Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16][C:17]2([C:21]([OH:23])=[O:22])[CH2:20][CH2:19][CH2:18]2)[CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].[BH4-].[Na+].Cl>[OH-].[Na+].CC(O)C>[C:21]([C:17]1([CH2:16][CH2:15][CH2:14][CH2:13][CH:12]([OH:24])[CH2:11][CH2:10][CH2:9][CH2:8][C:4]2([C:1]([OH:3])=[O:2])[CH2:5][CH2:6][CH2:7]2)[CH2:18][CH2:19][CH2:20]1)([OH:23])=[O:22]
Reactant: O=C(CCCCC1(C(=O)O)CCC1)CCCCC1(C(=O)O)CCC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O=C(O)C1(CCCCC(O)CCCCC2(C(=O)O)CCC2)CCC1
Reaction time: 3.5 h
Yield: 103.9 %

Procedure:
To a solution of 1-[9-(1-carboxycyclobutyl)-5-oxononyl]-1-cyclo-butanecarboxylic acid (7.83 g, 23.1 mmol) in aqueous NaOH (1M, 70 mL) and i-PrOH (70 mL) was added NaBH4 (0.659 g, 17.3 mmol). After stirring for 3.5 h, the reaction mixture was acidified to pH˜1 with conc HCl and extracted with Et2O (1×250 mL, 2×150 mL). The combined organic layers were washed with brine (250 mL), dried (Na2SO4) and concentrated in vacuo. The remaining residue was dried under high vacuum to give 1-[9-(1-carboxycyclobutyl)-5-hydroxynonyl]-1-cyclobutanecarboxylic acid (8.17 g, 97%, contains 7% % (w/w) Et2O) as a thick, colorless oil. 1H NMR (CDCl3): δ=8.56 (br s, 3H), 3.58 (br s, 1H), 2.55-2.30 (m, 4H), 2.00-1.80 (m, 8H), 1.78 (t, J=7.7 Hz, 4H), 1.52-1.15 (m, 12H). 13C NMR (CDCl3): δ=183.0 (2×), 71.7, 47.7 (2×), 38.0 (2×), 37.1 (2×), 30.2 (2×), 30.1 (2×), 25.9 (2×), 25.0 (2×), 15.7 (2×).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1.[H-].[Na+].I[CH3:15]>CN(C=O)C.[NH4+].[OH-]>[CH3:15][N:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]#[N:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: N#Cc1cccc2[nH]ccc12
Reactant: CI
Agent: [H-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1ccc2c(C#N)cccc21
Temperature: 25 °C
Yield: 90.9 %

Procedure:
Add slowly a solution of indole-4-carbonitrile (1.0 g, 7.04 mmol) in anhydrous DMF (5 mL) to a suspension of sodium hydride (60% dispersion in mineral oil, 0.6 g, 8.64 mmol) in anhydrous DMF (2 mL) at 0° C. and warm the reaction mixture to ambient temperature. Add iodomethane (0.7 mL, 10.6 mmol) and stir the reaction for 1 h at ambient temperature. Dilute the reaction mixture with 1M aqueous NH4OH (30 mL) and extract with diethyl ether (3×10 mL). Combine the organic extracts, dry over anhydrous Na2SO4, concentrate in vacuo and purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1, 4:1 and 7:3) to obtain the desired intermediate as a yellow oil (1.0 g, 87%). GC-MS m/z: 156 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8].[C:26]1(=O)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.C([BH3-])#N.[Na+]>CO.C(O)(=O)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[C:6]([CH:17]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][N:11]=1)=[O:8]
Reactant: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCNCC2)nc1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(NC(=O)c2cc(Cl)ccc2NCC2CCN(C3CCCCC3)CC2)nc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 61.7 %

Procedure:
A solution of 5-chloro-N-(5-methylpyridin-2-yl)-2-[(4-piperidinylmethyl)amino]benzamide from Example 99-A (0.45 g, 1.25 mmol) in 10 mL of 95:5 methanol-acetic acid was treated with excess cyclohexanone (1.30 mL, 12.5 mmol), followed by sodium cyanoborohydride (5.0 ml of a 1 M solution in tetrahydrofuran, 6.0 mmol). After stirring at 50° C. for 48 h, the mixture was concentrated in vacuo; and the residue was subjected to silica gel chromatography. Elution with 9:1 dichloromethane-methanol afforded 0.34 g (62%) of the title compound as a yellow solid.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(N(CC)CC)C.C(O[C:40]1(O[Si](C)(C)C)[CH2:42][CH2:41]1)C.C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[ClH:1].[ClH:1].[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][N:26]([CH:40]5[CH2:42][CH2:41]5)[CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCNC1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(C2CC2)C1
Reaction time: 6 h

Procedure:
To a solution of 250 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride in 10 ml of methanol were added 157 μl of triethylamine, 300 mg of Molecular Sieves 3A, 323 μl of acetic acid, 1.53 ml of [(1-ethoxy cyclopropyl)oxy](trimethyl)silane, and 146 mg of sodium cyanoborohydride under ice-cooling, followed by stirring for 6 hours under heating to reflux. The insoluble material was removed by filtration and the filtrate was concentrated under reduced pressure. To the obtained residue were added saturated aqueous sodium bicarbonate and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. To a mixture of the obtained purified product, ethyl acetate, and methanol was added a 4 M hydrogen chloride/ethyl acetate solution under ice-cooling, and the solvent was evaporated under reduced pressure. To the obtained residue was added ethyl acetate and hexane, followed by stirring. The resulting solid was collected by filtration and dried to obtain 136 mg of 8-(cyclohexylmethoxy)-N-[(3S)-1-cyclopropylpiperidin-3-yl]-2-methylimidazo[1,2-a]pyridine-3-carboxamide dihydrochloride.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([O:21]CC)=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1.[OH-].[K+].C(O)C.O>>[CH3:1][C:2]1([CH3:26])[C:7]2[CH:8]=[CH:9][C:10]([C:12]([NH:14][C:15]3[CH:25]=[CH:24][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=3)=[O:13])=[CH:11][C:6]=2[S:5][CH2:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)SCCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(C)CCSc2cc(C(=O)Nc3ccc(C(=O)O)cc3)ccc21

Procedure:
Hydrolysis of the foregoing ester with potassium hydroxide/ethanol/water in analogy to Example 57 gave p-(3,4-dihydro-4,4-dimethyl-2H-1-benzothiopyran-7-carboxamido)benzoic acid, melting point 274°-276° C.
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C@H:8]([C:12]([N:14]1[CH2:36][CH2:35][CH2:34][C@H:15]1[C:16]([NH:18][C@@H:19]([CH:31]([CH3:33])[CH3:32])[CH:20]([C:22]1[O:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1)[OH:21])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10].[C:37]([O:41][C:42]([CH2:44][N:45]1[C:50](=[O:51])[CH:49]=[CH:48][N:47]([CH2:52][C:53](O)=[O:54])[C:46]1=[O:56])=[O:43])([CH3:40])([CH3:39])[CH3:38].Cl.N=C=N>O>[C:37]([O:41][C:42]([CH2:44][N:45]1[C:50](=[O:51])[CH:49]=[CH:48][N:47]([CH2:52][C:53]([NH:7][C@H:8]([C:12]([N:14]2[CH2:36][CH2:35][CH2:34][C@H:15]2[C:16]([NH:18][C@@H:19]([CH:31]([CH3:32])[CH3:33])[CH:20]([C:22]2[O:23][C:24]3[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=3[N:26]=2)[OH:21])=[O:17])=[O:13])[CH:9]([CH3:11])[CH3:10])=[O:54])[C:46]1=[O:56])=[O:43])([CH3:40])([CH3:38])[CH3:39]
Reactant: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](N)C(C)C)C(O)c1nc2ccccc2o1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)ccn(CC(=O)O)c1=O
Agent: Cl
Agent: N=C=N
Solvent: c1ccncc1
Solvent: O
Product: CC(C)[C@H](NC(=O)[C@@H]1CCCN1C(=O)[C@@H](NC(=O)Cn1ccc(=O)n(CC(=O)OC(C)(C)C)c1=O)C(C)C)C(O)c1nc2ccccc2o1
Temperature: 25 °C
Reaction time: 15 h
Yield: 91.5 %

Procedure:
To pyridine (20 ml) containing L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.0 g) are added 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetic acid (0.7 g) obtained in Example 4 and 1-ethyl-3-dimethylaminopropyl)carbodiimide hydrochloride (0.6 g), and the mixture is stirred at room temperature for 15 hours. The reaction solution is poured into water, and the mixture is extracted with ethyl acetate. The extract is washed successively with 1 mol/liter hydrochloric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated brine, and dried over anhydrous magnesium sulfate. The solvent is removed by evaporation under reduced pressure to give the desired 2-(3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl)acetyl-L-valyl-N-[(1S)-2-(2-benzoxazolyl)-1-isopropyl-2-hydroxyethyl]-L-prolinamide (1.5 g) as powders.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH2:7])[S:5][CH:6]=1.Cl[C:9]1[CH:14]=[C:13]([S:15][C:16]2[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:11][N:10]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:9]2[CH:14]=[C:13]([S:15][C:16]3[CH:17]=[C:18]([CH:23]=[CH:24][CH:25]=3)[C:19]([O:21][CH3:22])=[O:20])[CH:12]=[CH:11][N:10]=2)[S:5][CH:6]=1
Reactant: Cc1csc(N)n1
Reactant: COC(=O)c1cccc(Sc2ccnc(Cl)c2)c1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: COC(=O)c1cccc(Sc2ccnc(Nc3nc(C)cs3)c2)c1
Yield: 73.6 %

Procedure:
Using the method of Example 3, Step B, 4-methylthiazol-2-amine (59.5 mL, 23.8 mmol), methyl 3-(2-chloropyridin-4-ylthio)benzoate (6.05 g, 21.6 mmol), potassium phosphate (5.05 g, 23.8 mmol), Pd2(dba)3 (0.495 g, 0.541 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethyl-9H-xanthene (0.338 g, 0.584 mmol) were reacted to provide methyl 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-ylthio)benzoate (5.68 g, 73.5% yield). 1H NMR (d6-DMSO) δ 11.06 (s, 1H), 8.10 (m, 3H), 7.87 (m, 1H), 7.70 (t, 1H), 6.72 (s, 1H), 6.64 (dd, 1H), 6.53 (s, 1H), 3.88 (s, 1H), 2.19 (s, 3H); Mass spectrum (apci) m/z=358.1 (M+H).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][C@@H:16]1[NH:21][CH2:20][CH2:19][NH:18][C:17]1=[O:22].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:15][C@H:16]1[C:17](=[O:22])[NH:18][CH2:19][CH2:20][N:21]1[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(Cl)nc12
Reactant: C[C@@H]1NCCNC1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cccc2oc(N3CCNC(=O)[C@@H]3C)nc12
Yield: 98.8 %

Procedure:
A mixture of methyl 2-chlorobenzoxazole-4-carboxylate (370 mg, 1.75 mmol), (S)-3-methylpiperazin-2-one (200 mg, 1.75 mmol) and K2CO3 (605 mg, 4.38 mmol), in DMF (15 mL), was stirred at ambient temperature for 17 h. The reaction mixture was diluted with H2O (30 mL) and extracted with CH2Cl2 (2×50 mL). The combined organic layers were washed with H2O (3×20 mL), brine (20 mL), dried (Na2SO4). The material was concentrated under reduced pressure to give (S)-methyl 2-(2-methyl-3-oxopiperazine-1-yl)benzoxazole-4-carboxylate (500 mg, 73%) as a yellow oil. 1H NMR consistent.
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].[CH2:18]([O:20][C:21]([C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1)=[O:22])[CH3:19]>>[CH2:18]([O:20][C:21](=[O:22])[C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:14]2[CH:15]=[N:16][C:2]([NH2:1])=[C:3]([C:4](=[O:5])[NH:6][C:7]3[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=3)[CH:13]=2)[CH:28]=1)[CH3:19]
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Product: CCOC(=O)c1cccc(-c2cnc(N)c(C(=O)Nc3ccncc3)c2)c1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 3-ethoxycarbonyl-phenylboronic acid gives “A67”; method 1: HPLC/MS: 1.48 min, [M+H]=363;
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:35])[F:34])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][NH:14][CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])=[O:9].Cl[C:38]1[S:39][C:40]2[C:45]([Cl:46])=[N:44][C:43]([CH:47]3[CH2:49][CH2:48]3)=[N:42][C:41]=2[N:50]=1.C(N(CC)C(C)C)(C)C>C(Cl)(Cl)Cl>[F:2][C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][C:31]=1[O:32][C:33]([F:36])([F:34])[F:35])[CH2:6][NH:7][C:8]([C@H:10]1[CH2:15][N:14]([C:38]2[S:39][C:40]3[C:45]([Cl:46])=[N:44][C:43]([CH:47]4[CH2:48][CH2:49]4)=[N:42][C:41]=3[N:50]=2)[CH2:13][CH2:12][N:11]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=1)(=[O:17])=[O:18])=[O:9]
Reactant: Clc1nc2nc(C3CC3)nc(Cl)c2s1
Reactant: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CNCCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(OC(F)(F)F)c(F)c1)[C@H]1CN(c2nc3nc(C4CC4)nc(Cl)c3s2)CCN1S(=O)(=O)c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 74.1 %

Procedure:
To a mixture of the crude product (about 0.095 mmol) obtained in Step 5 and 2,7-dichloro-5-cyclopropyl-thiazolo[4,5-d]pyrimidine (24 mg) in chloroform (1.0 ml) was added N,N-diisopropylethylamine (42 μl) at room temperature. After stirring at room temperature for 2 hr, the reaction mixture was concentrated under reduced pressure, and the residue was purified by thin layer silica gel chromatography (methanol:chloroform=1:10) to give the title compound (52 mg). 1H-NMR (CDCl3, 300 MHz) δ: 1.03-1.09 (2H, m), 1.17-1.22 (2H, m), 2.18-2.27 (1H, m), 3.14-3.35 (2H, m), 3.43-3.53 (1H, m), 3.96 (1H, d, J=13.6 Hz), 4.22-4.36 (2H, m), 4.45-4.69 (3H, m), 6.97-7.06 (3H, m), 7.20 (1H, t, J=8.5 Hz), 7.83 (2H, d, J=8.3 Hz), 8.02 (2H, d, J=8.3 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][C:10]([O:13][Si](C)(C)C)=[CH:9]2)=[CH:4][N:3]=1.Cl>C1COCC1.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)OC1=CC(c2ccc(Cl)nc2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C1CCC(c2ccc(Cl)nc2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.2 %

Procedure:
2-Chloro-5-(3-trimethylsilanyloxycyclopent-2-enyl)pyridine (0.58 g, 2.2 mmol) was dissolved in THF (10 mL) in a 100 mL round bottom flask and treated with 1N HCl (2 mL) with stirring at room temperature. After 1 h, the mixture was diluted with EtOAc and sat. NaHCO3 and the layers separated. The aqueous phase was extracted with EtOAc and the combined organic layers dried (Na2SO4), filtered, concentrated, and purified by flash silica gel chromatography (hexanes:EtOAc/2:1) to give 3-(6-chloropyridin-3-yl)cyclopentanone (0.16 g, 37%) as a dark oil: LC/MS (ESI) m/z 195, 1H NMR (300 MHz, CDCl3) δ 8.31 (d, 1H, J=2.7 Hz), 7.54 (dd, 1H, J=8.4, 2.7 Hz), 7.31 (d, 1H, J=8.4 Hz), 3.43 (m, 1H), 2.70 (m, 1H), 2.56-2.22 (m, 4H), 1.97 (m, 1H).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][NH:4][C@@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19].[F:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26](O)=[O:27].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CC(N(C)C)=O.CCOC(C)=O>[F:20][C:21]1[CH:22]=[CH:23][C:24]([I:30])=[C:25]([CH:29]=1)[C:26]([N:4]1[CH2:5][CH2:6][CH2:7][C@@H:2]([CH3:1])[C@H:3]1[CH2:8][N:9]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]1=[O:19])=[O:27]
Reactant: O=C(O)c1cc(F)ccc1I
Reactant: C[C@@H]1CCCN[C@@H]1CN1C(=O)c2ccccc2C1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN(C(=O)c2cc(F)ccc2I)[C@@H]1CN1C(=O)c2ccccc2C1=O
Reaction time: 16 h
Yield: 62.4 %

Procedure:
To a stirred solution of 2-(((2S,3R)-3-methylpiperidin-2-yl)methyl)isoindoline-1,3-dione (440 mg, 1.70 mmol), 5-fluoro-2-iodobenzoic acid (543 mg, 2.04 mmol), and DIPEA (438 mg, 3.40 mmol) in anhydrous DMA (10 mL) was added HATU (971 mg, 2.55 mmol) at rt under nitrogen and the reaction stirred for 16 h. The reaction mixture was diluted with EtOAc (100 mL), washed with 10% aq. LiCl (3×50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (0% to 70% EtOAc/hexanes) to afford the title compound as a yellow oil (537 mg, 62%). ESI MS (M+H) 507.
Reaction SMILES: Cl.[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][NH2:12])=[CH:3]1.F[C:14]1[CH:22]=[N:21][CH:20]=[CH:19][C:15]=1[C:16]([OH:18])=[O:17]>>[O:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([CH2:11][NH:12][C:19]2[CH:20]=[N:21][CH:22]=[CH:14][C:15]=2[C:16]([OH:18])=[O:17])=[CH:3]1
Reactant: NCc1coc2ccccc12
Reactant: O=C(O)c1ccncc1F
Agent: Cl
Product: O=C(O)c1ccncc1NCc1coc2ccccc12
Yield: 8 %

Procedure:
The title compound was prepared in 8% yield from (1-benzofuran-3-yl)methylamine hydrochloride and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 5. 1H NMR (400 MHz, DMSO-d6): δ 13.39 (br s, 1H), 8.33 (s, 1H), 7.97 (s, 1H), 7.77 (d, 1H, J=5.0 Hz), 7.68 (br s, 1H), 7.57 (d, 1H, J=7.6 Hz), 7.48-7.52 (m, 2H), 7.17-7.28 (m, 2H), 4.64 (s, 2H). [M+H] calc'd for C15H12N2O3, 267. found 267.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].Cl.Cl.[NH2:17][CH:18]([CH2:24][NH:25][C:26]([CH:28]1[CH2:33][CH2:32][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:30][CH2:29]1)=[O:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:17][CH:18]([CH2:24][NH:25][C:26]([CH:28]1[CH2:29][CH2:30][N:31]([C:34]2[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=2)[CH2:32][CH2:33]1)=[O:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:13])=[O:12]
Reactant: CCOC(=O)C(N)CNC(=O)C1CCN(c2ccncc2)CC1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: Cl
Product: CCOC(=O)C(CNC(=O)C1CCN(c2ccncc2)CC1)NS(=O)(=O)c1ccc2ccccc2c1
Yield: 37 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-naphthylsulphonyl chloride was reacted with ethyl 2-amino-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate dihydrochloride salt to give ethyl 2-(2-naphthalenesulphonamido)-3- [1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionate as a foam in 37% yield;
Reaction SMILES: [CH3:1][S:2][CH:3]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)[C:4]([O:6][CH3:7])=[O:5].[H-].[Na+].[CH3:22]I.[Cl-].[NH4+]>CN(C)C=O>[CH3:1][S:2][C:3]([C:8]1[CH:17]=[CH:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=2)[CH:9]=1)([CH3:22])[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)C(SC)c1ccc2cc(OC)ccc2c1
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(SC)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86 %

Procedure:
Methyl α-methylthio-α-(6-methoxy-2-naphthyl)acetate (420 mg) was dissolved in 5 ml of dimethylformamide, and 60 mg (65% content) of sodium hydride was added. The mixture was stirred at room temperature for 10 minutes. Then, 0.20 ml of methyl iodide was added, and the mixture was stirred at room temperature for 30 minutes. An aqueous solution of ammonium chloride (0.5g/30ml) was added and the mixture was extracted three times with 20 ml of diethyl ether. The organic layer was washed twice with 10 ml of water and dried over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was chromatographed on a silica gel using benzene as an eluent to afford 378 mg of methyl α-methylthio-α-(6-methoxy-2-naphthyl)propionate in a yield of 86%.
Reaction SMILES: [Cl-].[F:2][C:3]([F:29])([F:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=2)([OH:17])[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.C(N(C(C)C)CC)(C)C.[CH2:39]([O:41][P:42]([C:47]1[CH:52]=[CH:51][C:50]([CH2:53]Cl)=[CH:49][CH:48]=1)([O:44][CH2:45][CH3:46])=[O:43])[CH3:40]>CS(C)=O.O>[CH2:45]([O:44][P:42]([C:47]1[CH:48]=[CH:49][C:50]([CH2:53][N:14]2[CH2:13][CH2:12][CH:11]([C:10]([C:7]3[CH:6]=[CH:5][C:4]([C:3]([F:2])([F:28])[F:29])=[CH:9][CH:8]=3)([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:25])[F:26])=[CH:20][CH:19]=3)[OH:17])[CH2:16][CH2:15]2)=[CH:51][CH:52]=1)([O:41][CH2:39][CH3:40])=[O:43])[CH3:46]
Reactant: CCOP(=O)(OCC)c1ccc(CCl)cc1
Reactant: OC(c1ccc(C(F)(F)F)cc1)(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Agent: [Cl-]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCOP(=O)(OCC)c1ccc(CN2CCC(C(O)(c3ccc(C(F)(F)F)cc3)c3ccc(C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 1.3 grams (0.004 mole) of 4-(diethylphosphono)phenylmethanol and two drops of pyridine in 10 mL of methylene chloride was added 0.39 mL (0.005 mole) of thionyl chloride. Upon completion of the addition, the reaction mixture was stirred for 30 minutes, then washed with 10 mL of water and 10 mL of an aqueous solution saturated with sodium chloride. The organic layer was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding the intermediate 4-(diethylphosphono)phenylmethyl chloride. The chloride was not further characterized. A solution of 2.7 grams (0.005 mole) of 4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine (prepared as in Step A of Example 17) in 10 mL of dimethyl sulfoxide was stirred, and 2.5 mL (excess) of diisopropylethylamine was added. To this was then added a solution of the methyl chloride, prepared above, in one mL of dimethyl sulfoxide. Upon completion of the addition, the reaction mixture was stirred at ambient temperature for one hour, then poured into water, and the mixture was extracted with one 150 mL portion of methylene chloride. The extract was washed with one 50 mL portion of an aqueous solution saturated with ammonium chloride and one 50 mL portion of water. The extract was concentrated under reduced pressure to a residue, which was subjected to column chromatography on silica gel, with pure ethyl acetate as the eluant. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.6 grams of N-[4-(diethylphosphono)phenylmethyl]-4-[bis(4-trifluoromethylphenyl)hydroxymethyl]piperidine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][N:2]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1B1OC(C)(C)C(C)(C)O1)[S:3]([CH2:6][CH:7]([CH3:9])[CH3:8])(=[O:5])=[O:4].Br[C:26]1[CH:31]=[CH:30][C:29]([C:32]2[N:33]=[CH:34][C:35]([NH2:38])=[N:36][CH:37]=2)=[C:28]([F:39])[CH:27]=1>>[NH2:38][C:35]1[N:36]=[CH:37][C:32]([C:29]2[CH:30]=[CH:31][C:26]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:2]([CH3:1])[S:3]([CH2:6][CH:7]([CH3:8])[CH3:9])(=[O:4])=[O:5])=[CH:27][C:28]=2[F:39])=[N:33][CH:34]=1
Reactant: Nc1cnc(-c2ccc(Br)cc2F)cn1
Reactant: CC(C)CS(=O)(=O)N(C)c1ccccc1B1OC(C)(C)C(C)(C)O1
Product: CC(C)CS(=O)(=O)N(C)c1ccccc1-c1ccc(-c2cnc(N)cn2)c(F)c1

Procedure:
The title compound was prepared using methods analogous to those described in Step B of Example 369 using N-methyl-N-(2-(4,4,5,5,-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-2-methylpropanesulfonamide and 5-(4-bromo-2-fluoro-phenyl)pyrazin-2-amine yielding the title compound after purification by HPLC (32 mg, 41%). MS (ESI): mass calcd. C21H23FN4O2S, 414.15; m/z found, 415.1 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.11 (d, J=1.3, 1H), 8.04-7.94 (m, 1H), 7.47-7.37 (m, 4H), 7.36-7.31 (m, 1H), 7.30-7.24 (m, 1H), 4.69 (s, 2H), 3.13 (s, 3H), 2.70 (d, J=6.6, 2H), 2.26-2.11 (m, 1H), 1.00 (d, J=6.7, 6H).