Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[O:14])[CH2:9][CH2:8]2)=[C:4]([N:27]2[CH2:32][CH2:31][O:30][CH2:29][CH2:28]2)[CH:3]=1.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])([O-])=O.[K+].[K+].C1COCC1>C(Cl)Cl.C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl.O>[O:30]1[CH2:31][CH2:32][N:27]([C:4]2[CH:3]=[C:2]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH:26]=[CH:25][C:5]=2[CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([O:15][CH:16]([C:21]([F:24])([F:23])[F:22])[C:17]([F:20])([F:19])[F:18])=[O:14])[CH2:9][CH2:8]2)[CH2:28][CH2:29]1
Reactant: OB(O)c1ccccc1
Reactant: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(Br)cc2N2CCOCC2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(OC(C(F)(F)F)C(F)(F)F)N1CCN(Cc2ccc(-c3ccccc3)cc2N2CCOCC2)CC1
Temperature: 70 °C
Yield: 60.3 %

Procedure:
A round bottom flask was charged with 1,1,1,3,3,3-hexafluoropropan-2-yl 4-(4-bromo-2-morpholinobenzyl)piperazine-1-carboxylate (Example 57, 30 mg, 0.0562 mmol), Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (5 mg, 6.13 μmol), phenylboronic acid (10 mg, 82.0 μmol), and K2CO3 (21 mg, 152 μmol). THF (4 mL) and H2O (0.4 mL) were added and the reaction was heated to 70° C. for 2 h. The reaction was diluted in CH2Cl2 and washed with sat Na2CO3 (2×) and brine (1×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% to 80% hexanes in EtOAc) and yielded 1,1,1,3,3,3-hexafluoropropan-2-yl 4-((3-morpholino-[1,1′-biphenyl]-4-yl)methyl)piperazine-1-carboxylate (18 mg, 60%). 1H NMR 400 MHz (CDCl3) δ 7.54-7.48 (m, 2H), 7.45-7.34 (m, 3H), 7.31-7.20 (m, 3H), 5.68 (h, J=6.3 Hz, 1H), 3.84-3.71 (m, 4H), 3.57 (s, 2H), 3.53-3.39 (m, 4H), 3.00-2.93 (m, 4H), 2.47 (dt, J=9.9, 5.0 Hz, 4H). LCMS (ESI, m/z): 532 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:22])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH2:21])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)=[CH:5][CH:4]=1.N1C=CC=CC=1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[CH3:35][O:36][CH2:37][C:38]([NH:21][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:22])=[CH:15][CH:16]=1)=[O:39]
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN)cc3)nc12
Reactant: COCC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: COCC(=O)NCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 71 %

Procedure:
N-(4-Methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-aminometyl-benzamide (100 mg, 0.24 mmol), dissolved in dichloromethane (5 ml) is treated with pyridine (29 μl, 0.36 mmol) and methoxy-acetyl chloride (24 μl, 0.32 mmol) and stirred at ambient temperature for 15 h. Saturated aqueous sodium carbonate (6 ml) is added, the phases are separated and the aqueous solution extracted twice with each 5 ml dichloromethane. The combined organic phases are dryed over sodium sulphate, filtered and evaporated to dryness. Flash chromatography (silica, eluent: dichloromethane containing 3% methanol) afforded the title compound as white crystals (71% yield). MS: m/e=471(M+H+).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][OH:34]>>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:30][CH2:31][CH2:32][CH2:33][OH:34])=[O:27])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCCCO
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Product: O=C(NCCCO)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-benzyloxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 498) and 3-amino-propan-1-ol.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2].[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[CH2:1]([C:3]1[CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=[C:6]([CH2:10][CH3:11])[C:4]=1[NH2:5])[CH3:2]
Reactant: CCc1cccc(CC)c1N
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CCc1cc([N+](=O)[O-])cc(CC)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 2,6-diethylaniline (5.0 g, 34 mmol) in concentrated sulfuric acid (30 mL) at 0° C. was added dropwise concentrated nitric acid (15.9M, 2.10 mL, 34 mmol). The cooling bath was removed, and the reaction was stirred for 3 hours at ambient temperature. After pouring the reaction mixture into ice, the solution was neutralized using 4N sodium hydroxide and extracted with methylene chloride (3×50 mL). The extracts were dried with sodium sulfate, and solvents were removed in vacuo to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][NH:6][C:7](=[O:11])[CH:8]([CH3:10])[CH3:9])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH3:23][CH2:24][CH2:25]CCC.C(Br)C=C>C1COCC1>[CH2:1]([O:3][C:4](=[O:12])[CH:5]([NH:6][C:7](=[O:11])[CH:8]([CH3:9])[CH3:10])[CH2:25][CH:24]=[CH2:23])[CH3:2]
Reactant: CCOC(=O)CNC(=O)C(C)C
Reactant: CCCCCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CCC(NC(=O)C(C)C)C(=O)OCC

Procedure:
11.74 g of the above prepared isobutyrylamino-acetic acid ethyl ester (67.78 mmol) was dissolved in 250 ml of abs. THF and cooled down to −78°. 139 ml of 1M lithium hexamethyldisilazide in hexane (2.05 eq.) were added within 30 Min. via dropping funnel. After keeping the yellow suspension for additional 30 Min. at −78°, 6.021 ml of allyl bromide (1.05 eq.) was added and stirring continued for 15 Min. at the same temperature and for 30 Min. at 0°. Pouring of the homogeneous reaction mixture onto crashed ice/HCl, twofold extraction with AcOEt, twofold washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (SiO2, hexane/AcOEt=7/3) afforded. 11.70 g of the title compound as pale-yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:14]=[CH:13][C:11](N)=[CH:10][CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1.C(O)(=[O:19])C.N([O-])=O.[Na+].S(=O)(=O)(O)O>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:14]=[CH:13][C:11]([OH:19])=[CH:10][CH:9]=2)=[C:4]([O:15][CH3:16])[CH:3]=1
Reactant: CC(=O)O
Reactant: COc1cc(F)ccc1-c1ccc(N)cc1
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: COc1cc(F)ccc1-c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of 32.00 grams of 4-(4'-fluoro-2'-methoxyphenyl)-aniline in 120 ml. of glacial acetic acid is cooled to 10° - 12° C. To this solution is added slowly a solution of 12.25 grams of sodium nitrite in 120 ml. of water with stirring and continued cooling. Five minutes after this addition, the suspension of the diazonium acetate is added slowly to a boiling solution of 100 ml. of concentrated sulfuric acid and 200 ml. of water. After the final addition of the diazonium salt, the suspension is boiled for an additional 5 minutes and then allowed to cool to room temperature. The reaction mixture is then filtered and the cake dried in vacuo to yield 4-(4'-fluoro-2'-methoxyphenyl)-phenol.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[C:9]3[C:13](=[CH:14][CH:15]=2)[NH:12][C:11](=[O:16])[C:10]3(O)[C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)=[C:5]([CH3:23])[O:4][N:3]=1.N1C=CC=CC=1.O=S(Cl)[Cl:32]>C(Cl)Cl>[Cl:32][C:10]1([C:17]2[CH:21]=[CH:20][S:19][CH:18]=2)[C:9]2[C:13](=[CH:14][CH:15]=[C:7]([C:6]3[C:2]([CH3:1])=[N:3][O:4][C:5]=3[CH3:23])[CH:8]=2)[NH:12][C:11]1=[O:16]
Reactant: O=S(Cl)Cl
Reactant: Cc1noc(C)c1-c1ccc2c(c1)C(O)(c1ccsc1)C(=O)N2
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1noc(C)c1-c1ccc2c(c1)C(Cl)(c1ccsc1)C(=O)N2
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 5-(3,5-dimethylisoxazol-4-yl)-3-hydroxy-3-(thiophen-3-yl)indolin-2-one (500 mg, 1.53 mmol) in CH2Cl2 (75.0 mL) was added pyridine (1.21 g, 15.3 mmol) followed by SOCl2 (728 mg, 6.12 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h and the mixture was evaporated in vacuum to give crude product, which was used for the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(I)cc1
Reactant: OB(O)c1cccnc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1ccc(-c2cccnc2)cc1
Temperature: 80 °C
Yield: 84.4 %

Procedure:
To a mixture of 1.18 g 4-iodobenzoic acid methyl ester, 830 mg pyridine-3-boronic acid, and 158 mg bis(triphenylphosphine) palladium(II) chloride was added solvent (18 mL toluene and 5 mL methanol) followed by 4.5 mL of 2M sodium carbonate and the mixture heated to 80° C. on an oil bath. After 16 hours the mixture was cooled to room temperature diluted with ethyl acetate and filtered through diatomaceous earth. The organic portion was washed sequentially with 1.25N sodium hydroxide and brine, dried over magnesium sulfate and concentrated in vacuo. Purification by flash chromatography on silica gel (hexane:ethyl acetate, 80:20; then 70:30; then 60:40) gave the title compound (810 mg).
Reaction SMILES: [O:1]=[CH:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1.[BH4-].[Na+]>CO>[OH:1][CH2:2][CH2:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=3)[CH:11]=[CH:12][C:6]=2[O:5]1
Reactant: N#Cc1ccc(-c2ccc3c(c2)CC(CC=O)O3)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1ccc(-c2ccc3c(c2)CC(CCO)O3)cc1
Yield: 95.2 %

Procedure:
A solution of Example 67B (0.25 g, 0.95 mmol) and sodium borohydride (0.054 g, 1.42 mmol)in methanol (5 mL) was stirred for 1 hour, cooled on ice and quenched with aqueous NaHCO3 (50 mL). The mixture was extracted with dichloromethane (3×100 mL), the organic extracts combined and washed with water (1×150 mL), brine (1×150 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to provide the titled compound (0.24 g, 95%). 1HNMR (CDCl3): 1.90 (m, 2H), 2.90 (m, 2H), 3.46 (m, 2H), 5.40 (m, 1H), 6.85 (d, J=7 Hz, 1H), 7.38 (m, 2H), 7.65 (m, 4H); MS (DCI) 265 (M+), 283 (M+NH4+).
Reaction SMILES: [CH:1]1([C:4]2[O:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:5]=2[C:15](=[O:17])[CH3:16])[CH2:3][CH2:2]1.[Br:18]Br>C(Cl)(Cl)(Cl)Cl.CC(O)=O>[Br:18][CH2:16][C:15]([C:5]1[C:6]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[N:7][O:8][C:4]=1[CH:1]1[CH2:3][CH2:2]1)=[O:17]
Reactant: CC(=O)c1c(-c2ccccc2)noc1C1CC1
Reactant: BrBr
Solvent: CC(=O)O
Solvent: ClC(Cl)(Cl)Cl
Product: O=C(CBr)c1c(-c2ccccc2)noc1C1CC1
Temperature: 25 °C
Yield: 96 %

Procedure:
To a solution of 1-(5-cyclopropyl-3-phenyl-isoxazol-4-yl)-ethanone (3.34 g, 14.6 mmol) in carbontetrachloride (9.7 mL) and AcOH (0.4 mL) at 48° C. was added a solution of bromine (0.79 mL, 14.6 mmol) in carbontetrachloride (7.8 mL) over 10 min keeping the temperature below 50° C. After addition the reaction mixture was allowed to cool down to room temperature and poured into ice-water (50 mL). The layers were separated and the aqueous layer extracted with dichloromethane. The combined organic layers were then washed with water and brine, dried over sodium sulphate and evaporated. Purification by chromatography (SiO2, heptane:ethyl acetate: 100:0 to 80:20) afforded the title compound (4.29 g, 95%) which was obtained as an off-white solid. MS m/e (EI): 305.0/307.0 [M].
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[C:5](Cl)(=[O:7])[CH3:6].[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]2[CH:19]=[C:20]([C:22]([O:24][CH3:25])=[O:23])[S:21][C:11]1=2.O>ClCCCl>[C:5]([C:15]1[CH:14]=[C:13]2[C:18](=[CH:17][CH:16]=1)[N:10]([CH3:9])[C:11]1[S:21][C:20]([C:22]([O:24][CH3:25])=[O:23])=[CH:19][C:12]2=1)(=[O:7])[CH3:6]
Reactant: CC(=O)Cl
Reactant: COC(=O)c1cc2c3ccccc3n(C)c2s1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: ClCCCl
Product: COC(=O)c1cc2c3cc(C(C)=O)ccc3n(C)c2s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a slurry of 870 mg AlCl3 in 50 ml dry 1,2-dichloroethane was added 465 μl acetyl chloride. The mixture was stirred for 30 min. at room temperature. 800 mg of (6) was added, and stirring continued overnight. Another 870 mg AlCl3 and 465 μl acetyl chloride was added, and stirring continued overnight. Water was added, and the organic phase dried and evaporated to dryness giving a brown powder, which was crystallized from acetic acid and petrol ether giving (64). Yield 210 mg. M.p. 196-8° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N+:23]([O-])=O)=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=1)=[N:7][CH:6]=[CH:5]2>C(O)C.[Pd]>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:8]([NH:12][C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:20])[F:21])[CH:14]=3)=[N:7][CH:6]=[CH:5][C:4]=2[C:3]=1[NH2:23]
Reactant: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)nccc2c1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
6-Methyl-5-nitro-N-(3-(trifluoromethyl)phenyl)isoquinolin-1-amine (0.28 g, 0.81 mmol) was dissolved in ethanol (20 mL) and 10% palladium on carbon (0.086 g, 0.81 mmol) was added to the solution. The reaction stirred overnight at RT under a hydrogen atmosphere. The reaction was filtered through celite and concentrated to give the title compound as a pink film (0.25 g, 98%). MS (M+H)+ 318.
Reaction SMILES: C(OC([N:8]1[CH2:13][C@H:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)[C@@H:11]([C:31]2[CH:36]=[CH:35][C:34]([CH2:37][O:38][CH2:39][C@H:40]([O:42][CH2:43][CH3:44])[CH3:41])=[CH:33][CH:32]=2)[C@H:10]([CH2:45]O)[CH2:9]1)=O)(C)(C)C.[CH3:47][CH2:48][N:49](CC)[CH2:50][CH3:51].OS([O-])(=O)=O.[K+]>CS(C)=O.C(Cl)Cl.O>[CH2:43]([O:42][C@H:40]([CH3:41])[CH2:39][O:38][CH2:37][C:34]1[CH:35]=[CH:36][C:31]([C@H:11]2[C@H:10]([CH2:45][N:49]3[CH2:50][CH2:51][CH2:47][CH2:48]3)[CH2:9][NH:8][CH2:13][C@@H:12]2[O:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]3[O:24][CH2:23][CH2:22][N:21]([CH2:25][CH2:26][CH2:27][O:28][CH3:29])[C:20]=3[CH:30]=2)=[CH:32][CH:33]=1)[CH3:44]
Reactant: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CO)CN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Reactant: CCN(CC)CC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Solvent: CS(C)=O
Product: CCO[C@H](C)COCc1ccc([C@H]2[C@H](CN3CCCC3)CNC[C@@H]2OCc2ccc3c(c2)N(CCCOC)CCO3)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 1 mmol of (3S,4R,5R)-4-[4-((R)-2-ethoxy-propoxymethyl)-phenyl]-3-hydroxymethyl-5-[4-(3-methoxy-propyl)-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-piperidine-1-carboxylic acid tert-butyl ester (example 1a) in 1 ml of DMSO and 5 ml of CH2Cl2 at 0° C. are added 5 mmol of Et3N and 3 mmol of pyridine sulfur trioxide complex. The reaction mixture is allowed to stir for an additional 3 h at this temperature and then allowed to warm to RT and stirred at RT for 5 h, diluted with water and acidified by the addition of 1N KHSO4 and subsequently extracted with Et2O. The organic phases are dried over Na2SO4 and concentrated by evaporation The residue is purified by flash chromatography (SiO2 60F) to afford the title compound, which is identified based on the Rf value.
Reaction SMILES: Cl.Cl[C:3]1[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]2=[C:5]([Cl:12])[CH:4]=1.[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C([O-])([O-])=O.[K+].[K+].C1(C)C=CC=CC=1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.CCO>[Cl:12][C:5]1[CH:4]=[C:3]([C:18]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:13])[CH:19]=2)[N:8]=[C:7]2[CH2:9][CH2:10][CH2:11][C:6]=12
Reactant: Clc1cc(Cl)c2c(n1)CCC2
Reactant: OB(O)c1cccc(Cl)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: Clc1cccc(-c2cc(Cl)c3c(n2)CCC3)c1
Temperature: 90 °C
Reaction time: 4 h

Procedure:
An 18-mL vial was charged with 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (225 mg, 1 mmol, 1 eq.), (3-chlorophenyl)boronic acid (165 mg, 1.06 mmol, 1.06 eq.), tetrakis(triphenylphosphine)palladium(0) (84 mg, 0.07 mmol, 0.07 eq.), and K2CO3 (500 mg, 3.6 mmol, 3.6 eq.). Toluene (6 ml), EtOH (2 ml) and water (2.5 ml) were added. The resulting mixture was stirred under Ar at 90° C. for 4 hr. until the starting chloride was consumed. After cooling to room temperature, the aqueous layer was separated and the organic layer was concentrated on a rotary evaporator. The residue was purified by chromatography on silica gel using hexane/dichloromethane (9:1 then 8:1) as eluent to afford 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine, which was converted into its corresponding HCl salt by treating with 4N HCl in dioxane (228 mg, 76% yield).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][C:35]([F:38])([F:37])[F:36])[CH:10]=2)[CH2:4][CH2:3]1.[C:39](OC(=O)C)(=[O:41])[CH3:40].CCN(C(C)C)C(C)C>C(Cl)Cl>[C:39]([N:2]1[CH2:7][CH2:6][CH:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=4[CH3:30])[CH2:20][CH:19]3[C:31](=[O:33])[NH2:32])=[O:17])=[C:11]([O:34][C:35]([F:36])([F:37])[F:38])[CH:10]=2)[CH2:4][CH2:3]1)(=[O:41])[CH3:40]
Reactant: Cc1ccccc1N1CCN(C(=O)Cc2ccc(OC3CCNCC3)cc2OC(F)(F)F)C(C(N)=O)C1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)N1CCC(Oc2ccc(CC(=O)N3CCN(c4ccccc4C)CC3C(N)=O)c(OC(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-(4-(4-piperidinyloxy)-2-(trifluoromethoxy)phenylacetyl)-2-carbamoyl-4-(2-methylphenyl)piperazine hydrochloride (0.30 g, 0.5 mmol) from Example 33 in CH2Cl2 (50 mL) was added acetic anhydride (0.10 mL, 1.0 mmol) and DIEA (0.17 mL, 1.0 mmol). The solution was stirred at ambient temperature for 1 h and the solvent was removed under reduced pressure. The residue was dissolved in EtOAc (100 mL) and washed with 0.25 M aqueous citric acid (50 mL), H2O (25 mL), and saturated aqueous NaHCO3 (75 mL). The organic phase was dried (MgSO4), filtered, and the solvent was removed under reduced pressure to give the title compound as an amorphous solid.
Reaction SMILES: [O:1]=[C:2]1[C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[N:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:4][N:3]1[CH2:18][C:19]1[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=1)[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[NH:40][C:39](=[O:41])[N:38]([CH2:42][CH2:43][CH2:44]Cl)[C:37]=2[CH:46]=1.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Cl:32][C:33]1[CH:34]=[CH:35][C:36]2[NH:40][C:39](=[O:41])[N:38]([CH2:42][CH2:43][CH2:44][N:9]3[CH2:10][CH2:11][C:6]4([N:5]([C:12]5[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=5)[CH2:4][N:3]([CH2:18][C:19]5[CH:20]=[C:21]([CH:29]=[CH:30][CH:31]=5)[C:22]([O:24][C:25]([CH3:28])([CH3:26])[CH3:27])=[O:23])[C:2]4=[O:1])[CH2:7][CH2:8]3)[C:37]=2[CH:46]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2n1CCCCl
Reactant: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCNCC3)C2=O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CC(C)(C)OC(=O)c1cccc(CN2CN(c3ccccc3)C3(CCN(CCCn4c(=O)[nH]c5ccc(Cl)cc54)CC3)C2=O)c1
Temperature: 81 °C
Reaction time: 16 h
Yield: 20.3 %

Procedure:
A mixture of tert-butyl 3-((4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-3-yl)methyl)benzoate (329 mg, 0.7807 mmol, 1 equiv), 6-chloro-1-(3-chloropropyl)-1H-benzo[d]imidazol-2(3H)-one (219 mg, 0.7807 mmol, 1 equiv), sodium iodide (46.81 mg, 0.312 mmol, 0.4 equiv), and potassium carbonate (323.7 mg, 2.34 mmol, 3 equiv) in 2-butanone was stirred at 81° C. for 16 h. After cooling the reaction mixture, the crude mixture was partitioned between ethyl acetate and water. The organic layer was dried over MgSO4, filtered, concentrated, and the crude residue was purified using preparatory thin layer chromatography in 10% methanol in dichloromethane to afford the title compound as a white powder (100 mg, ˜20%); MS for C35H40ClN5O4 m/z 630.15 (M+H)+.
Reaction SMILES: Cl.C([S:6][CH2:7][CH2:8][N:9]1[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]([F:22])([F:21])[F:20])=[CH:17][C:12]=2[S:11][C:10]1=[NH:23])(C)(C)C.[BrH:24]>>[BrH:24].[NH:23]=[C:10]1[N:9]([CH2:8][CH2:7][SH:6])[C:13]2[CH:14]=[CH:15][C:16]([O:18][C:19]([F:22])([F:20])[F:21])=[CH:17][C:12]=2[S:11]1
Reactant: CC(C)(C)SCCn1c(=N)sc2cc(OC(F)(F)F)ccc21
Agent: Br
Agent: Cl
Product: N=c1sc2cc(OC(F)(F)F)ccc2n1CCS
Temperature: 0 °C

Procedure:
3-(2-tert-Butylthioethyl)-2-imino-6-trifluoromethoxybenzothiazoline hydrochloride (1.5 g) and 47% strength hydrobromic acid (15 cc) are heated for 4 hours to 100° C. After cooling of the mixture to 0° C., the precipitate formed is filtered off and washed with distilled water (2×25 cc) and then with ethyl ether (2×30 cc). 2-(2-Imino-6-trifluoromethoxy-3-benzothiazolinyl)ethanethiol hydrobromide (0.9 g), m.p. 180° C., is obtained.
Reaction SMILES: I[CH2:2][CH3:3].[NH:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH2:2]([N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[CH3:3]
Reactant: CCI
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 56.6 %

Procedure:
Iodoethane (1.34 g) was added to a mixture of benzyl (S)-pyrrolidine-2-carboxylate (1.0 g) and potassium carbonate (1.77 g) in dry DMF (7 mL) and the resultant mixture was stirred at room temperature for 3 days. The mixture was diluted with water, extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and pentane with a gradient of 10-20% to give benzyl (S)—N-ethylpyrrolidine-2-carboxylate (0.643 g) as a pale straw coloured oil.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[C:20]1([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccccc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: O=C1CCc2cccc(Nc3ncc(-c4ccccc4)o3)c2C1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 11B for the product of Example 1H.