Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH2:22])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[OH:24][C@@H:25]([C:29]([CH3:32])([CH3:31])[CH3:30])[C:26](O)=[O:27]>>[CH3:1][C:2]([N:11]1[CH:15]=[C:14]([NH:16][C:17](=[O:23])[CH:18]([NH:22][C:26](=[O:27])[CH:25]([OH:24])[C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:19][CH2:20][CH3:21])[N:13]=[CH:12]1)([CH3:10])[CH2:3][N:4]1[CH2:5][CH2:6][O:7][CH2:8][CH2:9]1
Reactant: CC(C)(C)[C@H](O)C(=O)O
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1
Product: CCCC(NC(=O)C(O)C(C)(C)C)C(=O)Nc1cn(C(C)(C)CN2CCOCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-morpholin-4-yl-ethyl)-1H-imidazol-4-yl]-amide was coupled with (S)-2-hydroxy-3,3-dimethyl-butyric acid to afford the title compound: C13 NMR (100 MHz, CDCl3) 13.9, 19.2, 25.9, 26.4, 35.2, 35.3, 52.8, 55.5, 59.1, 67.5, 68.9, 80.0, 105.2, 131.3, 137.2, 169.1, 173.3; MS m/z 438.2 (M+1).
Reaction SMILES: [C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]1[O:9][CH2:8]1)#[N:2].[NH2:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1>>[C:1]([C:3]1[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=1[O:5][CH2:6][CH:7]([OH:9])[CH2:8][NH:14][CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([C:24]2[CH:25]([CH3:31])[CH2:26][C:27](=[O:30])[NH:28][N:29]=2)[CH:21]=[CH:22][CH:23]=1)#[N:2]
Reactant: CC1CC(=O)NN=C1c1cccc(OCCN)c1
Reactant: N#Cc1ccccc1OCC1CO1
Product: CC1CC(=O)NN=C1c1cccc(OCCNCC(O)COc2ccccc2C#N)c1

Procedure:
Prepared analogously to Example 1 from 1-(2-cyanophenoxy)-2,3-epoxypropane and 6-[3-(2-aminoethoxy)phenyl]-4,5-dihydro-5-methyl-3(2H)-pyridazinone.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].C([O-])([O-])=O.[K+].[K+].[Na+].Cl[C:20]([F:25])([F:24])C([O-])=O>CN(C=O)C.O.CCOC(C)=O>[F:24][CH:20]([F:25])[O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[I:1]
Reactant: O=[N+]([O-])c1ccc(I)c(O)c1
Reactant: O=C([O-])C(F)(F)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(I)c(OC(F)F)c1
Temperature: 110 °C
Reaction time: 12 h

Procedure:
A mixture of 2-iodo-5-nitrophenol (8.98 g), K2CO3 (18.7 g) and 2-chloro-2,2-difluoro-acetic acid sodium salt (5.17 g) in DMF-H2O (60-6 mL) was stirred at 110° C. for 3.5 h and at room temperature for 12 h. The mixture was diluted with EtOAc and washed with 1H HCl, saturated NaHCO3 aq., water and brine, and dried over anhydrous Na2SO4. The solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (Hexane/EtOAc=9/1) to obtain compound aa4-1 (9.17 g) as a brown amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[CH:12]=[C:11](C=O)[O:10][C:9]=2[C:8]([O:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:7][CH:6]=1)=[O:4].[C:22](O)(=O)[CH2:23][C:24]([OH:26])=[O:25].N1CCCCC1.Cl>C1(C)C=CC=CC=1>[CH:17]1([O:16][C:8]2[C:9]3[O:10][C:11](/[CH:22]=[CH:23]\[C:24]([OH:26])=[O:25])=[CH:12][C:13]=3[C:5]([C:3]([O:2][CH3:1])=[O:4])=[CH:6][CH:7]=2)[CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(O)CC(=O)O
Reactant: COC(=O)c1ccc(OC2CCCC2)c2oc(C=O)cc12
Agent: Cl
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(OC2CCCC2)c2oc(/C=C\C(=O)O)cc12
Temperature: 25 °C
Yield: 66.3 %

Procedure:
To a well stirred solution of Methyl-2-formyl-7-cyclopentyloxybenzo[b]furan-4-carboxylate (21.0 g, 0.0868 moles) in toluene (250.0 mL) was added malonic acid (13.5 g, 0.1302 moles) and Piperidine (5.0 ml). The reaction mixture was then refluxed for 3-4 hours. Reaction mixture was cooled to room temperature, acidified with 10% aqueous HCl solution and extracted with ethyl acetate (2×250 mL). The combined organic layers were washed with water (2×100 mL) and dried over anhydrous sodium sulfate. Removal of solvent under vacuo gave product (19 g) as light yellow solid.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]([CH2:21][CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[CH2:21]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:10]([OH:9])=[CH:11]1)[CH3:22]
Reactant: CCn1cc(OC(=O)c2ccccc2)c(=O)c2ccccc21
Solvent: C1CCNCC1
Solvent: ClCCl
Product: CCn1cc(O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A mixture of 1-ethyl-4-oxo-1,4-dihydroquinol-3-yl benzoate (6.29 g), piperidine (2.1ml) and dichloromethane (60 ml) was stirred under nitrogen at ambient temperature for 3 days. Further piperidine (0.5 ml) was added and the mixture stirred for 24 hours. The solvent was removed by distillation and the residual solid triturated with diethyl ether (20 ml) to give the novel compound 1-ethyl-3-hydroxy-4-quinolone, m.p. 180°-182°.
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:18])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[CH:2]=1.[NH2:25][C:26]1[CH:31]=[C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)[CH:29]=[CH:28][C:27]=1[NH:37]C(=O)OC(C)(C)C.C(N(CC)CC)C>S(Cl)(Cl)=O.CN(C=O)C>[NH2:37][C:27]1[CH:28]=[CH:29][C:30]([C:32]2[S:33][CH:34]=[CH:35][CH:36]=2)=[CH:31][C:26]=1[NH:25][C:15](=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][C:8]([NH:7][C:3]1[CH:2]=[C:1]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][CH:4]=1)=[O:18]
Reactant: O=C(O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2cccs2)cc1N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: Nc1ccc(-c2cccs2)cc1NC(=O)CCCCCCC(=O)Nc1cccc(-c2ccccc2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 69.7 %

Procedure:
Acid 183 (0.103 g, 0.32 mmol) in thionyl chloride (3 mL) with a few drops of DMF was stirred at room temperature for 15 min then concentrated, diluted with dry THF (10 mL), cooled to 0° C. then treated with amine 4 (0.12 g, 0.41 mmol) and triethylamine (0.086 mL, 0.61 mmol). The reaction mixture was stirred at 0° C. for 30 min then quenched with aqueous NH4Cl, extracted with AcOEt, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography (eluent: 50% AcOEt-hexane) to give the title compound 184 (0.111 g, 52% yield).
Reaction SMILES: [O:1]([C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][NH:14]2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:25]=[CH:26]C(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[O:1]([C:8]1[CH:24]=[CH:23][C:11]([CH2:12][CH:13]2[C:22]3[CH2:21][CH2:20][CH2:19][CH2:18][C:17]=3[CH2:16][CH2:15][N:14]2[CH:26]=[O:25])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=CC(Cl)(Cl)Cl
Reactant: c1ccc(Oc2ccc(CC3NCCC4=C3CCCC4)cc2)cc1
Solvent: ClC(Cl)Cl
Product: O=CN1CCC2=C(CCCC2)C1Cc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 116.6 %

Procedure:
To a solution of 0.78 g (0.002 mol) of (±)-1-(p-phenoxybenzyl)-1,2,3,4,5,6,7,8-octahydroisoquinoline in 5 ml of chloroform was added 0.42 g of chloral in 1 ml of chloroform dropwise. After the mixture had been stirred at room temperature for 3 hrs it was diluted with 15 ml of chloroform and washed with 4N hydrochloric acid (10 ml) and water (10 ml). After drying, the solvent was removed under reduced pressure to give 0.81 g (96%) of crude (±)-1-(p-phenoxybenzyl)-2-formyl-1,2,3,4,5,6,7,8-octahydroisoquinoline. For characterization, a sample of this compound was distilled, bp 225°-227° (0.08 mm Hq).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C:19]([NH:21][C@@H:22]([C:33]([OH:35])=[O:34])[CH2:23][C:24]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[NH:26][CH:25]=1)=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.Br[CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]>O1CCCC1>[C:41]([O:40][C:38]([CH2:37][N:26]1[C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[C:24]([CH2:23][C@H:22]([C:33]([OH:35])=[O:34])[NH:21][C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)=[O:20])=[CH:25]1)=[O:39])([CH3:44])([CH3:43])[CH3:42]
Reactant: O=C(N[C@H](Cc1c[nH]c2ccccc12)C(=O)O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cc(C[C@@H](NC(=O)OCc2ccccc2)C(=O)O)c2ccccc21
Reaction time: 1 h
Yield: 101.7 %

Procedure:
600 ml of a solution of NaHMDS (sodium salt of 1,1,1,3,3,3-hexamethyldisilazane) (1M) in tetrahydrofuran are added dropwise, at -78° C. under an inert atmosphere, to a solution of 100 g of Nα-benzyloxycarbonyl-D-tryptophan in a liter of anhydrous tetrahydrofuran. After one hour, the temperature is brought to 0° C. and a solution of 64 g of tert-butyl bromoacetate in 50 ml of anhydrous tetrahydrofuran is added dropwise. The reaction mixture is then brought to ambient temperature and the solvent is subsequently evaporated off in vacuo. The residue is diluted with dichloromethane and the solution is acidified by adding an aqueous 4N hydrochloric acid solution. After extraction with dichloromethane, the organic phases are dried over sodium sulphate and then concentrated in vacuo. 136 g of the expected product are obtained.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C@H:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH3:10][CH2:11][CH:12]([N:14]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@@H:40]5[O:44][C@:43]([C:51]6[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=6[Cl:58])([CH2:45][N:46]6[N:50]=[CH:49][N:48]=[CH:47]6)[O:42][CH2:41]5)=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:15]1=[O:16])[CH3:13].CCC(N1N=CN(C2C=CC(N3CCN(C4C=CC(OC[C@@H]5O[C@](C6C=CC(Cl)=CC=6Cl)(CN6N=CN=C6)OC5)=CC=4)CC3)=CC=2)C1=O)C.[C:108]([OH:117])(=[O:116])[C@@H:109]([C@H:111]([C:113]([OH:115])=[O:114])[OH:112])O>C1COCC1>[CH3:10][CH2:11][CH:12]([N:14]1[N:19]=[CH:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][CH2:39][C@@H:40]5[O:44][C@:43]([C:51]6[CH:56]=[CH:55][C:54]([Cl:57])=[CH:53][C:52]=6[Cl:58])([CH2:45][N:46]6[N:50]=[CH:49][N:48]=[CH:47]6)[O:42][CH2:41]5)=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)[C:15]1=[O:16])[CH3:13].[C:1]([OH:9])(=[O:8])[CH:2]([CH2:4][C:5]([OH:7])=[O:6])[OH:3].[CH2:109]([C:108]([OH:117])=[O:116])[C@H:111]([OH:112])[C:113]([OH:115])=[O:114]
Reactant: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: CCC(C)n1ncn(-c2ccc(N3CCN(c4ccc(OC[C@H]5CO[C@](Cn6cncn6)(c6ccc(Cl)cc6Cl)O5)cc4)CC3)cc2)c1=O
Agent: O=C(O)C[C@H](O)C(=O)O
Solvent: C1CCOC1
Product: O=C(O)CC(O)C(=O)O

Procedure:
Co-crystals of itraconazole and malic acid were prepared. To prepare the L-malic acid co-crystal salt of cis-itraconazole, 100.4 mg of cis-itraconazole free base, 0.50 mL of THF, and a magnetic stir bar were charged into a screw cap vial. A solution of 191.3 mg of L(−)malic acid in 5.0 mL of THF was prepared. 0.50 mL of the L-malic acid solution was added to the vial containing cis-itraconazole and the solution was heated with a heat gun to dissolve. The solution was allowed to cool and was then seeded with <1 mg of the salt from cis-itraconazole-L-tartaric acid co-crystal. The cooled crystals were filtered in a centrifuge filter tube. The filter cake was broken-up and allowed to air-dry prior to analysis. (See FIGS. 18 and 19)
Reaction SMILES: [CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C@H:21]([OH:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([OH:24])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1.[C:25](=O)([O-])[O-].[K+].[K+].O>CO.CI>[CH2:1]1[CH2:10][O:9][CH:8]2[CH:3]([C@:4]3([CH2:22][C@H:21]([OH:23])[C@H:20]4[C@@H:11]([CH2:12][CH2:13][C:14]5[CH:15]=[C:16]([O:24][CH3:25])[CH:17]=[CH:18][C:19]=54)[C@@H:6]3[CH2:7]2)[CH3:5])[O:2]1
Reactant: C[C@]12C[C@H](O)[C@@H]3c4ccc(O)cc4CC[C@H]3[C@@H]1CC1OCCOC12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CO
Solvent: O
Product: COc1ccc2c(c1)CC[C@@H]1[C@@H]2[C@@H](O)C[C@]2(C)C3OCCOC3C[C@@H]12

Procedure:
A mixture of 15 g of 17-ethylenedioxyestra-1,3,5(10) trien-3,11β-diol and 30 g of anhydrous potassium carbonate in 75 ml of methanol and 60 ml of methyl iodide is stirred and heated under reflux for 3 hours. The mixture is then cooled and diluted by the addition of 200 ml of water. The methanol and methyl iodide are removed by distillation under reduced pressure and the aqueous residue is extracted twice with methylene chloride. The combined organic extracts are washed with saturated sodium chloride solution and dried over sodium sulfate. Removal of the solvent gives a residue which is crystallized from ether to yield 17-ethylenedioxy-11β-hydroxy-3-methoxyestra-1,3,5(10)-triene, m.p. 125° - 126° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[CH2:22][C:6]2[NH:7][C:8]([C:10]3[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=3)[C:15]([O:17]C)=[O:16])=[N:9][C:5]=2[CH2:4]1.[OH-].[Na+]>CO.O>[CH3:1][O:2][CH:3]1[CH2:4][C:5]2[NH:9][C:8]([C:10]3[C:11]([CH3:21])=[CH:12][C:13]([CH3:20])=[C:14]([CH:19]=3)[C:15]([OH:17])=[O:16])=[N:7][C:6]=2[CH2:22]1
Reactant: COC(=O)c1cc(-c2nc3c([nH]2)CC(OC)C3)c(C)cc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC1Cc2nc(-c3cc(C(=O)O)c(C)cc3C)[nH]c2C1
Temperature: 70 °C
Reaction time: 8 h
Yield: 103.5 %

Procedure:
Into around-bottom flask, was placed a solution of methyl 5-(5-methoxy-1,4,5,6-tetrahydrocyclopenta[d]imidazol-2-yl)-2,4-dimethylbenzoate (compound 461.6, 100 mg, 0.270 mmol, 1.00 equiv, 80%) in methanol (3 mL). A solution of sodium hydroxide (67.0 mg, 1.68 mmol, 5.00 equiv) in water (3 mL) was added and the resulting mixture was stirred overnight at 70° C., then concentrated in vacuo. The residue was diluted with water (3 mL) and the pH of the solution was adjusted to 2-3 with aqueous hydrogen chloride (12 M). The mixture was extracted ethyl acetate (3×10 mL), and the combined organics was concentrated in vacuo to obtain the title compound as a brown solid (80 mg, 84%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:6][CH:7]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[O:32])=[CH:26][CH:25]=1>O1CCCC1>[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:32])[NH:1][C:2]2[CH:3]=[C:4]([C:8]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH:5]=[CH:6][CH:7]=2)=[CH:26][CH:25]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: COC(=O)CCCC=C(c1cccnc1)c1cccc(N)c1
Solvent: C1CCOC1
Product: O=C(O)CCCC=C(c1cccnc1)c1cccc(NC(=O)Nc2ccc(Cl)cc2)c1
Reaction time: 1 h

Procedure:
2.4 g of methyl 6-(3-aminophenyl)-6-(3-pyridyl)-hex-5-enoate and 1.5 g of 4-chlorophenylisocyanate are stirred in 50 ml of tetrahydrofuran at ambient temperature for one hour. The reaction mixture is evaporated down, the residue is mixed with water and extracted with ethyl acetate/ethanol (9:I). The organic phase is evaporated down and the residue is saponified in 60 ml of ethanol and 6 ml of 4N sodium hydroxide solution at 50° C. for one hour. The reaction mixture is evaporated down, the residue is taken up in 100 ml of water and extracted with ethyl acetate. The aqueous phase is neutralised by the addition of citric acid, whereupon the product is precipitated. The precipitate is suction filtered, washed with water and diisopropylether and recrystallised from ethyl acetate/diisopropylether.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:28]=[CH:27][C:24]([C:25]#[N:26])=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.O[NH2:30].[C:31]([O-:34])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[N:13]([CH3:14])[C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:11][C:10]=2[C:21]2[CH:22]=[CH:23][C:24]([C:25]3[N:30]=[CH:31][O:34][N:26]=3)=[CH:27][CH:28]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cn1c(-c2ccccc2)nc(-c2ccc(C#N)cc2)c1Sc1ccc(Cl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: Cn1c(-c2ccccc2)nc(-c2ccc(-c3ncon3)cc2)c1Sc1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
To 4-{5-[(4-chlorophenyl)thio]-1-methyl-2-phenyl-1H-imidazol-4-yl}benzonitrile (Example 2, 30 mg, 0.075 mmol) in 2 mL EtOH was added 0.25 mL of HONH2 and catalytic amount of K2CO3. The reaction was heated at 120° C. for 60 min via microwave. The reaction mixture was concentrated to dryness and the residue was dissolved in 5 mL triethylorthoformate. Catalytic amount of TFA was added and the reaction was heated at 130° C. for 3 h. The volatiles were removed and the residue was purified by reverse phase HPLC to afford the title compound. 1H NMR (500 MHz, (CDCl3): 8.74 (s, 1H), 8.27 (d, 2H), 8.18 (d, 2H), 7.72 (m, 2H), 7.53 (m, 3H), 7.25 (d, 2H), 7.06 (d, 2H), 3.68 (s, 3H). LCMS: m/z 445 (M+H)+.
Reaction SMILES: [CH2:1]([N:4]1[CH:8]=[C:7]([CH2:9][Si:10]([CH3:13])([CH3:12])[CH3:11])[N:6]=[N:5]1)[CH2:2][CH3:3].[I:14][CH3:15]>C(#N)C>[I-:14].[CH3:15][N+:6]1[C:7]([CH2:9][Si:10]([CH3:11])([CH3:13])[CH3:12])=[CH:8][N:4]([CH2:1][CH2:2][CH3:3])[N:5]=1
Reactant: CI
Reactant: CCCn1cc(C[Si](C)(C)C)nn1
Solvent: CC#N
Product: CCCn1cc(C[Si](C)(C)C)[n+](C)n1
Product: [I-]

Procedure:
1-propyl-4-((trimethylsilyl)methyl)-1H-1,2,3-triazole and excess iodomethane were added to a vial. The reaction was heated for 19.5 hours and 5 mL ACN was added. The reaction was heated for another 2 hours. The precipitate was filtered, rinsed with ether and dried in vacuo overnight. The following 3-methyl-1-propyl-4-((trimethylsilyl)methyl)-1H-1,2,3-triazol-3-ium iodide structure was confirmed:
Reaction SMILES: N1C(Cl)=NC(Cl)=NC=1[Cl:3].CN(C)C=O.[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27](O)[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19].C(Cl)Cl>>[Br:15][C:16]1[C:23]([O:24][CH2:25][CH3:26])=[C:22]([CH:27]([Cl:3])[CH3:28])[CH:21]=[C:20]([Cl:30])[C:17]=1[C:18]#[N:19]
Reactant: Clc1nc(Cl)nc(Cl)n1
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1Br
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1Br
Yield: 75.8 %

Procedure:
Cyanuric chloride (0.11 g, 0.59 mmol) was dissolved in N,N-dimethylformamide (3 mL, 40 mmol). After stirring for a few minutes, a solution of 2-bromo-6-chloro-3-ethoxy-4-(1-hydroxyethyl)benzonitrile (150 mg, 0.49 mmol) in methylene chloride (3 mL, 50 mmol) was added. The resulting mixture was stirred at room temperature overnight. The reaction was partitioned between water and dichloromethane. The organic layer was washed with sat. NaHCO3 solution, water, brine, dried over MgSO4, and concentrated. The crude product was purified by flash column chromatography, eluting a gradient of 0-30% EtOAc/Hexane to give 2-bromo-6-chloro-4-(1-chloroethyl)-3-ethoxybenzonitrile (0.12 gm, 75%) as a semisolid, LCMS calculated for C11H10BrCl2NO m/z=323.9, 320.9; found: (poor ionization).
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]([C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)[N:10]1C(=O)C2C(=CC=CC=2)C1=O)([CH3:4])([CH3:3])[CH3:2].O.NN>C1COCC1.CO>[C:1]([O:5][C:6](=[O:28])[NH:7][CH2:8][CH:9]([NH2:10])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([Cl:27])[CH:22]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NCC(N)c1cccc(Cl)c1
Temperature: 55 °C

Procedure:
To a stirred solution of [2-(3-chloro-phenyl)-2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethy]-carbamic acid tert-butyl ester (2.5 g, 6.2 mmol) in THF (10 mL) and methanol (10 mL) was added hydrazine hydrate (3.1 g, 62 mmol). The mixture was heated a 55° C. for 1 hour. Then it was concentrated to dryness, dissolved in H2O (5 mL) and extracted with ethyl acetate (50 mL). The organic mixture was concentrated and purified by column chromatography (methanol:dichloromethane, 1:100) to afford [2-amino-2-(3-chloro-phenyl)-ethyl]-carbamic acid tert-butyl ester. (Yield 1.325 g, 79%). LC-MS: [M+H]+ 271.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:19])[CH3:18])[CH2:14][C:6]=3[C:5]=2[CH:4]=1)#[N:2].[OH-:21].[Na+].[CH3:23]O>O>[CH3:23][O:21][N:2]=[CH:1][C:3]1[CH:11]=[CH:10][C:9]2[NH:8][C:7]3[CH2:12][CH:13]([NH:15][C:16](=[O:20])[CH:17]([CH3:18])[CH3:19])[CH2:14][C:6]=3[C:5]=2[CH:4]=1
Reactant: CC(C)C(=O)NC1Cc2[nH]c3ccc(C#N)cc3c2C1
Reactant: [OH-]
Reactant: CO
Agent: [Na+]
Solvent: O
Product: CON=Cc1ccc2[nH]c3c(c2c1)CC(NC(=O)C(C)C)C3
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Mix (±)-N-[7-cyano-1,2,3,4-tetrahydro-cyclopenta[b]indol-2-yl]-isobutyramide (5 g, 18.7 mmol) and Al—Ni catalyst (15 g) in water/96% formic acid, 1/10 (110 mL). Reflux for 18 h, add Al—Ni catalyst (13 g) and reflux another 5 h. Cool and dilute with MeOH and filter off the inorganics. Concentrate the filtrate, add EtOH (200 mL) and sonicate for 15 min. Filter insoluble material and to the crude aldehyde solution add O-methoxyamine-HCl (120 mmol) dissolved in water (25 mL) and make the mixture basic (pH=9-12) with 5.0 N NaOH. Stir at room temperature for 18 h and remove most of the solvent under reduced pressure. Mix the residue with water and sonicate for 30 min. Isolate 4.39 g of a brown solid. Purify the material on silica gel using 30-100% EtOAc/hexane to give 530 mg (10%) title compound as a pale yellow solid. MS (m/z): 300 (M+1), 298 (M−1).
Reaction SMILES: C(OC([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=O)(C)(C)C.FC(F)(F)C(O)=O.[Cl:28]CCl>>[ClH:28].[NH2:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10]
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)OC(C)(C)C)cc1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc([C@H](C)N)cc1
Product: Cl
Yield: 95 %

Procedure:
Methyl 4-{(1S)-1-[(tert-butoxycarbonyl)amino]ethyl}benzoate (step 4, 12.83 g, 45.9 mmol) was treated with trifluoroacetic acid (100 mL) and dichloromethane (100 mL) at room temperature for 16 hours. After removal of the solvent, the residue was diluted with 10% hydrogen chloride solution in methanol (100 mL). The mixture was concentrated under reduced pressure and the residue was washed with ethylacetate to give 9.40 g (95%) of the title compound as white solids:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([F:42])[C:6]([NH:29][CH:30]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:31][C:32]([O:34]CC)=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[N:11](S(C2C=CC(C)=CC=2)(=O)=O)[CH:10]=1)#[N:2].[Li+].[OH-].O.C(OCC)(=O)C>C1COCC1>[C:1]([C:3]1[CH:4]=[C:5]([F:42])[C:6]([NH:29][CH:30]([C:37]([CH3:41])([CH3:40])[CH2:38][CH3:39])[CH2:31][C:32]([OH:34])=[O:33])=[N:7][C:8]=1[C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([F:18])[CH:16]=2)[NH:11][CH:10]=1)#[N:2]
Reactant: CCOC(=O)CC(Nc1nc(-c2cn(S(=O)(=O)c3ccc(C)cc3)c3ncc(F)cc23)c(C#N)cc1F)C(C)(C)CC
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CCC(C)(C)C(CC(=O)O)Nc1nc(-c2c[nH]c3ncc(F)cc23)c(C#N)cc1F
Temperature: 70 °C

Procedure:
Ethyl 3-[[5-cyano-3-fluoro-6-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]-2-pyridyl]amino]-4,4-dimethyl-hexanoate, 159a, (0.27 g, 0.45 mmol) was dissolved in THF (7 mL) and treated with LiOH (4.50 mL of 1 M, 4.50 mmol). The reaction mixture was heated to 70° C. for 10 hours. After cooling to room temperature, water (20 mL) and ethyl acetate (20 mL) were added and the layers were separated. The aqueous layer was brought to a neutral pH by addition of 1N HCl, and the resulting precipitate was collected by filtration, washed with water and concentrated in vacuo to provide 77 mg of the desired product: 1H NMR (400 MHz, DMSO-d6) δ 12.37 (s, 1H), 12.12 (s, 1H), 8.75 (d, J=9.9 Hz, 1H), 8.32 (s, 2H), 7.83 (d, J=11.4 Hz, 1H), 7.48 (d, J=9.5 Hz, 1H), 5.00 (t, J=9.1 Hz, 1H), 2.71-2.54 (m, 2H), 1.30 (d, J=7.4 Hz, 2H), 0.80 (t, J=18.7 Hz, 9H); LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=3.14 minutes (M+H) 414.31.