Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[NH:17][CH:16]=2)=[CH:6][C:3]=1[C:4]#[N:5].[C:22]([C:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1)#[N:23].N1C=CC=CC=1.CN(C)C=O>O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C.O>[NH2:1][C:2]1[N:9]=[C:8]([C:10]2[O:11][CH:12]=[CH:13][CH:14]=2)[C:7]([C:15]2[CH:20]=[CH:19][C:18](=[O:21])[N:17]([C:27]3[CH:28]=[CH:29][C:24]([C:22]#[N:23])=[CH:25][CH:26]=3)[CH:16]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1cc(-c2ccc(=O)[nH]c2)c(-c2ccco2)nc1N
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(-n2cc(-c3cc(C#N)c(N)nc3-c3ccco3)ccc2=O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 30.9 %

Procedure:
2-Amino-6-(2-furyl)-5-(6-oxo-1,6-dihydro-3-pyridinyl)nicotinonitrile (20 mg, 0.071 mmol), 4-cyanophenylboronic acid (35 mg, 0.24 mmol), copper acetate monohydrate (3.0 mg, 0.015 mmol), pyridine (0.015 mL, 0.19 mmol) and N,N-dimethylformamide (1.0 mL) were introduced into a reaction vessel and stirred at room temperature for 20 hours. Water was added to the reaction solution, followed by extracting with ethyl acetate. The organic layer was dried, and then dissolved in dimethyl sulfoxide (1.0 mL) and purified by high performance liquid chromatography, to give the title compound as a yellow solid (8.32 mg, 62%).
Reaction SMILES: [Sn](Cl)Cl.Cl.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([F:19])([F:18])([F:17])([F:16])[F:15])=[CH:10][CH:9]=1)([O-])=O.[OH-].[Na+]>ClCCl>[NH2:5][C:8]1[CH:13]=[CH:12][C:11]([S:14]([F:19])([F:15])([F:16])([F:17])[F:18])=[CH:10][CH:9]=1
Reactant: O=[N+]([O-])c1ccc(S(F)(F)(F)(F)F)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Agent: [Na+]
Solvent: ClCCl
Product: Nc1ccc(S(F)(F)(F)(F)F)cc1
Temperature: 80 °C
Yield: 99.3 %

Procedure:
A solution of tin(II) chloride (1465 g., 7.73 mol) in concentrated (32 percent) aqueous HCl solution was heated with stirring to 80° C. and then, with ice cooling, 4-nitrophenylsulfur pentafluoride (584 g., 2.344 mol) was introduced in 8 portions over the course of 1 h. The internal temperature was kept below 100° C. during this. Subsequently, the mixture was stirred at an internal temperature of 85° C. for 1.5 h and then cooled to 45° C. over the course of a further hour. A mixture of ice (12 kg), NaOH (2 kg) and dichloromethane (1.5 l) was prepared and added to the reaction mixture with vigorous stirring. The phases were separated, the aqueous phase was extracted 3 times with 1 l of dichloromethane each time, and the combined organic phases were dried over Na2SO4 and evaporated in vacuo. 510 g (99%) of 4-aminophenylsulfur pentafluoride were obtained as a pale yellow crystalline powder, m.p. 63-65° C. (Bowden, R. D., Comina, P. J., Greenhall, M. P., Kariuki, B. M., Loveday, A., Philip, D. Tetrahedron 2000, 56, 3399: 56-59° C.).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2.[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21]Br)[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH2:17]([O:19][CH:20]([O:23][CH2:24][CH3:25])[CH2:21][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C@H:7]([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6][CH2:5]2)[CH3:18]
Reactant: CCOC(CBr)OCC
Reactant: CCOC(=O)C[C@@H]1CCc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C[C@@H]1CCc2cc(OCC(OCC)OCC)ccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
To a solution of ethyl [(1S)-5-hydroxy-2,3-dihydro-1H-inden-1-yl]acetate (Example 6, 1.55 g, 7.04 mmol) and bromoacetaldehyde diethyl acetal (4.85 g, 24.6 mmol) in DMF (10 mL) was added Cs2CO3 (2.75 g, 8.44 mmol) followed by water (5 mL). The reaction mixture was heated to reflux for 5 h, cooled to rt, and stirred for 18 h. The solvents were then evaporated under reduced pressure and the residue was dissolved in EtOAc. The organic solution was washed with water, dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to afford the product (1.62 g, 68%) containing minor impurities. 1H NMR (400 MHz, CDCl3) δ 1.21-1.29 (m, 9H) 1.72-1.78 (m, 1H), 2.35-2.48 (m, 2H), 2.74-2.89 (m, 3H), 3.53-3.78 (m, 7H), 4.16 (d, 2H), 4.69 (t, 1H), 6.71 (d, 1H), 6.78 (s, 1H) 7.05 (d, 1H).
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34]>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]([CH3:36])([CH3:35])[CH2:33][OH:34])[C:5]=1[O:21][CH3:22]
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Reactant: CC(C)(CO)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1OCC(C)(C)CO
Temperature: 80 °C
Yield: 7.9 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (100 mg, 0.31 mmol) in acetonitrile (10 mL) was added potassium carbonate (128 mg, 0.930 mmol) and 3-bromo-2,2-dimethyl-propan-1-ol (155 mg, 0.930 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by prep TLC to afford title compound as a solid (10 mg, 8%).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:10][C:4]=2[CH:3]=1.Cl[CH2:24][CH2:25][N:26]1[CH2:30][CH2:29][O:28][C:27]1=[O:31].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>C(O)CCC>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]2[O:6][C:7]3[CH:20]=[CH:19][CH:18]=[CH:17][C:8]=3[CH:9]([N:11]3[CH2:12][CH2:13][N:14]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][O:28][C:27]4=[O:31])[CH2:15][CH2:16]3)[CH2:10][C:4]=2[CH:3]=1
Reactant: O=C1OCCN1CCCl
Reactant: Clc1ccc2c(c1)CC(N1CCNCC1)c1ccccc1O2
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CCCCO
Product: O=C1OCCN1CCN1CCN(C2Cc3cc(Cl)ccc3Oc3ccccc32)CC1

Procedure:
8.5 G. of 1-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-piperazine are stirred at reflux for 4 hours together with 8.1 g. of 3-(2-chloro-ethyl)-2-oxazolidinone, 2.95 g. of sodium carbonate and 0.4 g. of sodium iodide in 50 ml. of butanol. Then, the solvent is evaporated under reduced pressure and the residue partitioned between water and chloroform. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is recrystallized from methanol, and there is obtained 3-[2-{4-[2-chloro-10,11-dihydro-dibenz[b,f]oxepin-10-yl]-1-piperazinyl}-ethyl]-2-oxazolidinone having a melting point of 159°-160° C. The maleate, prepared in acetone, melts at 175°-177° C. (with decomposition). The dihydrochloride hydrate, prepared in ethanol, melts at 179°-181° C. (with decomposition).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[NH:26][C:27](=[O:31])[CH:28]([CH3:30])[NH2:29].C(N(CC)CC)C>O1CCOCC1>[Cl:15][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:29][CH:28]([C:27](=[O:31])[NH:26][C:17]1[CH:18]=[CH:19][C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=1)[CH3:30])[C:11]([C:12]([OH:14])=[O:13])=[CH:10]2
Reactant: CC(N)C(=O)Nc1ccc2ccccc2c1
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)Nc1ccc2ccccc2c1
Temperature: 135 °C
Reaction time: 24 h
Yield: 59.5 %

Procedure:
A mixture of 2,6-dichloroquinoline-3-carboxylic acid (194 mg, 0.8 mmol), DL-alanine-β-naphthylamide (251 mg, 1 mmol) and triethylamine (900 mg, 8.9 mmol) in dioxane (1 mL) is stirred for 24 h at 135° C. in closed reaction vial. After evaporation of solvents in vacuo, the residue is acidified by addition of 2N HCl, and the precipitated solid is collected on filter, washed with water and recrystallized from MeOH-water to give the title compound (200 mg, 60%) as yellow needles.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=O.Cl.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16]N)=[CH:12][CH:11]=1>C(O)(=O)C.O>[Br:9][C:10]1[CH:11]=[C:12]2[C:13](=[CH:14][CH:15]=1)[NH:16][CH:6]=[C:5]2[CH2:4][CH2:3][CH2:2][Cl:1]
Reactant: O=CCCCCCl
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Product: ClCCCc1c[nH]c2ccc(Br)cc12
Temperature: 25 °C
Yield: 24.5 %

Procedure:
5-Chloropentanal (ca. 70% pure, 8.0 g) was added to a suspension of 4-bromophenylhydrazine hydrochloride (13.4 g) in aqueous acetic acid (50%, 300 ml). The mixture was heated rapidly to boiling with vigorous stirring and maintained at reflux for 7 hours. The resulting dark brown solution was cooled to room temperature, diluted with water (300 ml) and extracted with ethyl acetate (4×150 ml). The combined extracts were washed with water (200 ml) and saturated aqueous sodium hydrogen carbonate (4×250 ml), dried (MgSO4), filtered and evaporated to a dark brown oil (14.7 g), which was purified on a silica column (Kieselgel 60, 200 g) eluted with ethyl acetate:light petroleum (b.p. 60°-80°) (1:2) followed by bulb to bulb distillation twice in vacuo to give the title compound as a yellow oil (4 g) b.p. 200° C., 0.5 mm, which rapidly darkened on storage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH3:13])[C:4]=1[C:5](Cl)=[O:6].[NH2:14][C:15]1[N:19]=[CH:18][NH:17][N:16]=1>>[NH:17]1[CH:18]=[N:19][C:15]([NH:14][C:5](=[O:6])[C:4]2[C:3]([O:2][CH3:1])=[CH:11][CH:10]=[CH:9][C:8]=2[O:12][CH3:13])=[N:16]1
Reactant: Nc1nc[nH]n1
Reactant: COc1cccc(OC)c1C(=O)Cl
Product: COc1cccc(OC)c1C(=O)Nc1nc[nH]n1

Procedure:
2,6-Dimethoxybenzoyl chloride was reacted with 3-amino-1H-1,2,4-triazole according to the procedure of Example 118 to provide N-(1H-1,2,4-triazol-3-yl)-2,6-dimethoxybenzamide.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[NH2:14].[Cl:15][NH:16][CH2:17][CH2:18][N:19]([C:21](=[O:23])[CH3:22])[Cl:20].[OH:24][CH:25]1O[C@@H](CO)[C@H](O)[C@H](O)[C@H:26]1O>C(#N)C>[Cl:15][NH:16][CH2:17][CH2:18][N:19]([C:21](=[O:23])[CH3:22])[Cl:20].[O:23]=[C:21]1[NH:19][CH2:18][CH2:17][NH:16][C:25](=[O:24])[CH2:26][NH:14][CH:9]2[CH:8]([CH2:13][CH2:12][CH2:11][CH2:10]2)[NH:7][CH2:22]1
Reactant: N[C@@H]1CCCC[C@H]1N
Reactant: OC[C@@H]1OC(O)[C@H](O)[C@@H](O)[C@H]1O
Agent: CC(=O)N(Cl)CCNCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: O=C1CNC2CCCCC2NCC(=O)NCCN1

Procedure:
Sodium carbonate (226 g., 2.13 mol.) and trans-1,2-diaminocyclohexane (14.1 ml., 117 mmol.) were added to a solution of N,N'-dichloroacetylethylenediamine (25 g., 117 mmol.) in dry acetonitrile (3.75 l.) under nitrogen. N,N'-dichloroacetylethylenediamine was prepared as reported by Lin W.C., Fiqueira, J. A. D and Alt, H. G. in "New multidentate potential inophors of ether-amide type", Monat. Chem., 1985, 116, 217-221. The reaction mixture was refluxed for 20 hours. The insoluble material formed was filtered off and the volume of the filtrate was reduced to 1 l. by evaporation. Crystals of the compound (A) slowly formed at room temperature. They were collected by filtration and the product was purified by crystallization in acetonitrile. The yield was 7.43 g. of a white solid.
Reaction SMILES: [CH:1]1([N:4]2[CH:8]=[CH:7][CH:6]=[N:5]2)[CH2:3][CH2:2]1.[Br:9]Br>C(Cl)(Cl)Cl.[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])(O)=O.[Na+]>[Br:9][C:7]1[CH:6]=[N:5][N:4]([CH:1]2[CH2:3][CH2:2]2)[CH:8]=1
Reactant: BrBr
Reactant: c1cnn(C2CC2)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Brc1cnn(C2CC2)c1
Reaction time: 1 h

Procedure:
To a solution of crude 1-cyclopropyl-1H-pyrazole (108 mg, 1.00 mmol) in CHCl3 (4 mL) at room temperature was added Br2 (51 uL, 1.0 mmol) via syringe. The orange solution was stirred for 1 h. The reaction was diluted with saturated aqueous Na2S2O3 (3 mL) and saturated aqueous NaHCO3 (3 mL). The mixture was extracted with CH2Cl2 (3×5 mL). The combined organic layers were dried over Na2SO4 and concentrated on a rotary evaporator without heating the sample to give 4-bromo-1-cyclopropyl-1H-pyrazole as a volatile, light yellow liquid that was used without further purification, m/z 187.3 [M+H]+.
Reaction SMILES: [C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][NH:19][CH2:18]1)([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2].[CH3:23][C:24]1[CH:32]=[CH:31][C:27]([CH2:28][CH2:29]Br)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:4]([CH:17]1[CH2:22][CH2:21][CH2:20][N:19]([CH2:29][CH2:28][C:27]2[CH:31]=[CH:32][C:24]([CH3:23])=[CH:25][CH:26]=2)[CH2:18]1)([C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)(=[O:3])[NH2:2]
Reactant: Cc1ccc(CCBr)cc1
Reactant: NC(=O)C(c1ccccc1)(c1ccccc1)C1CCCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(CCN2CCCC(C(C(N)=O)(c3ccccc3)c3ccccc3)C2)cc1

Procedure:
A mixture containing 3-(R,S)-(1-carbamoyl-1,1-diphenylmethyl)piperidine (0.26 g), 4-methylphenethyl bromide (0.2 g), anhydrous potassium carbonate (0.3 g) and acetonitrile (10 ml) was heated under reflux for 4.5 hours. The mixture was partitioned between dichloromethane (30 ml) and 10% aqueous sodium carbonate (30 ml), the layers separated, and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were dried (MgSO4) and concentrated in vacuo to give a colourless solid which was recrystallised from methanol to give the title compound, yield 0.13 g, m.p. 167°-169° C.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].C1C=C(O)C2N=CC=CC=2C=1>OCC(CO)O>[CH2:11]([OH:12])[C@H:9]([C@H:7]([C@@H:5]([C@@H:3]([CH2:2][OH:1])[OH:4])[OH:6])[OH:8])[OH:10]
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: Oc1cccc2cccnc12
Solvent: OCC(O)CO
Product: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO

Procedure:
The sorbitol was obtained from Roquette Corporation under the designation "Neosorb P60." The gum base used was a conventional chewing gum base. The glycerin was obtained from Proctor and Gamble Co. under the designation "Superol 99.5 U.S.P. Glycerin." The mannitol was also obtained from the Roquette Corporation under the designation "Mannitol-F." The lycasin was also obtained from Roquette. The lecithin was obtained from Central Soya. The color was obtained from Warner Jenkins.
Reaction SMILES: O=[C:2]1[O:7][C:6](=[O:8])[C:5]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:4]=2[NH:3]1>CN(C)C1C=CN=CC=1.CN(C)C=O.CO.C(OCC)(=O)C>[NH2:3][C:4]1[CH:12]=[CH:11][C:10]([C:13]([OH:15])=[O:14])=[CH:9][C:5]=1[C:6]([O:7][CH3:2])=[O:8]
Reactant: O=C(O)c1ccc2[nH]c(=O)oc(=O)c2c1
Agent: CN(C)c1ccncc1
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(=O)O)ccc1N
Yield: 83.8 %

Procedure:
150 mg (1.21 mmol) of 4-dimethylaminopyridine are added to 2.5 g (12.1 mmol) of 2,4-dioxo-1,4-dihydro-2H-3,1-benzoxazine-6-carboxylic acid [described in J. Med. Chem., (1981), 24(6), 735-742] in solution in 10 ml of dimethylformamide and 10 ml of methanol, and the mixture is heated at 60° C. for 3 hours. The reaction medium is concentrated under reduced pressure. The residue is taken up in water and extracted with ethyl acetate. The organic phase is washed with a saturated sodium chloride solution, dried over sodium sulphate and concentrated under reduced pressure. The solid obtained is taken up in ethyl acetate, filtered and dried. 1.98 g of a white powder are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[CH3:21][N:22](C=O)C>C(OCC)(=O)C.[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:21]([C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1)#[N:22]
Reactant: CN(C)C=O
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc(Br)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(C#N)c2)CC1
Temperature: 80 °C
Reaction time: 12 h
Yield: 80 %

Procedure:
A suspension of 1,1-dimethylethyl 4-(3-bromophenyl)piperazine-1-carboxylate obtained in Reference Example 112 (3.10 g, 9.09 mmol), zinc cyanide (0.587 g, 5.00 mmol) and tetrakis(triphenylphosphine)palladium (0.525 g, 0.454 mmol) in DMF (30 mL) was stirred at 80° C. for 12 hr under nitrogen atmosphere. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (25%-40% ethyl acetate/hexane), and crystallized from hexane to give the title compound as a white powder (2.10 g, 80%).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[CH3:6][N:7]([CH3:11])[C:8]([NH2:10])=[O:9]>C(#N)C>[CH3:6][N:7]([C:8]1[O:9][C:2](=[O:3])[S:4][N:10]=1)[CH3:11]
Reactant: CN(C)C(N)=O
Reactant: O=C(Cl)SCl
Solvent: CC#N
Product: CN(C)c1nsc(=O)o1
Temperature: 23 °C
Reaction time: 1 h

Procedure:
A solution of chlorocarbonylsulfenyl chloride (11.5 g) in acetonitrile was added to a suspension of N,N-dimethylurea (25.0 g) in acetonitrile (200 ml), over a period of 20 minutes. The reaction mixture was stirred for 1 hour at 23° C., then filtered. Methanol (20 ml) was added to the filtrate to decompose excess chlorocarbonylsulfenyl chloride. The solvents were removed in vacuo. The residue was purified by chromatography on silica using dichloromethane in hexane (3:1) to afford the product as a yellow oil. 1H NMR (250 MHz, CDCl3) d 3.04 (6H, s, (CH3)2); MS (CI+) m/z 164 (M+ +NH4+)
Reaction SMILES: [OH:1][CH2:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH2:7][OH:8].CO[CH:12](OC)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C=O)C.C(OCC)(=O)C>[C:13]1([CH:12]2[O:9][CH:3]([CH2:4][CH2:5][CH2:6][CH2:7][OH:8])[CH2:2][O:1]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: OCCCCC(O)CO
Reactant: COC(OC)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCCCCC1COC(c2ccccc2)O1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
To a solution of 1,2,6-trihydroxyhexane (10.0 g, 74.6 mmol) and benzaldehyde dimethylacetal (15.0 g, 98.7 mmol) in dry DMF (10 mL) was added Amberlyst 15 (5.0 g). The mixture was stirred at 100° C. for 5 min, then cooled and filtered. The filtrate was concentrated and residue obtained was re-dissolved in ethyl acetate. After being washed with water and brine, the solution was dried over Na2SO4. The crude product obtained after evaporation of the solvent was chromatographed on silica eluting with ethyl acetate. Concentration of the proper fractions afforded 11.0 g (66%) of the title product (a mixture of diastereomers) as a colorless oil: 1H NMR (CDCl3, 300 MHz, ppm) 7.48 (m, 2H), 7.39 (m, 3H), 5.92 (s, 0.4H), 5.80 (s, 0.6H), 4.3-4.1 (m, 2H), 3.64 (m, 3H), (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH3:10][C:11]1[CH:17]=[CH:16][C:15]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:12]=1[NH2:13].C(N(C(C)C)CC)(C)C>C(O)C>[C:18]([C:15]1[CH:16]=[CH:17][C:11]([CH3:10])=[C:12]([NH:13][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH:14]=1)([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccc(C(C)(C)C)cc1N
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1ccc(C(C)(C)C)cc1Nc1nc(Cl)ncc1F
Temperature: 25 °C
Yield: 68.3 %

Procedure:
A solution of 2,4-dichloro-5-fluoropyrimidine (307 mg, 1.84 mmol), 2-methyl-5-t-butylaniline (300 mg, 1.84 mmol) and diisopropylethylamine (2 mL) in ethanol (2 mL) was heated at 80° C. for 16 h in an oil bath. The mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel Biotage 40M, eluting with EtOAc/hexane to afford the product (369 mg, 68%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2=[N:18][C:19]([C:22]3[CH:23]=[N:24][NH:25][CH:26]=3)=[CH:20][N:21]=[C:16]2[N:15]=[N:14]1.I[CH2:28][CH2:29][OH:30].C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[CH2:12][N:13]1[C:17]2=[N:18][C:19]([C:22]3[CH:26]=[N:25][N:24]([CH2:28][CH2:29][OH:30])[CH:23]=3)=[CH:20][N:21]=[C:16]2[N:15]=[N:14]1
Reactant: Fc1cc2ncccc2cc1Cn1nnc2ncc(-c3cn[nH]c3)nc21
Reactant: OCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: OCCn1cc(-c2cnc3nnn(Cc4cc5cccnc5cc4F)c3n2)cn1
Temperature: 120 °C
Yield: 31.7 %

Procedure:
7-fluoro-6-{[6-(1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl]methyl}quinoline (95 mg, 0.274 mmol), 2-iodoethanol (378 mg, 2.198 mmol), K2CO3 (75.8 mg, 0.548 mmol), DMAC 95 ml) were combined and heated in microwave at 120° C. for 4 h. The reaction mixture was concentrated and the resulting residue was purified via flash column chromatography eluted with 0-5% MeOH:CH2Cl2 to give the desired product as a solid (33.9 mg, 31%).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:25])[C:11]2[CH:16]=[C:15]([NH2:17])[C:14]([NH:18][CH3:19])=[CH:13][C:12]=2[N:20]([CH3:24])[CH2:21][C:22]#[N:23])[CH2:5][CH2:4]1.[Cl:28][C:29]1[C:42]([N:43]=[C:44]=S)=[C:41]([Cl:46])[CH:40]=[CH:39][C:30]=1[CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35].CC(C)N=C=NC(C)C>CN(C=O)C>[F:1][C:2]([F:26])([F:27])[C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:11]2[C:12]([N:20]([CH3:24])[CH2:21][C:22]#[N:23])=[CH:13][C:14]3[N:18]([CH3:19])[C:44]([NH:43][C:42]4[C:41]([Cl:46])=[CH:40][CH:39]=[C:30]([CH2:31][NH:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[C:29]=4[Cl:28])=[N:17][C:15]=3[CH:16]=2)=[O:25])[CH2:5][CH2:4]1
Reactant: CNc1cc(N(C)CC#N)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1N
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CN(CC#N)c1cc2c(cc1C(=O)N[C@H]1CC[C@H](C(F)(F)F)CC1)nc(Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl)n2C

Procedure:
The title compound is prepared in analogy to 1e from N-(trans-4-trifluoromethyl-cyclohexyl)-2-[N-methyl-N-cyanomethyl-amino]-4-methylamino-5-amino-benzoic acid amide (48 mg, 0.125 mmol), and N-(2,4-dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (40 mg, 0.125 mmol), DIC (19 μL) and DMF (2.0 mL).
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:31]=[C:32]([C:43]([OH:45])=O)[CH:33]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=2)[CH:35]=1)=[O:5])C.[CH3:46][NH2:47]>>[C:4]([CH2:6][CH2:7][C:8]1[C:9]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[C:34]([C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[CH:33]=[C:32]([C:43](=[O:45])[NH:47][CH3:46])[CH:31]=2)=[CH:10][CH:11]=[CH:12][C:13]=1[O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])([OH:3])=[O:5]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)O)cc(-c3cccc(F)c3)c2)c1CCC(=O)OCC
Reactant: CN
Product: CNC(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1

Procedure:
The title compound was prepared according to the general procedure described in Steps 7 and 8 of Method C starting from 5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-3′-fluoro-biphenyl-3-carboxylic acid and methylamine.