Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:4])[CH3:3].OS(O)(=O)=O.[CH2:40](O)[CH2:41][OH:42]>O>[OH:42][CH2:41][CH2:40][O:1][C:2]([C:5]1[N:6]=[CH:7][C:8]([N:11]2[CH2:15][C@@:14]3([CH2:20][CH2:19][CH2:18][C@@:17]([CH2:22][N:23]4[C:27]5[CH:28]=[C:29]([C:32]#[N:33])[CH:30]=[CH:31][C:26]=5[N:25]=[CH:24]4)([CH3:21])[CH2:16]3)[O:13][C:12]2=[O:34])=[N:9][CH:10]=1)([CH3:3])[CH3:4]
Reactant: OCCO
Reactant: CC(C)(O)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Agent: O=S(=O)(O)O
Solvent: O
Product: CC(C)(OCCO)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Temperature: 60 °C
Yield: 21 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-hydroxypropan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (500 mg, 1.086 mmol, example 147) in ethylene glycol (4.93 mL) was added concentrated H2SO4 (0.5 mL, 9.38 mmol) at RT and heated at 60° C. overnight. The reaction mixture was cooled to RT, diluted with water, and extracted 5×DCM. The combined DCM layers were washed with brine, concentrated, and purified by reverse phase HPLC (Waters Sunfire 30×150 mm column, acetonitrile:water 0.1% TFA long 20-60%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (121 mg, 21%). MS (m/z) 505.3 (M+H+).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([NH:14][CH:15]([C:19]1[CH:48]=[CH:47][C:22]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])[C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])=[CH:21][CH:20]=1)[CH2:16][CH2:17][CH3:18])=[O:13])(OCC)=O)C.[Br:49][C:50]1[N:55]=[C:54]([CH:56]=O)[CH:53]=[CH:52][CH:51]=1>O1CCCC1>[Br:49][C:50]1[N:55]=[C:54](/[CH:56]=[CH:11]/[C:12]([NH:14][CH:15]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][N:32]([C:40]([O:42][C:43]([CH3:44])([CH3:46])[CH3:45])=[O:41])[C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])=[CH:47][CH:48]=2)[CH2:16][CH2:17][CH3:18])=[O:13])[CH:53]=[CH:52][CH:51]=1
Reactant: CCCC(NC(=O)CP(=O)(OCC)OCC)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Reactant: O=Cc1cccc(Br)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC(NC(=O)/C=C/c1cccc(Br)n1)c1ccc(OCCOCCOCCN(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a suspension of NaH (52 mg 60% in mineral oil, 1.31 mmol) in tetrahydrofuran (1.0 mL) at ice bath temperature was added a solution of (2-(2-(2-(4-(1-(2-(diethoxyphosphoryl)acetamido)butyl)phenoxy)ethoxy)ethoxy)ethyl)imidodicarbonic acid, 1,3-bis-tert-butyl ester (49; 295 mg, 0.43 mmol) in tetrahydrofuran (2 mL). The resulting mixture was stirred at room temperature for 30 minutes and then treated drop-wise with 6-bromopicolinaldehyde (81 mg, 0.43 mmol) in tetrahydrofuran (2 mL). The mixture was stirred for another 30 minutes, and then carefully quenched with water. The solution was extracted with ethyl acetate (3×), and the combined organic extracts were washed with sat. brine, dried over sodium sulfate, and concentrated to an oil. Purification by flash silica gel column chromatography, eluting with 7:3 hexanes/ethyl acetate, afforded 50 (205 mg, 67%) as a clear oil: MS (ES+) m/z 706.2 (M+H)+.
Reaction SMILES: [C:1]([C@@H:4]([NH:9][C:10]([C@H:12]([CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[C:26]([CH3:36])[CH:25]=1)[CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[O:11])[C:5]([CH3:8])([CH3:7])[CH3:6])(O)=[O:2].[N:37]1[CH:42]=[CH:41][CH:40]=[C:39]([C@H:43]([NH2:45])[CH3:44])[CH:38]=1>>[C:17]([O:16][C:14](=[O:15])[CH2:13][C@H:12]([C:10]([NH:9][C@H:4]([C:1]([NH:45][C@@H:43]([C:39]1[CH:38]=[N:37][CH:42]=[CH:41][CH:40]=1)[CH3:44])=[O:2])[C:5]([CH3:8])([CH3:7])[CH3:6])=[O:11])[CH2:21][CH2:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)=[C:26]([CH3:36])[CH:25]=1)([CH3:18])([CH3:20])[CH3:19]
Reactant: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)O)C(C)(C)C)ccc1-c1ccccc1
Reactant: C[C@@H](N)c1cccnc1
Product: Cc1cc(CCC[C@H](CC(=O)OC(C)(C)C)C(=O)N[C@H](C(=O)N[C@H](C)c2cccnc2)C(C)(C)C)ccc1-c1ccccc1
Yield: 89.5 %

Procedure:
According to the method of Example 25(a), tert-butyl (3R)-3-({[(1S)-1-(carboxy)-2,2-dimethylpropyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]hexanoate (Preparation 19c)(497 mg, 1.0 mmol) was reacted with (R)-(+)-1-(3-pyridyl)ethylamine (122 mg, 1.0 mmol) at room temperature for 2.5 h, followed by the same work up and purification by flash chromatography (gradient elution with hexane:ethyl acetate 4:1 to 100% ethyl acetate) gave tert-butyl-(3R)-3-({[(1S)-2,2-dimethyl-1-{[(1R)-1-(3-pyridyl)ethylamino]carbonyl}propyl]amino}carbonyl)-6-[3-methyl-(4-phenyl)phenyl]-hexanoate (537 mg, 89%) as a colourless foam.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=1[Cl:20].C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([Cl:19])=[CH:13][C:12]=2[Cl:20])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: Cc1cnc(Cl)nc1N
Reactant: COc1cc(Br)c(Cl)cc1Cl
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COc1cc(Nc2nc(Cl)ncc2C)c(Cl)cc1Cl

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (44.8 mg, 0.31 mmol) in 1,4-dioxane (20 mL) was added 1-bromo-2,4-dichloro-5-methoxybenzene (96 mg, 0.37 mmol), Cs2CO3 (408 mg, 1.25 mmol), Pd2(dba)j (37 mg, 0.04 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 70 mg, 0.12 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed in vacuo. The crude product was used for next reaction without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4]([O:21]CC1C=CC=CC=1)=[CH:5][C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:7]2.FC(F)(F)C(O)=O>>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[CH:5]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[NH:7]2
Reactant: O=C(c1ccccc1)c1cc(OCc2ccccc2)c2c(Cl)cc(Cl)cc2n1
Solvent: O=C(O)C(F)(F)F
Product: O=C(c1ccccc1)c1cc(=O)c2c(Cl)cc(Cl)cc2[nH]1

Procedure:
Combine 5,7-dichloro-4-benzyloxy-2-benzoylquinoline (1.07 g, 2.6 mmol) and trifluoroacetic acid (65 mL) and heat to 70° C. After 4 hours evaporate the reaction mixture in vacuo to give a residue. Recrystallize the residue from acetonitrile to give the title compound; mp, 242°-243° C. Rf =0.33 TLC/silica gel/2% acetone in dichloromethane. Elem. Anal. Calcd. for C16H9Cl2NO2 : C, 60.40; H, 2.85; N, 4.40. Found: C, 60.35; H, 2.89; N, 4.50.
Reaction SMILES: [Br:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=[O:8])[N:6]=1.[OH-].[Li+]>C1COCC1.CO.O>[Br:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=[O:8])[N:6]=1
Reactant: CCOC(=O)c1coc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1coc(Br)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.4 %

Procedure:
Ethyl 2-bromo-1,3-oxazole-4-carboxylate (2.5 g, 11.36 mmo) was dissolved in THF/methanol mixture (9:1) and 1M lithium hydroxide (22.73 ml, 22.73 mmol) was added slowly. The reaction mixture was stirred at RT for 1 h, diluted with water and pH was adjusted to 2. Formed precipitate was filtered and dried to yield the title compound (1.1 g). The filtrate was extracted three times with ethyl acetate. Ethyl acetate phases were combined, dried and evaporated to dryness to yield the title compound 0.85 g. Total yield 88%. m/z [192.0+1]
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[N:8]=[N:9][C:10]([Cl:13])=[CH:11][CH:12]=1.[C:14]12(C(O)=O)[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+].N>O.[N+]([O-])([O-])=O.[Ag+]>[C:14]12([C:12]3[CH:11]=[C:10]([Cl:13])[N:9]=[N:8][C:7]=3[Cl:6])[CH2:20][CH:17]([CH2:18][CH2:19]1)[CH2:16][CH2:15]2
Reactant: Clc1ccc(Cl)nn1
Reactant: O=C(O)C12CCC(CC1)C2
Agent: [Ag+]
Agent: N
Agent: O=S(=O)(O)O
Solvent: O
Product: Clc1cc(C23CCC(CC2)C3)c(Cl)nn1
Temperature: 70 °C
Yield: 98.7 %

Procedure:
Concentrated sulphuric acid (2.17 ml, 40 mM) was added carefully to a suspension of 3,6-dichloropyridazine (2.11 g, 14.3 mM) in water (50 ml). This mixture was then heated to 70° C. and bicyclo[2.2.1]heptane-1-carboxylic acid (Org. Synth., 59, 85; 2.0 g, 14.3 mM) was added. After ten minutes a solution of silver nitrate (0.48 g, 2.8 mM) in water (5 ml) was added dropwise over two minutes. A solution of ammonium persulphate (9.8 g, 43 mM) in water (20 ml) was added over 20 minutes. The reaction was heated at 70° C. for a further 40 minutes and then allowed to cool to room temperature. The mixture was poured onto ice and basified with concentrated aqueous ammonia; the temperature was kept below 10° C. by addition of more ice. The aqueous phase was extracted with dichloromethane (3×200 ml) and the combined extracts were dried (MgSO4), filtered and evaporated to give the crude product, which was purified by column chromatography using ethyl acetate/hexane mixtures as the eluent to give the title compound (3.4 g). 1H NMR (250 MHz, CDCl3) δ1.49-2.00 (8H, m), 2.17 (2H, m), 2.43 (1H, m), 7.45 (1H, s); MS (ES+) m/e 244 [MH]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:38])[C:5]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)([CH3:28])[CH:6]([C:14]1[CH:19]=[CH:18][C:17]([O:20]CC2C=CC=CC=2)=[CH:16][CH:15]=1)OC(=O)C(F)(F)F)[CH3:2]>C(OCC)(=O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:38])[C:5]([O:29][C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([CH3:37])[CH:31]=1)([CH3:28])[CH2:6][C:14]1[CH:15]=[CH:16][C:17]([OH:20])=[CH:18][CH:19]=1)[CH3:2]
Reactant: CCOC(=O)C(C)(Oc1ccc(C)c(C)c1)C(OC(=O)C(F)(F)F)c1ccc(OCc2ccccc2)cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(C)c(C)c1
Reaction time: 20 h

Procedure:
3-(4-Benzyloxyphenyl)-2-(3,4-dimethylphenoxy)-2-methyl-3-(2,2,2-trifluoroacetoxy)propionic acid ethyl ester (2.1 mmol) was dissolved in ethyl acetate (30 mL) and treated with 5% palladium on carbon (300 mg), and stirred under an atmosphere of hydrogen for 20 h. The suspension was filtered through celite and concentrated in vacuo to an oil.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13](Br)[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4].[CH3:25][Sn](C)(C)C.CCOC(C)=O.Cl>CN(C=O)C.[Cl-].[Na+].O.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>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:24])=[C:7]2[C:12](=[C:13]([CH3:25])[N:14]=1)[N:11]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10](=[O:23])[CH2:9][CH2:8]2)=[O:4]
Reactant: C[Sn](C)(C)C
Reactant: COC(=O)c1nc(Br)c2c(c1O)CCC(=O)N2Cc1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1nc(C)c2c(c1O)CCC(=O)N2Cc1ccccc1
Temperature: 120 °C
Yield: 79.5 %

Procedure:
A mixture of 1-benzyl-8-bromo-5-hydroxy-2-oxo-1,2,3,4-tetrahydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (145 mg, 0.37 mmol), tetramethyltin (0.3 mL, 1.85 mmol), and PdCl2(PPh3)2 (52 mg, 0.074 mmol) in DMF (5 mL) was heated at 120° C. under nitrogen atmosphere for 2 h. After the mixture was cooled to r.t., EtOAc (50 mL) and brine (10 mL) were added. 1M HCl was added until pH about 3. The aqueous layer was extracted with additional EtOAc, and the organic layers were combined and washed with water and dried over MgSO4. After the solvent was evaporated in vacuo, the crude product was chromatographed (0-60% EtOAc/hexanes+2% AcOH) to give 96 mg of the title compound. MS: (+) m/z 327.11 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][CH:10]=[C:11]([CH:19]=[CH:20][C:21]#[N:22])[C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1>O1CCCC1.CO.[Pd]>[C:21]([CH2:20][CH2:19][C:11]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)[NH:9][CH:10]=1)#[N:22]
Reactant: N#CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: N#CCCc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
2.94 g (10.16 mmol) of 3-[2-(4-fluorophenyl)-3-(pyridin-4-yl)-1H-pyrrol-4-yl]acrylonitrile [prepared as described in step (iv) above] were dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of methanol, after which 2.94 g of 10% palladium on carbon were added to the solution. The mixture was stirred under a hydrogen atmosphere at room temperature for 8 hours. At the end of this time, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The resulting residue was washed with a mixture of 30 ml of diethyl ether and 30 ml of ethanol to give 1.80 g (yield 61%) of the title compound as a pale orange powder.
Reaction SMILES: [C:1]([CH2:11][C:12]#[N:13])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[N:14]([O-])=[O:15].[Na+]>C(O)(=O)C.O>[OH:15][N:14]=[C:11]([C:1](=[O:10])[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:12]#[N:13]
Reactant: N#CCC(=O)C=Cc1ccccc1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CC(=NO)C(=O)C=Cc1ccccc1
Temperature: 3 °C
Reaction time: 1.5 h
Yield: 78.3 %

Procedure:
Cinnamoyl acetonitrile (5.1 g; 0.03 mol) is dissolved in 50 ml of acetic acid. 10 ml of H2O are added and the mixture is cooled to 3° C. in an ice/salt bath. Partial precipitation occurs, but the mixture remains well stirrable. Sodium nitrite (4.14 g; 0.06 mol) is added by portions over 10 min, keeping the temperature between 3 and 5° C. Complete solution is observed during addition, but precipitation occurs again towards the end. The mixture is then stirred at 0° C. for 1.5 h. The mixture is diluted with 100 ml of iced water with stirring, the light ochre precipitate is filtered, and washed with ca 100 ml of water. The humid cake is redissolved in ether (100 ml), washed with water, brine and dried over magnesium sulfate. Rotary evaporation and drying affords 2-hydroxyimino-3-oxo-5-phenyl-pent-4-enenitrile (4.7 g; 78%) as a dark yellow solid (mp 144-145° C. dec) which is used without further purification in the next reaction step.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:12]=2)[CH2:7][CH2:6][NH:5][CH2:4]1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[Br-].[CH3:36][CH:37]1[O:41][C:40](=[N+:42]([CH3:44])[CH3:43])[C:39]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:38]1>O>[CH3:1][O:2][C@H:3]1[C@H:8]([NH:9][C:10](=[O:21])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:18])[F:19])[CH:12]=2)[CH2:7][CH2:6][N:5]([CH:37]([CH3:36])[CH2:38][C:39]([C:51]2[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=2)([C:45]2[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:40]([N:42]([CH3:43])[CH3:44])=[O:41])[CH2:4]1
Reactant: CC1CC(c2ccccc2)(c2ccccc2)C(=[N+](C)C)O1
Reactant: CO[C@@H]1CNCC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: CO[C@@H]1CN(C(C)CC(C(=O)N(C)C)(c2ccccc2)c2ccccc2)CC[C@H]1NC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 22.5 %

Procedure:
A mixture of 3.0 parts of trans-N-(3-methoxy-4-piperidinyl)-3-(trifluoromethyl)benzamide, 2.65 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone was stirred for 30 minutes at reflux temperature, using a water separator. After cooling 3.96 parts of N-(dihydro-5-methyl-3,3-diphenyl-2(3H)-furanylidene)-N-methylmethanaminium bromide were added and stirring was continued for 5 hours at reflux. After cooling overnight at room temperature, the reaction mixture was washed twice with 50 parts of water, dried, filtered and evaporated in vacuo. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 8 parts of acetonitrile. The product was filtered off and dried, yielding 1.3 parts (22.5%) of trans-3-methoxy-N,N,γ-trimethyl-α,α-diphenyl-4-[[3-(trifluoromethyl)benzoyl]amino]-1-piperidinebutanamide; mp. 197.8° C. (compound 52).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([OH:18])=O)[O:9][N:8]=1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[OH:30][CH:31]([C:45]1[CH:50]=[CH:49][C:48](/[C:51](=[N:53]/O)/[NH2:52])=[CH:47][CH:46]=1)[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:34]1>ClCCl>[OH:30][CH:31]([C:45]1[CH:50]=[CH:49][C:48]([C:51]2[N:53]=[C:16]([C:10]3[O:9][N:8]=[C:7]([C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=4)[C:11]=3[C:12]([F:13])([F:14])[F:15])[O:18][N:52]=2)=[CH:47][CH:46]=1)[CH2:32][N:33]1[CH2:38][CH2:37][CH2:36][C@H:35]([CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[CH2:34]1
Reactant: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(/C(N)=N/O)cc2)C1
Reactant: O=C(O)c1onc(-c2ccccn2)c1C(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCOC(=O)C[C@H]1CCCN(CC(O)c2ccc(-c3noc(-c4onc(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Under an argon atmosphere, 3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazole-5-carboxylic acid, Int-IV (40 mg, 0.155 mmol) was suspended in dichloromethane (1.5 mL) with sonication and DMF (5 μl, 0.065 mmol) was added. Oxalyl chloride (54.3 μl, 0.620 mmol) was added dropwise over 1-2 minutes. The reaction vial was flushed with argon and sealed. After 3 h, the contents were concentrated in vacuo. The material was re-constituted in dichloromethane and a solution of ethyl 2-((3R)-1-(2-hydroxy-2-(4-((Z)—N′-hydroxycarbamimidoyl)phenyl)ethyl)piperidin-3-yl)acetate (54.1 mg, 0.155 mmol) in DCM (1-2 mL) was added. The reaction mixture was stirred for 3 days at room temperature and then purified by Prep HPLC to afford ethyl 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetate which was suspended in dioxane (2-3 mL) and 3N aq HCl (1 mL) was added. The mixture was placed in a sand bath heated to 50° C. overnight. The solution was evaporated, re-evaporated from chloroform-d and then placed under high vacuum to give 2-((3R)-1-(2-hydroxy-2-(4-(5-(3-(pyridin-2-yl)-4-(trifluoromethyl)isoxazol-5-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid as a clear colorless film. 1H NMR (500 MHz, MeOD) δ ppm 8.69 (1 H, d, J=4.72 Hz), 8.14 (2H, d, J=8.32 Hz), 7.95 (1H, td, J=7.70, 1.80 Hz), 7.86 (1H, d, J=7.77 Hz), 7.61 (2H, d, J=8.32 Hz), 7.49-7.56 (1H, m), 5.17 (1H, dd, J=9.71, 4.16 Hz), 3.80 (1H, br. s.), 3.52-3.67 (4H, m), 2.89 (1H, br. s.), 2.73 (1H, t, J=11.93 Hz), 2.18-2.39 (3H, m), 1.79-1.94 (3H, m). HPLC RT=0.77 min, MH+=544. Waters Masslynx instrument equipped with a BEH 2.1×50 mm 17 uM C18 column and a method of 2-98% B solvent over 1.6 min at a flow rate of 0.8 mL/min. Solvent A is water; solvent B is acetonitrile and both contain 0.5% TFA.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH2:3][CH2:4][NH:5][C:6](N1CCN(C2C=CC(F)=CC=2)CC1)=[O:7].C(N1C=CN=C1)(N1C=CN=C1)=O.CN(CCN)C.[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49].[ClH:56]>O1CCCC1>[ClH:56].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([N:50]2[CH2:51][CH2:52][N:53]([C:6]([NH:5][CH2:4][CH2:3][N:2]([CH3:21])[CH3:1])=[O:7])[CH2:54][CH2:55]2)[CH:45]=[CH:46][C:47]=1[O:48][CH3:49]
Reactant: COc1ccc(N2CCNCC2)cc1OC
Reactant: CN(C)CCNC(=O)N1CCN(c2ccc(F)cc2)CC1
Agent: CN(C)CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(N2CCN(C(=O)NCCN(C)C)CC2)cc1OC

Procedure:
This compound was prepared according to the procedure used to synthesize the compound of Example 11. A mixture of 1.6 g (0.01 mole) of 1,1'-carbonyldiimidazole, 0.87 g (0.01 mole) of unsym-dimethylethylenediamine, and 2.2 g (0.01 mole) of 1-(3,4-dimethoxyphenyl)piperazine in a total volume of 50 ml of tetrahydrofuran gave an oil as residue. The hydrochloride was formed in ethereal hydrogen chloride and the collected solid was recrystallized twice from methanolethyl ether to yield 2.3 g (57%) of the title compound as an off-white solid, m.p. 208°-210° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])=[CH:8][C:7]([OH:21])=[CH:6][CH:5]=2.CN(C=O)C.C(N(CC)CC)C.[F:34][C:35]([F:50])([S:46](F)(=[O:48])=[O:47])[C:36]([F:45])([F:44])[C:37]([F:43])([F:42])[C:38]([F:41])([F:40])[F:39]>C(Cl)Cl.C(Cl)Cl.CO>[CH2:14]([O:13][C:11]([C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:21][S:46]([C:35]([F:34])([F:50])[C:36]([F:44])([F:45])[C:37]([F:42])([F:43])[C:38]([F:41])([F:40])[F:39])(=[O:48])=[O:47])[CH:8]=2)[NH:3][C:2]=1[CH3:1])=[O:12])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: Cc1[nH]c2ccc(O)cc2c1C(=O)OCc1ccccc1
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1[nH]c2ccc(OS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F)cc2c1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 86 %

Procedure:
2-Methyl-3-benzyloxycarbonyl-5-hydroxyindole (5.90 g, 21.0 mmol, 1 eq) was suspended in dry CH2Cl2 (100 mL) and dry DMF (2 mL) under Ar. Triethylamine (8.77 mL, 63 mmol, 3 eq) was added followed by the addition of perfluorobutanesulfonyl fluoride (4.2 mL, 23.4 mmol, 1.1 eq). The reaction mixture was stirred at room temperature and followed by TLC (CH2Cl2/MeOH 98/2). After 18 hours, the reaction was quenched with aqueous hydrochloric acid. The organic phase was washed with water (2×) and the combined aqueous phases extracted with CH2Cl2. The combined organic extracts were washed with brine and dried over Na2SO4. After removing the solvent, the residue was loaded on silica gel and chromatographed eluting with methanol/CH2Cl2(98/2). 10.17 g (86% yield) of the indole-nonaflate was obtained as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].Cl[CH:15](Cl)C.S(Cl)(Cl)=O.CO.Cl>CN(C=O)C.C(=O)(O)[O-].[Na+]>[CH3:15][O:12][C:11]([C:4]1[CH:5]=[C:6]([CH:10]=[C:2]([CH3:1])[CH:3]=1)[C:7]([OH:9])=[O:8])=[O:13]
Reactant: Cc1cc(C(=O)O)cc(C(=O)O)c1
Reactant: CC(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: CO
Product: COC(=O)c1cc(C)cc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
5-Methylisophthalic acid (1.21 g, 6.5 mmol), dichloroethane (20 mL), DMF (3 drops), and thionyl chloride (2.42 g, 20 mmol) was heated to 80° C. for 4 hrs. The reaction was concentrated to dryness and a solution of MeOH (208 mg, 6.5 mmol) was added slowly and the reaction was stirred overnight at rt. 1 N Hydrochloric acid (10 mL) was added and reaction stirred for 1 hr. The pH was adjusted with sat'd sodium bicarbonate (50 mL) and the aqueous solution was extracted with methylene chloride to remove the diester. The aqueous portion was then acidified with 1 N HCl and extracted with methylene chloride/MeOH 95:5. The organic extracts were dried over sodium sulfate, filtered, concentrated, and the product was isolated via preparative reverse-phase HPLC.