Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O-]CC.[Na+].[C:5]([O:9][C:10]([NH:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([C:19]([N:23]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:24][C:25]#[C:26][CH3:27])=[N:20][C:21]#[N:22])[CH2:14]1)=[O:11])([CH3:8])([CH3:7])[CH3:6].Cl>C(O)C>[NH2:22][C:21]1[N:20]=[C:19]([N:15]2[CH2:16][CH2:17][CH2:18][CH:13]([NH:12][C:10]([O:9][C:5]([CH3:8])([CH3:6])[CH3:7])=[O:11])[CH2:14]2)[N:23]([CH2:24][C:25]#[C:26][CH3:27])[C:28]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CC#CCN(CC(=O)OCC)C(=NC#N)N1CCCC(NC(=O)OC(C)(C)C)C1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC#CCn1c(N2CCCC(NC(=O)OC(C)(C)C)C2)nc(N)c1C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
2.5 g sodium ethoxide are added to a solution of 12.5 g (approx. 90%) 3-tert-butoxycarbonylamino-N-(ethoxycarbonylmethyl)-N-(but-2-ynyl)-N′-cyano-piperidine-1-carboxamidine in 100 ml dry ethanol. The reaction solution is stirred for 3 h at ambient temperature and then neutralised with 1 M hydrochloric acid. The solvent is removed, water is added and the mixture is extracted with ethyl acetate. The organic extracts are dried over sodium sulphate, the solvent is removed, and the residue is purified on silica (cyclohexane/ethyl acetate 3:1->1:5).
Reaction SMILES: [N+](=[CH2:3])=[N-].[OH:4][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH3:16])[CH:9]=1)=[O:7]>CCOCC>[CH2:15]([O:14][C:10]1[CH:9]=[C:8]([C:6](=[O:7])[CH2:5][O:4][CH3:3])[CH:13]=[CH:12][CH:11]=1)[CH3:16]
Reactant: C=[N+]=[N-]
Reactant: CCOc1cccc(C(=O)CO)c1
Solvent: CCOCC
Product: CCOc1cccc(C(=O)COC)c1
Yield: 65 %

Procedure:
Boron trifluoride-diethyl ether complex (3 drops) and an ether solution of diazomethane were added to a solution of 2-hydroxy-3′-ethoxyacetophenone (1.6 g, 8.9 m mol) in ether (60 ml). The ether solution of diazomethane was added until thin-layer reveals that the spot of 2-hydroxy-3′-ethoxyacetophenone has disappeared. After insoluble matter was filtered off, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to chromatography on silica gel (40 g) using ethyl acetate-hexane (1:4). Thus, the desired compound (1.13 g, 65%) was obtained as a colorless oily material.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:8][C:3]=1[CH2:4][N:5]=[C:6]=[O:7].[C:18]([NH:21][NH2:22])(=[O:20])[CH3:19]>O1CCCC1>[C:18]([NH:21][NH:22][C:6]([NH:5][CH2:4][C:3]1[CH:8]=[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=[CH:11][C:2]=1[CH3:1])=[O:7])(=[O:20])[CH3:19]
Reactant: Cc1ccc(-c2ccccc2)cc1CN=C=O
Reactant: CC(=O)NN
Solvent: C1CCOC1
Product: CC(=O)NNC(=O)NCc1cc(-c2ccccc2)ccc1C
Temperature: 25 °C
Yield: 28.3 %

Procedure:
To a solution of 2.47 g (11.1 mmol) of crude 2-methyl-5-phenylbenzylisocyanate in 50 ml of tetrahydrofuran was added 0.82 g of acetohydrazide and the mixture was heated under reflux for 1 hour. After allowing to cool to room temperature, the reaction mixture was concentrated, and the residue was recrystallized from ethanol to obtain 0.93 g (3.13 mmol) of 1-acetyl-4-(2-methyl-5-phenylbenzyl)semicarbazide.
Reaction SMILES: [NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([OH:12])[CH2:4][CH2:3]1.[H-].[Na+].F[C:16]1[CH:17]=[CH:18][C:19]([C:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[O:23])=[N:20][CH:21]=1>CN(C=O)C>[NH2:1][C@@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C@H:5]([O:12][C:16]2[CH:17]=[CH:18][C:19]([C:22]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[O:23])=[N:20][CH:21]=2)[CH2:4][CH2:3]1
Reactant: O=C(c1ccc(F)cn1)N1CCOCC1
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N[C@H]1CC[C@@H](Oc2ccc(C(=O)N3CCOCC3)nc2)c2ccccc21
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
Intermediate A (150 mg, 0.92 mmol) was added to a suspension of sodium hydride (60% in mineral oil, 147 mg, 3.66 mmol) in DMF (3.0 mL). The reaction was stirred for 20 min, then Intermediate 17a (280 mg) in DMF (3.0 mL) was added and the reaction heated to 60° C. for 90 min. The mixture was cooled and quenched by dropwise addition of MeOH. The solution was diluted with MeOH and loaded onto an SCX-2 cartridge, which was washed sequentially with MeOH and 2M NH3 in MeOH. The basic fractions were evaporated in vacuo then purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (234 mg, 0.66 mmol, 72%). LCMS (Method 4): Rt 1.60 min, m/z 354 [MH+].
Reaction SMILES: [CH:1]12[CH:6]([N:7]3[C:11](=[O:12])[C:10]([CH2:20][C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)([CH2:13][C:14]4[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=4)[NH:9][C:8]3=[CH:27][C:28]([C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][CH:31]=3)=[O:29])[CH:5]1[CH2:4][NH:3][CH2:2]2.[CH3:38][CH:39]1[CH2:44][CH2:43][N:42]([S:45](Cl)(=[O:47])=[O:46])[CH2:41][CH2:40]1>>[CH3:38][CH:39]1[CH2:44][CH2:43][N:42]([S:45]([N:3]2[CH2:4][CH:5]3[CH:1]([CH:6]3[N:7]3[C:11](=[O:12])[C:10]([CH2:20][C:21]4[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=4)([CH2:13][C:14]4[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=4)[NH:9][C:8]3=[CH:27][C:28]([C:30]3[CH:31]=[CH:32][C:33]([C:34]#[N:35])=[CH:36][CH:37]=3)=[O:29])[CH2:2]2)(=[O:47])=[O:46])[CH2:41][CH2:40]1
Reactant: CC1CCN(S(=O)(=O)Cl)CC1
Reactant: N#Cc1ccc(C(=O)C=C2NC(Cc3ccncc3)(Cc3ccncc3)C(=O)N2C2C3CNCC32)cc1
Product: CC1CCN(S(=O)(=O)N2CC3C(C2)C3N2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC1
Yield: 93.1 %

Procedure:
According to the procedure of Example 13, 4-{[1-(3-aza-bicyclo[3.1.0]hex-6-yl)-5-oxo-4,4-bis-pyridin-4-ylmethyl-imidazolidin-2-ylidene]-acetyl}-benzonitrile (50 mg, 0.102 mmol) and 4-methyl-piperidine-1-sulfonyl chloride (60.2 mg, 0.306 mmol) were reacted to generate the title compound as an off-white solid (62 mg, 0.095 mmol, 93% yield).
Reaction SMILES: C(S([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)(=O)=O)C.C(N(CC)CC)C.[CH2:47]([N:49]=[C:50]=[O:51])[CH3:48]>C(Cl)Cl>[CH2:47]([NH:49][C:50]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([C:21]3[O:22][C:23]4[C:28]([C:29](=[O:31])[CH:30]=3)=[CH:27][C:26]([F:32])=[CH:25][C:24]=4[N:33]3[CH2:34][CH2:35][N:36]([CH3:39])[CH2:37][CH2:38]3)=[O:20])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:51])[CH3:48]
Reactant: CCN=C=O
Reactant: CCS(=O)(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)N1CCN(c2ccc(NC(=O)c3cc(=O)c4cc(F)cc(N5CCN(C)CC5)c4o3)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Fluoro-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 71) (150 mg, 0.216 mmol) was placed in a 50 mL flask with 10 of CH2Cl2. This suspension was treated with triethylamine (0.1 mL, 0.67 mmol) and ethylisocyanate (0.21 mL, 18.7 mg, 0.26 mmol) and the reaction stirred at room temperature for 18 hours. The reaction was concentrated (1 mm Hg pressure) and the concentrate purified by chromatography on silica eluting with 1% methanol in chloroform, then concentrated (1 mm Hg pressure). Then triturated with either to yield a yellow powder with was dried under high vacuum for 48 h at 50° C. (79 mg) LCMS-AP+ 537.4, mp=236-238° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:5]1([CH2:4][CH2:3][CH2:2][N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: C1CNCCN1
Reactant: ClCCCc1ccccc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(CCCN2CCNCC2)cc1
Temperature: 100 °C
Reaction time: 0.2 h

Procedure:
A solution of 1-chloro-3-phenylpropane (5.4 g) in toluene (10 ml) was added to a stirred solution of piperazine (15.0 g) and triethylamine (3.5 g) in toluene (20 ml) at 100° C. The reaction mixture was heated with stirring at 100° C. for 0.2 hours and then heated under reflux for 18 hours. The reaction mixture was allowed to cool to room temperature and then filtered. The filtrate was evaporated and the residual oil was purified by column chromatography, eluting with dichloromethane/methanol (19:1), then methanol, to give 1-(3-phenylpropyl)piperazine as an oil.
Reaction SMILES: C[O:2]C.[F:4][C:5]([F:12])([F:11])[C:6]([F:10])=[C:7](F)[F:8].C[O-].[Na+]>CO>[F:10][CH:6]([C:5]([F:12])([F:11])[F:4])[C:7]([F:8])=[O:2]
Reactant: COC
Reactant: FC(F)=C(F)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(F)C(F)C(F)(F)F
Yield: 82 %

Procedure:
The above methyl ether (49.5 g, prepared from the reaction of hexafluoropropene with sodium methoxide in methanol) in a still pot was cooled in a Dry Ice-acetone bath and 2.70 g of SbF5 was added. The mixture was stirred on a still with a Dry Ice-acetone trap attached and the cooling bath removed. Evolution of CH3F was vigorous below room temperature. The mixture was warmed until all of the product had collected in the Dry Ice-acetone trap. Material in the trap was redistilled in a low-temperature still to give 33 g (82%) of 2,3,3,3-tetrafluoropropionylfluoride, b.p. 25°.
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH3:16].[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[NH:27][CH2:28][CH2:29][NH2:30].C(N(CC)CC)C>CS(C)=O>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([NH:30][CH2:29][CH2:28][NH:27][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)[C:9]([O:14][CH3:15])=[C:8]2[C:3]=1[C:4](=[O:20])[C:5]([C:17]([OH:19])=[O:18])=[CH:6][N:7]2[CH3:16]
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C)c12
Reactant: NCCNc1ccccn1
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: COc1c(NCCNc2ccccn2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C)c12
Temperature: 0 °C
Yield: 59.2 %

Procedure:
A solution 5-amino-1-methyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxoquinoline-3-carboxylic acid (170 mg, 0.598 mmol), N-2-pyridyl-1,2-ethanediamine (123 mg, 0.897 mmol) and triethylamine (0.125 mL, 0.897 mmol) in DMSO (2 mL) was stirred at 100° C. After 4 h the reaction mixture was poured into ice water and the resulting precipitate was removed by filtration, washed with ethanol, and dried to yield 5-amino-6-fluoro-1,4-dihydro-8-methoxy-1-methyl-4-oxo-7-[2-(2-pyridylamino)ethylamino]quinoline-3-carboxylic acid (142 mg, 59%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.Br[C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1.C([Li])CCC.[Cl-].[NH4+]>O1CCCC1.C(OCC)C.CCCCCC>[Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[C:4]([C:14]1[CH:15]=[N:16][CH:17]=[N:18][CH:19]=1)=[O:6]
Reactant: Brc1cncnc1
Reactant: COC(=O)c1ccc(Cl)cc1Cl
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(c1cncnc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
61.8 g (0.3 mole) of methyl 2,4-dichlorobenzoate and 52.2 g (0.33 mole) of 5-bromopyrimidine are dissolved in a mixture of 400 ml of tetrahydrofuran and 200 ml of diethyl ether. After the addition of 30 g of molecular sieve, the reaction mixture is stirred for 1/2 hour at room temperature and then cooled to about -120° C. 187.2 ml (0.3 mole) of butyl lithium as a 1.6 molar solution in hexane are added dropwise at this temperature. The reaction mixture is then stirred for 11/2 hours in the temperature range from -100° to -130° C. Subsequently, while allowing the temperature to increase to room temperature, stirring is continued until the reaction is complete. 300 ml of 10% ammonium chloride solution are then added dropwise, and the reaction mixture is extracted three times with ethyl acetate. The organic solution is dried over sodium sulfate and then filtered, and the filtrate is concentrated. The resultant crude product is then purified through a flash column packed with silica gel (eluant: a 3:1 mixture of petroleum ether and ethyl acetate), affording 45 g (59.3% of theory) of the title compound with a melting point of 75°-78° C.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3([C:31]#N)[CH2:30][CH2:29]3)=[CH:24][CH:23]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.CC(C[AlH]CC(C)C)C.Cl.C([O-])(O)=[O:44].[Na+]>C1(C)C=CC=CC=1>[CH3:6][N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([O:21][C:22]2[CH:23]=[CH:24][C:25]([C:28]3([CH:31]=[O:44])[CH2:29][CH2:30]3)=[CH:26][CH:27]=2)=[CH:19][CH:20]=1
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(Oc2ccc(C3(C#N)CC3)cc2)cc1
Agent: CC(C)C[AlH]CC(C)C
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CN1CCC[C@@H]1COc1ccc(Oc2ccc(C3(C=O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
To a 25 mL vial which contained a solution of (R)-2-{4-[4-(1-Cyano-cyclopropyl)-phenoxy]-phenoxymethyl}-pyrrolidine-1-carboxylic acid tert-butyl ester 3 (110 mg, 0.25 mmol) in anhydrous toluene (2 mL) were added DIBAL (0.5 mL 1M in hexane)) at −78° C. under the atmosphere of argon. The reaction mixture was allowed to warm to rt and stir at rt for 0.5 h. After cooled to ° C., 0.5 mL HCl was added to the mixture, the mixture was stirred for 10 min and then was neutralized with the addition of sat. NaHCO3 solution. This mixture was extracted with EtOAc (3×30 mL). The combined organic layers were washed with water (2×30 mL), brine (30 mL) and dried over anhydrous Na2SO4. The solvent was removed under vacuo to obtain the crude product which was purified by silica gel flash chromatography to afford the title product, (50 mg, 65%); LCMS; 95%, APCI+ Calcd: 351.5, found m/z: 353.1 (M+1); 1HNMR (400 MHz, CDCl3); δ 1.36-1.39 (m, 2H), 1.54-1.56 (m, 2H), 1.70-2.10 (m, 4H), 2.26-2.33 (m, 1H), 2.48 (s, 3H), 2.60-2.70 (m, 1H), 3.09-3.13 (m, 1H), 3.85-3.99 (m, 2H), 6.88-6.93 (m, 4H), 6.95-6.99 (m, 2H), 7.20-7.30 (m, 2H) 9.22 (s, 1H),
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[C:23]([F:25])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][N:7]1C(OC)=O.Br>>[F:25][C:23]1[CH:22]=[C:4]([CH:3]=[C:2]([F:1])[CH:24]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:16][NH:15][C:14](=[O:17])[CH:13]=2)[CH2:9][CH2:8][NH:7]1
Reactant: COC(=O)N1CC[C@@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(F)cc(F)c1
Agent: Br
Product: O=c1cc([C@@H]2CCN[C@@H](Cc3cc(F)cc(F)c3)C2)o[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.1 %

Procedure:
(2R,4R)-Methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.244 g, 0.69 mmol) was dissolved in hydrogen bromide (33% in acetic acid, 5.46 mL, 31.16 mmol) and the mixture was stirred at room temperature overnight. The solvent was evaporated and the residue purified by preparative HPLC (Instrument: FractionLynx II, Mobilphase: gradient 5-95% MeCN in 0.2% NH3, pH 10, Column: Xbridge Prep C18 5 μm OBD 19*150 mm) to yield 5-((2R,4R)-2-(3,5-difluorobenzyl)piperidin-4-yl)isoxazol-3(2H)-one (51 mg, 25%). 1H NMR (600 MHz, dmso) δ 1.44-1.51 (m, 1H), 1.65-1.80 (m, 3H), 2.52-2.60 (m, 1H), 2.65-2.70 (m, 2H), 2.76-2.83 (m, 1H), 2.86-2.94 (m, 1H), 3.09-3.14 (m, 1H), 5.74 (s, 1H), 6.90-6.95 (m, 2H), 7.00 (tt, 1H). HRMS Calculated for [C15H16F2N2O2+H]+: 295.1258. Found: 295.1276
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([NH:10][C:11](=O)[CH:12]([CH3:14])[CH3:13])[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[C:5]=1[F:23].[N-:25]=[N+:26]=[N-:27].[Na+].[Si](Cl)(Cl)(Cl)Cl>C(#N)C>[CH3:1][O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([N:10]2[C:11]([CH:12]([CH3:14])[CH3:13])=[N:27][N:26]=[N:25]2)[CH:7]=[C:6]([C:16]2[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][N:17]=2)[C:5]=1[F:23]
Reactant: COC(=O)c1cc(NC(=O)C(C)C)cc(-c2ccc(C)cn2)c1F
Reactant: [N-]=[N+]=[N-]
Agent: Cl[Si](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)c1cc(-n2nnnc2C(C)C)cc(-c2ccc(C)cn2)c1F
Temperature: 25 °C
Yield: 90822.2 %

Procedure:
2-Fluoro-5-isobutyrylamino-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester (690 mg, 1.89 mmol), NaN3 (1.1 g, 17 mmol) and SiCl4 (964 mg, 5.67 mmol) were added 20 mL acetonitrile, and the reaction mixture refluxed for 18 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was dissolved in saturated aqueous NaHCO3, and the resulting mixture was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give 610 g (83%) of 2-fluoro-5-(5-isopropyl-tetrazol-1-yl)-3-(5-methyl-pyridin-2-yl)-benzoic acid methyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:9]([NH2:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([Cl:20])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:11][C@@H:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH3:10])[C:16]([Cl:20])=[CH:15][N:14]=1
Reactant: COc1cccc([C@@H](C)N)c1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc([C@@H](C)Nc2nc(Cl)ncc2Cl)c1
Yield: 90.6 %

Procedure:
To a solution of (1R)-1-(3-methoxyphenyl)ethanamine (1.50 g, 9.92 mol) (R-isomer, >98% ee purity) and 2,4,5-trichloropyrimidine (1.19 mL, 10.4 mmol) in N,N-dimethylformamide (30 mL) was added potassium carbonate (4.1 g, 30 mmol). The resultant mixture was stirred over two days at room temperature. The reaction was quenched with water. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc twice. The combined organic layers were washed with water and brine successively, then dried (Na2SO4), filtered, concentrated, and triturated with cold EtOAc to give the desired product as a light yellow gel (2.81 g, 95%). LCMS for C13H14Cl2N3O (M+H)+: m/z=298.0.
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=O)[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1>C(O)C.O>[Cl:9][C:10]1[CH:11]=[C:12]([CH:29]=[N:2][OH:3])[C:13]2[O:18][CH:17]([C:19]([F:22])([F:21])[F:20])[C:16]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][C:14]=2[CH:28]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(C=O)c2OC1C(F)(F)F
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOC(=O)C1=Cc2cc(Cl)cc(C=NO)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.4 h

Procedure:
Hydroxylamine hydrochloride (1.30 g, 18.7 mmol), sodium acetate (1.50 g, 19.4 mmol), and a mixture of ethanol-water (80:20, 15 mL) were stirred at room temperature for 0.4 hours. The aldehyde (Example 76, Step 3) (3.07 g, 9.0 mmol) was dissolved in a solution of ethanol-water (4:1, 25 mL) and added to this mixture and stirred at 100° C. for 1 hour. The reaction was filtered hot and the filtrate allowed to cool to room temperature. An orange solid crystallized in the filtrate which was collected by vacuum filtration. The solid was dissolved in ethyl acetate and the solution washed with water, brine, dried over MgSO4, concentrated in vacuo. The resulting solid was recrystallized from ethyl acetate-hexane yielding the oxime as a tan powder (1.50 g, 47%): mp 186.6–187.6° C. 1H NMR (acetone-d6/300 MHz) 10.87 (s, 1H), 8.34 (s, 1H), 7.90 (s, 1H), 7.77 (d, 1H, J=2.6 Hz), 7.60 (d, 1H, J=2.6 Hz), 6.02 (q, 1H, J=7.1 Hz), 4.35 (m, 2H), 1.34 (t, 3H, J=7.0 Hz).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[C:7]([C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH:16]([OH:19])[CH2:17][CH3:18])[C:3]=1[C:20]([NH:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1)=[O:21].[C:28](O)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[C:28]([O:19][CH:16]([C:4]1[C:3]([C:20]([NH:22][C:23]2[S:24][CH:25]=[CH:26][N:27]=2)=[O:21])=[C:2]([OH:1])[C:11]2[C:6](=[C:7]([C:12]([F:14])([F:13])[F:15])[CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:17][CH3:18])(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(O)c1ccccc1
Reactant: CCC(O)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Product: CCC(OC(=O)c1ccccc1)c1nc2c(C(F)(F)F)cccc2c(O)c1C(=O)Nc1nccs1
Yield: 73.7 %

Procedure:
Using the procedure of Example 15, 5 g of 4-hydroxy-2-(1-hydroxypropyl)-N-(2-thiazolyl)-8-trifluoromethyl-3-quinoline carboxamide and 1.7 g of benzoic acid were reacted to obtain 4.65 g of 2-[1-(benzoyloxy)-propyl]-4-hydroxy-N-(2-thiazolyl)-8-(trifluoromethyl)-3-quinoline carboxamide melting at 230° C.
Reaction SMILES: [CH3:1][CH:2]([CH3:18])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[CH:7]=1)=[O:4].[F:19][C:20]([F:34])([F:33])[C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:28]=1)[CH2:24]Br.C(N(C(C)C)CC)(C)C.N>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl.O1CCOCC1>[F:19][C:20]([F:33])([F:34])[C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:28]=1)[CH2:24][N:15]1[CH2:16][CH2:17][CH:12]([C:8]2[CH:7]=[C:6]([NH:5][C:3](=[O:4])[CH:2]([CH3:18])[CH3:1])[CH:11]=[CH:10][CH:9]=2)[CH2:13][CH2:14]1
Reactant: FC(F)(F)c1cc(CBr)cc(C(F)(F)F)c1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: N
Agent: [I-]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cc(C(F)(F)F)cc(C(F)(F)F)c3)CC2)c1
Yield: 25.8 %

Procedure:
A mixture of 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide (28.3 mg, 0.100 mmol), 3,5-bis(trifluoromethyl)benzyl bromide (38.4 mg, 0.125 mmol), diisopropylethylamine (0.50 mL), catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL). Chromatography using silica preparative TLC plates [2.5% of NH3 (2.0 M in methanol) in CHCl3] gave the desired product (12.2 mg, 25.8% yield) as a thick oil: 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 2H), 7.77 (s, 1H), 7.53 (s, 1H), 7.30-7.21 (m, 2H), 7.16 (s, 1H), 6.98 (apparent d, 1H, J=7.6 Hz), 3.62 (s, 2H), 2.94 (d, 2H, J=9.4 Hz), 2.51 (apparent sept, partially hidden, 2H, J=6.6 Hz), 2.14 (m, 2H), 1.82 (m, 4H), 1.25 (d, 6H, J=6.6 Hz); ESMS m/e: 473.2 (M+H)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@@H:14]2[O:19][C@H:18]([CH3:20])[CH2:17][N:16]([C:21]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]4[C:22]=3[CH:23]=[CH:24][CH:25]=[N:26]4)[CH2:15]2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]1[CH2:12][CH2:11][N:10]([CH2:13][C@H:14]2[CH2:15][N:16]([C:21]3[CH:30]=[CH:29][C:28]([C:31]#[N:32])=[C:27]4[C:22]=3[CH:23]=[CH:24][CH:25]=[N:26]4)[CH2:17][C@@H:18]([CH3:20])[O:19]2)[CH2:9]1
Reactant: C[C@@H]1CN(c2ccc(C#N)c3ncccc23)C[C@H](CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)O1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1CN(c2ccc(C#N)c3ncccc23)C[C@H](CN2CC[C@@H](N)C2)O1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a stirred solution of tert-butyl((R)-1-(((2S,6R)-4-(8-cyanoquinolin-5-yl)-6-methylmorpholin-2-yl)methyl)-pyrrolidin-3-yl)carbamate (1.35 g, 3.0 mmol) in DCM (10 mL) was added TFA (8.1 mL). The reaction was stirred at rt after which time it was concentrated and azeotroped to dryness three times with toluene (10 mL each) and then dried under vacuo to provide crude 5-((2S,6R)-2-(((R)-3-aminopyrrolidin-1-yl)methyl)-6-methylmorpholino)quinoline-8-carbonitrile (1.39 g, 3.0 mmol, 100% yield) as the TFA salt.