Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[CH3:9][N:10]1[C:14](B(O)O)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[N:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O.O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:9][N:10]1[C:14]([C:2]2[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=2)=[CH:13][C:12]([C:18]([F:21])([F:20])[F:19])=[N:11]1
Reactant: Oc1ccc(I)cc1
Reactant: Cn1nc(C(F)(F)F)cc1B(O)O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nc(C(F)(F)F)cc1-c1ccc(O)cc1
Temperature: 90 °C
Yield: 74.1 %

Procedure:
To a solution of 4-iodophenol (75 mg, 0.34 mmol) in a mixture of water (1 mL) and 1,4-dioxane (2 mL) was added [1-methyl-3-(trifluoromethyl)-1H-pyrazol-5-yl]boronic acid (Preparation 7, 90 mg, 0.46 mmol), dichlorobis(triphenylphosphine)palladium(II) (18.3 mg, 0.03 mmol) and cesium carbonate (240 mg, 0.74 mmol). The resulting mixture was heated at 90° C. in a Reactivial™ for 4 hours. The reaction mixture was cooled to room temperature and partitioned between ethyl acetate (10 mL) and brine (2×10 mL). The organic extract was dried over anhydrous sodium sulfate and evaporated in vacuo. The crude material was purified by flash column chromatography using the ISCO™ system (12 g column), eluting with 70:30 heptane/ethyl acetate. Fractions containing product were combined and concentrated in vacuo to afford the title compound as a white solid (61 mg, 73%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:54]1[CH:55]=[C:56]2[C:61](=[CH:62][CH:63]=1)[N:60]=[C:59]([CH3:64])[C:58]([C:65](=[O:70])[C:66]([F:69])([F:68])[F:67])=[C:57]2[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1.[NH:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1>CCCCCCC.C(O)(C)(C)C.O1CCOCC1>[F:67][C:66]([F:69])([F:68])[C:65]([C:58]1[C:59]([CH3:64])=[N:60][C:61]2[C:56]([C:57]=1[C:71]1[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1)=[CH:55][C:54]([N:77]1[CH2:82][CH2:81][CH2:80][CH2:79][CH2:78]1)=[CH:63][CH:62]=2)=[O:70]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCCCCCC
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Product: Cc1nc2ccc(N3CCCCC3)cc2c(-c2ccccc2)c1C(=O)C(F)(F)F
Reaction time: 0.02 h
Yield: 74 %

Procedure:
The title compound was prepared according to the general procedure of method B. Following a methodology developed by J. P. Wolfe and S. L. Buchwald (J. Org. Chem. 2000, 65, 1144-1157) a screw-topped pressure-resistant glass vial (50 mL) equipped with a magnetic stirring bar was flushed with a stream of argon and charged with tris(dibenzylideneacetone)dipalladium chloroform complex (0.01 mmol), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.02 mmol), dioxane (7.5 mL) and tert.-butanol (7.5 mL) and then stirred for 1 min before adding cesium carbonate (1.4 mmol), 1-(6-Bromo-2-methyl-4-phenyl-quinolin-3-yl)-2,2,2-trifluoro-ethanone [example 3] (1 mmol), and piperidine (1.2 mmol). The glass vial was covered with a pressure-resistant seal, firmly locked by a screw-cap and heated with stirring in an oil bath at 120° C. during 2 h. The glass vial was cooled in ice before opening, the reaction mixture was diluted with heptane (5 mL) and filtered through a plug of Dicalite filter-aid and rinsed with heptane. The filtrate was evaporated and the residue purified by chromatography on silica gel in heptane/ethyl acetate (4:1). Yield: 74%; MS: m/z=399 (M+H).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[Li+].[OH-]>C(O)C.O>[S:1]1[C:5]2[CH:6]=[C:7]([NH:10][C:11]3[CH:21]=[C:20]([NH:22][CH:23]([CH3:25])[CH3:24])[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]=3)[CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CCOC(=O)c1cnc(Nc2ccc3ncsc3c2)cc1NC(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)Nc1cc(Nc2ccc3ncsc3c2)ncc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Ethyl 6-(benzo[d]thiazol-6-ylamino)-4-(isopropylamino)nicotinate (3) (1 g, 2.8 mmol) in ethanol (20 mL) and water (5 mL) was stirred at rt then added LiOH (14 mmol, 5 equiv.). The reaction mixture was stirred at room temperature for 4 h, the then heated at 70° C. for 1 h. The solvent was concentrated under reduced pressure, diluted with EtOAc and added water. The aqueous layer was collected and acidified to pH 3-4 using solid citric acid. Solid material precipitated out. Filtered the solid material and dried under vacuum to furnish the title compound (4). LC/MS: Acquity BEH C18 2.1×50 mm, 1.8 micron; Solvent A=0.1% TFA in water; Solvent B=0.1% TFA in ACN; gradient 0-100% B over 2 min; retention time: 0.65 min; LCMS (ES-API), m/z 329.8 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12](=[O:13])[CH2:11][CH2:10][C@H:9]1[CH:14]([CH3:16])[CH3:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:19].[OH-].[Na+].S(=O)(=O)(O)[O-].[Na+]>O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH:14]([CH3:16])[CH3:15])[CH2:10][CH2:11][C:12]([OH:19])=[O:13])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Reactant: CC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
A 2 L, one-necked flask (equipped with a magnetic stir bar and a nitrogen inlet) was charged with (S)-2-isopropyl-5-oxo-pyrrolidine-1-carboxylic acid, tert-butyl ester prepared in Step C above (77.4 g, 0.341 mol) and acetone (260 mL). To this solution was added 1M aqueous sodium hydroxide (408 mL, 0.408 mol), and the reaction mixture was stirred 30 minutes. The acetone was removed in vacuo and the resulting aqueous slurry was acidified, with vigorous stirring, by addition of solid sodium bisulfate (55 g, 0.45 mol) and diluted to 1 L with deionized water. The slurry was stirred for 2 h and the resulting white solid was collected by filtration, washed with deionized water, and dried in a vacuum oven to yield the product as a white solid.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH:27]=[O:28])=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:32])(=O)=O>CC(O)=O.C(Cl)Cl>[Cl:32][C:10]1[C:9]([O:8][CH2:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:17][CH:16]=[C:15]2[C:11]=1[CH:12]=[C:13]([CH:27]=[O:28])[N:14]2[S:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:19])=[O:20]
Reactant: O=Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Reactant: O=S(=O)(Cl)Cl
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=Cc1cc2c(Cl)c(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole-2-carbaldehyde (3.22 g, 8.22 mmol) in 1:1 AcOH—CH2Cl2 (140 mL) was added sulfuryl chloride (1.24 g, 9.19 mmol) dropwise and the resulting mixture was stirred at rt for 15 h. Additional sulfuryl chloride (0.084 g, 0.62 mmol) was added and stirring was continued for 1 h. The mixture was partially concentrated to ˜½ volume under a stream of N2 and the resulting light yellow crystals were collected by filtration and washed sequentially with cold AcOH and hexanes, to afford the title compound (2.58 g, 74% yield): 1H NMR (400 MHz, CDCl3) δ 10.49 (s, 1H), 8.05 (d, J=9.3 Hz, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.58-7.54 (m, 2H), 7.46-7.30 (m, 7H), 7.22 (d, J=9 Hz, 1H), 5.19 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Br:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH2:18]Br)=[O:5])[CH3:2].[CH2:20]([O:22][C:23](=[O:33])[CH2:24][NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH3:21].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([Br:11])[N:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]=1[CH2:18][N:25]([C:26]([O:28][C:29]([CH3:30])([CH3:32])[CH3:31])=[O:27])[CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:33])=[O:5])[CH3:2]
Reactant: CCOC(=O)CNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(Br)n(-c2ccccc2)c1CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CN(Cc1c(C(=O)OCC)cc(Br)n1-c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.8 %

Procedure:
5-bromo-2-bromomethyl-1-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (400 mg, 0.94 mmol) and tert-butoxycarbonylamino-acetic acid ethyl ester (182 mg, 0.897 mmol) were dissolved in dry N,N-dimethylformamide (7 mL) at 0° C. Sodium hydride (44 mg, 1.08 mmol) was then added in one portion; the mixture was stirred for 30 min at 0° C., quenched by addition of saturated ammonium chloride aqueous solution, and then extracted with ethyl acetate. The organic phase was subsequently washed with saturated sodium chloride aqueous solution, dried with anhydrous sodium sulfate, and filtered, concentrated to give an oil, which was purified by column to give the title compound (392 mg); ESI MS (m/z): 531 (M+Na+).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1.[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[OH:25])[CH3:18].C([O-])([O-])=O.[K+].[K+]>CC#N>[CH2:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[O:25][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:13]=[C:12]([C:14]([NH2:16])=[O:15])[O:11][N:10]=2)=[CH:5][CH:4]=1)[CH3:18]
Reactant: CCc1ccccc1O
Reactant: NC(=O)c1cc(-c2ccc(CBr)cc2)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCc1ccccc1OCc1ccc(-c2cc(C(N)=O)on2)cc1
Temperature: 90 °C
Yield: 58 %

Procedure:
To a mixture of 3-(4-bromomethyl-phenyl)-isoxazole-5-carboxylic acid amide (which may be prepared as described in Preparation of Intermediate 14; 30 mg, 0.107 mmol) in CH3CN (2 mL) were added 2-ethylphenol (21 μL, 0.178 mmol) and K2CO3 (30 mg, 0.22 mmol). The mixture was heated at 90° C. for 16 h and then evaporated to dryness. The residue was purified by chromatography (66-75% EtOAc/hexanes) to give 3-[4-(2-ethyl-phenoxymethyl)-phenyl]-isoxazole-5-carboxylic acid amide (20 mg, 58%) as a white powder. 1H NMR (300 MHz, DMSO-d6) δ ppm 8.39 (br. s., 1H), 8.01 (br. s., 1H), 7.93 (d, J=8.1 Hz, 2H), 7.55-7.64 (m, 3H), 7.08-7.19 (m, 2H), 7.01 (d, J=8.1 Hz, 1H), 6.87 (t, J=7.3 Hz, 1H), 5.19 (s, 2H), 2.63 (q, J=7.4 Hz, 2H), 1.10-1.19 (m, 3H).
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([CH:24]=4)[C:22]#[N:23])=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1.Cl[C:30]([O:32][CH3:33])=[O:31]>C(Cl)Cl>[CH3:33][O:32][C:30](=[O:31])[NH:2][C@@H:3]1[C:11]2[C:6](=[C:7]([C:12]3[S:16][C:15]([C:17]4[CH:18]=[CH:19][C:20]([O:25][CH:26]([CH3:28])[CH3:27])=[C:21]([C:22]#[N:23])[CH:24]=4)=[N:14][N:13]=3)[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4]1
Reactant: CC(C)Oc1ccc(-c2nnc(-c3cccc4c3CC[C@@H]4N)s2)cc1C#N
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Product: COC(=O)N[C@H]1CCc2c(-c3nnc(-c4ccc(OC(C)C)c(C#N)c4)s3)cccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.1 %

Procedure:
Prepared using General Procedure 8. To a stirred solution of (S)-5-(5-(1-amino-2,3-dihydro-1H-inden-4-yl)-1,3,4-thiadiazol-2-yl)-2-isopropoxybenzonitrile hydrochloride 4 (15 mg, 0.03 mmol) and TEA (11 mg, 0.1 mmol) in DCM (1 mL) was added methyl chloroformate (10 mg, 0.1). The reaction mixture was stirred at room temperature for 16 h. The solvent was evaporated and water (2 mL) was added. The resulting solid was filtered, washed with water, and dried under high vacuum to afford 12 mg (92%) of (S)-methyl(4-(5-(3-cyano-4-isopropoxyphenyl)-1,3,4-thiadiazol-2-yl)-2,3-dihydro-1H-inden-1-yl)carbamate 16 as white solid. LCMS-ESI (m/z) calculated for C23H22N4O3S: 434.1; found 435.3 [M+H]+, tR=3.69 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:23])=[N:18][NH:19]3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12].[C:24]1([CH3:36])[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([CH3:31])[C:25]=1[S:32](Cl)(=[O:34])=[O:33].CN(C1C=CC=CN=1)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:23])=[N:18][N:19]3[S:32]([C:25]3[C:26]([CH3:31])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=3[CH3:36])(=[O:34])=[O:33])=[CH:15][CH:14]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][O:11][CH3:12]
Reactant: COCOc1ccc(-c2ccc3c(C=O)n[nH]c3c2)cc1OC
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Product: COCOc1ccc(-c2ccc3c(C=O)nn(S(=O)(=O)c4c(C)cc(C)cc4C)c3c2)cc1OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 53.6 %

Procedure:
6-(3-methoxy-4-methoxymethoxy-phenyl)-1H-indazole-3-carbaldehyde (441 mg, 1.41 mmol, 1.0 equiv) was taken up as a suspension in dichloromethane (15 mL) and was cooled to 0° C. This mixture was treated with mesitylene sulfonyl chloride (324 mg, 1.48 mmol, 1.05 equiv) and dimethylamino pyridine (DMAP) (181 mg, 1.48 mmol, 1.05 equiv). The mixture was allowed to stir for 1 h at 0° C. and was quenched with the addition of water. The mixture was partitioned between water and a 1:1 ethyl acetate/hexane organic layer. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude material which was purified by silica gel chromatography (50 mL silica, 3:7 ethyl acetate/hexane) to give 6-(3-methoxy-4-methoxymethoxy-phenyl)-1-(2,4,6-trimethyl-benzenesulfonyl)-1H-indazole-3-carbaldehyde (374 mg, 54%): Rf sm 0.17, p 0.53 (ethyl acetate-hexane 4:6); 1H NMR (CDCl3) δ 10.20 (s, 1H), 8.41 (s, 1H), 8.37 (d, 1H, J=8.5 Hz), 7.73 (dd, 1H, J=1.4, 8.4 Hz), 7.3 (m, 3H), 7.08 (s, 2H), 5.36 (s, 2H), 4.08 (s, 3H), 3.71 (s, 3H), 2.74 (s, 6H), 2.40 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:17]O>>[OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[CH:7][C:3]=1[C:4]([O:6][CH3:17])=[O:5]
Reactant: Cc1cc(I)cc(C(=O)O)c1O
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)cc(C)c1O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 2.0 g (7.19 mmol) 2-hydroxy-5-iodo-3-methyl-benzoic acid in 5.0 mL thionyl chloride (69.0 mmol) is stirred for 20 min at 80° C. Thionyl chloride is eliminated i.vac. and the residue is combined with 20 mL MeOH and stirred for 20 min at RT. The product is precipitated out of the reaction. MeOH is eliminated i.vac. down to 5 mL and the residue is suction filtered. The product is further reacted without any more purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH:5]([F:9])[CH2:6][CH2:7]Br)[CH3:2].[NH2:11][C:12]1[N:20]=[C:19]2[C:15]([NH:16][CH:17]=[N:18]2)=[C:14]([Cl:21])[N:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:10])[CH:5]([F:9])[CH2:6][CH2:7][N:18]1[CH:17]=[N:16][C:15]2[C:19]1=[N:20][C:12]([NH2:11])=[N:13][C:14]=2[Cl:21])[CH3:2]
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(=O)C(F)CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(F)CCn1cnc2c(Cl)nc(N)nc21
Yield: 73.7 %

Procedure:
4-Bromo-2-fluorobutyric acid ethyl ester (0.23 g), 2-amino-6-chloropurine (0.19 g) and anhydrous potassium carbonate (0.15 g) were mixed and stirred in dimethylformamide (3.7 ml) at room temperature for two days. The solution was filtered and evaporated in vacuo. The residue was triturated with chloroform (4+2 ml) and the clear chloroform solution was evaporated to give the desired product (0.24 g, 72%). TLC (silica gel, i-propanol-water-conc. ammonia 8-1-1): Rf =0.76. NMR (CDCl3, Me4Si)δ: 1.26 (t, CH3); 2.4-2.5 (m, CH2); 4.2-4.3 (t and q, NCH2 and CO2CH2); 4.77 and 5.03 (CHF, J=51 Hz); 5.2 (NH2); 7.77 (8-CH).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[CH:12]1[CH:17]([F:18])[CH2:16][CH2:15][N:14](C(OCC2C=CC=CC=2)=O)[CH2:13]1>C(O)C.C(OCC)(=O)C.[Pd]>[F:18][C@H:17]1[CH2:16][CH2:15][NH:14][CH2:13][C@H:12]1[N:3]1[C:2](=[O:1])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]1=[O:11]
Reactant: O=C(OCc1ccccc1)N1CCC(F)C(N2C(=O)c3ccccc3C2=O)C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CNCC[C@@H]1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of (+/−)-benzyl 3-(1,3-dioxoisoindolin-2-yl)-4-fluoropiperidine-1-carboxylate (1.0 equiv.) in ethanol and ethyl acetate (1:1, 0.2 M solution) was added Pd/C (20 wt %) under N2 atmosphere. The reaction mixture was flushed with H2 gas, equipped with H2 gas balloon, and stirred for 16 h at room temperature. The reaction mixture was filtered through Celite® Pad and the filtrate was dried in vacuo. The crude (+/−)-2-(4-fluoropiperidin-3-yl)isoindoline-1,3-dione was used for the next step without further purification (>99%). LCMS (m/z): 249.1 (MH+), Rt=0.49 min.
Reaction SMILES: [NH2:1][CH:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[CH:18](OCC)=O>C(OCC)C>[CH3:3][C@H:2]([NH:1][CH3:18])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(N)Cc1ccccc1
Reactant: CCOC=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: CCOCC
Product: CN[C@@H](C)Cc1ccccc1
Temperature: 100 °C

Procedure:
Amphetamine free base (100 mg, 0.71 mmol) was dissolved in ethyl formate (10 mL). The solution was heated under pressure in an ACE pressure reactor for 2 hours at 100° C. The reaction mixture was cooled down, and the solvent was evaporated under reduced pressure. The resulting carbamate derivative was dissolved in dried diethyl ether (5 mL). The solution was added dropwise to a suspension of lithium aluminium hydride (40.4 mg, 1.07 mmol) in diethyl ether (10 mL). The reaction mixture was refluxed for 5 hours. Thereafter, water was carefully added after the reaction mixture had been cooled down to 0° C. on an ice bath. The lithium salt was filtered over Celite™ diatomaceous earth in Buchner funnel. The granules obtained were washed thoroughly with excess diethyl ether. The combined ether phases were washed with 5% sodium hydroxide and brine before being dried with magnesium sulfate. The solvent was evaporated to yield 96 mg methamphetamine free base.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10]2([CH2:26][CH:27]=[CH2:28])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:11]2=3)=[CH:6][CH2:5]1)(=[O:3])[CH3:2].C12BC(CCC1)CCC2.[OH-:38].[Na+].OO>C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][C:7]([C:10]2([CH2:26][CH2:27][CH2:28][OH:38])[C:16]3=[N:17][CH:18]=[CH:19][CH:20]=[C:15]3[CH2:14][CH2:13][C:12]3[CH:21]=[C:22]([Cl:25])[CH:23]=[CH:24][C:11]2=3)=[CH:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: C=CCC1(C2=CCN(C(C)=O)CC2)c2ccc(Cl)cc2CCc2cccnc21
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N1CC=C(C2(CCCO)c3ccc(Cl)cc3CCc3cccnc32)CC1
Temperature: 0 °C
Reaction time: 4 h
Yield: 15.6 %

Procedure:
Dissolved 1-acetyl-4-(8-chloro-5, 6-dihydro-11-(2-propenyl)-11H-benzo[5,6]-cyclohepta[1,2-b]pyridin-11-yl)-1,2,5,6-tetrahydropyridine(1.0 g, 2.5 mmol) in 50 mL of dry THF, and cooled to 0° C. under a nitrogen atmosphere. Added 9-borabicyclo-[3.3.1]nonane (12.5 mL of 0.5M, 6.25 mmol) via syringe. Warmed slowly room temperature, and stirred for 4 hours. Added 25 weight % NaOH (7.8 mL, 20 mmol) and 30 weight % hydrogen peroxide (4.9 mL, 17.5 mmol), and stirred at room temperature for 16 hours. Added dichloromethane, and washed with saturated NaHSO3, water, and then saturated NaCI. Dried organic solution with MgSO4, filtered, and evaporated. Purified crude product by flash chromatography on silica gel eluting with 10% MeOH-EtOAc. Combined appropriate fractions, and evaporated to give 0.16 g (16% yield) of 1-acetyl-4-(8-chloro-5,6-dihydro-11-(3-hydroxypropyl)-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-1,2,5,6-tetrahydropyridine as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][OH:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C1(C)C=CC=CC=1>[CH3:12][S:13]([O:11][CH2:10][C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)(=[O:15])=[O:14]
Reactant: O=[N+]([O-])c1ccc(CO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: CS(=O)(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 72.9 %

Procedure:
To a solution of (4-nitrophenyl)methanol (2 g, 13.06 mmol) in toluene (10 mL) was slowly added methane sulfonylchloride (1.21 mL, 15.67 mmol) at room temperature. The reaction mixture was heated to 80° C. for 4 h. TLC showed complete consumption of starting material. The reaction mixture was cooled to room temperature. The mixture was extracted with ethyl acetate and washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give 4-nitrobenzyl methanesulfonate (2.2 g, 72%).
Reaction SMILES: CC(C)([O-])C.[Na+].C1(P(C2C=CC=CC=2)C2(P(C3C=CC=CC=3)C3C=CC=CC=3)CC=C3C(C=CC=C3)=C2C2C3C(=CC=CC=3)C=CC=2)C=CC=CC=1.[NH:53]1[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]1.Br[C:65]1[CH:70]=[CH:69][C:68]([Cl:71])=[CH:67][N:66]=1.[Cl-].[NH4+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:71][C:68]1[CH:69]=[CH:70][C:65]([N:53]2[CH2:58][CH2:57][CH:56]([C:59]([O:61][CH2:62][CH3:63])=[O:60])[CH2:55][CH2:54]2)=[N:66][CH:67]=1
Reactant: Clc1ccc(Br)nc1
Reactant: CCOC(=O)C1CCNCC1
Agent: [Pd]
Agent: C1=c2ccccc2=C(c2cccc3ccccc23)C(P(c2ccccc2)c2ccccc2)(P(c2ccccc2)c2ccccc2)C1
Agent: CC(C)(C)[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(Cl)cn2)CC1
Reaction time: 1 h
Yield: 52.6 %

Procedure:
Sodium t-butoxide (1.25 g, 13.0 mmol), 2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.485 g, 0.779 mmol), and tris(dibenzylideneacetone)dipalladium(0) (0.238 g, 0.260 mmol) were added to a solution of ethyl piperidine-4-carboxylate (2.00 g, 10.4 mmol) and 2-bromo-5-chloropyridine (2.00 g, 10.4 mmol) in toluene (50 mL), and the mixture was stirred for 1 hour under heating to reflux. A saturated ammonium chloride aqueous solution was added to the reaction solution, followed by extraction with toluene twice. The obtained organic layer was washed with brine and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography [elute: hexane/ethyl acetate=85/15] to obtain the title compound (1.47 g, yield: 53%).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][S:5](=[O:8])(=[O:7])[NH:4][CH2:3]1.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:23][CH2:22][N:21]([C:24]3[C:29]([CH3:30])=[CH:28][C:27]([CH:31]4[CH2:33][CH2:32]4)=[CH:26][N:25]=3)[CH2:20][CH2:19]2)=[O:17])=[C:12]([F:34])[CH:11]=1>>[CH:31]1([C:27]2[CH:28]=[C:29]([CH3:30])[C:24]([N:21]3[CH2:20][CH2:19][N:18]([C:16]([C:13]4[CH:14]=[CH:15][C:10]([N:4]5[CH2:3][C@H:2]([CH3:1])[CH2:6][S:5]5(=[O:8])=[O:7])=[CH:11][C:12]=4[F:34])=[O:17])[CH2:23][CH2:22]3)=[N:25][CH:26]=2)[CH2:32][CH2:33]1
Reactant: C[C@H]1CNS(=O)(=O)C1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2F)CC1
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3C[C@H](C)CS3(=O)=O)cc2F)CC1
Yield: 40.6 %

Procedure:
Using (S)-4-methylisothiazolidine 1,1-dioxide (110 mg) described in Preparation Example 4 and (4-bromo-2-fluorophenyl)[4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (227 mg) described in Preparation Example 121 and by the reaction and treatment in the same manner as in Example 4, the title compound (104 mg) was obtained.