Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:24]#[C:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.[H][H].C(Cl)(Cl)Cl.CO>C(O)C.[C].[Pd]>[CH3:1][C:2]1[CH:3]=[C:4]([CH2:24][CH2:25][CH2:26][N:27]2[CH2:32][CH2:31][N:30]([CH3:33])[CH2:29][CH2:28]2)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:21])[F:22])=[CH:15][CH:14]=1)[CH2:7]2
Reactant: Cc1cc(C#CCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: Cc1cc(CCCN2CCN(C)CC2)cc2c1C(=O)N(Cc1ccc(OC(F)(F)F)cc1)C2
Yield: 94.3 %

Procedure:
A mixture of 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-prop-1-ynyl)-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.076 g, 0.17 mmol) and 10% palladium-carbon (0.015 g) in ethanol (25 mL) was reduced under 45 p.s.i. hydrogen. Workup and silica gel column chromatography using 5:1 CHCl3-MeOH afforded 7-methyl-5-[3-(4-methyl-piperazin-1-yl)-propyl]-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.074 g, 95%). 1H NMR (300 MHz, CDCl3): δ (ppm) 1.79 (m, 2H), 2.22-2.78 (m, 18H), 4.20 (s, 2H), 4.76 (s, 2H), 7.02 (d, 2H), 7.18 (d, 2H), 7.36 (d, 2H).
Reaction SMILES: [C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[CH:19]=[C:18](I)[CH:17]=[N:16][C:15]=3[Cl:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH2:23]([OH:26])[CH:24]=[CH2:25].C(=O)(O)[O-].[Na+].O>[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]12([CH2:11][NH:12][C:13](=[O:22])[C:14]3[CH:19]=[C:18]([CH2:25][CH2:24][CH:23]=[O:26])[CH:17]=[N:16][C:15]=3[Cl:21])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCO
Reactant: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(I)cnc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: O=CCCc1cnc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Yield: 36.1 %

Procedure:
A mixture of N-(1-adamantylmethyl)-5-iodo-2-chloronicotinamide (Example 3(i)) (2.15 g), allyl alcohol (0.58 g), palladium (II) acetate (0.015 g), sodium bicarbonate (1.05 g) and tetra-butyl ammonium chloride (1.39 g) were stirred together in anhydrous N,N-dimethylformamide (20 ml) for 20 hours. The reaction mixture was poured into water (100 ml) and extracted into ethyl acetate (3×25 ml). The combined extracts were dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by chromatography on silica gel eluting with ethyl acetate:iso-hexane (1:1) to afford the sub-titled compound (0.65 g).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1I.CC1(C)C(C)(C)OB([C:46]2[CH:51]=[CH:50][C:49]([CH:52]3[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:61])([F:60])[F:59])[CH2:53]3)=[CH:48][CH:47]=2)O1>O1CCOCC1.C(Cl)Cl>[Cl:9][C:10]1[CH:11]=[C:12]2[N:19]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[C:18]([O:28][C@H:29]3[C@H:33]4[O:34][CH2:35][C@@H:36]([OH:37])[C@H:32]4[O:31][CH2:30]3)=[N:17][C:13]2=[N:14][C:15]=1[C:46]1[CH:47]=[CH:48][C:49]([CH:52]2[CH2:56][CH2:55][N:54]([CH2:57][C:58]([F:60])([F:59])[F:61])[CH2:53]2)=[CH:50][CH:51]=1
Reactant: CC1(C)OB(c2ccc(C3CCN(CC(F)(F)F)C3)cc2)OC1(C)C
Reactant: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(I)c(Cl)cc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(O[C@@H]2CO[C@H]3[C@@H]2OC[C@H]3O)nc2nc(-c3ccc(C4CCN(CC(F)(F)F)C4)cc3)c(Cl)cc21
Temperature: 80 °C
Reaction time: 18 h

Procedure:
Tripotassium phosphate 2.0 M aqueous solution (0.6 ml, 1.200 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (25.2 mg, 0.031 mmol) were added to a stirred solution of (3R,3aR,6R,6aR)-6-[6-chloro-5-iodo-1-(2-trimethylsilylethoxymethyl)imidazo[4,5-b]pyridin-2-yl]oxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-3-ol (147.1 mg, 0.266 mmol) and 3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-1-(2,2,2-trifluoroethyl)pyrrolidine (94.6 mg, 0.266 mmol) in dioxane (2.1 ml). The reaction mixture was degassed (3×) and placed under nitrogen before being heated to 80° C. After 18 hours, the reaction mixture was cooled to room temperature before being partitioned between EtOAc (50 ml) and water (50 ml). The aqueous layer was separated and extracted with EtOAc (2×50 ml). The organic layers were combined, washed with brine (1×30 ml), dried over MgSO4, filtered, and evaporated under reduced pressure to give a yellow residue. The residue was dissolved in DCM, loaded onto a 5 g silica solid load cartridge, and purified using an ISCO Rf and a 12 g silica column (CV=16.8 ml) by eluting as follows: 100% Hex (5 CV), 0-70% EtOAc/Hex gradient (50 CV), 70% EtOAc/Hex (35 CV) at 30 ml/min. The product fractions were combined and evaporated under reduced pressure to give the desired product as a yellow residue. LC-MS: calculated for C30H38ClF3N4O5Si 654.23 observed m/e: 655.32 (M+H)+ (Rt 1.37/2 min)
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=O)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[N:35]=[C:36]([NH2:45])[CH2:37][C:38](=[O:44])[N:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>ClCCl>[CH:15]1([CH2:14][CH2:13][CH2:12][C@@H:8]([C:9]2[O:11][N:45]=[C:36]([CH2:37][C:38](=[O:44])[N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)[N:35]=2)[CH2:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:21])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: NC(CC(=O)N1CCCC1)=NO
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CC(=O)N2CCCC2)no1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A solution of (2R)-2-[2-(tert-butoxy)-2-oxoethyl]-5-cyclohexylpentanoic acid (Preparation 1) (500 mg, 1.70 mmol) in dichloromethane (30 ml) was treated with 1,1′-carbonyldiimidazole (272 mg, 1.70 mmol) and the solution was stirred at room temperature for 1 hour. N′-hydroxy-3-oxo-3-(1-pyrrolidinyl)propanimidamide (Patent FR 73-36858 731016) (291 mg, 1.70 mmol) was then added and the mixture was stirred for 17 hours. The solvent was removed under reduced pressure and the residue was heated neat at 110° C. under a nitrogen atmosphere for 2 hours. The crude product was then purified by column chromatography on silica gel eluting with dichloromethane:methanol (99:1) to afford the title compound as a colourless oil (309 mg).
Reaction SMILES: [H-].[Na+].[CH3:3][NH:4][CH2:5][CH2:6][CH2:7][OH:8].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19](F)=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:30])([F:29])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1.[C:35]([OH:42])(=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39]>C1COCC1.C(OC)(C)(C)C.O>[OH2:8].[OH2:39].[C:35]([OH:42])(=[O:41])[CH2:36][CH2:37][C:38]([OH:40])=[O:39].[Cl:9][C:10]1[C:15]([C:16]2[C:21]([F:22])=[CH:20][C:19]([O:8][CH2:7][CH2:6][CH2:5][NH:4][CH3:3])=[CH:18][C:17]=2[F:24])=[C:14]([NH:25][C@@H:26]([CH3:31])[C:27]([F:29])([F:30])[F:28])[N:13]2[N:32]=[CH:33][N:34]=[C:12]2[N:11]=1
Reactant: CNCCCO
Reactant: C[C@H](Nc1c(-c2c(F)cc(F)cc2F)c(Cl)nc2ncnn12)C(F)(F)F
Agent: O=C(O)CCC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: CNCCCOc1cc(F)c(-c2c(Cl)nc3ncnn3c2N[C@@H](C)C(F)(F)F)c(F)c1
Temperature: 60 °C
Reaction time: 0.5 h

Procedure:
To a suspension of NaH (40.9 g, 1.02 mol, 60% in oil) in anhydrous THF (750 mL) is added 3-methylamino-propan-1-ol (115 g, 1.21 mol) at about 20-30° C. dropwise over 30 min. The mixture is stirred for 30 min. Then, a solution of [5-chloro-6-(2,4,6-trifluoro-phenyl)-[1,2,4]triazolo[1,5-a]pyrimidin-7-yl]-((1S)-2,2,2-trifluoro-1-methyl-ethyl)-amine (150 g, 0.379 mol) in THF (150 mL) is added slowly over 15 min. The mixture is heated to 60° C. and stirred for 16 h, then cooled to 0-6° C. Cold water (1500 mL) is added dropwise while maintain the temperature between 10±3° C. THF is removed by distillation. The reaction mixture is extracted with t-butylmethyl ether (TBME, 2×1000 mL) and to the separated aqueous phase is added in portions succinic acid (296 g, 2.51 mol) is added in portions and followed by addition of TBME (1000 mL). The mixture is cooled to 3±3° C. and stirred for 1 h. The crude solid product is filtered, washed with cold water (150 mL) and TBME (2×400 mL). The wet solid is dissolved into water (2000 mL) at about 75° C. The solution is filtered at 60-70° C. and cooled to 0° C. over 1 h and stirred for 1 h at this temperature. The solid is filtered and dried at 35° C./10 mmHg for 20 h to give a white solid in anhydrous form (175 g, 80%, >99% HPLC area purity and 99% ee). A small portion of the anhydrous compound is placed in a drying dish of 80%-100% relative humidity at about 20° C. to about 30° C. for 24 h. It absorbed 5.8% wt of water and stopped. This dihydrate is stable at about 20° C. to about 30° C. and at 5%-100% relative humidity. 1H NMR (CDCl3): δ 10.2 (bs, 1H), 8.26 (s, 1H), 6.80 (d, 2H, J=10.5 Hz), 5.79 (m, 1H), 4.13 (t, 2H, J=6.3 Hz), 3.03 (t, 2H, J=7.2 Hz), 2.57 (s, 3H), 2.35 (s, 4H), 2.07 (m, 2H), 1.27 (d, J=6.0, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:4][CH:3]=1.[C:20]([N:28]=C=O)(=[O:27])C1C=CC=CC=1.C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CCOC(C)=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[CH:10][O:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C:20]([NH2:28])=[O:27])[CH:14]=2)=[CH:6][CH:7]=1
Reactant: O=C=NC(=O)c1ccccc1
Reactant: Nc1cc(-c2ocnc2-c2ccc(F)cc2)ccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCO
Product: NC(=O)Nc1cc(-c2ocnc2-c2ccc(F)cc2)ccn1
Temperature: 50 °C
Yield: 61 %

Procedure:
4-[4-(4-Fluoro-phenyl)-oxazol-5-yl]-pyridin-2-ylamine (57 mg, 0.22 mmol) and benzoyl isocynate (39 mg, 0.27 mmol) are mixed in DCM (2.0 mL). The reaction is sealed and heated at 50° C. for 16 hrs. Then the solvent is removed and to the residue are added ethanol (2.0 mL) and potassium carbonate (46 mg, 0.34 mmol). The mixture is then heated at 80° C. for 55 min. The solvent is removed and the residue is partitioned between water (25 mL) and EtOAc (35 mL). The aqueous layer is separated and extracted with EtOAc (2×30 mL). The organic layers are combined and concentrated to give the crude product. EtOAc (2 mL) is added into the crude and a solid is formed. The solid is filtered, rinsed with more EtOAc and dried to give 40 mg of the titled product.
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH2:19][CH2:20][NH:21]4)([CH3:16])[CH2:11][C:12]([O:14]C)=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2].O.[Li+].[OH-].[OH-].[Na+]>C1COCC1.CO>[C:1]([C:3]1[CH:30]=[CH:29][C:6]2[NH:7][C:8]([C:10]([C:17]3[C:25]([O:26][CH3:27])=[CH:24][C:23]([CH3:28])=[C:22]4[C:18]=3[CH:19]=[CH:20][NH:21]4)([CH3:16])[CH2:11][C:12]([OH:14])=[O:13])=[N:9][C:5]=2[CH:4]=1)#[N:2]
Reactant: COC(=O)CC(C)(c1nc2cc(C#N)ccc2[nH]1)c1c(OC)cc(C)c2c1CCN2
Agent: [Li+]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: COc1cc(C)c2[nH]ccc2c1C(C)(CC(=O)O)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
(±)-Methyl 3-(5-cyano-1H-benzo[d]imidazol-2-yl)-3-(5-methoxy-7-methylindolin-4-yl)butanoate (Example 156-K) (25 mg, 0.062 mmol) was dissolved in THF (0.371 mL), water (0.124 mL) and MeOH (0.124 mL). LiOH (13 mg, 0.304 mmol) was then added and the reaction was stirred for 18 hours at room temperature. At this point, NaOH (1 mL, 2.000 mmol), MeOH (1 mL) and THF (3 mL) were added and the reaction was stirred for further 4 hours. The reaction was then concentrated and diluted with EtOAc and water. The layers were separated, the aqueous layer was adjusted to pH=1 and directly purified using RP-HPLC (HC-A) to isolate the title compound. 1H NMR (TFA salt, 400 MHz, DMSO-d6) δ ppm 11.01 (br. s., 1H) 8.11 (br. s., 1H) 7.68 (q, J=7.66 Hz, 2H) 7.22 (br. s., 1H) 6.74 (s, 1H) 5.95 (br. s., 1H) 3.55 (d, J=15.16 Hz, 1H) 3.43 (s, 1H) 3.39 (s, 3H) 2.44 (s, 3H) 1.99-2.15 (m, 3H). HRMS calcd. for C22H20N4O3 (M+H)+ 389.1614. found 389.1609.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1.[CH3:27][N:28]([CH3:33])[C:29](=[O:32])[CH:30]=[CH2:31].P(OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1.C([O-])([O-])=O.[Na+].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[Br-].CC(N(C)C)=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:27][N:28]([CH3:33])[C:29](/[CH:30]=[CH:31]/[C:2]1[CH:3]=[C:4]([C:23]([O:25][CH3:26])=[O:24])[C:5]2[O:9][C:8]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[O:7][C:6]=2[CH:22]=1)=[O:32]
Reactant: C=CC(=O)N(C)C
Reactant: COC(=O)c1cc(Br)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cc(/C=C/C(=O)N(C)C)cc2c1OC(c1ccccc1)(c1ccccc1)O2
Temperature: 25 °C

Procedure:
A solution of methyl 6-bromo-2,2-diphenyl-1,3-benzodioxole-4-carboxylate (130 mg, 0.32 mmol), N,N-dimethylacrylamide (47 mg, 0.47 mmol, 1.5 eq.), P(OPh)3 (980 mg, 3.16 mmol, 10 eq.), Bu4NBr (20 mg, 0.06 mmol, 0.2 eq.), Na2CO3 (40 mg, 0.38 mmol, 1.2 eq.) and Pd(OAc)2 (10 mg, 0.03 mmol, 0.1 eq.) in 10 mL dimethylacetamide was stirred at 140° C. for 72 h. After cooling to r.t. the mixture was partitioned between EtOAc and H2O. The organic layer was washed twice with saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The crude product was purified using flash chromatography (silica gel, hexane/EtOAc 5:1→3:2) to yield the desired compound as a colorless, slowly solidifying viscous oil.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:8](=[O:10])[CH3:9])=[N:4][CH:5]=[CH:6][N:7]=1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.[Br:31]N1C(=O)CCC1=O>O.C(Cl)(Cl)Cl>[Br:31][CH2:9][C:8]([C:3]1[C:2]([CH3:1])=[N:7][CH:6]=[CH:5][N:4]=1)=[O:10]
Reactant: CC(=O)c1nccnc1C
Reactant: O=C1CCC(=O)N1Br
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1nccnc1C(=O)CBr
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
To a chloroform (7.5 mL) solution of 1-(3-methylpyrazin-2-yl)ethanone (0.50 g), under ice cooling in a nitrogen atmosphere, 2,6-lutidine (0.75 mL) and trimethylsilyl trifluoromethanesulfonate (0.80 mL) were added, and the resultant was stirred for 30 minutes. Then, N-bromosuccinimide (0.73 g) was added thereto, and the resultant was stirred for 1 hour under ice cooling. Water was added to the reaction solution, and the resultant was stirred for 10 minutes, followed by extraction with chloroform. An organic layer was separated using a phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (OH-type silica gel; hexane/ethyl acetate-gradient elution=95/5→85/15) to obtain the title compound (0.58 g) as a brown solid.
Reaction SMILES: CN1CCC[C@@H](OC(=O)C(O)(C2SC=CC=2)C2SC=CC=2)C1.O(CC[Br:32])C1C=CC=CC=1.[Br-].[OH:34][C:35]([C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)([C:55]1[S:56][CH:57]=[CH:58][CH:59]=1)[C:36]([O:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][N+:41]([CH3:54])([CH2:45][CH2:46][O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40]1)=[O:37]>C(#N)C>[Br-:32].[OH:34][C:35]([C:55]1[S:56][CH:57]=[CH:58][CH:59]=1)([C:60]1[S:61][CH:62]=[CH:63][CH:64]=1)[C:36]([O:38][C@@H:39]1[CH2:44][CH2:43][CH2:42][N@+:41]([CH3:54])([CH2:45][CH2:46][O:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH2:40]1)=[O:37]
Reactant: C[N+]1(CCOc2ccccc2)CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Reactant: BrCCOc1ccccc1
Agent: CN1CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Agent: [Br-]
Solvent: CC#N
Product: C[N@+]1(CCOc2ccccc2)CCC[C@@H](OC(=O)C(O)(c2cccs2)c2cccs2)C1
Temperature: 25 °C

Procedure:
Hydroxy-di-thiophen-2-yl-acetic acid (R)-1-methyl-piperidin-3-yl ester (0.57, 0.00169 mol) is dissolved in acetonitrile (3 ml) at 60° C. and 2-phenoxyethyl bromide (0.51 g, 0.00254 mol) in Acetonitrile (1 ml) is added dropwise. The reaction mixture is refluxed for 96 hours, cooled to room temperature and left in the refrigerator. This gives an approximately 1:1 mixture of isomers (1R/S,3R)-3-(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-methyl-1-(2-phenoxy-ethyl)-piperidinium bromide (97a). The suspension is filtered off and washed with cold acetonitrile to yield (1R,3R)-3-(2-hydroxy-2,2-dithiophen-2-yl-acetoxy)-1-methyl-1-(2-phenoxy-ethyl)-piperidinium bromide (97b) as a white solid.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[CH3:5][C:6]1[CH:7]=[C:8]([SH:13])[CH:9]=[C:10]([CH3:12])[CH:11]=1.[C:14](Cl)(=[O:18])[C:15](Cl)=[O:16]>C(Cl)Cl>[CH3:12][C:10]1[C:9]2[C:15](=[O:16])[C:14](=[O:18])[S:13][C:8]=2[CH:7]=[C:6]([CH3:5])[CH:11]=1
Reactant: Cc1cc(C)cc(S)c1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1)SC(=O)C2=O
Temperature: 25 °C
Yield: 36.1 %

Procedure:
To a solution of AlCl3(0.4 g, 3.6 mmol) in CH2Cl2 (4 mL) at −20° C. under nitrogen are added 3,5-dimethylbenzenethiol (1 g, 7.2 mmol) and oxalyl chloride (0.6 mL, 7.2 mmol) respectively. The solution is warmed to room temperature for 1 hour and is heated to 120° C. in a microwave reactor for 15 minutes. The solution is cooled and is poured into crushed ice. The solution is extracted with CH2Cl2 and the organic layer is collected. The solution is dried with MgSO4 and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography with 5% EtOAc in Hexane as the eluent to afford 4,6-dimethyl-benzo[b]thiophene-2,3-dione (500 mg, 35%).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[C:17](OCC)(=[O:19])[CH3:18].CC(C)([O-])C.[K+]>CC(OC)(C)C>[C:13]([O:12][C:10]([N:7]1[CH2:6][CH2:5][CH:4]([C:1](=[O:3])[CH2:2][C:17](=[O:19])[CH3:18])[CH2:9][CH2:8]1)=[O:11])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CCOC(C)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COC(C)(C)C
Product: CC(=O)CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
A solution of 2.27 g (10.0 mmol) of 4-acetyl-1-(tert-butoxycarbonyl)piperidine (from Step A), 1.95 mL (20.0 mmol) of ethyl acetate and 2.24 g (20.0 mmol) of potassium t-butoxide in 25 mL of MTBE was stirred at rt for 20 h. The reaction was quenched with 50 mL of 0.5 N KHSO4 and extracted with 150 mL of ether. The extract was dried over MgSO4 and concentrated. Flash chromatography on 70 g of silica gel using 20:1 v/v hexanes/acetone as the eluant afforded the title compound. The enol form predominated in CDCl3 solution: 1H NMR (500 MHz, CDCl3) δ 1.46 (s, 9H), 1.53 (dq, J=4.5, 12.5, 2H), 1.81 (app d, J=13.5, 2h), 2.07 (s, 3H), 2.44–2.33 (m, 1H), 2.72–2.79 (m, 2H), 4.18–4.28 (br s, 2H), 5.50 (s, 1H).
Reaction SMILES: B(F)(F)F.CCOCC.Br[CH2:11][C:12]([C:14]1[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=1)=O.[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29](=[O:31])[NH2:30]>C1COCC1>[CH3:22][O:23][C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[O:31][CH:11]=[C:12]([C:14]2[C:19]([O:20][CH3:21])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:30]=1
Reactant: COC(=O)CCCCC(N)=O
Reactant: COc1cccnc1C(=O)CBr
Agent: FB(F)F
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)CCCCc1nc(-c2ncccc2OC)co1
Temperature: 80 °C
Yield: 33.4 %

Procedure:
Add boron trifluoride etherate (0.30 mL, 1.00 mmol) to a sealed tube containing 2-bromo-1-(3-methoxy-pyridin-2-yl)-ethanone (231 mg, 1.00 mmol), 5-carbamoyl-pentanoic acid methyl ester (222 mg, 1.39 mmol), and THF (anhydrous, 3 mL). Flush with N2, seal, heat at 80° C. overnight. Partition between saturated aqueous NaHCO3 solution and 20% i-PrOH/CHCl3, separate layers. Extract from aqueous layer with 20% i-PrOH/CHCl3 (×3), dry combined organic layers with MgSO4 and concentrate. Adsorb on SiO2 and purify by flash chromatography on silica gel eluting with 1-3% methanol/CHCl3 to afford the title compound (97 mg, 33%). MS (IS) 291 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]([O:18]C)=[O:17])[CH:5]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][C:9]=2[F:15])[CH:7]=1.[NH:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[OH-].[Na+]>CN(C)C(=O)C.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.[Pd].CO>[F:15][C:9]1[CH:10]=[C:11]([CH3:14])[CH:12]=[CH:13][C:8]=1[C:6]1[CH:7]=[C:2]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[CH:3]=[C:4]([C:16]([OH:18])=[O:17])[CH:5]=1
Reactant: COC(=O)c1cc(Br)cc(-c2ccc(C)cc2F)c1
Reactant: C1COCCN1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(C=Cc1ccccc1)C=Cc1ccccc1
Solvent: CO
Solvent: CC(=O)N(C)C
Product: Cc1ccc(-c2cc(C(=O)O)cc(N3CCOCC3)c2)c(F)c1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
To a solution of methyl 5-bromo-2′-fluoro-4′-methylbiphenyl-3-carboxylate (408.0 mg, 1.263 mmol) in N,N-dimethylacetamide (5 mL) was added morpholine (0.17 mL, 1.9 mmol), cesium carbonate (1.23 g, 3.79 mmol), palladium dibenzylidene acetone (116.0 mg, 0.13 mmol), and 2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′biphenyl (XPhos; 90.0 mg, 0.19 mmol) and the mixture heated to 100° C. After 16 h the reaction was allowed to cool to ambient temperature, filtered with methanol, and sodium hydroxide (1M in water; 3.0 mL, 3.0 mmol) was added. After 16 h, reaction was concentrated, acidified with trifluoroacetic acid, and purified by reverse phase HPLC (C-18, 95% water/acetonitrile→20% water/acetonitrile with 0.1% trifluoroacetic acid). Extraction with dichloromethane and 1M aqueous hydrochloric acid gave the title compound. MS 316.1 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[OH-].[Na+].[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29]Cl>CO>[N:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][O:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][C:10]2[CH:9]=[C:8]([C:7]3[C:2]([NH2:1])=[N:3][CH:4]=[CH:5][CH:6]=3)[O:12][N:11]=2)=[CH:15][CH:16]=1
Reactant: Nc1ncccc1-c1cc(Cc2ccc(O)cc2)no1
Reactant: ClCc1ccccn1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Nc1ncccc1-c1cc(Cc2ccc(OCc3ccccn3)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.8 %

Procedure:
To a mixture of 4-(5-(2-amino-pyridin-3-yl)isoxazol-3-ylmethyl)-phenol (4.2 mg, 0.016 mmol) described in Manufacturing Example 5-1-1 and methanol (0.4 mL) was added 1 N aqueous sodium hydroxide solution (16 μL, 0.016 mmol), which was then concentrated under a reduced pressure. To a mixture of the residue and N,N-dimethylformamide (0.5 mL) was added 2-picolyl chloride (3.1 mg, 0.019 mmol), which was stirred for 2 hours at room temperature. The reaction mixture was purified as is by reverse-phase high performance liquid chromatography (using an acetonitrile-water mobile phase containing 0.1% trifluoroacetic acid) to obtain the title compound (3.6 mg, 39%) as a ditrifuoracetic acid salt.