Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:13]([OH:15])=O)=[CH:7][N:8]2[CH2:11][CH3:12])=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:13]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][CH3:12])[CH:7]=1)=[O:15]
Reactant: CCn1cc(C(=O)O)c2ccc(Cl)cc21
Reactant: Nc1nccs1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCn1cc(C(=O)Nc2nccs2)c2ccc(Cl)cc21
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 8.3 %

Procedure:
A solution of 6-chloro-1-ethyl-1H-indole-3-carboxylic acid (240 mg, 1.07 mmol) in methylene chloride (3 mL) was cooled to 0° C. and then treated with N,N-dimethylformamide (1 drop) and oxalyl chloride (0.14 mL, 1.61 mmol). The reaction was stirred at 0° C. for 15 min and then was allowed to warm to 25° C. where it was stirred for 1 h. At this time, the reaction was concentrated in vacuo. The residue was dissolved in methylene chloride (1 mL), and this mixture was then added to a solution of 2-aminothiazole (214 mg, 2.14 mmol) and triethylamine (0.30 mL, 2.14 mmol) in N,N-dimethylformamide (2 mL). This mixture was stirred at 25° C. for 16 h. At this time, the reaction was partitioned between water (40 mL) and ethyl acetate (40 mL). This mixture was then treated with a 1N aqueous hydrochloric acid solution (15 mL). The organic layer was washed with a saturated aqueous sodium bicarbonate solution (1×30 mL), water (1×30 mL), and a saturated aqueous sodium chloride solution (1×30 mL). The organic layer was then dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate afforded 6-chloro-1-ethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide (27 mg, 8%) as a pale yellow solid: mp 234-236° C.; EI-HRMS m/e calcd for C14H12ClN3OS (M+) 305.0390, found 305.0383.
Reaction SMILES: C(C1C=CC=CC=1C#N)#C.[CH3:11][Si:12]([C:15]#[CH:16])([CH3:14])[CH3:13].[I:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1I>[Pd]>[CH3:11][Si:12]([CH3:14])([CH3:13])[C:15]#[C:16][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[I:17]
Reactant: C#C[Si](C)(C)C
Reactant: Ic1ccccc1I
Agent: [Pd]
Agent: C#Cc1ccccc1C#N
Product: C[Si](C)(C)C#Cc1ccccc1I
Yield: 58 %

Procedure:
Alternatively, 2-ethynylbenzonitrile (a3) may be prepared according to the procedures set forth in M. J. Wu et al. (1999), Organic Letters, 1 (5):767-768, which is incorporated herein by reference in its entirety. Specifically, palladium-catalyzed coupling reaction of trimethylsilylacetylene with 1,2-diiodobenzene produced 2-(2-trimethylsilylethynyl)iodobenzene in 58% yield; 2-(2-trimethylsilylethynyl)iodobenzene was then coupled with Zn(CN)2 using palladium(0) as a catalyst to give 2-(2-trimethylsilylethynyl)benzonitrile in 45% yield; and finally, 2-(2-trimethylsilylethynyl)benzonitrile was treated with tetrabutylammonium fluoride to give 2-ethynylbenzonitrile (a3) in 97% yield.
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([S:20]([C:23]3[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=3)(=[O:22])=[O:21])[C:6]=2[CH:34]=1.[CH:35]([Mg]Cl)([CH3:37])C.Cl.[C:41]([O-])([OH:43])=[O:42].[Na+]>C1COCC1>[F:31][C:30]([F:33])([F:32])[O:29][C:26]1[CH:27]=[CH:28][C:23]([S:20]([N:7]2[C:6]3[CH:34]=[C:2]([C:41]([O:43][CH2:35][CH3:37])=[O:42])[CH:3]=[CH:4][C:5]=3[NH:11][C:10]3[N:12]=[C:13]([C:16]([F:19])([F:18])[F:17])[CH:14]=[CH:15][C:9]=3[CH2:8]2)(=[O:22])=[O:21])=[CH:24][CH:25]=1
Reactant: O=S(=O)(c1ccc(OC(F)(F)F)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21
Reactant: CC(C)[Mg]Cl
Reactant: O=C([O-])O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc2c(c1)N(S(=O)(=O)c1ccc(OC(F)(F)F)cc1)Cc1ccc(C(F)(F)F)nc1N2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 8-iodo-6-{[4-(trifluoromethoxy)phenyl]sulfonyl}-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (380 mg, 0.618 mmol, intermediate 61) in 2 ml of THF was added a solution of isopropyl magnesium chloride (1.54 ml, 3.08 mmol) in THF (2M) at 0° C. and the solution was stirred for 30 min at 0° C. Then the reaction mixture was added to a solution of ethyl cyanidocarbonate in 3 mL of THF and stirred for 30 min at 0° C. The reaction mixture was poured into 2 mL of 2N HCl and 5 mL of ice-water, and the pH was adjusted to 7-8 with aqueous NaHCO3 at 0° C. The solution was extracted with ethyl acetate (3×20 ml), and the combined organic extracts were dried over Na2SO4. The solution was concentrated under reduced pressure and the residue was purified by silica gel chromatography using with hexane/ethyl acetate (6/1) to give the title compound as a white solid; Mass Spectrum: m/e=562 (M+1).
Reaction SMILES: [C:1]([O:4][C:5]([CH2:11][CH2:12][CH3:13])([CH2:8][CH2:9][CH3:10])[C:6]#[CH:7])(=[O:3])[CH3:2].[CH2:14]([NH:16][CH2:17][CH3:18])[CH3:15].C=O.O1CCOC[CH2:22]1>CCOCC>[CH2:14]([N:16]([CH2:17][CH3:18])[CH2:22][C:7]#[C:6][C:5]([O:4][C:1](=[O:3])[CH3:2])([CH2:8][CH2:9][CH3:10])[CH2:11][CH2:12][CH3:13])[CH3:15]
Reactant: C1COCCO1
Reactant: C#CC(CCC)(CCC)OC(C)=O
Reactant: CCNCC
Agent: C=O
Solvent: CCOCC
Product: CCCC(C#CCN(CC)CC)(CCC)OC(C)=O

Procedure:
A mixture of 3-acetoxy-3-propyl-1-hexyne (115.2 g., 0.634 mole), diethylamine (51 g., 0.7 mole), paraformaldehyde (24.9 g., 0.83 mole) and dioxane (120 ml.) is stirred and heated on the steam bath for 2 hours. The reaction mixture is cooled, treated with ether and the product extracted into ice-cold 5% hydrochloric acid. The cold acidic solution is then basified with ice-cold 10% sodium hydroxide. The oily amine is taken up in ether, washed with water and brine and dried over sodium sulfate. Distillation yields 99.5 g. (59%) of the amine product, b.p. 101°-110° C./0.1 mm.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([OH:16])=O)=[C:9]2[CH3:17])=[CH:4][CH:3]=1.[NH2:18][CH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=1.C(Cl)(=O)C(Cl)=O.C(N(CC)CC)C.Cl.[NH2:42][OH:43]>ClCCl.C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]([NH:25][CH2:24][C:23]3[CH:26]=[CH:27][C:20]([C:19](=[N:42][OH:43])[NH2:18])=[CH:21][CH:22]=3)=[O:16])=[C:9]2[CH3:17])=[CH:6][CH:7]=1
Reactant: Cc1cc(C(=O)O)c(C)n1-c1ccc(F)cc1
Reactant: NO
Reactant: N#Cc1ccc(CN)cc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cc(C(=O)NCc2ccc(C(N)=NO)cc2)c(C)n1-c1ccc(F)cc1

Procedure:
30 g of 1-(4-fluorophenyl)-2,5-dimethyl-pyrrole-3-carboxylic acid was reacted with 1 equivalent of 4-(aminomethyl)benzonitrile, in the presence of 1.1 equivalents of oxalyl chloride, 3 equivalents of triethylamine in dichloromethane at room temperature for 3 h. The product was then reacted with hydroxylamine hydrochloride (3 equivalents) in ethanol at 80° C. for 3 h. The target compound (36 g) was obtained as a tan-colored powder following solvent removal by evaporation. Purity assessed by HPLC was 97.8%, and mass was verified by LC/MS/MS (predicted m+1=381.2, obtained m+1=381.2). 1H-NMR (DMSO): δ 1.93 (3H), 2.21 (3H), 4.39-4.40 (2H), 5.76 (2H), 6.42 (1H), 7.26-7.28 (2H), 7.35-7.40 (4H), 7.60-7.62 (2H), 8.22 (1H), 9.56 (1H).
Reaction SMILES: [CH3:1][C@H:2]1[CH2:11][C@@H:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7](B3OC(C)(C)C(C)(C)O3)[CH:8]=2)[N:3]1[C:31](=[O:33])[CH3:32].Br[C:35]1[CH:44]=[CH:43][C:38]([C:39]([O:41][CH3:42])=[O:40])=[CH:37][N:36]=1.[C:45](=O)([O-])[O-].[K+].[K+].C1(C)C=CC=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].C(O)C>[C:31]([N:3]1[C:4]2[C:9](=[CH:8][C:7]([C:35]3[CH:44]=[CH:43][C:38]([C:39]([O:41][CH2:42][CH3:45])=[O:40])=[CH:37][N:36]=3)=[CH:6][CH:5]=2)[C@H:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][N:14]=2)[CH2:11][C@@H:2]1[CH3:1])(=[O:33])[CH3:32]
Reactant: COC(=O)c1ccc(Br)nc1
Reactant: CC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)cc2[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@@H]1C
Reactant: O=C([O-])[O-]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [K+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(-c2ccc3c(c2)[C@H](Nc2ccc([N+](=O)[O-])cn2)C[C@H](C)N3C(C)=O)nc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 68.3 %

Procedure:
to a flask charged with 1-((2S,4R)-2-methyl-4-((5-nitropyridin-2-yl)amino)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 24)(1.03 g, 2.277 mmol), methyl 6-bromonicotinate (0.541 g, 2.505 mmol), potassium carbonate (0.944 g, 6.83 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.263 g, 0.228 mmol) was added a previously degassed mixture of toluene (10 mL) and ethanol (10 mL). The resulting mixture was stirred at 90° C. under nitrogen. After 3 h, further portions of methyl 6-bromonicotinate (0.271 g, 1.252 mmol), potassium carbonate (0.472 g, 3.42 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.132 g, 0.114 mmol) were added and reaction mixture heated for a further 4 h. The reaction was cooled to room temperature and concentrated in vacuo. The crude residue was partitioned between EtOAc and water, the phases separated and aqueous phase extracted with EtOAc. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by chromatography, eluting with an EtOAc/hexanes gradient gave ethyl 6-((2S,4R)-1-acetyl-2-methyl-4-((5-nitropyridin-2-yl)amino)-1,2,3,4-tetrahydroquinolin-6-yl)nicotinate (740 mg, 1.556 mmol, 68.3% yield) as a yellow foam.
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])[CH2:3]1.[Br:38][C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:48]Br>>[Br:38][C:39]1[C:44]([N+:45]([O-:47])=[O:46])=[CH:43][CH:42]=[CH:41][C:40]=1[CH2:48][O:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[O:26][CH3:27])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:28]([O:30][CH2:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[O:29])[CH2:3]1
Reactant: O=[N+]([O-])c1cccc(CBr)c1Br
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2O)cc1
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2cccc([N+](=O)[O-])c2Br)cc1

Procedure:
Analogously to Method D, 1.30 g of benzyl 3-hydroxy-4-{4-[3-(2-methoxybenzyloxy)propoxy]-phenyl}piperidine-1-carboxylate (Example 10f) and 1.0 g of 2-bromo-1-bromomethyl-3-nitrobenzene are reacted. The title compound is obtained as a yellowish oil. Rf=029 (1:1 EtOAc-heptane); Rt=6.12.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:6][CH:7]=1.[I-:18].[Na+].CN[C@@H]1CCCC[C@H]1NC>O1CCOCC1.[Cu]I>[I:18][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([CH2:15][CH3:16])[C:9]2=[O:17])=[N:6][CH:7]=1
Reactant: CCN1C(=O)N(c2ncc(Br)cn2)CC1(C)C
Reactant: [I-]
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN1C(=O)N(c2ncc(I)cn2)CC1(C)C
Temperature: 100 °C
Reaction time: 16 h
Yield: 86.4 %

Procedure:
(350 mg, 1.17 mmol) 1-(5-Bromo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (Example 143, step 2) was dissolved in dioxane (20 ml) and sodium iodide (700 mg, 4.68 mmol, 4 equiv.), copper(I)iodide (21 mg, 0.234 mmol, 0.2 equiv.) and trans-N,N′-dimethylcyclohexane-1,2-diamine (33 mg, 37 μl, 0.234 mmol, 0.2 equiv.) were added. The mixture was stirred for 16 hours at 100° C. The reaction mixture was cooled and extracted with saturated NaHCO3 solution and two times ethyl acetate. The organic layers were extracted with brine, dried over sodium sulfate and evaporated to dryness. The desired 1-(5-iodo-pyrimidin-2-yl)-3-ethyl-4,4-dimethyl-imidazolidin-2-one (350 mg, 86% yield) was obtained as a brown solid, MS: m/e=347.0 (M+H+) and was used without further purification in the next step.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C[O:10][C:11]([C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1)=O.CC#N>C1COCC1>[OH:17][CH2:16][C:13]1([C:11](=[O:10])[CH2:2][C:3]#[N:5])[CH2:15][CH2:14]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(CO)CC1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CC#N
Product: N#CCC(=O)C1(CO)CC1

Procedure:
To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL,×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2H) 4.03 (s, 1H) 3.58 (br. s., 2H) 1.15-1.16 (m, 2H) 0.92-0.95 (m, 2H).
Reaction SMILES: [OH-].[Li+].[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:6]=1[C:7]([O:9]C)=[O:8].Cl>O.O1CCCC1.CO>[CH3:3][O:4][C:5]1[CH:14]=[CH:13][C:12]([CH:15]=[O:16])=[CH:11][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(C=O)ccc1OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C=O)cc1C(=O)O
Reaction time: 8 h

Procedure:
Lithium hydroxide (1.04 g, 0.043 mol, 3 eq) in water (10 mL) was added to a stirred solution of methyl 2-methoxy-5-formylbenzoate (2.8 g, 0.014 mol, 1 eq) in a mixture of tetrahydrofuran (30 mL) and methanol (20 mL). The solution was stirred overnight, acidified to pH 1 with 10% HCl and the organic solvents removed in vacuo. The aqueous solution was extracted with ethyl acetate (100 mL) and the organic solution washed with brine (100 mL), then extracted with saturated aqueous sodium bicarbonate (3×100 mL). The basic solution was washed with ethyl acetate (100 mL), then acidified to pH 1 with 10% HCl and back extracted with dichloromethane (3×100 mL). The organic solution was dried over sodium sulfate and evaporated in vacuo to give a cream coloured powder (2.01 g, 77%). 1H NMR (CDCl3) δ9.99 (s, 1H, O═C—H), 4.14 (s, 3H, CH3).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([O:10]CC2C=CC(OC)=CC=2)[N:7]=[CH:6][C:5]=1[C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]2[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[O:32][N:31]=2)=[O:28])=[C:22]([F:42])[CH:21]=1)[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]1[C:5]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[CH:34]=[C:33]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:37])[F:38])[O:32][N:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)=[CH:6][NH:7][C:8](=[O:10])[CH:9]=1)[CH3:2]
Reactant: CCOc1cc(OCc2ccc(OC)cc2)ncc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)on2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cc(=O)[nH]cc1-c1ccc(CC(=O)Nc2cc(C(C)(C)C(F)(F)F)on2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 77.1 %

Procedure:
To a suspension of 2-(4-(4-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (100 g, 170 mmol) in DCM (1 L) was added TFA (80 mL, 1077 mmol) dropwise. The mixture was stirred at 25° C. for 2 h. The mixture was then concentrated. To the residue was added H2O (500 mL) dropwise and then neutralized with saturated Na2CO3 solution to adjust pH=7.5. The precipitate was filtered, washed with H2O (350 mL×3) and dried in vacuo. To the solid was added PE/EA (3:1, v/v, 300 mL) and stirred for 0.5 h. The solid was filtered and washed with PE/EA (3:1, v/v, 100 mL×2). The solid was redissolved in DCM/MeOH (20:1, v/v, 1.5 L) and then concentrated in vacuo to a minimal amount of solvent (about 150 mL). The solid was filtered, washed with CH3CN (50 mL×2) and dried in vacuo. The residual solid was added to EtOH (2.5 L) and heated to 80° C. After the solid was dissolved completely, the mixture was concentrated in vacuo to give a white solid of 2-(4-(4-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(5-(1,1,1-trifluoro-2-methylpropan-2-yl)isoxazol-3-yl)acetamide (61.4 g, 131 mmol, 77% yield): 1H NMR (400 MHz, CD3OD) δ 7.40-7.30 (m, 2H), 7.25-7.18 (m, 2H), 6.88 (s, 1H), 5.98 (s, 1H), 4.11 (q, J=7.2 Hz, 2H), 3.81 (s, 2H), 1.56 (s, 6H), 1.37 (t, J=7.2 Hz, 3H); ES-LCMS m/z: 468 (M+H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH2:11][OH:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([CH:11]=[O:12])=[CH:8][CH:9]=2)[N:4]=[C:3]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=1
Reactant: Cn1c(COc2ccc(C#N)cc2)nc2nc(CO)ccc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cn1c(COc2ccc(C#N)cc2)nc2nc(C=O)ccc21
Reaction time: 96 h

Procedure:
3.65 g (12.5 mmol) of 1-methyl-2-[(4-cyanophenyl)oxymethyl]-5-hydroxymethylimidazo[4,5-b]pyridine were dissolved in 500 ml of dichloromethane and mixed with 15.0 g of manganese dioxide. After 96 hours at room temperature, the mixture was filtered through kieselguhr and the solvent was distilled off. The filtrate obtained was evaporated down, the crystalline precipitate was triturated with ether, suction filtered, and dried.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([NH:13][C@H:14]1[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15]1)[CH:7]=[CH:6]2.[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[C:8]([NH:13][C@H:14]2[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH2:16][CH2:15]2)[CH:7]=[CH:6]3)=[CH:26][CH:25]=1
Reactant: NCc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: O=Cc1ccc(F)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Fc1ccc(CNCc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 55.3 %

Procedure:
A solution of (6-aminomethyl-quinolin-2-yl)-(R)-indan-1-yl-amine (example 54, step A) (130 mg, 0.45 mmol), 4-fluorobenzaldehyde (61 mg, 0.49 mmol) and acetic acid (108 mg, 1.8 mmol) in 1,2-dichloroethane (5 ml) was stirred at room temperature for 30 min. Afterwards sodium triacetoxy-borohydride (222 mg, 0.94 mmol) was added, the reaction mixture was allowed to stir for 2.5 days at room temperature, poured into ice/saturated sodium bicarbonate solution (30 ml) and extracted with dichloromethane (2×40 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was purified by flash chromatography (ethyl acetate/heptane) on silica gel to yield the title compound as a colorless oil (99 mg, 55%). MS: m/e=398.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13](Cl)=[O:14].[CH2:17]([OH:19])[CH3:18]>>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][N:11]=[C:12]([Cl:16])[C:13]([O:19][CH2:17][CH3:18])=[O:14]
Reactant: O=C(Cl)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCO
Product: CCOC(=O)C(Cl)=NNc1c(Cl)cc(Cl)cc1Cl

Procedure:
A solution consisting of 17.0 g. )0.05 mole) chloroglyoxyloyl chloride (2,4,6-trichlorophenyl)hydrazone and 200 ml. ethanol was heated at the reflux temperature for 30 min. This reaction solution was then concentrated to a volume of about 50 ml. and cooled. The solids that separated were recovered on a filter, and the solids on the filter were recrystallized two times from technical hexane to give ethyl chloroglyoxylate 2-(2,4,6-trichlorophenyl)-hydrazone having a melting range at 65° to 73° C.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[C:11]([CH2:13]C(O)=O)#[N:12].[NH:17]1CCC[CH2:19][CH2:18]1.C(=O)=O>N1C=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]([CH2:13][C:11]#[N:12])[CH2:19][C:18]#[N:17]
Reactant: C1CCNCC1
Reactant: N#CCC(=O)O
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: O=C=O
Solvent: c1ccncc1
Product: N#CCC(CC#N)c1c(Cl)cccc1Cl

Procedure:
A solution consisting of 31.5 grams (g) of 2,6-dichlorobenzaldehyde, 39 g of cyanoacetic acid and 2.5 milliliters (ml) of piperidine in 100 ml of pyridine is heated on a steambath for 7 hours. The initial rapid evolution of carbon dioxide gradually diminishes over the reaction time. Most of the solvent is removed under reduced pressure and the residue is dissolved in about 400 ml of benzene. The solution is washed three times with water, three times with dilute sodium bisulfite, again with water, and finally with saturated sodium bicarbonate. The solvent is removed under vacuum and the residue is recrystallized once from 50 ml of methanol and once more from 50 ml of isopropanol to give 12.3 g of 3-(2,6-dichlorophenyl)glutaronitrile having a melting point (mp) of 104°-6° C.
Reaction SMILES: [Li]CCCC.C[N:7]([CH3:12])[CH2:8][CH2:9]NC.N1C=[CH:17][CH:16]=[C:15]([CH:19]=[O:20])C=1.IC>C1COCC1>[CH3:17][C:16]1[CH:9]=[CH:8][N:7]=[CH:12][C:15]=1[CH:19]=[O:20]
Reactant: CNCCN(C)C
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: Cc1ccncc1C=O
Reaction time: 0.25 h

Procedure:
n-BuLi (1.6 M in hexanes) (2.2 mmol, 1.37 ml) was added dropwise to a stirred solution of N,N,N'-trimethylethylenediamine (2.4 mmol, 0.245 g) in THF at -78° C. A solution of 3-pyridinecarboxaldehyde (2 mmol, 0.214 g) in THF was added and the mixture stirred for 15 min before adding a further portion of n-BuLi (1.6M in hexanes) (4 mmol, 2.5 ml). After stirring for 2 h at -70° C., iodomethane was added, the mixture stirred at RT for 30 min, then poured into aqueous NaCI solution, extracted twice with Et2O, dried (MgSO4), filtered and concentrated in vacuo. The residue was subjected to chromatography (SiO2 ; Et2O) to afford the title compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:22]([CH:23]([CH3:27])[C:24](O)=[O:25])[N:21]=[C:20]([C:28]([F:31])([F:30])[F:29])[N:19]=1.C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:24](=[O:25])[CH:23]([N:22]3[C:18]([CH3:17])=[N:19][C:20]([C:28]([F:29])([F:30])[F:31])=[N:21]3)[CH3:27])[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(N)cnn1-c1ccc(F)cc1
Reactant: Cc1nc(C(F)(F)F)nn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(F)(F)F)nn1C(C)C(=O)Nc1cnn(-c2ccc(F)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 30.7 %

Procedure:
To a solution of 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (0.050 g, 0.23 mmol) in DMF (1.0 mL) was added 2-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl]propanoic acid (0.051 g, 0.23 mmol), followed by diisopropylethylamine (0.059 g, 0.46 mmol) and HATU (0.105 g, 0.28 mmol). After stirring at room temperature for 1 h, the reaction was diluted with water and the aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resulting crude product was purified by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.03 g, 0.0706 mmol, 31%). 1H NMR (400 MHz, CDCl3) δ 8.24 (s, 1H), 8.04-7.99 (m, 1H), 7.35-7.25 (m, 2H), 7.22-7.11 (m, 2H), 5.13 (q, J=7.2 Hz, 1H), 3.05-2.93 (m, 1H), 2.62 (s, 3H), 1.93 (d, J=7.2 Hz, 3H), 1.27 (dd, J=7.2, 2.9 Hz, 3H), 1.10 (d, J=7.1 Hz, 3H); MS: (ES) m/z calculated for C19H20F4N6O [M+H]+ 425.2, found 425.0.