Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[CH:8]=[C:9](B3OC(C)(C)C(C)(C)O3)[C:10]([NH2:13])=[N:11][CH:12]=2)[CH2:3][CH2:2]1.Cl[C:24]1[CH:33]=[C:32]([F:34])[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([C:35]#[N:36])[CH:25]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C([O-])(O)=O.[Na+]>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].CCOC(C)=O.O.COCCOC>[NH2:13][C:10]1[C:9]([C:24]2[CH:33]=[C:32]([F:34])[C:27]([C:28]([O:30][CH3:31])=[O:29])=[C:26]([C:35]#[N:36])[CH:25]=2)=[CH:8][C:7]([CH:4]2[CH2:3][CH2:2][O:1][CH2:6][CH2:5]2)=[CH:12][N:11]=1
Reactant: COC(=O)c1c(F)cc(Cl)cc1C#N
Reactant: CC1(C)OB(c2cc(C3CCOCC3)cnc2N)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: COC(=O)c1c(F)cc(-c2cc(C3CCOCC3)cnc2N)cc1C#N
Temperature: 100 °C
Yield: 36.5 %

Procedure:
To a 2 mL microwave vial were added 5-(tetrahydro-2H-pyran-4-yl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (638 mg, 1.049 mmol), methyl 4-chloro-2-cyano-6-fluorobenzoate (140 mg, 0.655 mmol), Pd2(dba)3 (30.0 mg, 0.033 mmol), XPhos (31.2 mg, 0.066 mmol), NaHCO3 (275 mg, 3.28 mmol), DME (3 mL) and H2O (1.5 mL). The solution was heated under microwave at 100° C. for 15 min. Water and EtOAc were added and the aqueous layer was extracted three times with EtOAc. The organic layers were combined, dried over Na2SO4 and concentrated. The residue was purified on a silica gel column (heptane:EtOAc 1:0 to 1:4) to give the product as a yellow foam (85 mg). LCMS (m/z) 356.1 (MH+), 0.58 min.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[CH2:17]([NH2:21])[CH2:18][CH2:19][CH3:20].CCN(C(C)C)C(C)C>Cl.CCCCO>[CH2:17]([NH:21][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[N:5]=[CH:6][N:7]=1)[CH2:18][CH2:19][CH3:20]
Reactant: COc1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: CCCCN
Agent: Cl
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: CCCCNc1cc(Nc2ccc(OC)cc2)ncn1
Temperature: 200 °C
Yield: 81 %

Procedure:
75 mg of 6-chloro-N-(4-methoxyphenyl)pyrimidine-4-amine in the form of a hydrochloride, 23 mg of butan-1-amine and 90 mg of DIPEA were dissolved in 1 mL of n-BuOH and charged into a microwave vial and the vial obtained was heated to 200° C. for 45 minutes under microwave irradiation. The reaction was monitored by TLC. The crude product was obtained by evaporating n-BuOH. Purification was carried out by column chromatography using EtOAc. N4-Butyl-N6-(4-methoxyphenyl)pyrimidine-4,6-diamine in the form of a colorless solid was obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[C:3](=O)[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([C:10](OC)=[O:11])=[CH:8][C:7]=1[O:16][CH3:17].CCOCC.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH3:1][N:2]([CH3:19])[CH2:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([CH2:10][OH:11])=[CH:8][C:7]=1[O:16][CH3:17]
Reactant: COC(=O)c1ccc(OCC(=O)N(C)C)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: COc1cc(CO)ccc1OCCN(C)C
Temperature: 5 °C
Yield: 100 %

Procedure:
Methyl 4-{[2-(dimethylamino)-2-oxoethyl]oxy}-3-(methyloxy)benzoate (for a preparation see Intermediate 22) (1.4 g, 5.2 mmol) was dissolved in THF (50 ml) and cooled in an ice-bath under nitrogen. The mixture was then treated cautiously with 1M ether solution of lithium aluminium hydride (5.5 mL) and the mixture was stirred at 5° C. allowing to warm to RT overnight. The reaction mixture was quenched by cautious addition of aq. saturated NaHCO3 solution (1 mL), followed by MgSO4 (2 g) and stirring for 30 min. The solids were removed by filtration, washed with ethyl acetate, and the filtrate was evaporated to give the title compound (1.18 g, 100%) as a yellow oil: LCMS (System A) RT=0.34 min, ES+ve m/z 226 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=O)C.[N:20]#[C:21][NH2:22].C([O-])(=O)C>>[C:1]([O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][C:21]([NH2:22])=[NH:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CN
Reactant: NCCOCCOC(=O)c1ccccc1
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: N=C(N)NCCOCCOC(=O)c1ccccc1
Temperature: 90 °C
Yield: 62.1 %

Procedure:
2.14 g (10.2 mmol) of 2-(2-aminoethoxy)ethyl benzoate and 0.624 g (10.4 mmol) of acetic acid were placed in a 50 ml two neck flask. While heating the flask in a 90° C. oil bath, 0.680 g (16.2 mmol) of cyanamide was added. After 6 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=1/2 containing 0.5% acetic acid) to obtain 1.97 g of the title compound (wax-like, 6.33 mmol, 62.0% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]=[C:12]=[S:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2].[C:14](O)(=[O:22])[C:15]1[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=1)[NH2:17]>C(O)(=O)C>[CH:1]([O:4][C:5]1[CH:6]=[C:7]([N:11]2[C:14](=[O:22])[C:15]3[C:16](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:17][C:12]2=[S:13])[CH:8]=[CH:9][CH:10]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Oc1cccc(N=C=S)c1
Reactant: Nc1ccccc1C(=O)O
Solvent: CC(=O)O
Product: CC(C)Oc1cccc(-n2c(=S)[nH]c3ccccc3c2=O)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of 3-isopropoxy aniline (6.0 g, 40 mmol), in 150 mL of CHC3 was added dropwise thiophosgene (2.81 mL, 44 mmol) at 0° C. After the addition of thiophosgene, triethylamine (7.0 mL, 48 mmol) was added slowly and the reaction mixture was stirred for 2 hours at room temperature. It was then concentrated and diluted with 200 mL of ethyl acetate. The triethylamine hydrochloride salt was filtered off and the filtrate was concentrated to yield crude 3-isopropoxyphenyl isothiocyanate. The crude 3-isopropoxyphenyl isothiocyanate was dissolved in 150 mL of acetic acid, and anthranilic acid (6.04 g, 44 mmol) was added. The resulting reaction mixture was refluxed for 16 hours and then cooled to room temperature. The white solid was separated which was filtered to yield 9.0 g of the title compound (72.1%), mp 288°-290° C.
Reaction SMILES: Cl.[OH:2][CH2:3][CH:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.F[C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1.C(N(C(C)C)C(C)C)C>>[C:15]([C:14]1[CH:17]=[CH:18][C:11]([N:7]2[CH2:8][CH2:9][CH:4]([CH2:3][OH:2])[CH2:5][CH2:6]2)=[CH:12][CH:13]=1)#[N:16]
Reactant: OCC1CCNCC1
Reactant: N#Cc1ccc(F)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1ccc(N2CCC(CO)CC2)cc1

Procedure:
A solution of 12.2 g of 4-hydroxymethyl-piperidine-hydrochloride, 9.8 g of 4-fluorobenzonitrile and 28.3 ml of N-ethyl-diisopropylamine is heated to 140° C. for 4 hours. After cooling, it is chromatographed over silica gel using methylene chloride and methylene chloride/ethyl acetate (1:1) as eluant. After the solvent has been removed under reduced pressure the residue remaining is triturated with petroleum ether and suction filtered. Yield: 5.1 g (29% of theory), Melting point: 148°-150° C.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[O-:24][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:27])=[O:26]>>[N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]3[S:19][C:18]4[CH:20]=[CH:21][C:22]([O:27][S:25]([C:28]([F:31])([F:30])[F:29])(=[O:26])=[O:24])=[CH:23][C:17]=4[CH:16]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: c1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1
Reactant: O=S(=O)([O-])C(F)(F)F
Product: O=S(=O)(Oc1ccc2sc(-c3ccc(OCCN4CCCC4)cc3)cc2c1)C(F)(F)F
Yield: 56 %

Procedure:
The title compound was prepared from 5-methoxy-[2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophene in 56% yield for 2 steps via demethylation previously described and triflate formation by a conventional method.
Reaction SMILES: C([BH3-])#N.[Na+].[C:5]1([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH:13]=[CH:14][NH:15]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[OH-].[Na+].C(OCC)(=O)C>FC(F)(F)C(O)=O>[C:5]1([C:11]2[CH:19]=[CH:18][CH:17]=[C:16]3[C:12]=2[CH2:13][CH2:14][NH:15]3)[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: c1ccc(-c2cccc3[nH]ccc23)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: c1ccc(-c2cccc3c2CCN3)cc1
Temperature: -5 °C
Reaction time: 2 h
Yield: 48.8 %

Procedure:
1.0 g of sodium cyanoborohydride is gradually added to a solution of 1.5 g of 4-phenylindole in 20 ml of trifluoroacetic acid under argon, cooled to a temperature of about −5° C. The reaction mixture is stirred at a temperature of about 0° C. for 2 hours, and is then poured into 50 g of ice and alkalinized with 30 ml of a concentrated sodium hydroxide solution. After the addition of 100 ml of ethyl acetate, the mixture is stirred at ambient temperature and treated with 10 ml of concentrated sodium hydroxide, and then separated by settling out. The organic phase is dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is treated again with a mixture of 50 ml of water, 50 ml of ethyl acetate and 10 ml of a concentrated sodium hydroxide solution and stirred at ambient temperature for 15 minutes, and then separated by settling out. The organic phase is separated and the aqueous phase is extracted with 2×50 ml of ethyl acetate. The organic phases are combined, dried over anhydrous magnesium sulfate, filtered, and then concentrated to dryness under reduced pressure. The residue is triturated from 20 ml of diisopropyl ether and then concentrated to dryness under reduced pressure. The residue is purified by chromatography on a 50 g column of 20-45 μm silica, elution being carried out with pure dichloromethane. 0.74 g of 4-phenyl-2,3-dihydro-1H-indole is thus obtained in the form of a cream-colored solid, the characteristics of which are the following:
Reaction SMILES: [CH:1]([O:3][CH2:4][CH3:5])=[CH2:2].[CH3:6][C:7]([OH:12])([CH:10]=[CH2:11])[C:8]#[CH:9]>>[CH2:1]([O:3][CH:4]([O:12][C:7]([CH3:6])([CH:10]=[CH2:11])[C:8]#[CH:9])[CH3:5])[CH3:2]
Reactant: C#CC(C)(O)C=C
Reactant: C=COCC
Product: C#CC(C)(C=C)OC(C)OCC

Procedure:
By reacting ethyl vinyl ether with 3-methyl-4-penten-1-yn-3-ol in the manner of Example 1, the compound 1-ethoxy-1-[3-methyl-4-penten-1-yn-3-oxy]ethane was produced.
Reaction SMILES: O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.I[C:18]1[C:23]([F:24])=[CH:22][C:21]([N:25]2[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]2=[O:35])=[CH:20][C:19]=1[F:36].C[Sn](C)(C)[C:39]1[CH:45]=[CH:44][C:43](=[O:46])[C:42]([O:47][CH3:48])=[CH:41][CH:40]=1>O1CCOCC1.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.C(Cl)(Cl)Cl.[Pd].[Pd]>[CH3:48][O:47][C:42]1[C:43](=[O:46])[CH:44]=[CH:45][C:39]([C:18]2[C:23]([F:24])=[CH:22][C:21]([N:25]3[CH2:29][C@H:28]([CH2:30][NH:31][C:32](=[O:34])[CH3:33])[O:27][C:26]3=[O:35])=[CH:20][C:19]=2[F:36])=[CH:40][CH:41]=1
Reactant: COc1ccc([Sn](C)(C)C)ccc1=O
Reactant: CC(=O)NC[C@H]1CN(c2cc(F)c(I)c(F)c2)C(=O)O1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1coc(P(c2ccco2)c2ccco2)c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-c2c(F)cc(N3C[C@H](CNC(C)=O)OC3=O)cc2F)ccc1=O
Temperature: 110 °C
Reaction time: 0.75 h
Yield: 68.4 %

Procedure:
The tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (450 mg, 0.492 mmol) and the trifurylphosphine (460 mg, 1.969 mmol) were stirred together for 5 min in 1,4-dioxane (25 mL), followed by the addition of (S)-N-[[3-(4-iodo-3,5-difluorophenyl)-2-oxo-5-oxazolidinyl]methyl]acetamide (1.3 g, 3.28 mmol). After degassing the solution three times with N2, the trimethyl(4-methoxy-5-oxo-1,3,6-cycloheptatrien-1-yl)tin (1.47 g, 4.92 mmol) was added. The solution was degassed again (3×) and then the solution was heated to reflux (110 ° C.) for 12 h under N2. Upon cooling, the reaction was determined to be complete by TLC (10% MeOH/CHCl3, UV short wave). The reaction was concentrated under reduced pressure and then redissolved in CH2Cl2 (100 mL). This solution was stirred over aqueous KF (100 mL) for 45 min and then separated. The organic portion was washed with brine (100 mL) and then dried over anhydrous Na2SO4. After drying, it was filtered and concentrated under reduced pressure to yield a brown solid. The crude product was chromatographed on silica gel (175 g of silica gel, packed with 10% CH3CN/CHCl3, eluting with a gradient of 1-5% MeOH in 10% CH3CN/CHCl3) to give a pale yellow solid. This solid was recrystalized by dissolving it in CH2Cl2 /MeOH and triturating with ether to yield 907 mg (68%) of the title compound as an off-white solid with mp 129 ° C (dec) and a HRMS (M+) calculated for C20H18N2O5F2 404.1184, found 404.1183.
Reaction SMILES: [Cl-].Cl[C:3](=[N+:10]([CH3:12])[CH3:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:13]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[CH:13]1([N:19]=[C:3]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:10]([CH3:12])[CH3:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: NC1CCCCC1
Reactant: C[N+](C)=C(Cl)c1ccccc1
Agent: [Cl-]
Solvent: ClCCl
Product: CN(C)C(=NC1CCCCC1)c1ccccc1
Reaction time: 8 h
Yield: 49 %

Procedure:
To the solution of (α-chlorobenzylidene)dimethylammonium chloride in methylenechloride described in Example 1, there was added dropwise, a solution of 49.6 g (0.5 mole) of cyclohexylamine in 100 ml of methylenechloride. The temperature of the ensuing exothermal reaction rose from 24.5° to 42.5° C. thus keeping the solvent in reflux. After the reaction subsided, the reaction mixture, consisting of a slurry of white solids in a pale yellow solution, was heated to reflux with stirring. After standing overnight, the slurry was filtered, and the solution was stripped of the solvent and the oily residue distilled. The novel amidine (also called N'-cyclohexyl-N,N-dimethylbenzenecarboximidamide) was obtained as a colorless oil, boiling between 78° and 79° C. at 0.04 mm of mercury pressure and having a refractive index of nD 21.6, 1.5400, in 56.0 g corresponding to a 49% yield. Proton nmr infrared and elemental analysis confirmed its proposed structure.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCCCCC.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][N:20]([C:26]2[N:31]=[CH:30][C:29]([C:2]3[N:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:3]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:22]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: c1cc(N2CCOCC2)ncc1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=O.C(O)C.[O-][Si]([O-])=O.[Mg+2].[N+:16]([CH3:19])([O-:18])=[O:17]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][NH:4][C:3]1=[CH:19][N+:16]([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: CC1CCNC1=O
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CCNC1=C[N+](=O)[O-]

Procedure:
A solution of 12.7 grams (0.10 mole) of the ethyl imidate of 3-methyl-2-pyrrolidone in 30 milliliters of nitromethane was refluxed for four days with occasional distillation of ethanol by-product to bring the reflux temperature back to 100°C. Excess nitromethane (and ethanol present) then was evaporated under reduced pressure to give a dark oily residue. The residue was dissolved in ethyl acetate and passed through a Florisil column. Evaporation of the solvent from the filtrate left a crystalline residue, which when recrystallized from ether, gave 4.6 grams of 3-methyl-2-(nitromethylene)pyrrolidine, as a white solid, melting point: 47- 47.5°C.
Reaction SMILES: BrC1C=NN([C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH2:16][CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:14])=[CH:11][N:10]=2)C=1OC.Cl.CN(C)C1C=C(B2OC(C)(C)C(C)(C)O2)C=CN=1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[O:20]1[CH2:21][CH2:22][CH:17]([CH2:16][NH:15][C:13](=[O:14])[C:12]2[CH:23]=[CH:24][CH:9]=[N:10][CH:11]=2)[CH2:18][CH2:19]1
Reactant: COc1c(Br)cnn1-c1ccc(C(=O)NCC2CCOCC2)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CN(C)c1cc(B2OC(C)(C)C(C)(C)O2)ccn1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(NCC1CCOCC1)c1cccnc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Combined 6-(4-bromo-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (80 mg, 0.202 mmol), N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine hydrochloride (173 mg, 0.607 mmol), PdCl2(dppf)-CH2Cl2 adduct (16.53 mg, 0.020 mmol) and sodium bicarbonate (136 mg, 1.619 mmol) in dioxane (0.6 mL) and water (0.15 mL) was let stir for 15 min. The mixture was then capped and heated at 110° C. for 1 h in the microwave. Additional PdCl2(dppf)-CH2Cl2 adduct (17 mg) was then added and the heating continued at 110° C. for 1 h in the microwave. The reaction mixture was diluted with EtOAc, concentrated onto Celite® and purified on a 10 g NH silica gel column eluted with 10 to 100% EtOAc in hexanes to give 64442-(dimethylamino)pyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide as a brown oil. MS m/z 437 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C@:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([OH:9])[C:6]([OH:8])=O)[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:43][C:44]1[CH:45]=[C:46]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[NH2:50].O>CN(C=O)C.C(OCC)(=O)C>[NH2:43][C:44]1[CH:45]=[C:46]([NH:51][S:52]([CH3:55])(=[O:54])=[O:53])[CH:47]=[CH:48][C:49]=1[NH:50][C:6](=[O:8])[C@@:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=1)([OH:9])[C:4]([O:3][CH2:1][CH3:2])=[O:18]
Reactant: CS(=O)(=O)Nc1ccc(N)c(N)c1
Reactant: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)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: CCOC(C)=O
Product: CCOC(=O)[C@@](O)(Cc1ccc(F)cc1)C(=O)Nc1ccc(NS(C)(=O)=O)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-3-ethoxy-2-(4-fluorobenzyl)-2-hydroxy-3-oxopropanoic acid (1.28 g, 5 mmol), HATU (1.9 g 5 mmol), N-(3,4-diaminophenyl) methanesulfonamide (1 g, 5 mmol) in 4 mL of DMF was stirred at rt overnight. To this mixture was added water (20 ml) and ethyl acetate (50 ml). The organic layer was separated and washed with water (10 ml) and then concentrated in vacuo after being dried over anhydrous MgSO4. The residue was purified by PREP-HPLC to give the product as white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]([O:12][C:13](=[O:15])[NH2:14])[CH2:7][C:8]([N:10]=[O:11])=[O:9].[N+:16]([O-])([OH:18])=[O:17]>C(OC(=O)C)(=O)C.C(O)(=O)C>[N+:16]([C:5]1[S:1][C:2]([CH:6]([O:12][C:13](=[O:15])[NH2:14])[CH2:7][C:8]([N:10]=[O:11])=[O:9])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: NC(=O)OC(CC(=O)N=O)c1cccs1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: NC(=O)OC(CC(=O)N=O)c1ccc([N+](=O)[O-])s1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 11.7 %

Procedure:
In 4 ml of acetic anhydride there was suspended (2-(2-thienyl)-2-carbamoyloxyethyl)oxocarboxamide (0.50 g) and the resulting mixture was cooled to 0°. A mixture of nitric acid (60% in water 0.37 g) in 4 ml of acetic acid was added dropwise and the mixture was stirred at room temperature for 1.5 hours, poured into 100 ml of ice water, extracted with ethyl acetate and washed with saturated brine. The extracts were dried over sodium sulfate, filtered, concentrated and purified by recrystallization from ether to yield the title compound as a yellow solid (0.07 g, yield 12%). M.p. 145-1847 (from ether).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)=[O:7])[N:3]=[CH:2]1.[CH2:20]([Mg]Br)[CH:21]([CH3:23])[CH3:22]>C1COCC1>[NH:1]1[CH:5]=[C:4]([C:6]([C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[C:13]([O:18][CH3:19])[CH:14]=3)[CH:9]=2)([OH:7])[CH2:20][CH:21]([CH3:23])[CH3:22])[N:3]=[CH:2]1
Reactant: COc1ccc2cc(C(=O)c3c[nH]cn3)ccc2c1
Reactant: CC(C)C[Mg]Br
Solvent: C1CCOC1
Product: COc1ccc2cc(C(O)(CC(C)C)c3c[nH]cn3)ccc2c1

Procedure:
In a similar manner to that described in Example 1-(iv), the reaction of (1H-imidazol-4-yl)-(6-methoxynaphthalen-2-yl)ketone (0.60 g) with absolution of isobutylmagnesium bromide in THF (1.0 M, 2.4 ml) was carried out to give the titled compound (0.14 g) as a colorless solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:16]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([N:16]2[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH3:9])[CH2:4][CH2:3]1
Reactant: CN1CCC(C(C)(c2ccccc2)N2CCN(C(=O)OC(C)(C)C)CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN1CCC(C(C)(c2ccccc2)N2CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
To a solution of tert-butyl 4-[1-(1-methylpiperidin-4-yl)-1-phenylethyl]piperazine-1-carboxylate 0.16 g (0.41 mmol) in methylene chloride (20 ml) was added trifluoroacetic acid (5 ml) and resulting mixture stirred at room temperature for 2 hours. The reaction mixture was concentrated, dissolved in methylene chloride and washed with saturated sodium bicarbonate and brine. The methylene chloride solution was dried over sodium sulfate and concentrated to give 0.1 g (yield 82%) of desired product.
Reaction SMILES: [Li].Br[C:3]1(Br)[CH2:8][CH:7]=[CH:6][CH:5]=[C:4]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:16](Cl)(Cl)([Cl:18])[Cl:17]>CCCCC.CCOCC>[Cl:17][Si:16]1([Cl:18])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:4]2[C:3]1=[CH:8][CH:7]=[CH:6][CH:5]=2
Reactant: Cl[Si](Cl)(Cl)Cl
Reactant: BrC1(Br)CC=CC=C1c1ccccc1
Agent: [Li]
Solvent: CCCCC
Solvent: CCOCC
Product: Cl[Si]1(Cl)c2ccccc2-c2ccccc21

Procedure:
Lithium wire (3.33 g, 0.08 mol) was washed with pentane, carefully cut into small pieces, and suspended in 150 mL of Et2O. While stirring, 2,2-dibromobiphenyl (25 g, 0.08 mol) 100 mL of diethyl ether was added dropwise over 1 hour and the contents were allowed to stir for 10 hours. The mixture was filtered through a frit to remove any unreacted Li and LiBr. The filtrated was loaded into an addition funnel and slowly dropped into a solution containing SiCl4 (50 g, 0.08 mol) in 200 mL of Et2O. After addition, the contents were stirred at room temperature for 5 hours. The solvent was removed in vacuo and 300 mL of pentane was added. The solution was filtered to remove LiCl and the solvents were again removed in vacuo. The solids were then loaded into a sublimator and allowed to sublime at 150° C. under full vacuum. Yield was 10.0 g (51%).