Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]2[N:11]=[C:10]([CH2:12][N:13]3[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]3)[CH:9]=[CH:8][C:6]=2[N:7]=1.[CH3:29][C:30]1[C:31]([NH2:45])=[N:32][CH:33]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:35]=1>>[NH2:45][C:31]1[N:32]=[CH:33][C:34]([C:2]2[N:3]=[C:4]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[C:5]3[N:11]=[C:10]([CH2:12][N:13]4[CH2:18][CH2:17][CH:16]([C:19]([OH:22])([CH3:21])[CH3:20])[CH2:15][CH2:14]4)[CH:9]=[CH:8][C:6]=3[N:7]=2)=[CH:35][C:30]=1[CH3:29]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Product: Cc1cc(-c2nc(N3CCOCC3)c3nc(CN4CCC(C(C)(C)O)CC4)ccc3n2)cnc1N

Procedure:
2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol (0.185 g) was reacted with 3-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine via General Procedure A to produce 90.9 mg of 132 following reverse phase HPLC purification. MS (Q1) 478.3 (M)+
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:29])[C:5]2[C:10]([C:11]#[C:12][CH2:13][CH2:14][C:15]([OH:17])=O)=[CH:9][N:8]([CH2:18][C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:6]=2[N:7]=1.[NH:30]([CH2:33][CH3:34])[CH2:31][CH3:32].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CCOC(C)=O.CCCCCC.CN(C=O)C>[CH2:31]([N:30]([CH2:33][CH3:34])[C:15](=[O:17])[CH2:14][CH2:13][C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:29])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:18][C:19]2[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=2)[CH:9]=1)[CH3:32]
Reactant: COc1c(C)cnc(Cn2cc(C#CCCC(=O)O)c3c(Cl)nc(N)nc32)c1C
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)CCC#Cc1cn(Cc2ncc(C)c(OC)c2C)c2nc(N)nc(Cl)c12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 5-[2-amino-4-chloro-7-(4-methoxy-3,5-dimethyl-pyridin-2-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]-pent-4-ynoic acid (see previous example, 25 mg), Et2NH (100 μL), EDCI (87 mg), HOBt (50 mg), and DMF (1 mL) was stirred at rt for 16 h. Preparative plate chromatography (EtOAc/hexane 2:1) gave the title compound. tR=5.33 min. 1H NMR (CDCl3) δ 8.23 (s, 1H), 7.01 (s, 1H), 5.32 (s, 2H), 4.98 (s, 2H), 3.76 (s, 3H), 3.42 (q, 2H), 3.33 (q, 2H), 2.78 (dd, 2H), 2.64 (dd, 2H), 2.27 (s, 3H), 2.18 (s, 3H), 1.20 (t, 3H), 1.13 (t, 3H).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-])=O)=[CH:4][C:3]=1[O:11][CH3:12].[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18]([N:20]1[CH2:26][CH2:25][CH2:24][N:23]([C:2]2[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][C:3]=2[O:11][CH3:12])[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:14])[CH3:15]
Reactant: COc1cc([N+](=O)[O-])ccc1F
Reactant: CC(C)(C)OC(=O)N1CCCNCC1
Product: COc1cc(N)ccc1N1CCCN(C(=O)OC(C)(C)C)CC1

Procedure:
According to methods E and F 1-Fluoro-2-methoxy-4-nitro-benzene was reacted with [1,4]Diazepane-1-carboxylic acid tert-butyl ester and then the obtained nitro compound was hydrogenated. In this way the product was obtained with molecular weight 321.42 (C17H27N3O3); MS (ESI): 322 (M+H+).
Reaction SMILES: [C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[O:17]C)(=[O:5])[CH2:2][CH2:3][CH3:4].[B].C(C1C=NC2C(C=1Cl)=CC=CC=2O)(=O)CCC.[F:37][C:38]1[CH:44]=[CH:43][C:41]([NH2:42])=[C:40]([CH3:45])[CH:39]=1>ClCCl.O1CCOCC1>[C:1]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:42][C:41]1[CH:43]=[CH:44][C:38]([F:37])=[CH:39][C:40]=1[CH3:45])=[CH:13][CH:12]=[CH:11][C:10]=2[OH:17])(=[O:5])[CH2:2][CH2:3][CH3:4]
Reactant: Cc1cc(F)ccc1N
Reactant: CCCC(=O)c1cnc2c(OC)cccc2c1Cl
Agent: CCCC(=O)c1cnc2c(O)cccc2c1Cl
Agent: [B]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(=O)c1cnc2c(O)cccc2c1Nc1ccc(F)cc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 72.9 %

Procedure:
A solution of 3-butyryl-4-chloro-8-methoxyquinoline (131.9 g, 0.5 mol) in dichloromethane (1 liter), was cooled to -78° C., then boron tribomide (142 ml, 1.5 mol) added slowly over 10 minutes. The mixture was warmed slowly to 0°, stirred 2 hours, then allowed to warm to room temperature overnight. After recooling in ice the reaction was quenched cautiously with water, then the resulting solid filtered off and dried. This was heavily contaminated with boron-containing impurities, but was used without purification. Crude 3-butyryl-4-chloro-8-hydroxyquinoline (64 g) and 4-fluoro-2-methylaniline (16.7 ml, 0.15 mol) were dissolved in dioxan (300 ml), heated on a steam bath for 2 hours, then left to stand overnight. The dioxan was evaporated, dichloromethane and aqueous sodium bicarbonate added, the mixture stirred until all the solid had dissolved, then the organic layer dried and evaporated. Recrystallization from methanol gave 3-butyryl-4-(4-fluoro-2-methylphenylamino)-8-hydroxyquinoline (37 g) m.p. 121°-122°.
Reaction SMILES: [CH3:1][N+:2]([CH2:5][CH:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])(C)[CH3:3].[Cl-].N12CCN(CC1)CC2>CN(C=O)C>[CH3:1][N:2]([CH2:5][C@H:6]([OH:11])[CH2:7][C:8]([OH:10])=[O:9])[CH3:3]
Reactant: C[N+](C)(C)CC(O)CC(=O)O
Agent: C1CN2CCN1CC2
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CN(C)C[C@H](O)CC(=O)O
Temperature: 125 °C

Procedure:
L-carnitine chloride (1.5. g; 0.008 moles) and 1,4 diazabicyclo[2,2,2]octane (5.25 g; 0.05 moles) were dissolved in 50 cc of DMF at 80° C. The resulting solution was subsequently heated up to 125° C. for 2 hours. Upon reaction termination, the solution was cooled in an ice bath a 5° C. After about 2 hours the precipitate which formed consisting of the excess diazabicyclo octane and its N-methyl derivative was filtered off. DMF was distilled under vacuum and the residue dissolved in water and eluted on AMBERLITE IRA 402 resin activated in the OH-l form. The eluate having alkaline pH was shown to consist of diazabicyclo octane and its N-methyl derivative; L-norcarnitine which formed was retained on the resin and was eluted therefrom with 2N HCl.
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CS(O[CH2:18][CH2:19][C:20]1[CH:35]=[CH:34][C:23]2[O:24][CH2:25][C:26]3[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=3[C:28](=[O:29])[C:22]=2[CH:21]=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].O>CO>[O:29]=[C:28]1[C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[CH2:25][O:24][C:23]2[CH:34]=[CH:35][C:20]([CH2:19][CH2:18][N:10]3[CH2:11][CH2:12][N:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)[CH2:8][CH2:9]3)=[CH:21][C:22]1=2
Reactant: CS(=O)(=O)OCCc1ccc2c(c1)C(=O)c1ccccc1CO2
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1c2ccccc2COc2ccc(CCN3CCN(c4ccccc4)CC3)cc21
Yield: 31.5 %

Procedure:
A mixture of 6.3 g (0.039 m) of N-phenylpiperazine, 4.32 g (0.013 m) of 2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethanol methanesulfonate of Example 1 and 1.79 g (0.013 m) of K2CO3 in 50 ml of MeOH was refluxed overnight. The reaction mixture was poured into water, extracted with CH2Cl2, dried (Na2SO4), filtered and evaporated to give the crude product (6.5 g). Two recrystallizations from absolute ethanol gave 1.63 g (32%) of crystals of 1-[2-(6,11-dihydro-11-oxodibenz[b,e]oxepin-2-yl)ethyl]-4-phenylpiperazine, m.p. 107°-108° C.
Reaction SMILES: [Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([OH:14])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].N1C(C)=CC(C)=CC=1C.[Br:34][CH2:35][C:36](Br)=[O:37].ClCl>C(Cl)Cl.O>[Si:1]([O:8][C:9]1([O:16][C@@H:15]([CH3:17])[C@@H:13]([O:14][C:36](=[O:37])[CH2:35][Br:34])[C@@H:12]([NH:18][C:19](=[O:24])[C:20]([F:22])([F:21])[F:23])[CH2:11]1)[OH:10])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1O
Reactant: O=C(Br)CBr
Agent: ClCl
Solvent: O
Solvent: Cc1cc(C)nc(C)c1
Solvent: ClCCl
Product: C[C@@H]1OC(O)(O[Si](C)(C)C(C)(C)C)C[C@H](NC(=O)C(F)(F)F)[C@@H]1OC(=O)CBr
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a stirred solution of 1-t-butyl dimethylsilyloxy-3-trifluoroacetamido-2,3,6-trideoxy-L-lyxohexopyranose (81 mg, 0.18 mmol) in CH2Cl2 (2 ml) at 0° C. were added collidine (47 μl, 0.36 mmol), and bromoacetylbromide (24 μl, 0.27 mmol). After 1 hour, the reaction mixture was worked up with CH2 Cl2 and water. The organic layer was washed with brine and dried over MgSO4. The solvent was evaporated to give the titled compound (76 mg, 74%).
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[C:9]([O:15][CH3:16])[CH:8]=1)=O.N[C:19]1[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=C[NH:21][N:20]=1>C(O)(=O)C>[CH3:16][O:15][C:9]1[CH:8]=[C:7]([C:5]2[N:21]3[N:20]=[CH:19][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:12]=[CH:11][C:10]=1[O:13][CH3:14]
Reactant: CCOC(=O)c1c[nH]nc1N
Reactant: COc1ccc(C(=O)C=CN(C)C)cc1OC
Solvent: CC(=O)O
Product: CCOC(=O)c1cnn2c(-c3ccc(OC)c(OC)c3)ccnc12

Procedure:
A mixture of 2.35 g. of 3-dimethylamino-3',4'-dimethyoxyacrylophenone and ethyl 3-aminopyrazole-4-carboxylate in 25 ml. of glacial acetic acid is refluxed for 20 hours and worked up to give the product, m.p. 148°-149° C.
Reaction SMILES: [CH2:1]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9][C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.C([Li])CCC.[CH2:21]1[O:23][CH2:22]1>O1CCCC1.CCCCCC>[CH:4]1[C:3]2[CH2:2][CH2:1][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH:9]([CH2:21][CH2:22][OH:23])[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: C1CO1
Reactant: c1ccc2c(c1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OCCC1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 58.3 g of dibenzosuberane in 750 ml of tetrahydrofuran, stirred under argon, is cooled to about 10° in an ice-bath and treated dropwise with 190 ml of an about 2M solution of butyl lithium in hexane. The dark red solution is heated to boiling under reflux for 2 hours. Ethylene oxide is conducted for 15 minutes into the solution, cooled to about 10°, subsequently the mixture is stirred at room temperature for 1 hour and finally heated to boiling under reflux for an additional 30 minutes. The cooled mixture is poured into 300 ml of ice-cold 3N hydrochloric acid and extracted twice with 2 l of ether each time. The organic extracts are washed with 500 ml of 2N potassium bicarbonate solution, combined, dried over magnesium sulfate and evaporated. The residue is boiled up three times with 50 ml of pentane each time. There is obtained 10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ethanol in the form of a very viscous, yellowish oil, Rf: 0.25 (toluene/ethyl acetate, 9:1).
Reaction SMILES: [C:1]1([CH3:14])[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH:12]=[O:13])[CH:8]=2)[CH:2]=1.[CH3:15][Mg]Br.C(OCC)C>C1COCC1>[CH3:14][C:1]1[CH:2]=[C:3]([C:7]2[O:11][N:10]=[C:9]([CH:12]([OH:13])[CH3:15])[CH:8]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccc(-c2cc(C=O)no2)c1
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Product: Cc1cccc(-c2cc(C(C)O)no2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 103.2 %

Procedure:
The title compound of Example 5.3 (739 mg, 3.9 mmol) was dissolved in THF (20 mL) under Argon and the flask was immersed in ice. Methyl magnesium bromide (1 M solution/diethyl ether 6.6 mL, 19.7 mmol) was added dropwise while the reaction was cooled in ice. After fifteen minutes at 0° C., the ice bath was removed and the reaction was allowed to stir at room temperature for two hours. Aqueous NH4Cl (saturated) was added to quench the reaction and an aqueous workup was done extracting with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (3% MeOH/DCM) to yield the title compound as a clear oil (818 mg, 100%).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([CH2:9]Cl)[CH:6]=[NH+:7][CH:8]=1.C(N(CC)CC)C.[C:18]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].[K]>CN(C=O)C.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>[Br:2][C:3]1[CH:4]=[C:5]([CH2:9][N:25]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:26]([O:28][C:29]([CH3:30])([CH3:31])[CH3:32])=[O:27])[CH:6]=[N:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Reactant: ClCc1c[nH+]cc(Br)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(Cc1cncc(Br)c1)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 60.4 %

Procedure:
A solution of 5-bromo-3-chloromethylpyridinium hydrochloride (716 mg, 4.189 mmol) in anhydrous DMF (15 mL) under nitrogen at 0° C. was treated with triethylamine (0.65 mL, 4.61 mmol), tetrabutylammonium bromide (273 mg, 0.838 mmol), and potassium di-tert-butyl imidodicarbonate (1.284 g, 5.027 mmol). The reaction was heated to 50° C.-55° C. for 3.5 hours, then cooled to room temperature, diluted with ethyl acetate (150 mL), and washed with water (2×50 mL) and saturated aqueous sodium chloride. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated by rotary evaporation. The residue was purified by flash column chromatography on silica gel with 6% ethyl acetate/dichloromethane to give the title compound as a colorless oil (0.980 g, 60%). MS (ESI+) m/z 387/389 (M+H)+; 1H NMR (300 MHz, CDCl3) δ 1.49 (s, 18H), 4.75 (s, 2H), 7.83 (t, J=2.02 Hz, 1H), 8.50 (d, J=1.84 Hz, 1H), 8.58 (d, J=2.21 Hz, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.[F-].[K+].[CH2:29]([N:32]=[C:33]=[O:34])[CH:30]=[CH2:31].O>C1C=CC=CC=1>[CH2:29]([NH:32][C:33]([N:12]1[C:6]2[CH:7]=[N:8][C:9]3[CH:10]=[CH:11][C:2]([Br:1])=[CH:3][C:4]=3[C:5]=2[N:14]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([C:22]#[N:23])([CH3:24])[CH3:25])=[CH:17][CH:16]=2)[C:13]1=[O:26])=[O:34])[CH:30]=[CH2:31]
Reactant: C=CCN=C=O
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Agent: [F-]
Agent: [K+]
Solvent: c1ccccc1
Solvent: O
Product: C=CCNC(=O)n1c(=O)n(-c2ccc(C(C)(C)C#N)cc2)c2c3cc(Br)ccc3ncc21

Procedure:
To a suspension of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 0.040 g, 0.10 mmol) and potassium fluoride (0.009 g, 0.147 mmol) in dry benzene (6 ml) was added allylisocyanate (0.010 g, 0.10 mmol) at RT. The reaction was stirred at reflux temperature for 6 hours. The reaction mixture was cooled and poured into cold water, extracted with ethyl acetate (2×20 ml). Organic layer was washed with water dried over sodium sulfate and concentrated. The crude product was triturated with ethyl acetate, filtered and filtrate was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 0.020 g (41%); 1H NMR (DMSO-d6, 300 MHz): δ 9.653 (s, 1H), 8.723-8.761 (t, 1H), 7.971-8.001 (d, 1H, J=9 Hz), 7.874-7.903 (d, 2H, J=8.7 Hz), 7.769-7.798 (d, 2H, J=8.7 Hz), 7.723-7.761 (dd, 1H, J=9, 2.1 Hz), 6.808-6.814 (d, 1H, J=1.8 Hz), 5.904-5.996 (m, 1H), 5.234-5.296 (dd, 1H, J=17.1, 1.2 Hz), 5.134-5.173 (dd, 1H, J=10.5, 1.2 Hz), 4.010-4.045 (t, 2H), 1.806 (s, 6H); MS: m/z 492 (M+).
Reaction SMILES: [Si]([O:18][C@@H:19]1[CH2:44][CH2:43][C@H:22]2[C:23](=[O:42])[N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][C@@H:31]3[CH2:36][C@@:32]3([C:37]([O:39][CH3:40])=[O:38])[NH:33][C:34](=[O:35])[C@@H:21]2[CH2:20]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[OH:18][C@@H:19]1[CH2:44][CH2:43][C@H:22]2[C:23](=[O:42])[N:24]([CH3:41])[CH2:25][CH2:26][CH2:27][CH2:28][CH:29]=[CH:30][C@@H:31]3[CH2:36][C@@:32]3([C:37]([O:39][CH3:40])=[O:38])[NH:33][C:34](=[O:35])[C@@H:21]2[CH2:20]1
Reactant: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@H]1C(=O)N2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)N2
Agent: COC(=O)[C@@]12C[C@H]1/C=C\CCCCN(C)C(=O)[C@@H]1CC[C@@H](O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C[C@H]1C(=O)N2
Solvent: C1CCOC1
Product: COC(=O)[C@@]12C[C@H]1C=CCCCCN(C)C(=O)[C@@H]1CC[C@@H](O)C[C@H]1C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 42 (0.6 mmol) in dry THF (12 mL) was added dropwise a solution of tetrabutylammonium fluoride (1M in THF, 12 mL). The reaction was stirred at room temperature overnight, and then concentrated. The residue was dissolved in MeOH and purified by semi preparative HPLC (RP18) to yield compound 43, which was used without further purification directly in the next step. MS (ESI, EI+): m/z=379 (MH+).
Reaction SMILES: [F:1][C:2]([F:46])([F:45])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH2:35][O:36][Si](C(C)(C)C)(C)C)[N:34]=3)[C@H:14]2[CH3:44])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:46][C:2]([F:1])([F:45])[C:3]1[CH:4]=[C:5]([C@H:13]2[O:17][C:16](=[O:18])[N:15]([CH2:19][C:20]3[CH:25]=[C:24]([C:26]([F:28])([F:29])[F:27])[CH:23]=[CH:22][C:21]=3[C:30]3[S:31][CH:32]=[C:33]([CH2:35][OH:36])[N:34]=3)[C@H:14]2[CH3:44])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(CO[Si](C)(C)C(C)(C)C)cs1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1-c1nc(CO)cs1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a 0° C. solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-({[tert-butyl(dimethyl)silyl]oxy}methyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one (Example 178) (54.0 mg, 0.0774 mmol) in THF (10 mL) was added TBAF (194 μL of a 1M solution in THF, 0.194 mmol). The reaction was stirred at 0° C. for 30 minutes and then quenched by pouring into saturated NH4Cl (15 mL). The mixture was extracted with EtOAc (60 mL) and the organic layer was washed with water and brine (15 mL each). The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel (60% EtOAc/hexanes) afforded (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-[4-(hydroxymethyl)-1,3-thiazol-2-yl]-5-(trifluoromethyl)benzyl]-4-methyl-1,3-oxazolidin-2-one. Rf=0.11 (40% EtOAc/hexanes). LCMS=585.1 (M+1)+. 1H NMR (CDCl3, 500 MHz) δ 7.85 (s, 1H), 7.81 (d, J=8.0 Hz, 1H), 7.70-7.73 (m, 4H), 7.36 (s, 1H), 5.52 (d, J=8.0 Hz, 1H), 5.39 (d, J=15.3 Hz, 1H), 4.81 (s, 2H), 4.55 (d, J=15.3 Hz, 1H), 3.87 (m, 1H), 0.69 (d, J=6.7 Hz, 3H).
Reaction SMILES: [O:1]1[CH2:21][C@@H:2]1[CH2:3][O:4][C:5]1[C:6](C=O)=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2.ClC1C=C(C=CC=1)[C:26]([O:28]O)=[O:27].FC(F)(F)C(O)=O>ClCCl>[O:1]1[CH2:21][C@@H:2]1[CH2:3][O:4][C:5]1[C:6]([O:28][CH:26]=[O:27])=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOC(=O)c1cc2c(C=O)c(OC[C@H]3CO3)ccc2[nH]1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1cc2c(OC=O)c(OC[C@H]3CO3)ccc2[nH]1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A stirred solution of ethyl (R)-5-(2,3-epoxypropoxy)-4-formylindole-2-carboxylate (1.95 g; prepared by the method described above) in dichloromethane (40 ml) was cooled to 0° C. 3-Chloroperoxybenzoic acid (85%; 1.75 g) was then added in one portion followed by a solution of trifluoroacetic acid (0.77 g) in dichloromethane (10 ml), in portions. The mixture was stirred at 0° C. for 10 minutes and then at ambient temperature for 1 hour. The reaction mixture was diluted with dichloromethane (300 ml), washed successively with saturated aqueous sodium bisulphite solution (100 ml), saturated aqueous sodium bicarbonate solution (3×150 ml), dried over sodium sulphate and the solvent evaporated. The solid residue was purified by flash chromatography on silica eluting with a 1:1 mixture of petroleum ether (b.p. 40-60° C.) and ethyl acetate to give ethyl (R)-5-(2,3-epoxypropoxy)-4-formyloxyindole-2-carboxylate (1.55 g) as a pale yellow crystalline solid; m.p. 123-125° C.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28](O)=[O:29])=[CH:23][CH:22]=1>>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][C:28]([NH:1][N:2]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:19])=[O:29])=[CH:23][CH:22]=1
Reactant: Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O
Reactant: O=C(O)Cc1ccc(Cl)cc1
Product: O=C(Cc1ccc(Cl)cc1)Nn1nc(-c2ccc(Cl)cc2)c2ccccc2c1=O

Procedure:
The product of Example 86A and 2-(4-chlorophenyl)acetic acid were processed using a method similar to that described in Example 17C to afford the title compound. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.63-11.81 (bs, 1H), 8.39-8.42 (m, 1H), 7.90-8.03 (m, 2H), 7.69-7.76 (m, 1H), 7.60-7.66 (m, 4H), 7.34-7.46 (m, 4H), 3.71 (s, 2H); MS (ESI+) m/z 424 (M+H)+.
Reaction SMILES: Cl.Cl.[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=2[CH2:24][NH:25][CH2:26][CH3:27])[CH:13]=1)[CH3:4].[C:29]([OH:39])(=O)[CH2:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH2:3]([O:5][C:6](=[O:28])[CH2:7][C:8]1[CH:9]=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:22])([F:21])[F:23])=[CH:16][C:15]=2[CH2:24][N:25]([CH2:26][CH3:27])[C:29](=[O:39])[CH2:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:13]=1)[CH3:4]
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cncc(CC(=O)OCC)c1
Reactant: O=C(O)CCc1ccccc1
Agent: Cl
Product: CCOC(=O)Cc1cncc(-c2ccc(C(F)(F)F)cc2CN(CC)C(=O)CCc2ccccc2)c1

Procedure:
[5-(2-Ethylaminomethyl-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester, dihydrochloride and hydrocinnamic acid were reacted as described in Example 8, Step 6 to provide [5-(2-{[N-ethyl-N-(3-phenyl-propionyl)-amino]-methyl}-4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetic acid ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:10]([Cl:11])=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:20][CH2:19][CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:17]1[CH2:27][CH3:28]>>[CH2:27]([N:17]1[CH:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:19][CH2:20][CH:16]1[CH2:15][NH:14][C:6](=[O:8])[C:5]1[CH:9]=[C:10]([Cl:11])[C:2]([NH2:1])=[CH:3][C:4]=1[O:12][CH3:13])[CH3:28]
Reactant: CCN1C(CN)CCC1c1ccccc1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: CCN1C(CNC(=O)c2cc(Cl)c(N)cc2OC)CCC1c1ccccc1

Procedure:
By following general method B using 1.01 g. of 4-amino-5-chloro-2-methoxybenzoic acid and 1.0 g. of 2-aminomethyl-1-ethyl-5-phenylpyrrolidine, 1.8 g. of N-(1-ethyl-5-phenyl-2-pyrrolidinylmethyl)-4-amino-5-chloro-2-methoxybenzamide was obtained.
Reaction SMILES: [CH3:1]CN(CC)CC.C=O.[BH3-]C#N.[Na+].Cl.[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]2[CH2:27][NH:26][CH2:25][CH2:24][N:23]2[CH:28]=1)=[O:19])[CH3:16]>C(Cl)Cl.CO>[CH2:15]([O:17][C:18]([C:20]1[N:21]=[C:22]2[CH2:27][N:26]([CH3:1])[CH2:25][CH2:24][N:23]2[CH:28]=1)=[O:19])[CH3:16]
Reactant: CCN(CC)CC
Reactant: CCOC(=O)c1cn2c(n1)CNCC2
Agent: C=O
Agent: Cl
Agent: [BH3-]C#N
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)c1cn2c(n1)CN(C)CC2
Reaction time: 3.5 h

Procedure:
Et3N (3.44 mL), 37% HCHO aq. (2.02 mL) and NaBH3CN (1.78 g) were added successively to the MeOH (75 mL) solution of 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine-2-carboxylic acid ethyl ester, hydrochloride (5.2 g) at room temperature and stirred for 3.5 h under a nitrogen atmosphere. The mixture was diluted with CH2Cl2 and washed with 50% K2CO3 aq. The organic layer was dried (K2CO3) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica gel column chromatography, then the column was eluted with CHCl3-acetone (1/1˜1/2). The titled compound was obtained as orange oil. Yield: 2.68 g, 57%).