Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:5]1[CH:45]=[CH:44][C:8]([CH2:9][C:10]2[C:15]([C:16]#[N:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([C@:20]3([O:38][C@H:37]([CH2:39][O:40]C(=O)C)[C@@H:32]([O:33]C(=O)C)[C@H:27]([O:28]C(=O)C)[C@H:22]3[O:23]C(=O)C)[OH:21])[CH:11]=2)=[CH:7][CH:6]=1)[CH3:4].Cl>CO.C1COCC1>[CH2:3]([C:5]1[CH:6]=[CH:7][C:8]([CH2:9][C:10]2[C:15]([C:16]#[N:17])=[C:14]([O:18][CH3:19])[CH:13]=[C:12]([C@:20]3([O:38][C@H:37]([CH2:39][OH:40])[C@@H:32]([OH:33])[C@H:27]([OH:28])[C@H:22]3[OH:23])[OH:21])[CH:11]=2)=[CH:44][CH:45]=1)[CH3:4]
Reactant: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]3OC(C)=O)cc(OC)c2C#N)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Cc2cc([C@@]3(O)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)cc(OC)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aqueous sodium hydroxide solution (1.4 mL, 1 mol/L) is added to 6-(4-ethylbenzyl)-4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile (0.16 g) dissolved in methanol (1 mL) and THF (1 mL). The solution is stirred at room temperature for 1 h and then neutralized with hydrochloric acid (1 mol/L). After removal of the organic solvents, the residue is diluted with aqueous sodium bicarbonate solution and the resulting mixture is extracted with ethyl acetate. The combined organic extracts are dried (sodium sulphate) and the solvent is evaporated. The remainder is purified by chromatography on silica gel (dichloromethane/methanol 1:0->8:1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:8]2.[C:28]1([S:34](Cl)(=[O:36])=[O:35])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.Cl>CN(C)C=O>[Cl:3][C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[C:9]2[C:5]=1[C:6](/[CH:19]=[CH:20]/[C:21]([O:23][C:24]([CH3:26])([CH3:25])[CH3:27])=[O:22])=[C:7]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:8]2[S:34]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)(=[O:36])=[O:35]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1/C=C/C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(/C=C/C(=O)OC(C)(C)C)c2c(Cl)cc(Cl)cc2n1S(=O)(=O)c1ccccc1
Reaction time: 0.75 h

Procedure:
Sodium hydride (0:35 g) was dissolved in dry dimethylformamide (60 ml) and cooled at 0° then a solution of 4,6-dichloro-2ethoxycarbonyl-3-(E)-(2'-tert-butoxycarbonylethenyl)-1-H-indole (5.14 g) in dimethylformamide (40 ml) was added The reaction mixture was stirred for 45 min at 0° then phenylsulfonyl chloride (1.87 ml) was added and the solution stirred overnight at r.t. The solution was poured into a 0.5N aqueous solution of hydrochloric acid and extracted with ethyl acetate (400 ml). The organic phase was washed with a solution of sodium hydrogencarbonate and brine, then dried and evaporated obtaining the title compound as a yellow solid (6.64 g) Rf =0.78 (ethylacetate/cyclohexane=1/2 as eluant).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OCc1ccccn1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCc2ccccn2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 2-(hydroxymethyl)pyridine and DBU in dioxane. ES-MS m/e (%): 395 (M+H+, 100).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.CCN(CC)CC.ClC(OCC)=O.[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH2:28])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]>C1COCC1>[F:23][C:24]1[CH:30]=[CH:29][C:27]([NH:28][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[CH:26][C:25]=1[N+:31]([O-:33])=[O:32]
Reactant: O=C(O)c1cnccn1
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(F)c([N+](=O)[O-])c1)c1cnccn1
Temperature: 5 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
To a solution of pyrazine-2-carboxylic acid (2.00 g, 16.1 mmol) and Et3N (2.50 ml, 17.7 mmol) in THF (40 mL) was added ethyl chloroformate (1.74 mL, 17.7 mmol) dropwise at 5° C. and the mixture was stirred at 5° C. for 1 hour. 4-Fluoro-3-nitroaniline (2.80 g, 17.7 mmol) was added to the mixture at 5° C. The mixture was warmed to room temperature, stirred at room temperature for 4 hours, and then evaporated. The residue was suspended in a mixture of H2O (100 ml) and i-Pr2O (100 ml) and stirred at room temperature for 30 minutes. The resulting crystal was collected by filtration and washed with H2O and i-Pr2O to give the desired product as pale brown crystals (2.91 g, 69%).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.[NH2:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2>ClCCCl>[CH:2]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[NH:29][N:28]=[CH:27]2)([CH3:4])[CH3:1]
Reactant: CC(C)=O
Reactant: Nc1ccc2[nH]ncc2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)Nc1ccc2[nH]ncc2c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.1 %

Procedure:
Acetone (25 μl, 0.340 mmol), sodium triacetoxyborohydride (83 mg, 0.392 mmol) and acetic acid (18 μl, 0.314 mmol) were added in that order to a solution of 5-amino-1H-indazole (40 mg, 0.300 mmol) in 1,2-dichloroethane (1 ml), and the resulting mixture was stirred at room temperature for 20 hours. The reaction was terminated by the use of a saturated aqueous sodium hydrogencarbonate solution (4 ml), followed by extraction with ethyl acetate. The solvent was distilled off under reduced pressure to obtain a crude product. The crude product was purified by a silica gel column chromatography (eluent: chloroform/methanol=100/2) to obtain N-isopropyl-1H-indazol-5-amine (40 mg, 76%).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].[N+:18]([C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)([O-:20])=[O:19]>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:25][C:24]3[CH:27]=[CH:28][C:21]([N+:18]([O-:20])=[O:19])=[CH:22][CH:23]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc([N+](=O)[O-])cc1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide (100 mg) was suspended in EtOH (4 mL) and 4-nitrobenzaldehyde (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain 3-((3-chlorophenyl)amino)-5-((4-nitrobenzylidene)amino)-1H-pyrazole-4-carboxamide as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13](Br)=[CH:12][N:11]=1.BrC1C=CC(Br)=CN=1.O1C2C=CC=CC=2C=C1B(O)O.[S:37]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38]1>>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:39]2[CH:40]=[CH:41][S:37][CH:38]=2)=[CH:12][N:11]=1
Reactant: Brc1ccc(-c2cc3ccccc3o2)nc1
Reactant: OB(O)c1ccsc1
Agent: Brc1ccc(Br)nc1
Agent: OB(O)c1cc2ccccc2o1
Product: c1ccc2oc(-c3ccc(-c4ccsc4)cn3)cc2c1

Procedure:
It is easy to synthesis the following compound in the same manner as in Example 1 except that 2-(benzofuran-2-yl)-5-bromopyridine was synthesized from 2,5-dibromopyridine (made by Tokyo Kasei Kogyo K.K.) and 2-benzofuranboronic acid (made by Aldrich Co.) and is reacted with 3-thiopheneboronic acid (made by Aldrich Co.) to obtain 2-(benzofuran-2-yl)-5-(thiophene-3-yl)pyridine, which is used instead of 2-(5-trifluoromethylpyridine-2-yl)benzofuran.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(=O)([O-])[O-].[K+].[K+].Br[CH2:35][CH2:36][CH2:37][Cl:38]>CN(C)C=O>[C:1]([C:5]1[N:10]=[C:9]([N:11]2[CH2:12][CH2:13][N:14]([CH2:35][CH2:36][CH2:37][Cl:38])[CH2:15][CH2:16]2)[CH:8]=[C:7]([C:17]2([CH3:20])[CH2:19][CH2:18]2)[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: ClCCCBr
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C2(C)CC2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1nc(N2CCN(CCCCl)CC2)cc(C2(C)CC2)n1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 51.4 %

Procedure:
7 g of 2-tert-butyl-4-piperazin-1-yl-6-(1-methylcyclopropyl)-pyrimidine (25.5 mmol; prepared by analogy to steps a.2.1 to a.2.4 starting from 1-methylcyclopropyl carbonic acid chloride) were dissolved in 50 ml of dimethyl formamide. 2.58 of triethylamine (25.5 mmol), and 3.53 g of potassium carbonate were added, followed by dropwise addition of 4.62 g of 1-bromo-3-chloropropane. After stirring for 1.5 h at 50° C. the reaction mixture was stirred overnight at room temperature. The precipitate was filtered off and washed with dimethylformamide. The filtrate was partitioned between 150 ml of ethyl acetate and 50 ml of water. The organic layer was separated and the aqueous layer was extracted with 30 ml of ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and evaporated to dryness. The residue was purified by chromatography on silica gel (ethyl acetate) to yield 4.6 g of the title compound.
Reaction SMILES: [CH3:1][C@@H:2]([CH2:23][CH3:24])[C@H:3]([NH:11][CH2:12][CH2:13][NH:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=1)[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[N+](C1C=C[C:31]([O:34]C(=O)OC2C=CC([N+]([O-])=O)=CC=2)=CC=1)([O-])=O>CN(C)C=O>[CH3:1][C@@H:2]([CH2:23][CH3:24])[C@H:3]([N:11]1[CH2:12][CH2:13][N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N:17]=2)[C:31]1=[O:34])[C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5]
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: CC[C@H](C)[C@H](NCCNCc1cccc(C)n1)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@@H](C(=O)OC(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Yield: 57 %

Procedure:
A solution of the product of Example 32D in N,N-dimethylformamide (60 mL) was treated with bis-(p-nitrophenyl)carbonate (12.6 g, 1.2 equivalents) at 50° C. for 5 hrs. The solvents were evaporated, and the residue was partitioned between water and ethyl acetate. The organic layer was separated, washed with brine, dried over Na2SO4, filtered, and the solvents were evaporated, and the residue was purified using ethyl acetate:hexanes (2:1) to give 7.3 g (57%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([Br:14])[CH:4]=1.N1C=CN=C1.[Si:20](Cl)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.CCOCC>[Si:20]([O:1][CH2:2][C:3]1[N:8]=[C:7]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[C:5]([Br:14])[CH:4]=1)([C:33]([CH3:36])([CH3:35])[CH3:34])([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)c1cc(Br)cc(CO)n1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCOC(=O)c1cc(Br)cc(CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)n1
Reaction time: 3 h
Yield: 125.4 %

Procedure:
Predried ethyl 6-hydroxymethyl-4-bromopyridine-2-carboxylate (1.4 g, 5 4 mmol) and imidazole (1.1 g, 6.5 mmol) were dissolved in dry DMF (1.7 mL). TBDPS-chloride (1.78 g, 6.5 mmol) was added portionwise, and the reaction was allowed to proceed for 3 h at r.t. The reaction mixture was diluted with Et2O (50 mL) and washed with water and sat. NaHCO3. The organic phase was dried over Na2SO4 and evaporated to dryness. Purification on silica gel (petroleum ether, by 40-60° C./ethyl acetate 5:2) yielded 2.5 g (92%) of the title compound.
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)(=[O:4])=[O:3].Br[CH2:12][CH2:13][CH2:14][OH:15].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:12][CH2:13][CH2:14][OH:15])[CH2:7][CH2:6]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: OCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CS(=O)(=O)N1CCN(CCCO)CC1
Temperature: 40 °C
Reaction time: 4 h
Yield: 91.4 %

Procedure:
A suspension of 1-methylsulfonylpiperazine (1.58 g, 9.6 mmol), 3-bromo-1-propanol (1.13 ml, 12 mmol) and potassium carbonate (1.73 g, 12 mmol) in acetonitrile (10 ml) was stirred at 40° C. for 4 hours followed by 2 hours at 70° C. The mixture was cooled, filtered and the filtrate was evaporated under vacuum. The residue was purified by column chromatography eluting with methylene chloride/methanol (97/3 followed by 95/5) to give 3-(4-methylsulfonylpiperazin-1-yl)propan-1-ol (1.95 g, 91%).
Reaction SMILES: [C:1]12([C:11]3[CH:30]=[CH:29][C:14]([O:15][CH2:16][C:17]4[O:18][C:19]5[CH:25]=[CH:24][C:23](C(O)=O)=[CH:22][C:20]=5[N:21]=4)=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CNC.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:67][N:68]([CH:70]=[O:71])[CH3:69]>>[CH3:67][N:68]([CH3:69])[C:70]([C:23]1[CH:24]=[CH:25][C:19]2[O:18][C:17]([CH2:16][O:15][C:14]3[CH:13]=[CH:12][C:11]([C:1]45[CH2:8][CH:7]6[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]6)[CH2:2]4)[CH2:10]5)=[CH:30][CH:29]=3)=[N:21][C:20]=2[CH:22]=1)=[O:71]
Reactant: O=C(O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Reactant: CN(C)C=O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)c1ccc2oc(COc3ccc(C45CC6CC(CC(C6)C4)C5)cc3)nc2c1
Yield: 59 %

Procedure:
To solution of 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid (60.4 mg, 0.15 mmol), dimethyl amine (0.030 ml, in 2M THF) in DMF 5.0 mL was added HBTU (113.8 mg, 0.30 mmol) and DIPEA (0.052 ml, 0.30 mmol). After sting at room temperature, the mixture was partitioned between ethyl acetate and brine. The organic phase was dried (MgSO4 anh), and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc:MeOH=15:3:1) to give 2-(4-adamantan-1-yl-phenoxymethyl)-benzoxazole-5-carboxylic acid dimethylamide as a white solid (37.9 mg, 59% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)=[N:18][NH:19][C:20]([C:22]3[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=3)=[O:21])[C:12]=2[OH:38])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.[OH-].[Na+].Cl>O>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[N:15]([CH3:16])[N:14]=[C:13]([C:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)=[N:18][NH:19][C:20]([C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:30][CH:31]=3)=[O:21])[C:12]=2[OH:38])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccc(C(=O)NN=C(c2ccccc2)c2nn(C)c(-c3ccc(C(C)(C)C)cc3)c2O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cn1nc(C(=NNC(=O)c2ccc(C(=O)O)cc2)c2ccccc2)c(O)c1-c1ccc(C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.6 %

Procedure:
To methyl 4-({2-[[5-(4-t-butylphenyl)-4-hydroxy-1-methyl-1H-pyrazol-3-yl](phenyl)methylene]hydrazino}carbonyl)benzoate (0.196 mmol, 100 mg), methanol (4 mL) was added, and 1 M aqueous sodium hydroxide (0.981 mmol, 0.981 mL) was added at room temperature. After 15 minutes of stirring at room temperature and 1 hour of stirring at 60° C., the reactor was cooled to room temperature, and 1 M hydrochloric acid (0.981 mmol, 0.981 mL) and water were added. The precipitated solid was recovered by filtration, washed with water and dried by means of a vacuum pump to give the desired product as a yellow solid (93 mg, yield 95%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:20]([O-])=O)=[C:6]([NH:8][C:9]2[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][C:10]=2[C:11]#[N:12])[CH:7]=1.[Sn](Cl)[Cl:24]>C(O)C.Cl>[ClH:24].[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:20]=[C:11]([NH2:12])[C:10]3[CH:13]=[C:14]([CH:17]([CH3:19])[CH3:18])[CH:15]=[CH:16][C:9]=3[NH:8][C:6]=2[CH:7]=1
Reactant: CC(C)c1ccc(Nc2cc(F)ccc2[N+](=O)[O-])c(C#N)c1
Reactant: Cl[Sn]Cl
Agent: Cl
Solvent: CCO
Product: CC(C)c1ccc2c(c1)C(N)=Nc1ccc(F)cc1N2
Yield: 96 %

Procedure:
Heat a solution of 2-(5-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.372 g, 1.24 mmol) in ethanol (6 ml) to 60° C. Add a solution of tin (II) chloride (0.707 g, 3.73 mmol) in 5.0 N hydrochloric acid (6 ml) and heat the resulting mixture to reflux for 16 hours. Cool the reaction to room temperature, add 30 ml of 5.0 N hydrochloric acid and place the mixture in a freezer for 16 hours. Precipitate the product from the solution and collect by filtration. Wash solid with 5.0 N hydrochloric acid to obtain 0.365 g of the title compound (1.19 mmol, 96% yield) as a yellow amorphous solid: Mass Spectrum (m/e): 270(M+1).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14])#[N:2].[OH-:35].[Na+].OO>CC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[O:11][CH2:10][CH2:9][CH:8]2[C:13]([N:15]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]([CH3:34])[CH3:33])=[CH:28][CH:27]=1)[C:16]1[CH:21]=[CH:20][C:19]([CH:22]([CH3:24])[CH3:23])=[CH:18][CH:17]=1)=[O:14])(=[O:35])[NH2:2]
Reactant: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(C#N)cccc32)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCOc3c(C(N)=O)cccc32)cc1

Procedure:
8-Cyano-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (0.9 g) was dissolved in acetone (12.8 mL), and 1 mol/L-aqueous sodium hydroxide solution (6.4 mL) and 30% aqueous hydrogen peroxide (3.8 mL) were added. The mixture was heated under reflux for 2 hr. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 8-carbamoyl-N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)chroman-4-carboxamide (21 mg).
Reaction SMILES: Cl.Cl.[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:25][CH2:24][C@H:23]([NH2:26])[CH2:22][CH2:21]2)=[CH:4]1.[CH:27]1([C:31](O)=[O:32])[CH2:30][CH2:29][CH2:28]1>>[O:3]1[C:8]2=[CH:9][CH:10]=[CH:11][C:7]2=[CH:6][C:5]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH2:18][CH2:19][C@H:20]2[CH2:21][CH2:22][C@H:23]([NH:26][C:31]([CH:27]3[CH2:30][CH2:29][CH2:28]3)=[O:32])[CH2:24][CH2:25]2)=[CH:4]1
Reactant: N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1
Reactant: O=C(O)C1CCC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCCCC2c2coc3cccc-3c2)CC1)C1CCC1

Procedure:
The title compound, off-white solid (70 mg, 69%), MS (ISP) m/z=409.4 [(M+H)+], mp 180° C., was prepared in accordance with the general method of example 1 from trans-4-[2-(4-benzofuran-3-yl-piperidin-1-yl)-ethyl]-cyclohexylamine dihydrochloride (intermediate A) (100 mg, 0.25 mmol) and cyclobutanecarboxylic acid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[NH:11][N:10]=2)=[CH:5][CH:4]=1.[H-].[Na+].I[CH2:25][CH2:26][CH3:27]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:25][CH2:26][CH3:27])[N:10]=2)=[CH:7][CH:8]=1
Reactant: CCCI
Reactant: COc1ccc(-c2n[nH]c3c(C(F)(F)F)cccc23)cc1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2)c2cccc(C(F)(F)F)c21
Yield: 34.7 %

Procedure:
Prepared according to Method D step B from 3-(4-methoxyphenyl)-7-trifluoromethyl-1H-indazole (0.146 g, 0.5 mmol), sodium hydride (60% in oil, 0.024 g, 0.6 mmol) and 1-iodopropane (0.098 mL, 1.0 mmol) to give the title compound (0.058 g) as a white solid.
Reaction SMILES: [OH:1][N:2]1[C:6](=O)[CH2:5][CH2:4][C:3]1=O.C(N(CC)CC)C.[Br:16][C:17]([CH3:22])([CH3:21])[C:18](Br)=[O:19]>C(Cl)Cl>[N:2]1([O:1][C:18](=[O:19])[C:17]([Br:16])([CH3:22])[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(Br)C(=O)Br
Reactant: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(Br)C(=O)ON1CCCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.7 %

Procedure:
A solution of N-hydroxysuccinimide (NHS) (3.0 g, 26 mmol) in dry methylene chloride (300 mL) was stirred under an inert (argon or nitrogen) atmosphere. Triethylamine (7.3 mL, 52 mmol) was added, the mixture was cooled to 0° C., and 2-bromo-2-methylpropionyl bromide (3.9 mL, 31 mmol) was added dropwise over a period of 15 minutes. The mixture was stirred for 1 hour at 0° C., then warmed to room temperature and stirred overnight. Most of the solvent was removed by evaporation, and the remaining mixture was diluted with cold water (400 mL), and extracted with diethyl ether (3×30 mL), then washed with aqueous potassium carbonate (3×30 mL) and 1M HCl(aq) (3×30 mL). The organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated to give a brown solid. Crystallization from ethyl acetate gave the desired product as a white powder (2.62 g, 39%). 1H NMR (CDCl3) δ (ppm) 2.09 (s, 6H, CH3)2Br), 2.88 (s, 4H, HNHS); 13C NMR (CDCl3) δ (ppm) 25.7 (CNHS), 30.8 (C(CH3)2Br), 51.3 (C(CH3)2Br), 167.6 (C═O), 168.7 (CNHS═O).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]3[O:15][CH2:16][CH2:17][O:18][C:11]=3[CH:10]=2)[C:5]([F:19])=[CH:4][N:3]=1.[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[C:26]([F:28])[CH:27]=1)[NH2:24]>>[CH2:17]1[CH2:16][O:15][C:12]2[CH:13]=[CH:14][C:9]([NH:8][C:6]3[C:5]([F:19])=[CH:4][N:3]=[C:2]([NH:24][C:23]4[CH:22]=[C:21]([F:20])[CH:27]=[C:26]([F:28])[CH:25]=4)[N:7]=3)=[CH:10][C:11]=2[O:18]1
Reactant: Nc1cc(F)cc(F)c1
Reactant: Fc1cnc(Cl)nc1Nc1ccc2c(c1)OCCO2
Product: Fc1cc(F)cc(Nc2ncc(F)c(Nc3ccc4c(c3)OCCO4)n2)c1

Procedure:
In like manner to the preparation of 5-fluoro-N4-(3-hydroxyphenyl)-N2-[4-(3-phenyl-1,2,4-oxadiazol-5-yl)methyleneoxyphenyl]-2,4-pyrimidinediamine, 2-chloro-N4-(3,4-ethylenedioxyphenyl)-5-fluoro-4-pyrimidineamine and 3,5-difluoroaniline were reacted to provide N4-(3,4-ethylenedioxyphenyl)-5-fluoro-N2-(3,5-difluorophenyl)-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.94 (d, 1H, J=3.3 Hz), 7.20-7.11 (m, 3H), 7.02 (s, 1H), 6.92-6.90 (m, 2H), 6.65 (s, 1H), 6.39 (tt, 1H, J=2.4 and 9.0 Hz), 4.31 (s, 4H); 19F NMR (282 MHz, CDCl3): −31142, −47002; LCMS: purity: 97%; MS (m/e): 375 (MH+).
Reaction SMILES: [CH3:1][S@:2](=[O:24])([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[N:3][C:4](=[O:17])[C:5]1[CH:10]=[C:9]([C:11]#[C:12][Si](C)(C)C)[CH:8]=[N:7][CH:6]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[C:11]([C:9]1[CH:8]=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([N:3]=[S@@:2]([CH3:1])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)=[O:17])#[CH:12]
Reactant: C[Si](C)(C)C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: C#Cc1cncc(C(=O)N=[S@@](C)(=O)c2ccccc2)c1
Temperature: 0 °C

Procedure:
A solution of (S)-N-[methyl(oxo)phenyl-λ6-sulfanylidene]-5-[(trimethylsilyl)ethynyl]nicotinamide (806 mg, 2.3 mmol) in 70 mL THF/methanol (1:1 ratio) at room temperature was degassed with argon. The solution was cooled to 0° C. and K2CO3 (937 mg, 6.8 mmol) added. After 5 minutes the solution was decanted from the solids and partitioned between EtOAc and H2O. The EtOAc layer was washed with brine, dried with anhydrous Na2SO4 and concentrated. The brown oil was purified by chromatography (silica gel, CHCl3/EtOAc) to the title compound as a thick pale orange oil (630 mg, 98%).