Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([Cl:7])(Cl)[C:3](Cl)=[O:4].P(Cl)(Cl)(Cl)=O.[CH2:13]([O:15][CH:16]([CH2:26][CH3:27])[CH2:17][CH2:18][CH2:19][CH2:20][CH:21]1[CH2:25][CH2:24][CH:23]=[CH:22]1)[CH3:14].C(=O)(O)[O-].[Na+]>CCOCC.[Zn].[Cu]>[Cl:1][C:2]1([Cl:7])[CH:24]2[CH:25]([CH:21]([CH2:20][CH2:19][CH2:18][CH2:17][CH:16]([O:15][CH2:13][CH3:14])[CH2:26][CH3:27])[CH2:22][CH2:23]2)[C:3]1=[O:4]
Reactant: CCOC(CC)CCCCC1C=CCC1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Agent: [Cu]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(CC)CCCCC1CCC2C1C(=O)C2(Cl)Cl
Temperature: 25 °C

Procedure:
A solution containing trichloroacetyl chloride (187 g, 1.03 moles) and phosphorous oxychloride (158 g, 1.03 moles), both dissolved in 500 ml ether (1700 ml) is added dropwise to a reaction vessel containing zinc/copper couple (75 g, 1.15 moles), 3-(5-ethoxyheptyl)cyclopentene (170 g, 0.573 moles), and ether (1700 ml). After the addition is complete the reaction is refluxed for 4 hours. The reaction vessel is cooled to room temperature and the mixture neutralized by adding it to a saturated solution of sodium bicarbonate. The solution is filtered, the phases separated, and the aqueous layer is extracted with ether. The organic phases are combined and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is fractionally distilled under vacuum leaving the product as a clear, colorless oil of 7,7-dichloro-4-(5-ethoxyheptyl)bicyclo [3.2.0]heptan 6-one, BP 145° C./0.3 mm.
Reaction SMILES: [OH-].[Na+].CC(O)C.[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:11].[ClH:42]>O>[ClH:42].[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH:35]2[CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:11]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCC2CCN(C)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: CN1CCC(COc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.37 mL) was added to a 2-propanol (1.0 mL) suspension of the obtained methyl 2-(2-hydroxy-5-((1-methylpiperidin-4-yl)methoxy)benzamido)-4-phenylbenzoate (0.070 g), followed by stirring at 50° C. for 1 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then water was added thereto. After adjusting the pH to 6.0 with 1 mol/L hydrochloric acid, the solid substance was collected by filtration. Ethyl acetate (2.0 mL) and a 4 mol/L hydrogen chloride dioxane solution (0.20 mL) were added to the obtained solid substance, followed by stirring at room temperature for 2 hours. The solid substance was collected from the reaction mixture by filtration to obtain 0.058 g of 2-(2-hydroxy-5-(1-methylpiperidin-4-ylmethoxy)benzamido)-4-phenylbenzoic acid hydrochloride as a light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C@@H:5]([OH:9])[C:6]([OH:8])=[O:7].Cl.N[C@@H](C(O)=O)CCCN.[OH-].[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>CC(C)=O.O>[CH2:26]([O:25][C:23]([NH:1][CH2:2][CH2:3][CH2:4][C@@H:5]([OH:9])[C:6]([OH:8])=[O:7])=[O:24])[CH3:27]
Reactant: CCOC(=O)Cl
Reactant: NCCC[C@@H](O)C(=O)O
Agent: Cl
Agent: NCCC[C@@H](N)C(=O)O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)NCCC[C@@H](O)C(=O)O
Reaction time: 1 h

Procedure:
In an amount of 15.3 g of (R)-5-amino-2-hydroxypentanoic acid, which was synthesized from (D)-ornithine hydrochloride according to the method described in YAKUGAKU ZASSHI (Vol 87, (1967), 1184-1188), was dissolved in 150 ml of a mixed solvent of acetone/water (1:1), added dropwise simultaneously with 45.8 ml of 5 N aqueous sodium hydroxide and 11 ml of ethyl chloroformate under ice cooling over 40 minutes, and stirred under the same condition for 1 hour. The reaction system was washed with ethyl acetate, then the aqueous layer was adjusted to pH 1 by slowly adding 10 N hydrochloric acid, and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, and filtered. Then, the filtrate was concentrated under reduced pressure to obtain 24.4 g of crude (R)-5-ethoxycarbonylamino-2-hydroxypentanoic acid. Physicochemical Properties of this Compound
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:11][C:12]([OH:14])=O)[C:6]3[CH2:15][CH2:16][N:17]([CH3:19])[CH2:18][C:5]=3[C:4]=2[CH:3]=1.C(Cl)(=O)C(Cl)=O.[C:26]([N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1)(=[O:28])[CH3:27]>ClCCl.CN(C1C=CN=CC=1)C>[C:26]([N:29]1[CH2:34][CH2:33][N:32]([C:12](=[O:14])[CH2:11][N:7]2[C:8]3[CH:9]=[CH:10][C:2]([Cl:1])=[CH:3][C:4]=3[C:5]3[CH2:18][N:17]([CH3:19])[CH2:16][CH2:15][C:6]2=3)[CH2:31][CH2:30]1)(=[O:28])[CH3:27]
Reactant: CN1CCc2c(c3cc(Cl)ccc3n2CC(=O)O)C1
Reactant: CC(=O)N1CCNCC1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)Cn2c3c(c4cc(Cl)ccc42)CN(C)CC3)CC1
Reaction time: 3 h
Yield: 12 %

Procedure:
A mixture of 2-(8-chloro-1,2,3,4-tetrahydro-2-methylpyrido[4,3-b]indol-5-yl)acetic acid (125 mg, 0.45 mmol) and oxalyl chloride (2 ml) in dichloromethane (6.0 ml) was stirred at 25 deg C. for 3 h. The reaction mixture was concentrated to dryness. The resulting crude was dissolved in dichloromethane (6.0 ml) and DMAP (64 mg, 0.52 mmol) was added followed by addition of acetyl piperazine (56 mg, 0.43 mmol). The resulting mixture was stirred at 25 deg C. for 14 h. The solvent was removed in vacuo and purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 20 mg of 1-(4-Acetyl-piperazin-1-yl)-2-(8-chloro-2-methyl-1,2,3,4-tetrahydro-pyrido[4,3-b]indol-5-yl)-ethanone as trifluoroacetic acid salt.
Reaction SMILES: CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O[C:17]1([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][O:37][C:38]3[C:47]4[C:42](=[CH:43][CH:44]=[CH:45][CH:46]=4)[C:41]4=[N:48][N:49]=[C:50]([C:51]5[CH:55]=[C:54]([CH3:56])[O:53][N:52]=5)[N:40]4[N:39]=3)=[CH:32][N:31]=2)[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]1>ClCCCl>[CH3:56][C:54]1[O:53][N:52]=[C:51]([C:50]2[N:40]3[N:39]=[C:38]([O:37][CH2:36][C:33]4[CH:34]=[CH:35][C:30]([C:17]5[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH:18]=5)=[N:31][CH:32]=4)[C:47]4[C:42]([C:41]3=[N:48][N:49]=2)=[CH:43][CH:44]=[CH:45][CH:46]=4)[CH:55]=1
Reactant: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5(O)CCN(C(=O)OC(C)(C)C)CC5)nc4)nn23)no1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCCl
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4ccc(C5=CCN(C(=O)OC(C)(C)C)CC5)nc4)nn23)no1
Temperature: 25 °C
Yield: 99.7 %

Procedure:
Burgess reagent (262 mg, 1.1 mmol) was added to a stirred solution of 1,1-dimethylethyl 4-hydroxy-4-[5-({[3-(5-methylisoxazol-3-yl)[1,2,4]triazolo[3,4-α]phthalazin-6-yl]oxy}methyl)pyridin-2-yl]-1-piperidine carboxylate (307 mg, 0.55 mmol) in 1,2-dichloroethane (20 ml) at room temperature under N2 and the reaction heated at reflux for 90 min. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure while dry loading onto silica. The residue was purified by column chromatography on silica using 2% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (296 mg, 99%). 1H NMR (360 MHz, CDCl3) δ 8.86 (1H, s), 8.66 (1H, d, J=8.0 Hz), 8.20 (1H, d, J=8.0 Hz), 8.05-8.00 (1H, m), 7.95 (1H, t, J=8.0 Hz), 7.79 (1H, t, J=8.0 Hz), 7.43 (1H, d, J=8.1 Hz), 6.85 (1H, s), 6.66 (1H, m), 5.67 (2H, s), 4.17-4.11 (2H, m), 3.67-3.58 (2H, m), 2.68-2.60 (2H, m), 2.59 (3H, s), 1.49 (9H, s). m/z (ES+) 540 (M+H+).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:16]=[CH:15][C:7]([O:8][CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1.[C:19]1(=O)[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1.C(N(CC)CC)C.[C:34]1([CH3:44])[CH:39]=[CH:38][C:37]([S:40]([OH:43])(=[O:42])=[O:41])=[CH:36][CH:35]=1>C(O)C>[C:34]1([CH3:44])[CH:35]=[CH:36][C:37]([S:40]([OH:43])(=[O:41])=[O:42])=[CH:38][CH:39]=1.[OH:25][C:22]1[CH:23]=[CH:24][C:19]([N:12]2[CH2:11][CH2:10][CH:9]([O:8][C:7]3[CH:15]=[CH:16][C:4]([O:3][C:2]([F:1])([F:17])[F:18])=[CH:5][CH:6]=3)[CH2:14][CH2:13]2)=[CH:20][CH:21]=1
Reactant: FC(F)(F)Oc1ccc(OC2CCNCC2)cc1
Reactant: O=C1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: Oc1ccc(N2CCC(Oc3ccc(OC(F)(F)F)cc3)CC2)cc1

Procedure:
100 mg of 4-(4-trifluoromethoxyphenoxy)piperidine, 64 mg of 1,4-cyclohexanedione and 0.02 ml of triethylamine were heated in 15 ml of ethanol and reacted at 50° C. to 60° C. for 6 hours. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure and ethyl acetate was added thereto to prepare an ethyl acetate solution, to which p-toluenesulfonic acid was added. After leaving at room temperature for 30 minutes, the precipitate was filtrated and washed with ethyl acetate. The obtained crystal was air-dried and 139 mg of 1-(4-hydroxyphenyl)-4-(4-trifluoromethoxyphenoxy)piperidine p-toluenesulfonate was obtained.
Reaction SMILES: [O:1]=[C:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][C:13]([OH:15])=O.[NH2:16][C:17]1[S:18][CH:19]=[C:20]([CH3:26])[C:21]=1[C:22]([O:24][CH3:25])=[O:23]>>[CH3:26][C:20]1[C:21]([C:22]([O:24][CH3:25])=[O:23])=[C:17]([NH:16][C:13](=[O:15])[CH2:12][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[CH2:10][CH2:11][C:2]2=[O:1])[S:18][CH:19]=1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Reactant: COC(=O)c1c(C)csc1N
Product: COC(=O)c1c(C)csc1NC(=O)CN1C(=O)CCc2ccccc21

Procedure:
The title compound was prepared from 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid (0.43 g, 2.09 mmol) and methyl 2-amino-4-methylthiophene-3-carboxylate (0.358 g, 2.09 mmol) according to protocol B. Retention time (min)=6.895, method [7], MS (ESI) 359.1 (M+H).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10](=[N:23][NH2:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: NN
Reactant: CN(C)S(=O)(=O)Nc1cccc(C(=O)c2ccccc2)c1
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)Nc1cccc(C(=NN)c2ccccc2)c1
Yield: 109 %

Procedure:
A solution of 3-[N-(dimethylaminosulfonyl)amino]-benzophenone (200 mg) and hydrazine hydrate (100 mg) in ethanol (4 ml) is refluxed for 17.5 hours. The reaction mixture is concentrated in vacuum and the residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 3% methanol and methylene chloride. The eluate is concentrated in vacuum to give 3-[N-(dimethylaminosulfonyl)-amino]benzophenone hydrazone(228 mg) as an oil.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[N:3]1[CH:8]=[CH:7][CH:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])[CH:5]=[CH:4]1.[C:15](#[N:18])[CH:16]=[CH2:17]>>[CH3:1][Si:2]([CH3:14])([CH3:13])[N:3]1[CH:4]=[CH:5][C:6]([Si:9]([CH3:12])([CH3:11])[CH3:10])=[CH:7][CH:8]1[CH:16]([C:15]#[N:18])[CH3:17]
Reactant: C[Si](C)(C)C1C=CN([Si](C)(C)C)C=C1
Reactant: C=CC#N
Product: CC(C#N)C1C=C([Si](C)(C)C)C=CN1[Si](C)(C)C
Temperature: 25 °C
Yield: 71.4 %

Procedure:
To 22.6 g (0.1 mol) of 1,4-bis-(trimethylsilyl)-1,4-dihydropyridine are added by drops 5.31 g (0.1 mol) of acrylonitrile within 30 minutes in an inert atmosphere. The mixture is subsequently stirred for several hours at room temperature. Fractional distillation yields 19.9 g (72%) of 1,4-bis-(trimethylsilyl)-2-(1-cyanoethyl)-1,2-dihydropyridine; b.p. 78°C/0.003 mm; yellow oil.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Br:8][C:9]1[N:14]=[N:13][C:12]([NH2:15])=[CH:11][CH:10]=1>N1C=CC=CC=1.O>[Br:8][C:9]1[N:14]=[N:13][C:12]([NH:15][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[CH:11][CH:10]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1ccc(Br)nn1
Solvent: O
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1ccc(Br)nn1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Pivaloyl chloride (2.85 ml, 23.2 mmol) was added dropwise to a solution of 6-bromopyridazin-3-amine (2.00 g, 15.4 mmol) in pyridine (8 mL). The mixture stirred 12 h at room temperature, then was diluted with water and extracted with dichloromethane (3×). The combined organic layers were washed with water (2×) and brine, then dried (sodium sulfate), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (2−>20% EtOAc:Hex) to give title compound.
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[C:14]([Cl:22])[CH:13]=1)[CH2:5][CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1.[OH-].[K+]>C(O)C.O>[Cl:22][C:14]1[CH:13]=[C:12]([CH:4]([CH2:5][CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[C:3]([OH:23])=[O:2])[CH:17]=[CH:16][C:15]=1[S:18]([CH3:21])(=[O:19])=[O:20]
Reactant: COC(=O)C(CC1CCOCC1)c1ccc(S(C)(=O)=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CS(=O)(=O)c1ccc(C(CC2CCOCC2)C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 90.9 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid methyl ester (190 mg, 0.53 mmol) in ethanol (10 mL) was treated with a solution of potassium hydroxide (174 mg, 2.64 mmol) in water (4 mL). The reaction was stirred at 25° C. for 2.5 h. The reaction was then concentrated in vacuo to remove the ethanol and then acidified to pH=2 with a 1N aqueous hydrochloric acid solution. The resulting solution was then extracted with methylene chloride 3×10 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 2-(3-chloro-4-methanesulfonyl-phenyl)-3-(tetrahydro-pyran-4-yl)-propionic acid (167 mg, 92%) as a white foam: (ES)+-HRMS m/e calcd for C15H19ClO5S (M+Na)+ 369.0534. found 369.0536.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]1>CN1CCCC1=O>[CH3:8][C:6]1[CH:7]=[C:2]([N:18]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19]2)[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: OC1CCNC1
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: Cc1cc(N2CCC(O)C2)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h
Yield: 100 %

Procedure:
In a three necked flask, 38.78 g of 5-fluoro-2-nitrotoluene (0.25 mol), 41.4 g of potassium carbonate (0.3 mol) and 200 ml of N-methylpyrrolidinone were mixed. 26.13 g of 3-pyrrolidinol (0.3 mol) were added to this mixture. The heterogeneous mixture was agitated at ambient temperature for 12 hours. The reacting mixture was then poured on ice water. A yellow powder was then obtained. The powder was then filtered off and rinsed with water. After drying under vacuum with P2O5, 55.56 g of a yellow solid were obtained (yield) (95%).
Reaction SMILES: [F:1][CH:2]([F:26])[C:3]1[NH:4][C:5]([CH:23]([F:25])[F:24])=[C:6]([C:21]#[N:22])[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:8]=1[C:9]#[N:10].C(=O)([O-])O.[OH:31][CH2:32][CH2:33][N+:34]([CH3:37])([CH3:36])[CH3:35].C1COCC1>C(O)C>[C:9]([C:8]1[CH:7]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[C:14]3[CH3:20])[C:6]([C:21]#[N:22])=[C:5]([CH:23]([F:24])[F:25])[N-:4][C:3]=1[CH:2]([F:1])[F:26])#[N:10].[OH:31][CH2:32][CH2:33][N+:34]([CH3:37])([CH3:36])[CH3:35]
Reactant: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)NC(C(F)F)=C3C#N)cc12
Agent: C[N+](C)(C)CCO
Agent: O=C([O-])O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1n[nH]c2ccc(C3C(C#N)=C(C(F)F)[N-]C(C(F)F)=C3C#N)cc12

Procedure:
To a suspension of 80 mg (0.22 mmol) 2,6-bis(difluoromethyl)-4-(3-methyl-1H-indazol-5-yl)-1,4-dihydropyridine-3,5-dicarbonitrile (Example 13) in ethanol (1.52 ml) under argon atmosphere was added 31 μl (0.22 mmol) 2-hydroxy-N,N,N-trimethylethanaminium hydrogencarbonate solution (choline bicarbonate, 80% in water), and the mixture was stirred at reflux temperature for 1 h. Subsequently, a weak argon stream was led over the solution mixture. The crude product was treated with THF (1.5 ml) and stirred for 2 days under argon. The resulting precipitate was collected by centrifugation and dried in vacuo to yield 57 mg (54% of th.) of the title compound as a yellow solid.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH3:21])[CH:12]=3)[CH2:7][CH2:6]2)[O:4]CC1>C(O)(=O)C.O>[CH3:21][C:13]1[CH:12]=[C:11]([CH:8]2[CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1ccc(C2CCC3(CC2)OCCO3)cc1C
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C2CCC(=O)CC2)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of the title compound from Example 13 Step C (610 mg, 2.10 mmol) in acetic acid (7.8 mL) and water (2.6 mL) was stirred at 80° C. After 2 h, the mixture was allowed to cool to ambient temperature, then was concentrated in vacuo. The resulting oil was diluted with ether, then was washed successively with water, saturated aqueous sodium bicarbonate, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 50% EtOAc in hexanes, then 50 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 215.4 [M−CH3O]+; 1H NMR (500 MHz, CDCl3) δ 7.88 (d, J=8.5 Hz, 1H), 7.14-7.10°(m, 2H), 3.88 (s, 3H), 3.05-3.00 (m, 1H), 2.59 (s, 3H), 2.51 (app dd, J=8.5, 4.0 Hz, 4H), 2.24-2.20 (m, 2H), 1.97-1.92 (m, 2H).
Reaction SMILES: [C:1]1(=[O:7])[NH:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([Li])[CH2:9][CH2:10]C.BrCCC.O>O1CCCC1.CCCCCC>[CH2:8]([CH:2]1[CH2:3][CH2:4][CH2:5][NH:6][C:1]1=[O:7])[CH2:9][CH3:10]
Reactant: O=C1CCCCN1
Reactant: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCC1CCCNC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To delta-valerolactam (10 g) dissolved in 80 ml of dry tetrahydrofuran, under a dry nitrogen atmosphere was deopwise added n-butyllithium (1.6M, 125 ml) in hexane while the reaction mixture was chilled in a dry ice-acetone bath. After all the n-butyllithium was added, the reaction mixture was stirred at room temperature for one hour, refluxed for thirty minutes, and cooled to room temperature. 1-Bromopropane (12.3 g) was slowly added to the reaction mixture while the mixture was chilled in an ice bath. The reaction mixture was then stirred for sixteen hours at room temperature. 100 ml of water was added slowly to the reaction mixture and the resulting mixture was stirred at room temperature for thirty minutes. The layers separated and the aqueous layers were combined, dried over sodium sulfate, and then evaporated to yield 12.4 g (88% yield) of a dark, heavy oil, which crystallized on standing. The crystals were recrystallized from petroleum ether to yield 5.4 g of α-propylvalerolactam (m.p. 75°-76° C.). A portion of the α-propylvalerolactam (2.8 g) was refluxed in 25 ml of 6N hydrochloric acid under a nitrogen atmosphere for six hours. The water was evaporated to yield 2-propyl-5-amino-pentanoic acid (2.0 g; 51% yield) and recrystallized from ethanol-petroleum ether to yield a solid (m.p. 71°-73° C.). Equimolar amounts of 2-propyl-5-amino-pentanoic acid and 5-[(4,6-dichlorotriazin-2-yl)-amino]fluorescein were dissolved in methanol. The reaction was completed in about ten minutes to yield a crude product which was purified by silica gel thin-layer chromatography with chloroform/methanol (3:1) as the developing solvent to yield a 2-propyl-5-amino-pentanoic acid-DTAF conjugate of the formula: ##STR11##
Reaction SMILES: CN1CCOCC1.[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([OH:20])=O)[CH:13]=[CH:14][CH:15]=1)#[N:9].[N:27]1([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.Cl.CN(C)CCCN=C=NCC.O.OC1C2N=NNC=2C=CC=1>CN(C=O)C.O>[C:8]([C:10]1[CH:11]=[C:12]([NH:16][CH:17]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:18]([NH:37][C:36]2[CH:35]=[CH:34][C:33]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:39][CH:38]=2)=[O:20])[CH:13]=[CH:14][CH:15]=1)#[N:9]
Reactant: N#Cc1cccc(NC(C(=O)O)c2ccccc2)c1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: O
Solvent: CN1CCOCC1
Product: N#Cc1cccc(NC(C(=O)Nc2ccc(N3CCOCC3)cc2)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
87 μl (0.793 mmol) of 4-methylmorpholine are added to a solution of 200 mg (0.793 mmol) of (3-cyanophenylamino)-2-phenylacetic acid, 141 mg (0.793 mmol) of 4-morpholin-4-ylaniline, 152 mg (0.793 mmol) of N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (DAPECI) and 121 mg (0.793 mmol) of hydroxybenzotriazole hydrate (HOBt) in 3 ml of DMF, and the mixture is stirred at room temperature for 48 hours. The reaction mixture is introduced into water, and the precipitate is filtered off, giving 2-(3-cyanophenylamino)-N-(4-morpholin-4-ylphenyl)-2-phenylacetamide as a colourless solid; ESI 413.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:9]#[N:10])=[N:6][C:7]=1[CH3:8].O.NN.BrC1C=CC([C:22](=[NH:25])[NH:23]N)=NC=1C.C(O)=O>C(O)C.CO>[Br:1][C:2]1[C:7]([CH3:8])=[N:6][C:5]([C:9]2[N:25]=[CH:22][NH:23][N:10]=2)=[CH:4][CH:3]=1
Reactant: Cc1nc(C#N)ccc1Br
Reactant: Cc1nc(C(=N)NN)ccc1Br
Agent: NN
Solvent: CO
Solvent: O=CO
Solvent: CCO
Product: Cc1nc(-c2nc[nH]n2)ccc1Br
Temperature: 55 °C
Reaction time: 6 h

Procedure:
5-Bromo-6-methylpicolinamide (1 g, 4.65 mmol) and N,N-dimethylformamide dimethylacetal (20 mL) were combined in a 100 mL round-bottom flask with a stir bar and heated at 85° C. under a reflux condenser under nitrogen for 3 h. The resulting mixture was concentrated under reduced pressure and dried under vacuum to give yellow oil, which was used in the next step without purification. The residue was diluted with acetic acid (10 mL) and hydrazine (2.5 mL, 70.3 mmol) was added drop-wise and allowed to stir at room temperature for 5 h. The reaction mixture was poured into ice water. The resulting solid was filtered, washed with water and dried to give the desired product as a white solid. The aqueous filtrate was extracted with dichloromethane. The organic layer was concentrated under reduced pressure nearly to dryness to yield additional material. Combination of two batches gave the desired product (0.7 g, 2.9 mmol, 63% yield). MS (ESI) m/z 241.1 [M+2]+. Alternate approach: 5-Bromo-6-methylpicolinonitrile (1 equiv) and hydrazine monohydrate (2.0 equiv) were combined in absolute ethanol (4×vol) and heated to 55° C. for 24 h. The slurry was cooled to room temperature and filtered. The collected solids were washed with ethanol and methyl tent-butyl ether, and the solids were dried to deliver 5-bromo-6-methylpicolinimidohydrazide as a beige powder. 5-Bromo-6-methylpicolinimidohydrazide and formic acid (15 equiv) were combined and heated to 100° C. with stirring for 6 h. The reaction solution was cooled to 40° C., treated with methanol, stirred for 30 min and concentrated under reduced pressure to 20% of the reaction volume. The mixture was diluted with methanol and again concentrated under reduced pressure to 20% of the reaction volume. The resulting solids were filtered, washed with water, and dried to give the title compound as an off-white powder.