3:24])[CH3:25])[CH2:14]2)[CH2:33][CH2:34]1
Reactant: C1COCCN1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H]1CC[C@H](CN2CCOCC2)C1
Temperature: 0 °C

Procedure:
To a stirred solution of ((1S,3R)-3-(tert-butoxycarbonylamino)cyclopentyl)methyl 4-methylbenzenesulfonate (step 3, about 0.5 g) in DCM (50 ml), potassium carbonate (about 0.3 g) was added at room temperature and cooled to about 0° C. After ten minutes, morpholine (1 ml) was added and stirred the reaction at room temperature for about 6 hours. Completion of the reaction was monitored by TLC. The reaction mixture was neutralized and extracted with DCM, the organic layer was dried over Na2SO4 and concentrated under reduced pressure to furnish the title compound (0.60 g) as a light yellow liquid. 1H NMR (300 MHz, CDCl3): 1.24-1.29 (m, 1H); 1.39-1.40 (s, 9H); 2.29-2.60 (m, 7H); 2.79-2.80 (m, 1H); 3.70-3.73 (m, 4H); 4.63 (S, 1H); 5.37-5.39 (d, J=6 Hz, 1H); 5.72-5.81 (m, 2H); ES Mass: 283 (100%) [M+1].
Reaction SMILES: [CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:12]([O:14]C)=[O:13])[CH2:11][CH2:10][CH2:9][CH2:8]1.O.[OH-].[Li+]>C1COCC1.O.Cl>[CH3:1][CH:2]([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1([C:12]([OH:14])=[O:13])[CH2:8][CH2:9][CH2:10][CH2:11]1
Reactant: COC(=O)C1(CCCCC(C)C)CCCC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)CCCCC1(C(=O)O)CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 70.6 %

Procedure:
To a solution of methyl 1-(5-methyl-hexyl)cyclopentanecarboxylate (110 mg, 0.4 mmol) in 21 mL of THF cooled to 0° C. was added dropwise a solution of lithium hydroxide monohydrate (26 mg, 0.6 mmol) in 5.0 mL of water. The reaction mixture was stirred at rt for 16 h. THF was removed under reduced pressure to give a yellow oil which was diluted with 10 mL of 1 N HCl. The aqueous phase was extracted with CH2Cl2 (8×15 mL), and the extracts were combined, dried over Na2SO4, and concentrated to afford 60 mg (71%) of the desired product. MS [M+H]+213.
Reaction SMILES: [Br:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:11]Br>C(O)(=O)C.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[Br:11][CH2:9][C:8]([C:7]1[C:2]([Br:1])=[N:3][CH:4]=[CH:5][CH:6]=1)=[O:10]
Reactant: BrBr
Reactant: CC(=O)c1cccnc1Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(CBr)c1cccnc1Br
Temperature: 90 °C
Yield: 73.4 %

Procedure:
A solution of 1-(2-bromopyridin-3-yl)ethanone (2.10 g, 10.5 mmol) in acetic acid (28.0 mL) was treated with bromine (595 μL, 11.5 mmol) and heated at 90° C. for 1 h. The reaction mixture was diluted with ethyl acetate and saturated aqueous sodium bicarbonate solution. The aqueous layer was separated and further extracted with ethyl acetate (2×80 mL). The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the crude product. Purification by flash column chromatography (10% ethyl acetate/hexanes to 30% ethyl acetate/hexanes) gave the desired product (2.15 g, 73%). LCMS calculated for C7H6Br2NO (M+H)+: m/z=277.9, 279.9, 281.9. found: 277.7, 279.7, 281.8.
Reaction SMILES: C(OC([N:11]1[C@H:20]([C:21](O)=O)[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:12]1)=O)C1C=CC=CC=1.C(OC([N:34]1[C@@H:43]([C:44]([OH:46])=O)CC2[C:36](=CC=CC=2)[CH2:35]1)=O)C1C=CC=CC=1>>[N:34]1([CH2:21][C@H:20]2[CH2:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][NH:11]2)[CH2:35][CH2:36][O:46][CH2:44][CH2:43]1
Reactant: O=C(O)[C@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Reactant: O=C(O)[C@@H]1Cc2ccccc2CN1C(=O)OCc1ccccc1
Product: c1ccc2c(c1)CN[C@@H](CN1CCOCC1)C2

Procedure:
The procedure is in accordance with the process of Preparation 1′, replacing the (3S)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid used in Step A by (3R)-2-[(benzyloxy)carbonyl]-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid.