Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][CH3:6])=[O:4].C[S:8][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=S>C(#N)C>[CH3:6][NH:5][C:3](=[O:4])[CH2:2][NH:1][C:9]([C:11]1[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=1)=[S:8]
Reactant: CNC(=O)CN
Reactant: CSC(=S)c1cccnc1
Solvent: CC#N
Product: CNC(=O)CNC(=S)c1cccnc1
Temperature: 47.5 °C
Reaction time: 0.33 h
Yield: 70.9 %

Procedure:
A 5 liter three-necked round bottom flask was fitted with a nitrogen inlet over a dropping funnel, a mechanical stirrer, and a reflux condenser. A tube from the top of the condenser was plumbed through a 1 liter bump flask and then into a sparge tube in another 5 liter three-neck stirred flask filled with 2.5 liter of 12% pool bleach. The outlet of the bleach flask was plumbed through an alligator trap with about 250 mL of 12% bleach solution. The reactor was charged with 2-amino-N-methylacetamide (160 g, 1.81 mol) and acetonitrile (3 L) to give a cloudy solution. The dropping funnel was charged with methylpyridine-3-carbodithioate (307 g, 1.81 mol) and acetonitrile (200 mL). The addition of the dithioate took about 20 min and the reaction was swept with a good stream of nitrogen. A slight exotherm was noted upon the addition (about 3° C.). After the addition was complete, the dropping funnel was rinsed with 550 mL of acetonitrile to bring the total volume of acetonitrile to 3750 mL. After stirring for about 10 min, the red solution precipitated to give a cottage cheese-like solid which would not stir. The dropping funnel was replaced with a ¼ inch straight tube to bubble nitrogen into the reactor. The reactor was heated slowly to about 45-50° C. to form a reddish solution and then allowed to cool back down slowly to room temperature and crystallize to a fine yellowish needle-like solid which stirred easily. The needles were collected by vacuum filtration and washed with 100 mL of acetonitrile. The solid was dried under vacuum at 40° C. for 16 h to give N-methyl-2-(pyridine-3-carbothioamido)acetamide (268.6 g, 71%) as a light yellow solid: mp 135-137° C.; 1H NMR (400 MHz, DMSO-d6) δ 10.65 (s, 1H), 8.95 (dd, J=2.4, 0.7 Hz, 1H), 8.67 (dd, J=4.8, 1.6 Hz, 1H), 8.14 (ddd, J=8.0, 2.3, 1.7 Hz, 1H), 7.95 (d, J=4.3 Hz, 1H), 7.48 (ddd, J=7.9, 4.8, 0.7 Hz, 1H), 4.34 (s, 2H), 2.62 (d, J=4.6 Hz, 3H); 13C NMR (101 MHz, DMSO-d6) δ 194.98, 165.77, 150.37, 146.40, 135.25, 134.04, 121.51, 47.66, 24.41; Anal. Calcd. for C9H11N3OS: C, 51.65; H, 5.30; N, 20.08; S, 15.32. Found: C, 51.47: H, 5.30; N, 20.01; S, 15.53.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][OH:39])[CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:41])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:42]([NH:49][C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1CCC(N=C=NC2CCCCC2)CC1.CO.C(Cl)Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:45]([O:44][C:42]([NH:49][C@@H:50]([CH:51]([CH3:53])[CH3:52])[C:54]([O:39][CH2:38][C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:27]2[CH:26]=[N:25][C:24]([C:22]3[S:23][C:16]4[C:17](=[N:18][CH:19]=[CH:20][C:15]=4[O:14][C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[CH:9][C:10]=4[F:41])[CH:21]=3)=[CH:29][CH:28]=2)[CH2:36][CH2:35]1)=[O:40])=[O:55])=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(C(=O)CO)CC5)cn4)sc23)c(F)c1)NC1CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
To a stirred solution of 74 (117 mg, 0.20 mmol), Boc-L-valine (132 mg, 0.61 mmol) and DMAP (25 mg, 0.20 mmol) in anhydrous DMF (4 ml) under nitrogen was added DCC reagent (251 mg, 1.22 mmol), and the reaction mixture was stirred at rt for 24 h. The reaction mixture was partitioned between AcOEt and a saturated aqueous solution of sodium bicarbonate. After separation, the organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 25 g cartridge; MeOH/DCM: 1/99 to 10/90 over 20 CV, then 10/90 over 5 CV), to afford the desired product 74-A (151 mg, 0.195 mmol, 96% yield) as a colorless-white sticky foam. MS (m/z): 776.7 (M+H).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]=1.[NH2:12][C:13]1[CH:31]=[CH:30][CH:29]=[CH:28][C:14]=1[C:15]([NH:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:20][CH:19]=1)=[O:16].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.[Li]N([Si](C)(C)C)[Si](C)(C)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:28]=[CH:29][CH:30]=[CH:31][C:13]=2[NH:12][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][N:6]=[CH:7][CH:8]=3)[N:3]=2)=[CH:19][CH:20]=1)([CH3:27])([CH3:25])[CH3:26]
Reactant: Clc1ccc2ccncc2n1
Reactant: CC(C)(C)c1ccc(NC(=O)c2ccccc2N)cc1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(NC(=O)c2ccccc2Nc2ccc3ccncc3n2)cc1
Temperature: 70 °C
Reaction time: 24 h

Procedure:
2-Chloro-[1,7]naphthyridine (100 mg, 0.61 mmol), 2-amino-N-(4-tert-butyl-phenyl)-benzamide (164 mg, 0.61 mmol), Pd2(dba)3 (6 mg, 0.006 mmol), (2′-Dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (6 mg, 0.015 mmol), and 1M solution of LiN(TMS)2 in THF (1.83 mL), 1.83 mmol) were added to a reaction vessel. The vessel was sealed and the reaction was stirred at 70° C. for 24 h. The mixture was cooled to RT, and solvent was removed under vacuum. The crude was purified by flash column chromatography (gradiant, 0 to 100% EtoAC/Hexane) to give the product as tan solid. MS (ES−): 397.0 (M+H)+. Calc'd for C25H24N4O—396.20.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[C:3]=1[C:4]#[N:5].O=[C:18]([CH3:25])[CH2:19][C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH2:11][CH:12]([CH2:15][CH3:16])[CH2:13][CH3:14])[N:1]=[C:18]([CH3:25])[C:19]=1[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCC(CC)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(CC)CC)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(2-ethylbutoxy)benzonitrile (Example 22b) and ethyl 3-oxobutanoate as a white solid (89%). 1H NR (400 MHz, DMSO-d6) δ 0.90 (t, J=8 Hz, 6H), 1.32 (t, J=8 Hz, 3H), 1.48-1.41 (m, 4H), 1.79-1.73 (m, 1H), 2.54 (s, 3H), 4.08 (d, J=4 Hz, 2H), 4.31 (q, J=8 Hz, 2H), 6.92 (dd, J=2, 8 Hz, 1H), 7.23 (dd, J=2, 8 Hz, 1H), 7.50 (t, J=8 Hz, 1H), 8.04 (brs, 1H). MS 331 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[NH:13][C@@H:12]([C@@H:14]([OH:16])[CH3:15])[CH2:11][O:10][CH2:9]2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:23](Cl)(=[O:27])[C:24](Cl)=[O:25]>ClCCl.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:9][O:10][CH2:11][C@@H:12]3[C@H:14]([CH3:15])[O:16][C:23](=[O:27])[C:24](=[O:25])[N:13]23)=[CH:6][CH:7]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: C[C@H](O)[C@H]1COC[C@@H](c2ccc(Cl)cc2)N1
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: C[C@@H]1OC(=O)C(=O)N2[C@@H]1COC[C@H]2c1ccc(Cl)cc1
Reaction time: 1 h

Procedure:
To a solution consisting of (S)-1-[(3R,5R)-5-(4-chlorophenyl)morpholine-3-yl]ethanol (833 g) and pyridine (4 mL) in dichloromethane (15 mL) was dropwise added oxalyl chloride (833 μL) while cooling with ice. The resultant solution was stirred at the same temperature for 30 minutes, and then at room temperature for 1 hour. The reaction solution was diluted with water, and the organic layer was partitioned. The organic layer was then dried over anhydrous magnesium sulfate. Solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography (heptane/ethyl acetate→ethyl acetate), to thereby obtain the titled compound (686 mg). The physical properties of the compound were as follows. ESI-MS; m/z 296 [M++H]. 1H-NMR (CDCl3) δ (ppm): 1.51 (d, J=6.4 Hz, 3H), 3.52 (dd, J=12.0, 12.0 Hz, 1H), 3.78 (dd, J=12.4, 8.0 Hz, 1H), 4.02 (dd, J=11.6, 4.4 Hz, 1H), 4.18 (dd, J=12.4, 4.8 Hz, 1H), 4.51 (ddd, J=11.2, 4.0, 4.0 Hz, 1H), 4.61-4.67 (m, 1H), 4.89 (dd, J=8.0, 4.8 Hz, 1H), 7.32 (s, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:15])[CH2:9][CH2:10][CH2:11][C:12]([OH:14])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC(C)C)=O.[NH2:31][C:32]1[N:64]=[C:35]2[C:36]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:63])([F:62])[F:61])[CH:55]=3)=[C:37]([CH3:53])[C:38]([C:40]3[N:44]([C:45]4[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=4)[N:43]=[CH:42][CH:41]=3)=[CH:39][N:34]2[N:33]=1.C(OC(N(C)CCCC(OC(OCC(C)C)=O)=O)=O)(C)(C)C>C1COCC1>[C:1]([O:5][C:6](=[O:7])[N:8]([CH2:9][CH2:10][CH2:11][C:12](=[O:14])[NH:31][C:32]1[N:64]=[C:35]2[C:36]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([C:60]([F:62])([F:63])[F:61])[CH:55]=3)=[C:37]([CH3:53])[C:38]([C:40]3[N:44]([C:45]4[CH:52]=[CH:51][C:48]([C:49]#[N:50])=[CH:47][CH:46]=4)[N:43]=[CH:42][CH:41]=3)=[CH:39][N:34]2[N:33]=1)[CH3:15])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(N)nc2c1-c1cccc(C(F)(F)F)c1
Reactant: CN(CCCC(=O)O)C(=O)OC(C)(C)C
Agent: CC(C)COC(=O)Cl
Agent: CC(C)COC(=O)OC(=O)CCCN(C)C(=O)OC(C)(C)C
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cn2nc(NC(=O)CCCN(C)C(=O)OC(C)(C)C)nc2c1-c1cccc(C(F)(F)F)c1
Temperature: -22 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (109 mg, 0.50 mmol) in THF (5 mL) was treated with 4-methyl-morpholine (101 mg, 1.0 mmol) followed by isobutyl chloroformate (68 mg, 0.5 mmol) and cooled to −22° C. under argon. The reaction mixture was stirred for 20 mins while warming to −15° C. After re-cooling to −24° C., 4-{5-[2-amino-7-methyl-8-(3-trifluoromethyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-pyrazol-1-yl}-benzonitrile (Ex. 1, 230 mg, 0.50 mmol) was added and the resulting suspension was slowly warmed to RT and stirred for 16 hrs. The reaction mixture was treated with a fresh batch of 1-({[(4-{[(tert-butoxy)carbonyl] (methyl)-amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (218 mg, 1.0 mmol) in THF (5 mL), 4-methyl-morpholine (101 mg, 1.0 mmol) and isobutyl chloroformate (137 mg, 1.0 mmol) at RT. The reaction mixture was stirred at RT for 24 hrs and then heated at 60° C. for 7 hrs. After standing at RT for 18 hrs, the volatiles were removed in vacuo and the resulting residue was purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM. The product containing fractions were concentrated in vacuo and the resulting residue (456 mg, 0.5 mmol) in THF (5 mL) was treated with a fresh batch of 1-({[(4-{[(tert-butoxy)carbonyl] (methyl)amino}butanoyl)oxy]carbonyl}oxy)-2-methylpropane prepared from a solution of 4-(tert-butoxycarbonyl-methyl-amino)-butyric acid (1.09 g, 5.0 mmol) in THF (20 mL), 4-methyl-morpholine (760 mg, 7.55 mmol) and isobutyl chloroformate (680 mg, 5.01 mmol) at RT. The resulting mixture was heated at 50° C. for 65 hrs and then purified by flash chromatography eluting with a gradient of 0-100% EtOAc in DCM followed by 10% MeOH in DCM affording the title compound (241 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22]>>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:22]
Reactant: O=C(Cl)c1ccccc1F
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccccc4F)cc3c2C1
Yield: 71.8 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 5.4 mg (0.051 mMol) 2-fluorobenzoyl chloride, 11.6 mg (74%) of the title compound were recovered as a beige solid.
Reaction SMILES: [C:1]1([CH2:7][CH:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(C1C=CC=CC=1)(=O)C.C(=O)C1C=CC=CC=1.[H][H]>[Ni].[Mo].C1(C)C=CC=CC=1>[CH:4]1[CH:5]=[CH:6][C:1]([CH2:7][CH2:8][OH:9])=[CH:2][CH:3]=1
Reactant: [H][H]
Reactant: O=CCc1ccccc1
Agent: [Mo]
Agent: [Ni]
Solvent: CC(=O)c1ccccc1
Solvent: O=Cc1ccccc1
Solvent: Cc1ccccc1
Product: OCCc1ccccc1

Procedure:
The toluene layers (about 4.7 l) were collected and the toluene was evaporated under reduced pressure. The residual liquid was fed to a fractionating column under reduced pressure. Thus, the remaining toluene was at first evaporated, then styrene (35 g) was recovered at 35° C./10 mmHg and fractional distillation was further conducted at 100° to 110° C. (bath temperature) to obtain a distillate (73 g) boiling at 45° to 50° C./2 mmHg. This distillate was found to be a mixture of phenylacetaldehyde (78 wt.%), acetophenone (19 wt.%) and benzaldehyde (3 wt.%) according to gas chromatographic analysis. The thus obtained mixture, 100 ml of toluene and 5 g of Raney nickel catalyst modified with molybdenum (Mo/Ni=6/94 atomic ratio) were fed into an autoclave of 500 ml capacity equipped with a magnetic stirrer, and hydrogenation was carried out at room temperature under 500 atm. of hydrogen pressure for 20 hours. After the reaction, the catalyst was filtered off from the reaction mixture. The filtrate was evaporated to remove the toluene by a rotary evaporator. The remaining liquid was subjected to fractional distillation under reduced pressure of 10 mmHg, whereby benzyl alcohol (1.8 g) boiling at 75° C./10 mmHg, α-phenethyl alcohol (13.1 g) boiling at 87° C./10 mmHg and β-phenethyl alcohol (53.8 g) boiling at 97° C./10 mmHg were obtained. Thus-obtained β-phenethyl alcohol had a refraction index nD20 =1.533 and no halogen according to halogen-detective test and showed no other peaks on the gas chromatogram.
Reaction SMILES: O=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1.[C:12]([CH2:14][C:15]([O:17][CH3:18])=[O:16])#[N:13]>N1CCCCC1.C(O)(=O)C.C(O)C>[C:12]([C:14](=[CH:2][C:3]1[CH:11]=[CH:10][C:8]([OH:9])=[C:5]([O:6][CH3:7])[CH:4]=1)[C:15]([O:17][CH3:18])=[O:16])#[N:13]
Reactant: COC(=O)CC#N
Reactant: COc1cc(C=O)ccc1O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: COC(=O)C(C#N)=Cc1ccc(O)c(OC)c1

Procedure:
A mixture of vanillin (7.60 g, 0.05 mol), methyl cyanoacetate (4.95 g, 0.05 mol), ethanol (50 mL), piperidine (12 drops) and acetic acid (6 drops) is heated at reflux for 3 hours with stirring and then cooled. The pale yellow product crystallizes and additional ethanol (25 mL) is added to promote stirring and 5% HCl (10 mL) is added to neutralize any phenol salt present. The product, methyl 2-cyano-3-(4-hydroxy-3-methoxyphenyl)-2-propenoate, is collected by filtration, washed with ethanol and dried in air. A yield of 9.4 g (80.6%) is obtained. The identity of the product is supported by mass spectroscopy analysis and is shown below as compound I. ##STR16##
Reaction SMILES: [C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])(=[O:3])[CH3:2].CO[C:29](OC)([N:31]([CH3:33])[CH3:32])[CH3:30]>CN(C)C(=O)C>[CH3:32][N:31]([CH3:33])/[C:29](/[CH3:30])=[CH:2]/[C:1]([C:4]1[S:8][C:7]([N:9]2[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:24])[F:23])=[CH:17][CH:16]=3)[C:10]2=[O:25])=[N:6][C:5]=1[CH3:26])=[O:3]
Reactant: COC(C)(OC)N(C)C
Reactant: CC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C
Solvent: CC(=O)N(C)C
Product: C/C(=C\C(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)nc1C)N(C)C
Temperature: 110 °C
Yield: 90 %

Procedure:
To a solution of 1-(5-acetyl-4-methylthiazol-2-yl)-3-(4-(trifluoromethyl)benzyl)-imidazolidin-2-one (1.00 g, 2.60 mmol) in N,N-dimethylacetamide (10 mL) was added N,N-dimethylacetamide dimethyl acetal (1.0 mL, 6.15 mmol). The reaction mixture was heated for 20 hours at 110° C. The solvent was removed in vacuo, and the residue was washed with water to afford the title compound as a colorless solid in 90% yield (1.07 g): 1H NMR (300 MHz, DMSO-d6) δ 7.70 (d, J=8.1 Hz, 2H), 7.60 (d, J=8.1 Hz, 2H), 5.23 (s, 1H), 4.49 (s, 2H), 3.99-3.91 (m, 2H), 3.48-3.40 (m, 2H), 2.98 (s, 6H), 2.49-2.43 (m, 6H); MS (ES+) m/z 453.1 (M+1).
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[NH+]1C=CC=[CH:12][CH:11]=1.[NH+]1C=CC=CC=1.[F:22][C:23]([F:46])([F:45])[S:24]([O:27][C:28]1[C:29]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[N:30][C:31]([O:34][CH2:35][CH2:36][OH:37])=[CH:32][CH:33]=1)(=[O:26])=[O:25].C([Mg]Br)=C.[Cl-].[NH4+]>C(OCC)C.O1CCCC1.ClCCl>[F:46][C:23]([F:22])([F:45])[S:24]([O:27][C:28]1[C:29]([CH2:38][C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)=[N:30][C:31]([O:34][CH2:35][CH:36]([OH:37])[CH:11]=[CH2:12])=[CH:32][CH:33]=1)(=[O:25])=[O:26]
Reactant: O=S(=O)(Oc1ccc(OCCO)nc1Cc1ccccc1)C(F)(F)F
Reactant: c1cc[nH+]cc1
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: C=C[Mg]Br
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCOCC
Product: C=CC(O)COc1ccc(OS(=O)(=O)C(F)(F)F)c(Cc2ccccc2)n1
Reaction time: 3 h
Yield: 11 %

Procedure:
473 mg of pyridinium dichromate was added to a mixture of 395 mg of 2-benzyl-6-(2-hydroxyethyl)oxy-3-pyridyl trifluoromethanesulfonate, 1.4 g of molecular sieves 4A and 5 ml of dichloromethane at room temperature, followed by stirring for 3 hours. The mixture was filtered through Celite, and the solvent was removed. 236 μl of a tetrahydrofuran solution containing 1.1 mol of vinylmagnesium bromide was added to a solution of 5 ml of diethyl ether containing the residue at 0° C., followed by stirring at the same temperature for 40 minutes. An aqueous saturated ammonium chloride solution and diethyl ether were added to the reaction solution, and the organic phase was washed with water and brine, dried over anhydrous magnesium sulfate and the solvent was removed. The residue was subjected to silica gel column chromatography using 30% ethyl acetate/hexane, to give 46.5 mg of the target compound.
Reaction SMILES: C(OC([N:8]1[CH2:31][CH2:30][C:11]2[N:12]=[C:13]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:23]([C:13]1[N:14]=[C:15]([C:16]2[CH:17]=[CH:18][C:19]([F:22])=[CH:20][CH:21]=2)[C:10]2[CH2:9][NH:8][CH2:31][CH2:30][C:11]=2[N:12]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(Cc3ccccc3)nc(-c3ccc(F)cc3)c2C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(-c2nc(Cc3ccccc3)nc3c2CNCC3)cc1
Reaction time: 4 h
Yield: 84.3 %

Procedure:
A solution of the product from Step B (0.131 g, 0.312 mmol) in CH2Cl2 was treated with TFA. After stirring for 4 h, the mixture was concentrated and partitioned between saturated (satd.) aq. NaHCO3 and CH2Cl2 (2×). The combined organic layers were dried and concentrated. The resulting residue was purified via SiO2 chromatography (1-7% 2 M NH3 in MeOH/CH2Cl2) to give 0.084 g (84%) of the title compound. MS (ESI): exact mass calcd. for C20H18FN3, 319.15; m/z found, 320.4 [M+H]+. 1H NMR (CDCl3): 7.51 (dd, J=5.4, 8.8, 2H), 7.41 (d, J=7.4, 2H), 7.31-7.27 (m, 2H), 7.22-7.19 (m, 1H), 7.15 (dd, J=8.7, 2H), 4.27 (s, 2H), 3.95 (s, 2H), 3.24 (t, J=6.1, 2H), 2.97 (t, J=6.1, 2H).
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][NH:3]1.[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:19]=[C:18]([C:20](=[O:26])[N:21]([CH3:25])[CH2:22][CH2:23][CH3:24])[CH:17]=[C:13]([C:14](O)=[O:15])[CH:12]=1)[CH3:8].ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C>ClCCl>[CH2:7]([O:9][C:10](=[O:27])[C:11]1[CH:12]=[C:13]([C:14]([N:3]2[CH2:4][CH2:5][CH2:6][CH:2]2[CH3:1])=[O:15])[CH:17]=[C:18]([C:20]([N:21]([CH3:25])[CH2:22][CH2:23][CH3:24])=[O:26])[CH:19]=1)[CH3:8]
Reactant: CC1CCCN1
Reactant: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Agent: CC(C)N=C=NC(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)N2CCCC2C)c1
Temperature: 25 °C
Yield: 27.7 %

Procedure:
Add 2-methylpyrrolidine (204 mg, 2.4 mmol) to a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid monoethyl ester (640 mg, 2.18 mmol) in dichloromethane (8 mL) followed by 1-hydroxybenzotriazole (20 mg, 0.15 mmol) and diisopropyl carbodiimide (375 μL, 2.4 mmol). Stir the solution at room temperature over the weekend. Add ethyl acetate (25 mL) and wash with saturated aqueous ammonium chloride (2×10 mL), saturated aqueous sodium bicarbonate (10 mL), saturated aqueous sodium chloride (10 mL), dry (sodium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes) to give the title compound as an oil (218 mg, 28%).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Cl:13][C:14]1[N:22]=[C:21]([Cl:23])[C:20]([F:24])=[CH:19][C:15]=1[C:16]([OH:18])=[O:17].CN([CH:28]=[O:29])C.Cl>C1COCC1>[Cl:13][C:14]1[C:15]2[C:16](=[O:18])[O:17][CH:28]([OH:29])[C:19]=2[C:20]([F:24])=[C:21]([Cl:23])[N:22]=1
Reactant: CN(C)C=O
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: Cl
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C1OC(O)c2c(F)c(Cl)nc(Cl)c21
Reaction time: 0.5 h
Yield: 79.7 %

Procedure:
To a solution of diisopropylamine (96 g, 0.94 mol) in THF (800 mL) was slowly added n-butyllithium (379 mL, 0.95 mol, 2.5 M) at −78° C. The mixture was stirred at the same temperature for 30 minutes. To the mixture was added 2,6-dichloro-5-fluoronicotinic acid (90 g, 0.43 mol) in THF (500 mL). The solution was stirred for an additional 2 h. To the mixture was added DMF (154 mL, 1.94 mol) dropwise, The mixture was stirred for 1 h, after which 2N HCl (1.54 L) (pH<1) was introduced. The mixture was subsequently extracted with EtOAc and the organic layers were basified with aqueous NaHCO3 (pH>8). The aqueous layer was separated, acidified with 2N HCl (1.2 L) (pH<1), and extracted with EtOAc. The organic layer was washed with water and brine, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was washed with DCM to give the title compound as a reddish solid (81.6 g, 80%). 1H NMR (DMSO-d6, 400 MHz) δ ppm 6.85 (s, 1H), 8.83 (s, 1H). [M+H] calc'd for C7H2C12FNO3, 238. found, 238.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:2]=1.NC1C=NC=CC=1.C(#N)CC#N.O.[NH2:27][NH2:28]>C(O)C>[NH2:13][C:12]1[C:9](=[N:8][NH:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[C:10]([NH2:11])=[N:28][N:27]=1
Reactant: NN
Reactant: N#CC(C#N)=NNc1cccnc1
Agent: Nc1cccnc1
Solvent: CCO
Solvent: O
Solvent: N#CCC#N
Product: NC1=NN=C(N)C1=NNc1cccnc1
Temperature: 25 °C

Procedure:
This compound was prepared using 2-[(pyridin-3-yl)hydrazono]malononitrile (342 mg, 2 mmole), which was derived from 3-aminopyridine (940 mg, 10 mmole)) and malononitrile (858 mg, 13 mmol) as described in Example 8, and hydrazine hydrate (110 mg, 2.2 mmole) in ethanol. Solids had not formed after heating the reaction at 80° C. for 40 minutes, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to room temperature and the solvent was evaporated. The product was obtained after upon re-crystallization from ethanol as a yellow solid (150 mg). 1H NMR (ppm, DMSO-d6): 6.18 (br., s, 4H), 7.20 (dd, 1H), 8.00 (dd, 1H), 8.38 (d, 1H), 8.85 (s, 1H), 10.77 (br., s, 1H).