Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@H:1]1([OH:8])[CH2:6][CH2:5][CH2:4][C@H:3]([OH:7])[CH2:2]1.[H-].[Na+].[Cl:11][C:12]1[CH:19]=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]>O1CCCC1>[Cl:11][C:12]1[CH:19]=[C:18]([O:7][C@@H:3]2[CH2:4][CH2:5][CH2:6][C@@H:1]([OH:8])[CH2:2]2)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: O[C@H]1CCC[C@H](O)C1
Reactant: N#Cc1ccc(F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(O[C@@H]2CCC[C@@H](O)C2)cc1Cl
Reaction time: 0.17 h
Yield: 9.2 %

Procedure:
A commercial mixture of cis/trans 1,3-cyclohexanediol (7.77 g, 66.9 mmol) was dissolved in 50 mL anhydrous THF (tetrahydrofuran), under a nitrogen atmosphere, and cooled in an ice/acetone bath. NaH (60% suspension in oil, 2.69 g, 6.725 mmol) was then added and the solution stirred approximately 10 min. Then a solution of 2-chloro-4-fluorobenzonitrile (1.06 gms, 6.79 mmol)(in 20 mL anhydrous THF was added in a slow, steady stream (not dropwise). The cold bath was removed, and allowed to stir at room temperature overnight. The reaction was quenched with approximately 10 mL 5% citric acid and the THF was removed by rotovap. off. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted twice more with ethyl acetate and the organic layers were combined. The combined organic layers were washed twice with brine, then dried over magnesium sulfate, filtered and rotovapped. The resulting product was triturated with hexane, and the hexane decanted off. The crude product was chromatographed with an ethyl acetate hexane gradient (10% ethyl acetate to 50% ethyl acetate), and the desired fractions were combined, and the solvent removed. The results of two such runs were combined, and submitted for preparative reverse phase HPLC. The title compound (0.1575 g) was returned. HNMR (CDCl3, ppm) 7.5 (1H, d, J=8.8 Hz), 6.96 (1H, s), 6.82 (1H, d, J=8.8 Hz), 4.8-4.6 (1H, m), 4.2-4.1 (1H, m), 2.1-1.4 (9H, m).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([CH3:12])[C:10]#[N:11].[CH2:13](N)[CH2:14][NH2:15]>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([C:10]1[NH:15][CH2:14][CH2:13][N:11]=1)[CH3:12]
Reactant: CC(C#N)c1cccc(F)c1F
Reactant: NCCN
Product: CC(C1=NCCN1)c1cccc(F)c1F

Procedure:
rac-2-[1-(2,3-Difluoro-phenyl)-ethyl]-4,5-dihydro-1H-imidazole was prepared from rac-2-(2,3-difluoro-phenyl)-propionitrile and ethylene diamine in analogy to Example 19 b): off-white solid; MS (EI): 210.1 ((M+H)+.).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:17])[CH:11]=2)[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]1.[CH3:18][NH:19][CH3:20]>C1(C)C=CC=CC=1>[CH3:17][O:16][C:12]1[CH:11]=[C:10]([C:4]2([CH2:3][CH2:2][N:19]([CH3:20])[CH3:18])[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5]2)[CH:15]=[CH:14][CH:13]=1
Reactant: CNC
Reactant: COc1cccc(C2(CCCl)C=CCCC2)c1
Solvent: Cc1ccccc1
Product: COc1cccc(C2(CCN(C)C)C=CCCC2)c1
Reaction time: 5 h

Procedure:
1 g of 1-[1-(2-chloroethyl)-2-cyclohexen-1-yl]-3-methoxybenzene is dissolved in 10 ml of toluene, and the solution is treated with 10 ml of dimethylamine. The mixture is held at 150° C. for 5 hours in a bomb tube. After evaporation of the solvent, the residue is treated with 3 N hydrochloric acid. The aqueous phase is extracted with ether and made alkaline with an excess of ammonia, whereupon the precipitated rac. 1-(m-methoxyphenyl)-N,N-dimethyl-2-cyclohexene-1-ethylamine is taken up in methylene chloride. The hydrochloride of this compound melts at 161°-162° C.
Reaction SMILES: O.[C:2]1([C:8]([CH:10]=[O:11])=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>ClC(Cl)C.[Ti](Cl)(Cl)(Cl)Cl>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([CH:10]([OH:11])[C:8](=[O:9])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: O=CC(=O)c1ccccc1
Reactant: CC(C)(C)c1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)(C)c1ccc(C(O)C(=O)c2ccccc2)cc1

Procedure:
Phenylglyoxal monohydrate (304 mg, 2 mM) and tert-butylbenzene (0.62 ml, 4 mM) were dissolved in dichloroethane (2 ml), titanium tetrachloride (0.33 ml, 3 mM) was added, and reacted at room temperature for 2.5 hours. Using the same procedure as in Example 1, 4'-tert-butylbenzoin was obtained as crystal (216.9 mg, 40.5% yield).
Reaction SMILES: [C-:1]#[C-:2].[Li+].[Li+].[C:5]1([C:11]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[O:12])[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.Cl.O>C1COCC1>[CH:5]1([C:11]([OH:12])([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:1]#[CH:2])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: O=C(c1ccccc1)C1CCCCC1
Reactant: [C-]#[C-]
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: C#CC(O)(c1ccccc1)C1CCCCC1
Temperature: 0 °C

Procedure:
Lithium acetylide (47.84 g, 0.52 mole) was added to 70 ml of THF. The solution was cooled to 0° C. and a solution of cyclohexyl phenyl ketone in 100 ml of THF was added over a period of 15 minutes with stirring. The solution was allowed to warm to room temperature and stirred for 16 hours. The solution was then cooled to 0° C. and 50 ml of a 5N HCl was added. The solution was then warmed to room temperature and 200 ml of water was added. The solution was transferred to a separatory funnel and washed with ether. The ether washes were combined and dried. Upon removal of the ether under vacuum and vacuum distillation of the crude product a pale yellow oil was isolated (60.33 g, 82.9%): bp 111°-4° C. (0.8 mm), NMR (CDCl3) δ7.7-7.2(m, 5H), 2.6(s, 1H), 2.3(s, 1H), 2.1-0.9(m, 11H). IR (neat) 3433, 3304, 2111, 1448, 1016 cm-1.
Reaction SMILES: [NH2:1][C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:15])([CH3:14])[C@H:3]1[OH:16].[C:17]([N:19]=[C:20](OC)[CH2:21][CH2:22][CH2:23]Cl)#[N:18].C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:17]([N:19]=[C:20]1[CH2:21][CH2:22][CH2:23][N:1]1[C@@H:2]1[C:7]2[CH:8]=[C:9]([C:12]#[N:13])[CH:10]=[CH:11][C:6]=2[O:5][C:4]([CH3:14])([CH3:15])[C@H:3]1[OH:16])#[N:18]
Reactant: COC(CCCCl)=NC#N
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](N2CCCC2=NC#N)[C@@H]1O
Temperature: 25 °C
Yield: 12.2 %

Procedure:
A solution of trans-4-amino-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (5.0 g), methyl N-cyano-4-chlorobutyrimidate (7.36 g), triethylamine (4.8 ml), and toluene (12 ml) was stirred at 100° C. for 2 days. After being cooled to room temperature, the reaction mixture was concentrated. The residue was taken up in ethyl acetate and washed with brine, dried over anhydrous magnesium sulfate, and concentrated. After purification by column chromatography on silica gel (elution with chloroform-methanol 25:1), the crude product was further purified by recrystallization from ethyl acetate to give trans-4-(2-cyanoiminopyrrolidin-1-yl)-3,4-dihydro-2,2-dimethyl-3-hydroxy-2H-1-benzopyran-6-carbonitrile (0.87 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([NH2:10])=[CH:9][C:4]=2[CH2:3][CH2:2]1.CO.[CH:13](I)([CH3:15])[CH3:14]>C(N(CC)CC)C>[CH:13]([NH:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH2:2][CH2:3][C:4]=2[CH:9]=1)([CH3:15])[CH3:14]
Reactant: Nc1ccc2c(c1)CCO2
Reactant: CC(C)I
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)Nc1ccc2c(c1)CCO2

Procedure:
To a solution of 40 g. of 2,3-dihydro-5-benzofuranamine in 200 ml. of methanol is added 23 ml. of isopropyl iodide and 35 ml. of triethylamine. The solution is refluxed for 55 hours and then concentrated in vacuo. The resultant oil is extracted several times with diethyl ether, the extract combined, filtered through Celite, and the ether removed in vacuo to obtain an oil of N-isopropyl-2,3-dihydro-5-benzofuranamine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13](I)[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:31][CH2:32][CH2:33][CH2:34][S:35]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)(=[O:37])=[O:36]>>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([CH2:31][CH2:32][CH2:33][CH2:34][S:35]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:36])=[O:37])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[N:19]([CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:18](=[O:29])[CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCN1C(=O)CN(c2ccc(I)cc2OCc2ccccc2)S1(=O)=O
Reactant: O=S(=O)(CCCCI)Cc1ccccc1
Product: C[Si](C)(C)CCN1C(=O)CN(c2ccc(CCCCS(=O)(=O)Cc3ccccc3)cc2OCc2ccccc2)S1(=O)=O

Procedure:
The title compound is prepared from 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-2-(2-trimethylsilanylethyl)-1,2,5-thiadiazolidin-3-one and (4-iodobutane-1-sulfonylmethyl)-benzene analogous to Example 571 step B.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([CH:11]=[O:12])[C:5]=2[CH:4]=[CH:3]1.[Mg].Br[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22]>O1CCCC1>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[CH:11]([C:6]1[C:5]2[CH:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[CH:8][CH:7]=1)[OH:12]
Reactant: Cn1ccc2c(C=O)cccc21
Reactant: COc1ccccc1Br
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccccc1C(O)c1cccc2c1ccn2C

Procedure:
Using the procedure of Step B of Example 1, 36.8 g of the product of Step A and 104 ml of a solution of 2-bromo anisole magnesium compound in tetrahydrofuran titrating 1.94N were reacted. Extraction was carried out with ethyl acetate and the extracts were washed with salt water and brought to dryness. The residue was chromatographed on silica (eluant: methylene chloride) to obtain 46.5 g of the expected product melting at 95° C.
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[C:2]=[O:3].[N+:11](=[C:13]1[N:17]=[CH:16][N:15]=[C:14]1[C:18]([NH2:20])=[O:19])=[N-:12]>CS(C)=O>[C:18]([C:14]1[N:15]=[CH:16][N:17]2[C:2](=[O:3])[N:1]([CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:12]=[N:11][C:13]=12)(=[O:19])[NH2:20]
Reactant: [N-]=[N+]=C1N=CN=C1C(N)=O
Reactant: CCOC(=O)CCN=C=O
Solvent: CS(C)=O
Product: CCOC(=O)CCn1nnc2c(C(N)=O)ncn2c1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Ethyl 3-isocyanatopropionate (Alfa Lancaster) (0.504 mL, 3.83 mmol) was added drop wise to a suspension of 5-diazoimidazole-4-carboxamide (0.450 g, 3.65 mmol) in dry dimethylsulfoxide (4.5 mL) at room temperature under nitrogen. The reaction was stirred in the dark at room temperature. After 16 hours, the reaction mixture was poured onto ice (approximately 25 mL) and the resulting precipitate was washed with ethyl acetate (10 mL) and ether (10 mL) to afford the title compound as a pale brown solid. Yield: 770 mg, 2.75 mmol, 75%. LCMS (ES+), m/z 281 (M+H)+ at 1.60 minutes. 1H NMR (400 MHz, d6-DMSO) δ: 8.86 (1H, s), 7.75 (1H, br s), 7.62 (1H, br s), 4.51 (2H, t), 4.07 (2H, q), 2.89 (2H, t), 1.17 (3H, t).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)=[O:11].F[C:20]1[C:25]([C:26]2([F:32])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[N:24][CH:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O>[NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:20]2[C:25]([C:26]3([F:32])[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)=[N:24][CH:23]=[CH:22][N:21]=2)=[CH:14][CH:13]=1)=[O:11]
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Reactant: Fc1nccnc1C1(F)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2nccnc2C2(F)CCOCC2)cc1)c1nc2ccccc2[nH]1

Procedure:
A solution of (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (0.543 g, 2.278 mmol),2-fluoro-3-(4-fluorotetrahydro-2H-pyran-4-yl)pyrazine (0.304 g, 1.519 mmol), cesium carbonate (0.990 g, 3.04 mmol), and N-Methyl-2-pyrrolidinone (3.04 mL) in a sealed tube was heated to 100° C. overnight. Aqueous work up with DCM and washing with alternating water and brine washes. The organic layer was rotovapped and loaded onto a Biotage samplet. Purification by Biotage (0-100% EtOAc/hexane, slow gradient, over 12 CV). The product containing fractions were concentrated by rotovap. The residue was further purified by trituration with EtOH at room temperature overnight to produce product. MS (ESI, pos. ion) m/z: 419.1 (M+1). IC50 (uM) +++++.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[C:17]([OH:19])=O)[C:10](=[O:27])[CH:9]=2)[CH:7]=1.[NH2:30][C:31]1[CH:41]=[CH:40][C:34]([C:35]([O:37]CC)=[O:36])=[CH:33][CH:32]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:28]#[N:29])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][CH:21]3[CH2:22][CH2:23][O:24][CH2:25][CH2:26]3)[C:17]([NH:30][C:31]3[CH:41]=[CH:40][C:34]([C:35]([OH:37])=[O:36])=[CH:33][CH:32]=3)=[O:19])[C:10](=[O:27])[CH:9]=2)[CH:7]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cn(C(CC2CCOCC2)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: COc1cn(C(CC2CCOCC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
1.38 g (3.31 mmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-(tetrahydro-2H-pyran-4-yl)propanoic acid (racemate), 547 mg (3.31 mmol) of ethyl 4-aminobenzoate, 471 mg (3.31 mmol) of Oxima and 516 μl (3.31 mmol) of DIC in 33 ml of dimethylformamide were reacted according to General Method 5B. The crude product was purified by flash chromatography (120 g cartridge, 85 ml/min, cyclohexane/ethyl acetate gradient). Yield: 1.10 g (58% of theory)
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].I[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=1[CH3:19].[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][NH:23][C:22]1=[O:27].NCCN>O1CCOCC1.[Cu]I>[CH3:20][N:21]1[CH2:26][CH2:25][CH2:24][N:23]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][C:11]=2[CH3:19])[C:22]1=[O:27]
Reactant: Cc1cc([N+](=O)[O-])ccc1I
Reactant: CN1CCCNC1=O
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: NCCN
Solvent: C1COCCO1
Product: Cc1cc([N+](=O)[O-])ccc1N1CCCN(C)C1=O
Temperature: 110 °C
Reaction time: 19 h

Procedure:
16.1 g (76.1 mmol) of potassium phosphate and 0.362 g (1.90 mmol) of copper(I) iodide are initially charged, and the apparatus is baked out and then flushed with argon. 10.0 g (38.1 mmol) of 1-iodo-2-methyl-4-nitrobenzene, 6.51 g (57.0 mmol) of 1-methyltetrahydropyrimidin-2(1H)-one and 0.394 g (3.80 mmol) of N,N′-dimethylenediamine in 200 ml of dioxane are added, and the mixture is stirred at 110° C. After 19 h, after cooling, the mixture is filtered with suction through kieselguhr and then washed three times with 100 ml of ethyl acetate. The solvent is removed under reduced pressure and the residue is purified by chromatography on silica gel (2:1→1:1 cyclohexane/ethyl acetate). This affords 5.94 g (63% of theory) of the desired compound.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][C:9]1[C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=[C:11]([NH:19]C(=O)OC(C)(C)C)[CH:10]=1>C(Cl)Cl>[NH2:19][C:11]1[CH:10]=[C:9]([CH3:8])[C:14]2[NH:15][C:16](=[O:18])[O:17][C:13]=2[CH:12]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)cc2oc(=O)[nH]c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)cc2oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
400 μL (5.30 mmol) TFA were added to 230 mg (0.900 mmol) tert-butyl (4-methyl-2-oxo-2,3-dihydro-benzoxazol-6-yl)-carbamate in 5.0 ml DCM and the mixture was stirred for 1.5 h at RT. The reaction mixture was evaporated down and the residue was divided between semisaturated sodium hydrogen carbonate solution and EtOAc. The organic phase was dried on sodium sulphate, filtered and evaporated down.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10]([Si:12]([CH3:15])([CH3:14])[CH3:13])#[CH:11]>C(N(CC)CC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH3:13][Si:12]([C:10]#[C:11][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:15])[CH3:14]
Reactant: C#C[Si](C)(C)C
Reactant: O=Cc1cccc(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1cccc(C=O)c1
Temperature: 25 °C
Yield: 77.9 %

Procedure:
To a solution of 3-bromobenzaldehyde (10.00 g, 54.08 mmol) and triphenylphosphine (0.500 g, 1.91 mmol) in anhydrous triethylamine (100 mL) under argon were added ethynyltrimethylsilane (6.00 g, 61.09 mmol) and palladium (II) acetate (0.100 g, 0.445 mmol). The final mixture was heated to reflux for 2 hours, and was then cooled to room temperature and filtered. The filtrate was concentrated under vacuum to a thick oil, which was purified by column chromatography (dichloromethane/petroleum ether 1:4) to give 8.52 g (78.0% yield) of 3-(trimethylsilylethynyl)benzaldehyde [1H-NMR (CDCl3) δ ppm: 0.26 (s, 9H, SiMe3), 7.47 (t, 1H, ArH, J=7.5 Hz), 7.70 (d, 1H, ArH, J=7.5 Hz), 7.82 (d, 1H, ArH, J=7.5 Hz), 7.96 (s, 1H ArH), 9.98 (s, 1H, CHO)]. This compound (5.00 g, 24.74 mmol) was treated with K2CO3 (0.500 g) in methanol (50 mL) at 25° C. for 2 hours under argon. The solvent was removed under vacuum, and the residue was dissolved in dichloromethane (100 mL). This solution was washed once with a saturated aqueous NaHCO3 solution, and once with water, before being dried over anhydrous Na2SO4 and the solvent evaporated under vacuum. The yellow residue was purified by column chromatography using dichloromethane/petroleum ether 1:4 for elution, and recrystallized from cyclohexane to give 2.80 g (87.1% yield) of the title compound; MS (EI) m/e 130.0; (M+). 1H-NMR (CDCl3) δ ppm: 3.20 (s, 1H, CH), 7.51 (t, 1H, ArH, J=7.8 Hz), 7.74 (d, 1H, ArH, J=7.8 Hz), 7.87 (d, 1H, ArH, J=7.8 Hz), 7.99 (s, 1H, ArH), 10.02 (s, 1H, CHO).
Reaction SMILES: CS(O[CH:6]1[CH2:9][N:8]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH2:7]1)(=O)=O.[N-:23]=[N+:24]=[N-:25].[Na+]>CS(C)=O.C(Cl)Cl>[N:23]([CH:6]1[CH2:9][N:8]([C:10]([N:12]2[CH2:18][CH2:17][CH2:16][N:15]([CH:19]3[CH2:22][CH2:21][CH2:20]3)[CH2:14][CH2:13]2)=[O:11])[CH2:7]1)=[N+:24]=[N-:25]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Agent: [Na+]
Solvent: ClCCl
Solvent: CS(C)=O
Product: [N-]=[N+]=NC1CN(C(=O)N2CCCN(C3CCC3)CC2)C1
Temperature: 80 °C
Yield: 82.5 %

Procedure:
1-[(4-cyclobutyl-1,4-diazepan-1-yl)carbonyl]azetidin-3-yl methanesulfonate (200 mg, 0.61 mmol) was dissolved in DMSO (4 ml) and sodium azide (157 mg, 2.41 mmol) was added. The reaction was heated at 80° C. for 48 hours and then diluted with DCM (30 ml) and washed with water (10 ml), dried (MgSO4), filtered and concentrated at reduced pressure giving a yellow solid (140 mg, 83%), which was used directly in the next step.
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[C:22]([O:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30])(=[O:24])[CH3:23]>>[C:22]([O:25][C:26]1[CH:34]=[CH:33][CH:32]=[C:28]([C:29](=[O:30])[NH:2][C@H:3]([CH:19]([CH3:21])[CH3:20])[C:4]([N:6]2[CH2:11][CH2:10][CH:9]([C:12]3[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=3)[CH2:8][CH2:7]2)=[O:5])[CH:27]=1)(=[O:24])[CH3:23]
Reactant: CC(C)[C@@H](N)C(=O)N1CCC(c2ccc(Cl)cc2)CC1
Reactant: CC(=O)Oc1cccc(C(=O)O)c1
Agent: Cl
Product: CC(=O)Oc1cccc(C(=O)N[C@@H](C(=O)N2CCC(c3ccc(Cl)cc3)CC2)C(C)C)c1
Yield: 50 %

Procedure:
(R)-2-Amino-1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methylbutan-1-one hydrochloride was coupled with 3-acetoxy benzoic acid in a similar manner as described for the preparation of Example 75 to give (R)-3-((1-(4-(4-chlorophenyl)piperidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamoyl)phenyl acetate (115 mg, 50% yield). MS found: 457.3 (M+).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:28][C:29]([CH3:38])([CH3:37])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[NH:34][CH:35]=1>C(Cl)Cl>[CH3:28][C:29]([CH3:38])([CH3:37])[CH2:30][C:31]1[N:32]=[C:33]([CH3:36])[N:34]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:35]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(CC(C)(C)C)c[nH]1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(CC(C)(C)C)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Triethylamine (70 mL, 0.5 mol) followed by trityl chloride (90 g, 0.32 mol) were added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-methyl-1H-imidazole (49 g, 0.32 mmol) in methylene chloride (1 L). After stirring at ambient temperature for 30 min, the reaction mixture was washed with water and brine, dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 10-20% ethyl acetate/hexane afforded the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:20]([C:25]1C=C(C)C=C[C:26]=1S([O-])(=O)=O)[CH2:21][CH2:22]CC.O>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([CH:21]([CH2:20][CH2:25][CH3:26])[CH3:22])[CH:13]=[CH:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCc1cc(C)ccc1S(=O)(=O)[O-]
Reactant: c1ccc(COc2ccc3[nH]ccc3c2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(C)n1ccc2cc(OCc3ccccc3)ccc21
Temperature: 0 °C
Reaction time: 18 h

Procedure:
5-Benzyloxyindole (7) (8.81 g, 39.5 mmol, 1.0 equiv., supplied by Combi-Blocks) was dissolved in anhydrous DMF (100 mL) and the solution was cooled to 0° C. Dry sodium hydride (1.89 g, 78.9 mmol, 2.0 equiv.) was added slowly. The mixture was warmed to room temperature over 30 minutes. 2-Pentyl-tosylate was added dropwise. The mixture was stirred for 18 h. Water was added slowly (dropwise at first) to quench excess NaH. The resulting mixture was extracted once with ether, and then washed with water and brine, respectively. The organic phase was dried with MgSO4, and concentrated on a rotary evaporator to yield a crude oil. The crude product was purified by flash column chromatography (3:1 hexanes/ethyl acetate) to yield 5-(benzyloxy)-1-(pentan-2-yl)-1H-indole (8) as an amber oil (10.67 g) of approximately 90% purity, which was used in the next step without any further purification. 1H NMR (500 MHz, CDCl3) δ7.50 (d, J=7.3 Hz, 2H), 7.40 (t, J=7.3 Hz, 2H), 7.34 (d, J=7.3 Hz, 1H), 7.29 (d, J=9.0 Hz, 1H), 7.17 (dd, J=8.9, 2.4 Hz, 1H), 6.96 (dd, J=8.9, 2.4 Hz, 1H), 6.44 (d, J=3.1 Hz, 1H), 5.12 (s, 2H), 4.44 (m, 1H), 1.88 (m, 1H), 1.77 (m, 1H), 1.50 (d, J=6.8 Hz, 3H), 1.23 (m, 2H), 0.89 (t, J=7.4 Hz, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:14][OH:15].CC([O-])=O.[Na+]>CCO.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([NH2:11])[O:15][N:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: N#CCC(=O)c1cccc(Br)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2cccc(Br)c2)no1

Procedure:
To a solution of 3-(3-bromophenyl)-3-oxopropanenitrile (1.12 g; 5.00 mmol; Note 1) in EtOH (20 mL) was added a solution of hydroxylamine hydrochloride (1.74 g; 25 mmol) and NaOAc (2.46 g; 30 mmol) in water (20 mL). The mixture was heated under reflux for 1 h, cooled and concentrated in vacuo. The residue was slurried in 1N NaOH and extracted with Et2O (×1). The organic layer was washed (water, brine), dried over Na2SO4 and concentrated in vacuo affording the title compound as a pale yellow solid which was used without further purification. LC/MS (method B) 2.21 min, m/z 239, 241 (Br isotopes).