Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: S(Cl)(Cl)=O.Cl.[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH:31]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(#N)C>[CH:31]1([NH:36][C:28]([C:25]2[CH:24]=[CH:23][C:22]3[S:21][C:20]4[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=4)[N:14]([CH:12]([CH3:13])[CH2:11][N:6]4[CH2:7][CH2:8][CH2:9][CH2:10]4)[C:27]=3[CH:26]=2)=[O:30])[CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Reactant: NC1CCCC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Solvent: O=S(Cl)Cl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)NC3CCCC3)cc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Thionyl chloride (5.2 cc) is added to a suspension, cooled to 5° C., of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (3.9 g) in methylene chloride (120 cc). The suspension is stirred for 3 hours at 25° C. and then concentrated to dryness at 30° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow residue which is taken up in methylene chloride (50 cc) at 5° C. Cyclopentylamine (5 cc) is added and the mixture is stirred for 12 hours at 25° C., and saturated sodium bicarbonate solution (150 cc) is then added. The mixture is extracted with ethyl acetate (2×100 cc). The organic phase is washed successively with distilled water (100 cc) and with brine (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (30 mm Hg; 4 kPa) to give a yellow oil which is dissolved in boiling acetonitrile (70 cc). Crystallization is primed by scratching. After cooling, the solid is separated by filtration, washed with acetonitrile (2×3 cc) and dried at 40° C. under reduced pressure (1 mm Hg; 0.13 kPa). N-Cyclopentyl-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide (2.1 g) is obtained in the form of cream-coloured crystals, m.p. 132° C.
Reaction SMILES: C1C2C(=CC=CC=2)C=CC=1N[N:12]=[C:13]([C:16]#[N:17])[C:14]#[N:15].[NH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=1.C(#N)CC#N.O.[NH2:35][NH2:36]>>[CH:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:27]=[CH:28][C:19]=1[NH:18][N:12]=[C:13]1[C:14]([NH2:15])=[N:36][N:35]=[C:16]1[NH2:17]
Reactant: N#CC(C#N)=NNc1ccc2ccccc2c1
Reactant: Nc1ccc2ccccc2c1
Reactant: NN
Solvent: N#CCC#N
Solvent: O
Product: NC1=NN=C(N)C1=NNc1ccc2ccccc2c1

Procedure:
4-(naphthalen-2-ylhydrazono)-4H-pyrazole-3,5-diamine was prepared using 110 mg (0.5 mmol) of 2-[(naphthalen-2-yl)hydrazono]malononitrile, which was derived from 2-aminonaphthalene (143 mg, 1.0 mmol) and malononitrile (1.5 mmol), and hydrazine hydrate. The hydrazine hydrate was added to the solution at a temperature of 75° C. despite the fact that the starting material had not fully dissolved. The solution cleared briefly and then a precipitate formed. The resulting solid was isolated by filtration, washed with ethanol, and dried to yield 86 mg (67%) of the compound as a tan coloured solid.
Reaction SMILES: [CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31](/[CH:35]=[CH:36]/[C:37]([O:39]CC)=[O:38])[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[N:7]=1)[CH3:2].O1CCCC1.[OH-].[Na+].Cl>O.C(O)C>[CH2:1]([C:3]1[S:4][CH:5]=[C:6](/[CH:8]=[CH:9]/[C:10]2[C:11]([O:21][CH2:22][C:23]3[CH:43]=[CH:42][C:26]([O:27][CH2:28][C:29]4[N:30]=[C:31](/[CH:35]=[CH:36]/[C:37]([OH:39])=[O:38])[O:32][C:33]=4[CH3:34])=[C:25]([O:44][CH3:45])[CH:24]=3)=[N:12][N:13]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:14]=2)[N:7]=1)[CH3:2]
Reactant: CCOC(=O)/C=C/c1nc(COc2ccc(COc3nn(-c4ccccc4)cc3/C=C/c3csc(CC)n3)cc2OC)c(C)o1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(/C=C/C(=O)O)oc3C)c(OC)c2)cs1
Temperature: 50 °C
Reaction time: 2 h
Yield: 87.9 %

Procedure:
To a mixture of ethyl (2E)-3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoate (0.25 g), tetrahydrofuran (2 mL) and ethanol (2 mL) was added 1N aqueous sodium hydroxide solution (2 mL), and the mixture was stirred at 50° C. for 2 hrs. 1N hydrochloric acid and water were added to the reaction mixture to acidify the solution, and the precipitated crystals were collected by filtration to give (2E)-3-[4-({4-[({4-[(E)-2-(2-ethyl-1,3-thiazol-4-yl)ethenyl]-1-phenyl-1H-pyrazol-3-yl}oxy)methyl]-2-methoxyphenoxy}methyl)-5-methyl-1,3-oxazol-2-yl]-2-propenoic acid as colorless crystals (0.21 g, yield 88%). Recrystallization from acetone-hexane gave colorless prism crystals. melting point: 125-126° C.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:29])=[O:28])[CH:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[ClH:36].[NH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][O:15][C:16]2[C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[CH:19]=[C:18]([O:26][S:27]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[Cl:36])(=[O:28])=[O:29])[CH:17]=2)[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2cc(OS(=O)(=O)c3ccccc3Cl)cc3ccccc23)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=S(=O)(Oc1cc(OCC2CCNCC2)c2ccccc2c1)c1ccccc1Cl
Reaction time: 1 h
Yield: 201.3 %

Procedure:
To a solution of 319 mg (0.596 mmol) of 2-chlorobenzenesulfonic acid 1-[[1-N-(tert-butoxycarbonyl)piperidin-4-yl]methoxy]naphthalen-3-yl ester, as prepared in the preceding step, in 2 mL of methylene chloride was added 1.5 mL (6 mmol) of 4N HCl in dioxane. The reaction mixture was stirred for 1 h and triturated with diethyl ether to afford 281 mg of the title compound as a colorless powder. 1H-NMR (300 MHz, DMSO-d6) δ 8.94 (bd, 1H, J=9 Hz), 8.68 (bd, 1 H, J=10 Hz), 8.6 (d, 1H, J=8 Hz), 7.8-7.98 (m, 4 Hz), 7.50-7.6 (m, 3H), 7.18 (d, 1H, J=2 Hz), 6.69 (d, 1H, J=2H), 3.94 (d, 2H, J=7 Hz), 2.93 (q,2 H), 2.16 (bm, 1H), 1.96 (d, 2H), and 1.57-1.71 (m, 2H). Mass spectrum (MALDI-TOF; gentisic acid matrix) calcd. for C22H22ClNO4S: 432.1 (M+H). Found: 431.5.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11]CC)=[O:10])=[CH:7][CH:6]=1)=[NH:4].Cl.[Cl:18]CCN>Cl>[ClH:18].[CH3:1][N:2]([CH3:16])[C:3]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)=[NH:4]
Reactant: NCCCl
Reactant: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Agent: Cl
Product: CN(C)C(=N)c1ccc(C(=O)O)cc1

Procedure:
Ethyl 4-(N,N-dimethylamidino)benzoate (compound of step 1 in Example 7) was heated under reflux in 6 N hydrochloric acid for 6 hours, and then the solvent was distilled off to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH2:13][CH3:14])[C:8]([O:10]CC)=[O:9])=[C:4]([C:17]#[C:18][C:19]2[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:31])[CH:3]=1.[OH-].[Na+].Cl>CCO.O>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][CH:7]([CH2:13][CH3:14])[C:8]([OH:10])=[O:9])=[C:4]([C:17]#[C:18][C:19]2[CH:24]=[C:23]([S:25]([CH2:28][CH2:29][CH3:30])(=[O:27])=[O:26])[CH:22]=[CH:21][C:20]=2[CH3:31])[CH:3]=1
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCS(=O)(=O)c1ccc(C)c(C#Cc2cc(Cl)ccc2OC(CC)C(=O)O)c1
Temperature: 70 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 2-(4-chloro-2-{[2-methyl-5-(propylsulfonyl)phenyl]ethynyl}phenoxy)butanoate (Intermediate 268; 100 mg; 0.11 mmol) in EtOH (1 ml) was treated with a 1M solution of sodium hydroxide in water (0.16 ml; 0.16 mmol). After stirring at 70° C. for 45 minutes, a 1 N solution of HCl in water (65 μl) was added, the solvents removed under reduced pressure and the residue purified by preparative HPLC to afford the title compound as a beige solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].C(=O)([O-])[O-:16].[Na+].[Na+]>O.CC(C)=O>[OH:16][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13]
Reactant: O=C(O)c1ccc(CBr)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1ccc(CO)c([N+](=O)[O-])c1
Yield: 95.7 %

Procedure:
4-Bromomethyl-3-nitrobenzoic acid (3.00 g, 11.5 mmol) and sodium carbonate (6.12 g, 57.7 mmol) were dissolved in water (40 mL) and acetone (40 mL). The reaction mixture was refluxed for 4 hours and then concentrated under reduced pressure to remove acetone. The residue was washed with diethyl ether three times. The aqueous layer was acidified with 6M hydrochloric acid, and then extracted with ethyl acetate three times. The combined organic layer was washed with water and brine, dried with sodium sulfate, filtered, concentrated under the reduced pressure. The residue was dried by means of a vacuum pump to give the desired product as brown solid (2.17 g, yield 95%).
Reaction SMILES: [I:1]I.[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([NH2:10])=[N:8][CH:9]=1>C(O)C.S([O-])([O-])(=O)=O.[Ag+2]>[Cl:3][C:4]1[CH:5]=[C:6]([I:1])[C:7]([NH2:10])=[N:8][CH:9]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: II
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCO
Product: Nc1ncc(Cl)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.8 %

Procedure:
Iodine (7.55 g; 29.73 mmol) was added to a mixture of 5-chloropyridin-2-amine (3.00 g; 22.87 mmol) and silver sulphate (9.36 g; 29.73 mmol) in ethanol (150 mL) and the mixture was stirred overnight at room temperature. The mixture was filtered over celite, washed with ethanol, and the filtrate concentrated under reduced pressure. The residue was dissolved in dichloromethane, and the solution was washed with a saturated aqueous solution of sodium thiosulphate. The organic layer was dried over magnesium sulphate, concentrated under reduced pressure and the crude material purified by flash chromatography on silica gel (eluent: 0 to 30% of ethyl acetate in heptane) to give 3.71 g (64%) of 5-chloro-3-iodopyridin-2-amine as a beige solid.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].I[CH:14]([CH3:16])[CH3:15]>C1C=CC=CC=1>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:14]([CH3:16])[CH3:15])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[OH:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([O:1][CH:14]([CH3:16])[CH3:15])[CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1O
Reactant: CC(C)I
Solvent: c1ccccc1
Product: COC(=O)c1ccc(O)cc1OC(C)C
Product: COC(=O)c1ccc(OC(C)C)cc1O
Temperature: 100 °C

Procedure:
To a solution of methyl 2,4-dihydroxybenzoate (5.4 g) and 2-iodopropane (10.2 g) in benzene (200 mL) was added Ag2CO3 and the mixture was heated in a 100° C. oil bath for 1 h. Additional methyl 2,4-dihydroxybenzoate (5 g) and 2-iodopropane (5 g) were added and the mixture was heated at 100° C. for another 2 h. After cooling, the mixture was filtered and concentrated. The residue was purified by flash chromatography eluted with 30:1 toluene/EtOAc to give 3 g of the title compound along with 1.2 g of isomer methyl 4-hydroxy-2-isopropoxybenzoate.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:7]([C:17]([NH2:19])=O)=[N:6]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(N(CC)CC)C>>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:8][C:7]([C:17]#[N:19])=[N:6]1
Reactant: COCCn1nc(C(N)=O)cc1CC1CCOCC1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: COCCn1nc(C#N)cc1CC1CCOCC1
Yield: 99.8 %

Procedure:
The method described in Part F of Example 3 was used to treat 1-(2-methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carboxamide (3.41 g, 12.7 mmol) with trifluoroacetic anhydride (1.98 mL, 14.0 mmol) in the presence of triethylamine (3.86 g, 38.1 mmol) with the following modifications. Extractions were carried out four times with chloroform, and the automated flash chromatography column was eluted with ethyl acetate. 1-(2-Methoxyethyl)-5-(tetrahydro-2H-pyran-4-ylmethyl)-1H-pyrazole-3-carbonitrile (3.16 g) was obtained as a colorless oil.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9](I)=[C:8]([CH3:12])[C:6]=2[N:7]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1B(O)O.CC1(C)C(C)(C)OB([C:38]2[CH:46]=[CH:45][CH:44]=[C:43]3[C:39]=2[CH:40]=[N:41][NH:42]3)O1>C([O-])([O-])=O.[Na+].[Na+].C(#N)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH:42]1[C:43]2[C:39](=[C:38]([C:2]3[N:3]=[C:4]([N:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)[C:5]4[S:10][C:9]([C:22]5[CH:23]=[N:24][CH:25]=[CH:26][C:21]=5[O:20][CH3:19])=[C:8]([CH3:12])[C:6]=4[N:7]=3)[CH:46]=[CH:45][CH:44]=2)[CH:40]=[N:41]1
Reactant: COc1ccncc1B(O)O
Reactant: CC1(C)OB(c2cccc3[nH]ncc23)OC1(C)C
Reactant: Cc1c(I)sc2c(N3CCOCC3)nc(Cl)nc12
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccncc1-c1sc2c(N3CCOCC3)nc(-c3cccc4[nH]ncc34)nc2c1C
Temperature: 150 °C

Procedure:
2-Chloro-6-iodo-7-methyl-4-morpholinothieno[3,2-d]pyrimidine from Example 12 (0.1 g, 0.3 mmol), 4-Methoxy-3-pyridineboronic acid (42 mg, 0.3 mmol), and bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13 μmmol) in 1 M aqueous Na2CO3 (0.5 mL) and acetonitrile (0.5 mL) were heated to 100° C. in a sealed microwave reactor for 10 min. Upon completion, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole 7 (122 mg, 0.5 mmol), bis(triphenylphosphine)palladium(II) dichloride (9 mg, 13 mop, 1 M aqueous Na2CO3 (1 mL), and acetonitrile (1 mL) were added into the same pot. The reaction mixture was heated to 150° C. in a sealed microwave reactor for 20 min. The mixture was extracted with EtOAc and CH2Cl2. The combined organics were concentrated to yield 361 after reverse phase HPLC purification (28 mg). MS (Q1) 459 (M)+
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=1.[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[NH:15][C:14](=[O:20])[CH:13]=1.[OH-].[Na+]>C(O)C>[NH2:11][C:12]1[N:17]([CH3:18])[C:16](=[O:19])[N:15]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]#[N:10])=[CH:5][CH:4]=2)[C:14](=[O:20])[CH:13]=1
Reactant: Cn1c(N)cc(=O)[nH]c1=O
Reactant: N#Cc1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cn1c(N)cc(=O)n(Cc2ccc(C#N)cc2)c1=O
Reaction time: 1.75 h
Yield: 12.2 %

Procedure:
α-Bromo-p-tolunitrile (5.41 g, 27.6 mmol) was added at once with stirring to a solution of 6-amino-1-methyluracil (V. Papesch and E. F. Schroeder. J. Org. Chem. (1951), 16, 1879) (3.90 g, 27.6 mmol) in 1:1 ethanol: 1N sodium hydroxide (56 ml) at 42° C. After 1.75 hours. the mixture was cooled, filtered and washed with water. The resulting solid and second crop obtained by evaporation of the filtrate were combined (5.80 g) and partially purified by silica gel chromatography followed by repeated trituration with 1:2 methanol; ether to give crude 4-[(6-Amino-1,2,3,4-tetrahydro-1-methyl-2,4-dioxo-3-pyrimidinyl)methyl]benzonitrile (0.86 g), indentified by NMR.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>CCO.C(OCC)(=O)C.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:20]([C:22]1[CH:27]=[C:26]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:16]([O:18][CH3:19])=[O:17])[CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:25]=[CH:24][CH:23]=1)#[N:21]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: COC(=O)[C@@H](NS(=O)(=O)c1ccc(Br)cc1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)[C@@H](NS(=O)(=O)c1ccc(-c2cccc(C#N)c2)cc1)C(C)C
Yield: 97 %

Procedure:
A suspension of methyl N-[(4-bromophenyl)sulfonyl]valinate obtained in Reference Example 92 (5.00 g, 14.3 mmol), (3-cyanophenyl)boronic acid (2.52 g, 17.1 mmol), tetrakis(triphenylphosphine)palladium (0.330 g, 0.286 mmol) and 2N aqueous sodium carbonate solution (8.57 mL, 17.1 mmol) in EtOH (15 mL)-toluene (50 mL) was heated under reflux for 8 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 crystallized from hexane-ethyl acetate to give the title compound as a yellow powder (5.18 g, 97%).
Reaction SMILES: [O:1]1[C@H:8]([CH2:9][OH:10])[C@@H:6]([OH:7])[C@H:4]([OH:5])[CH:3]=[CH:2]1.[C:11](OC=C)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O1CCCC1>[C:11]([O:10][CH2:9][C@H:8]1[O:1][CH:2]=[CH:3][C@@H:4]([OH:5])[C@@H:6]1[OH:7])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: C=COC(=O)c1ccccc1
Reactant: OC[C@H]1OC=C[C@@H](O)[C@@H]1O
Solvent: C1CCOC1
Product: O=C(OC[C@H]1OC=C[C@@H](O)[C@@H]1O)c1ccccc1

Procedure:
1.0 g (6.85 mmol) of glucal is taken up in 1.5-2.0 ml of tetrahydrofuran and 3-5 ml of vinyl benzoate and stirred with 1 g of lipase from Candida cylindracea (Amano AY-20) at room temperature for 6 h. Filtering off the enzyme, concentration of the solution in vacuo, taking up the residue in ethyl acetate and extracting it with aqueous NaHCO3 solution, and subsequent chromatography on silica gel (ethyl acetate/hexane 1:1) result in 1.20 g (70%) of the desired 6-O-benzoylglucal.
Reaction SMILES: ClC1C=C(Cl)C=CC=1C1C(C2NC=CN=2)=CN=C(CCN)N=1.Cl[C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][N:25]=1.[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:47][CH:48]=[CH:49][N:50]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54]C2C=CC([N+]([O-])=O)=C(OC)N=2)[N:41]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]=1[C:40]1[C:45]([C:46]2[NH:50][CH:49]=[CH:48][N:47]=2)=[CH:44][N:43]=[C:42]([NH:51][CH2:52][CH2:53][NH:54][C:24]2[N:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=2)[N:41]=1
Reactant: COc1nc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)ccc1[N+](=O)[O-]
Reactant: N#Cc1ccc(Cl)nc1
Agent: NCCc1ncc(-c2ncc[nH]2)c(-c2ccc(Cl)cc2Cl)n1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
6-[(2-{[4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-yl]amino}ethyl)amino]pyridine-3-carbonitrile was prepared from [4-(2,4-dichlorophenyl)-5-imidazolylpyrimidin-2-ylethylamine and 2-chloro-5-cyanopyridine in accordance with the procedure described above for the preparation of [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(6-methoxy-5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.[F:21][C:22]1([F:41])[CH2:27][CH2:26][CH:25]([NH:28][C:29](=O)[O:30]C2C=CC([N+]([O-])=O)=CC=2)[CH2:24][CH2:23]1.CO>CC#N>[F:21][C:22]1([F:41])[CH2:23][CH2:24][CH:25]([NH:28][C:29]([N:10]2[CH2:11][CH2:12][C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[C@H:9]2[C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=2)=[O:30])[CH2:26][CH2:27]1
Reactant: FC(F)(F)c1ccc([C@H]2NCCc3ccccc32)cc1
Reactant: O=C(NC1CCC(F)(F)CC1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CO
Solvent: CC#N
Product: O=C(NC1CCC(F)(F)CC1)N1CCc2ccccc2[C@H]1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of (R)-1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (80 mg, 0.29 mmol) in MeCN (2 mL) was added 4-nitrophenyl 4,4-difluoro-cyclohexylcarbamate (217 mg, 0.72 mmol). The resulting mixture was then subjected to microwave irradiation at 120° C. for 15 min. Then, MeOH (0.5 mL) was added and the mixture was filtered. The filtrate was purified by preparative HPLC (0%-100% MeCN 0.1% TFA/H2O 0.1% TFA) to give the title compound, which was dissolved in MeOH (1 mL). The solution was then passed through PL-HCO3 and the resin was washed with MeOH (2×0.3 mL). The combined filtrates were concentrated and dried in vacuo to give the title compound as a light-yellow solid. MS (ESI, positive ion) m/z: 439 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C:4]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[O:9])[CH2:3]1.[CH3:31][I:32]>>[I-:32].[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:4]1([NH:7][C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:13][CH:12]=2)=[O:9])[CH2:5][CH2:6][N+:2]([CH3:31])([CH3:1])[CH2:3]1)[CH3:30]
Reactant: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CCN(C)C2)cc1
Reactant: CI
Product: CCCCCCCCc1ccc(NC(=O)NC2(CC(=O)OCC)CC[N+](C)(C)C2)cc1
Product: [I-]

Procedure:
According to the method described in example 2a, ethyl 2-(1-methyl-3-(3-(4-octylphenyl)ureido)pyrrolidin-3-yl)acetate was reacted with methyl iodide to give the title compound as a white solid (31 mg, quantitive). MS ESI 432.4 [M]+, calcd for [C25H42N3O3+] 432.32
Reaction SMILES: [C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.Cl.[NH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH:20]1[C:25]([OH:27])=[O:26].Cl>C(#N)C.[OH-].[Na+]>[C:1]1([N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([N:19]2[CH2:24][CH2:23][N:22]([C:8](=[O:9])[N:7]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:21][CH:20]2[C:25]([OH:27])=[O:26])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)N(c1ccccc1)c1ccccc1
Reactant: O=C(O)C1CNCCN1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=C(O)C1CN(C(=O)N(c2ccccc2)c2ccccc2)CCN1C(=O)N(c1ccccc1)c1ccccc1
Reaction time: 4 h
Yield: 25.9 %

Procedure:
A solution of 946 mg (4 mmole) of 98% diphenylcarbamoyl chloride in 4 ml of acetonitrile was added dropwise to a stirring solution of 406.2 mg (2 mmole) of piperazine-2-carboxylic acid dihydrochloride [E. Felder, S. Maffei, S. Pietra and D. Pitre, Helv. Chim., Acta, 43, 888 (1960)] in 4 ml of 2.5N sodium hydroxide at a temperature between 0° and 5° C. After the addition was completed, the stirring was continued for 4 hours and the solution was acidified with 2N hydrochloric acid while cooling in an ice bath. The reaction mixture was concentrated under reduced pressure and the residue was extracted with chloroform. After washing with water, the chloroform solution was dried over MgSO4 and concentrated in vacuo. The only product which solidified on cooling was triturated with isopropyl ether to give 270 mg (26%) of (±)-1,4-bis-(diphenylcarbamoyl)piperazine-2-carboxylic acid, m.p. 244°-246° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17]Br)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Cl:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][O:1][C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=2[O:10][CH3:11])=[CH:15][CH:14]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1cc(C=O)ccc1OCc1ccc(Cl)cc1
Yield: 92.6 %

Procedure:
To 4-hydroxy-3-methoxybenzaldehyde (105, 600.0 mg, 3.94 mmol) and 4-chlorobenzyl bromide (557, 1.20 g, 5.84 mmol) in acetonitrile (6 mL) was added potassium carbonate (0.390 g, 2.82 mmol). The reaction was microwaved on 300 watts, 120° C. for 10 minutes. The reaction was extracted with ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the volatiles removed by evaporation. The desired compound was purified by recrystallization from hexanes to provide 106 (1.01 g, 93%). MS (ESI) [M−H+]−=275.1.