Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:4]2[N:5]([CH:21]=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:11][CH2:10]1)#[N:2].O(Cl)Cl.[P+5].CN([CH:31]=[O:32])C>>[C:1]([C:3]1[C:4]2[N:5]([C:21]([CH:31]=[O:32])=[N:22][N:23]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:11][CH2:10]1)#[N:2]
Reactant: CN(C)C=O
Reactant: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2cnnc12
Agent: ClOCl
Agent: [P+5]
Product: N#Cc1c(N2CCC(c3ccccc3)CC2)ccn2c(C=O)nnc12
Yield: 26 %

Procedure:
D8 (0.25 g, 0.824 mmol) and phosphorus(V)oxychloride (0.116 ml, 1.236 mmol) in DMF (5 ml) was heated in a sealed tube at 80° C. for 4 h. After cooling, the mixture was concentrated in vacuo. The crude product was purified by column chromatography (silica gel; DCM/7M solution of NH3 in MeOH up to 3% as eluent). The desired fractions were collected and concentrated in vacuo to yield intermediate compound D9 (0.070 g, 26%).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]([CH2:33][CH3:34])=[C:10]([CH2:19][NH:20][C:21]([C:23]3[CH:24]=[C:25]([CH:29]=[C:30]([CH3:32])[CH:31]=3)[C:26](O)=[O:27])=[O:22])[C:11]([NH:12][CH:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[C:6]2[CH:5]=[N:4]1)[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[Br:60][C:61]1[CH:62]=[C:63]([CH2:68][NH2:69])[CH:64]=[CH:65][C:66]=1[F:67]>ClCCl>[Br:60][C:61]1[CH:62]=[C:63]([CH2:68][NH:69][C:26]([C:25]2[CH:29]=[C:30]([CH3:32])[CH:31]=[C:23]([C:21]([NH:20][CH2:19][C:10]3[C:11]([NH:12][CH:13]4[CH2:18][CH2:17][O:16][CH2:15][CH2:14]4)=[C:6]4[CH:5]=[N:4][N:3]([CH2:1][CH3:2])[C:7]4=[N:8][C:9]=3[CH2:33][CH3:34])=[O:22])[CH:24]=2)=[O:27])[CH:64]=[CH:65][C:66]=1[F:67]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)O)c1
Reactant: NCc1ccc(F)c(Br)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(F)c(Br)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.5 %

Procedure:
The 3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylbenzoic acid (931 mg, 2 mmol) was partially dissolved in dichloromethane (50 mL), and HBTU (758 mg, 2.000 mmol) was added followed sequentially by [(3-bromo-4-fluorophenyl)methyl]amine hydrochloride (481 mg, 2.000 mmol), and TEA (0.836 mL, 6.00 mmol). The mixture was allowed to stir under argon overnight at room temperature. The solvent was removed on a rotavap. The residue was taken up in EtOAc (100 mL) and washed 3× with water (50 mL) (emulsion, a few drops of 1N NaOH helps break emulsion), 1× with brine, dried over anhydrous Na2SO4, filtered and evaporated to give the crude residue. It was taken up in methylene chloride and absorbed on Isolute® Sorbent and purified by Combiflash using an 80 g silica column eluted with 0-10% DCM/MeOH. The product fractions were combined and concentrated to give N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (875 mg, 1.329 mmol, 66.5% yield) as a white solid. LC-MS m/z 651.3 (M+H)+, 0.98 min (ret time).
Reaction SMILES: CS(O[CH2:6][C@@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[CH3:22][S-:23].[Na+].O1CCOCC1>CO>[CH3:22][S:23][CH2:6][C@@H:7]([NH:14][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C[S-]
Reactant: CC(C)(C)OC(=O)N[C@H](COS(C)(=O)=O)c1ccccc1
Agent: [Na+]
Solvent: CO
Solvent: C1COCCO1
Product: CSC[C@@H](NC(=O)OC(C)(C)C)c1ccccc1
Temperature: 45 °C
Yield: 76.1 %

Procedure:
(S)-2-((tert-butoxycarbonyl)amino)-2-phenylethyl methanesulfonate (600 mg, 1.902 mmol) and sodium thiomethoxide (593 mg, 7.61 mmol) were added to a 20 mL microwave tube equipped with mechanical stir bar and charged with Dioxane (10 ml). The reaction was allowed to heat overnight at 45° C. The reaction was poured into 5 mL MeOH and 5 g silica, and the solvents were evaporated in vacuo. The dry-loaded crude product was purified on 50 g SNAP column 10-50% EtOAc/hexanes to provide (S)-tert-butyl (2-(methylthio)-1-phenylethyl)carbamate (387 mg, 1.447 mmol, 76% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[C:5]2[Cl:11].O1CCCC1.[F:17][C:18]1[CH:19]=[C:20]([S:24](Cl)(=[O:26])=[O:25])[CH:21]=[CH:22][CH:23]=1>C(N(CC)CC)C>[Cl:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][S:24]([C:20]3[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=3)(=[O:26])=[O:25])[CH:3]=2)[NH:7][N:6]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: Nc1ccc2[nH]nc(Cl)c2c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=S(=O)(Nc1ccc2[nH]nc(Cl)c2c1)c1cccc(F)c1
Yield: 37.2 %

Procedure:
N-(3-Chloro-1H-indazol-5-yl)-3-fluorobenzenesulfonamide can be obtained as described in Example 1 from 0.18 g of 5-amino-3-chloro-1H-indazole, 20 ml of tetrahydrofuran, 0.25 ml of triethylamine and 0.23 g of 3-fluorobenzenesulfonyl chloride. 0.13 g of N-(3-chloro-1H-indazol-5-yl)-3-fluorobenzenesulfonamide is thus obtained in the form of a yellow foam which decomposes at approximately 80° C. (analysis C13H9ClFN3O2S % calculated: 47.93; H, 2.78; Cl, 10.88; F, 5.83; N, 12.90; O, 9.82; S, 9.84. % found C, 48.11; H, 2.64; F, 5.14; N, 13.14; S, 8.22).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:18]
Reactant: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: Nc1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Yield: 84.7 %

Procedure:
To a solution of 6′-chloro-5′-nitro-3-trifluoromethyl-[2,3′]bipyridinyl (25 g, 0.082 mol) and calcium chloride (11 g, 0.1 mol) in ethanol (300 mL) and water (50 mL), add iron powder (45 g, 0.82 mol). Heat the solution to reflux for 1.5 hours, cool and filter through Celite. Concentrate the mixture under reduced pressure, re-dissolve in ethyl acetate (300 mL) and wash with brine (200 mL). Concentrate the solution under reduced pressure and purify by flash chromatography on silica gel (50/ether/50% hexane) to give the title compound (19 g, 85%) as a pale yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12](Br)[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2].[C:18]([Cu])#[N:19].[C-]#N.[Na+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[C:10]2[CH:11]=[C:12]([C:18]#[N:19])[CH:13]=[CH:14][C:9]=2[O:8][C:7]=1[CH3:16])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCOC(=O)Cc1c(C)oc2ccc(Br)cc12
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(C)oc2ccc(C#N)cc12
Temperature: 165 °C
Yield: 77.3 %

Procedure:
A mixture of (5-bromo-2-methyl-benzofuran-3-yl)-acetic acid ethyl ester (6.8 g, 22.9 mmol) and CuCN (3.1 g, 34.3 mmol) in anhydrous DMF (20 mL) is heated for 16 h at reflux (165° C.) under an argon atmosphere. After cooling to room temperature a solution of NaCN (5.8 g, 114 mmol) in water (30 mL) is added. The reaction mixture is partitioned between water and toluene, the layers are separated and the aqueous phase is extracted with toluene. The combined organic layers are washed with a 10% aqueous NaCN solution and brine, dried over Na2SO4, filtered and concentrated at reduced pressure to afford the title compound as a brown solid (4.31 g, 17.7 mmol, 77%). 1H NMR (400 MHz, CDCl3, 298 K): δ=7.82 (d, J=1.7 Hz, 1H), 7.51-7.43 (m, 2H), 4.16 (q, J=7.1 Hz, 2H), 3.59 (s, 2H), 2.46 (s, 3H), 1.26 (t, J=7.1 Hz, 3H). MS (ES+): 244 (M(C14H13NO3)+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([OH:10])=O)=[N:6][CH:7]=1.Cl.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]2[NH:23][C:22]3[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=3[N:20]=2)[CH2:15][CH2:14]1.Cl.C(N=C=N)C.C(N(CC)CC)C>ClC(Cl)C.CN(C)C1C=CN=CC=1>[NH:20]1[C:21]2[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=2[N:23]=[C:19]1[CH:16]1[CH2:17][CH2:18][N:13]([C:8]([C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]=2)=[O:10])[CH2:14][CH2:15]1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: c1ccc2[nH]c(C3CCNCC3)nc2c1
Agent: CCN=C=N
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: O=C(c1ccc(Br)cn1)N1CCC(c2nc3ccccc3[nH]2)CC1
Yield: 14 %

Procedure:
To a stirred mixture of 5-bromopyridine-2-carboxylic acid (177 mg, 0.88 mmol) and 2-(piperidin-4-yl)-1H-benzimidazole dihydrochloride (200 mg, 0.73 mmol) in dichloroethane (5 mL) is added ethylcarbodiimide hydrochloride (168 mg, 0.88 mmol), triethylamine (0.25 mL, 1.82 mmol) and 4-dimethylaminopyridine (44.6 mg, 0.36 mmol). After 3 h the reaction mixture is washed with saturated aqueous NaHCO3, water and brine. The organic layer is dried over Na2SO4, filtered and concentrated under reduced pressure. Trituration from hot EtOAc gives 39.4 mg of [4-(1H-benzimidazol-2-yl)piperidin-1-yl](5-bromopyridin-2-yl)methanone.
Reaction SMILES: F[C:2]1[C:7]([F:8])=[CH:6][C:5]([I:9])=[CH:4][N:3]=1.[CH3:10][C:11]1([CH3:17])[CH2:15][NH:14][C:13](=[O:16])[NH:12]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[F:8][C:7]1[C:2]([N:14]2[CH2:15][C:11]([CH3:17])([CH3:10])[NH:12][C:13]2=[O:16])=[N:3][CH:4]=[C:5]([I:9])[CH:6]=1
Reactant: CC1(C)CNC(=O)N1
Reactant: Fc1cc(I)cnc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: CC1(C)CN(c2ncc(I)cc2F)C(=O)N1
Temperature: 100 °C
Yield: 49.3 %

Procedure:
2,3-Difluoro-5-iodopyridine (300 mg, 1.24 mmol) was dissolved in 2 ml toluene. (140 mg, 1.24 mmol, 1 equiv.) 4,4-Dimethylimidazolidin-2-one (CAS 24572-33-6) and cesium carbonate (650 mg, 1.99 mmol, 1.6 equiv.) were added and the mixture was heated to 100° C. for 4 hours. The reaction mixture was loaded directly onto a silica gel column and purified by flash chromatography eluting with an ethyl acetate:heptane gradient 0:100 to 100:0. The desired 1-(3-fluoro-5-iodo-pyridin-2-yl)-4,4-dimethyl-imidazolidin-2-one (205 mg, 49% yield) was obtained as a white solid, MS: m/e=336.1 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[C:9]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])=[C:8]([Cl:33])[CH:7]=[C:6]([NH:34][C:35](=[O:42])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:5]=1[OH:43])([O-])=O>O1CCCC1.C(O)C.[Pd]>[NH2:1][C:4]1[C:9]([NH:10][C:11](=[O:32])[CH:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:23])[CH3:24])=[CH:18][C:17]=2[C:27]([CH2:30][CH3:31])([CH3:29])[CH3:28])[CH2:13][CH3:14])=[C:8]([Cl:33])[CH:7]=[C:6]([NH:34][C:35](=[O:42])[C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[C:5]=1[OH:43]
Reactant: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1c(Cl)cc(NC(=O)c2ccccc2)c(O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: CCC(Oc1ccc(C(C)(C)CC)cc1C(C)(C)CC)C(=O)Nc1c(Cl)cc(NC(=O)c2ccccc2)c(O)c1N

Procedure:
In 50 ml of tetrahydrofuran and 100 ml of ethanol was dissolved 21 g (13×10-3 mole) of 2-nitro-3-{2-(2,4-di-t-amylphenoxy)butanamido}-4-chloro-6-benzamidophenol and hydrogenation was effected by using 1.2 g of Pd-C as a catalyst. The color of the nitro derivative disappeared in 4 hours, and the Pd-C was removed by filtration and a solvent was evaporated therefrom under reduced pressure, followed by extraction of the residue with ethyl acetate. The ethyl acetate layer was washed with an aqueous sodium hydrogen carbonate solution and then with water, and after drying over magnesium sulfate, ethyl acetate was evaporated. Yield: 20 g.
Reaction SMILES: [N+:1]([CH:4]=[C:5](SC)[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2].[CH2:19]([NH2:22])[C:20]#[CH:21]>C(#N)C>[N+:1]([CH:4]=[C:5]([NH:22][CH2:19][C:20]#[CH:21])[NH:6][CH2:7][CH2:8][S:9][CH2:10][C:11]1[NH:15][CH:14]=[N:13][C:12]=1[CH3:16])([O-:3])=[O:2]
Reactant: CSC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Reactant: C#CCN
Solvent: CC#N
Product: C#CCNC(=C[N+](=O)[O-])NCCSCc1[nH]cnc1C
Yield: 87 %

Procedure:
A mixture of 1-nitro-2-methylthio-2-{2-[(4-methyl-1H-imidazol-5-yl)methylthio]ethylamino}ethylene prepared according to Belgian Pat. No. 814,941 (4.0 g, 0.014 mole) and distilled propargylamine (7.74 g, 0.14 mole) in acetonitrile (60 ml) was stirred at reflux temperature under a positive pressure of nitrogen for 18 hours. The reaction mixture was cooled, evaporated to dryness and then triturated under 20 ml of isopropyl alcohol to give the title compound (3.58 g, 87%). Column chromatography on silica gel by gradient elution using methylene chloride-methanol gave a pure sample; mp 159°-160° dec.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[NH:8][N:9]=1)([CH3:4])([CH3:3])[CH3:2].B(O)(O)[C:34]1[CH:35]=[CH:36][C:37]([CH3:40])=[CH:38][CH:39]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)Cl>[C:1]([C:5]1[CH:6]=[C:7]([NH:10][C:11]([NH:13][C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17]([O:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[CH:16][CH:15]=2)=[O:12])[N:8]([C:34]2[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][CH:35]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)[nH]n1
Reactant: Cc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(OCCN3CCOCC3)c3ccccc23)cc1

Procedure:
The title compound was prepared as described in the final step of Example 1 from 1-(5-tert-butyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)-naphthalen-1-yl]-urea (0.022 g, 0.050 mmol), and p-tolylboronic acid (0.014 g, 0.1 mmol), using copper (II) acetate (0.014 g, 0.075 mmol), pyridine (0.01 mL, 0.1 mmol), molecular sieves (4 Å activated, 0.030 g) and methylene chloride (2 mL). The title compound was obtained as a yellow-white solid (0.013 g, 50%), mp 144-146° C.; 1H NMR (DMSO) δ 1.26(s, 9H), 2.36(s, 3H), 2.53(t, 4H) 2.82(t, 2H), 3.52(t, 4H), 4.23(t, 2H), 6.32(s, 1H), 6.94(d, 1H), 7.33(d, 1H), 7.42(d, 1H), 7.54(m, 3H), 7.90(d, 1H), 8.15(d, 1H), 8.18(d, 1H), 8.82(s, 1H), 8.96(s, 1H); MS (CI) 528(M++H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH2:9]Br)[CH:3]=1.[O:11]1CCOCC1.C(=O)([O-])[O-].[Ca+2]>O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][OH:11])[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(CBr)c1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Product: Cc1cc(Br)cc(CO)c1

Procedure:
A mixture of 1-bromo-3-(bromomethyl)-5-methylbenzene (40.0 g, 151 mmol), 1,4-dioxane (150 mL), water (150 mL) and calcium carbonate (37.9 g, 379 mmol) was heated for 16 h at reflux. The mixture was filtered and the filtrate was concentrated in vacuum, then diluted with CH2Cl2 (150 mL). The organic layer was washed with HCl (2N, 50 mL) and a solution of saturated sodium bicarbonate (50 mL), dried (Na2SO4) and concentrated in vacuum to give 25.0 g of crude product (3-bromo-5-methylphenyl)methanol.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][OH:8])[CH:5]=[CH:4][N:3]=[CH:2]1.[H-].[Na+].F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1.O>CN(C)C=O>[N+:18]([C:15]1[CH:16]=[CH:17][C:12]([O:8][CH2:7][CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:13][CH:14]=1)([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: OCCn1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(OCCn2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A stirred solution of 2-imidazol-1-yl-ethanol (J. Med. Chem., 39(10), 1991, (1996)) (3.9 g, 35 mmol) in dimethylformamide (75 mL) at 15° C. was treated portionwise with 60% sodium hydride (0.84 g, 35 mmol) and stirred at room temperature for 30 minutes. The mixture was rechilled and 4-fluoro-1-nitrobenzene (4.93 g, 35 mmol) added dropwise. The mixture was stirred cold for 30 minutes and heated at 35-40° C. for 30 minutes. A little water was added and the volatiles were removed on a pump. The residue was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and evaporated. Chromatography on silica gel and eluting with methanol/triethyl-amine/dichloromethane (2:2:96) and crystallization of the purified product from dichloromethane/ether gave 3.4 g (42%) of 1-[2-(4-nitro-phenoxy)ethyl]-1H-imidazole as a colorless solid, mp 55-57° C. Mass spectrum (LR-APCI) MH+=234.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1>CCO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:14][CH2:15][N:16]([CH2:3][CH2:2][C:1]#[N:4])[CH2:17][CH2:18]2)=[CH:11][CH:12]=1
Reactant: COc1ccc(C2(c3ccccc3)CCNCC2)cc1
Reactant: C=CC#N
Solvent: CCO
Product: COc1ccc(C2(c3ccccc3)CCN(CCC#N)CC2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70.1 %

Procedure:
Acrylonitrile (1.03 mL, 15.7 mmol, 2.50 equiv) was added at 0° C. to a solution of 4-(4-methoxyphenyl)-4-phenylpiperidine (1.68 g, 6.28 mmol, 1.00 equiv) in EtOH (20 mL) and the resulting solution was stirred for 1.5 hours at room temperature. After removal of the solvent, the residue was purified by flash chromatography (SiO2, EtOAc-CHCl3 1:3) to give 1.41 g (70%) of colorless oil, which was characterized spectroscopically.
Reaction SMILES: [CH2:1](Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]1([CH3:16])[CH:14]=[CH:13][CH:12]=[C:11]([CH3:15])[CH:10]=1>>[CH3:16][C:9]1[CH:14]=[CH:13][C:12]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:11]([CH3:15])[CH:10]=1
Reactant: ClCc1ccccc1
Reactant: Cc1cccc(C)c1
Product: Cc1ccc(Cc2ccccc2)c(C)c1

Procedure:
To 100 g of 2,4-dimethyldiphenylmethane obtained by the reaction between meta-xylene and benzyl chloride, having the following formula (b.p. 295°-296° C/760 mmHg, specific gravity (D420) 0.9951); ##STR3## was dissolved 3 g of crystal violet lactone. The resulting solution was then added to a solution of 20 g of gum arabic and 160 g of water to emulsify. Thereafter, 20 g of acid processed gelatin and 160 g of water were added thereto and the pH thereof was reduced to 5 by the addition of acetic acid under constant stirring. 500 g of water was then added to cause coacervation. On coacervation, a dense liquid membrane of gelatin-gum arabic was formed around the oil droplets containing a color former. The pH was further reduced to 4.4, and 4 g of 37 percent formation was successively added for hardening the membrane. Said operation was carried out keeping the temperature of the system at a temperature of 50° C. Then the system was cooled to 10° C in order to gel the dense liquid membrane. Furthermore, in order to raise the effect of hardening, the pH thereof was raised to 9 and the system was allowed to stand for several hours to accomplish the encapsulation. The capsule solution thus obtained was coated on a sheet of paper by air knife coating, then dried. The pressure sensitive recording paper thus obtained had no unpleasant smell like that of the conventional pressure sensitive recording paper wherein chlorinated diphenyl was used as a solvent. When this paper (upper paper) was superposed on a clay paper (aforesaid lower paper coated with active clay substance) and writing was conducted with pressure, there was developed a blue image on a clayed paper in an instant. The density of this color developed image was remarkably high compared with that of the conventional pressure sensitive recording paper. In addition, even when this upper paper was exposed to sun light for a long time, the lowering in the color developing ability and colored fog were not recognized.
Reaction SMILES: [Li+].[Br-].[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16](Cl)[CH:17]=2)[C:12]2([CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[Br-].[CH2:27]([Zn+])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>CN1C(=O)CCC1.C(N1C=CN(C(C)C)C1=[Pd-3](Cl)(Cl)C1C(Cl)=CC=CN=1)(C)C>[C:3]([O:7][C:8]([N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:17]=2)[C:12]2([CH2:22][N:21]([C:23](=[O:25])[CH3:24])[CH2:20]2)[CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)c1cc(Cl)ccc12
Reactant: [Zn+]Cc1ccccc1
Agent: CC(C)n1ccn(C(C)C)c1=[Pd-3](Cl)(Cl)c1ncccc1Cl
Agent: [Br-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Product: CC(=O)N1CC2(C1)CN(C(=O)OC(C)(C)C)c1cc(Cc3ccccc3)ccc12
Reaction time: 4 h
Yield: 175.7 %

Procedure:
(1,3-Diisopropylimidazol-2-ylidene)(3-chloropyridyl)palladium (II) dichloride (2 mg, 10 mol %) and LiBr (41 mg, 0.47 mmol) were dissolved in dry NMP and the solution was degassed with N2 for 5 minutes. Then 1-acetyl-6′-chloro-1′,2′-dihydrospiro[azetidine-3,3′-indole]-1′-yl-carboxylic acid tert-butyl ester (100 mg, 0.29 mmol) and benzylzinc bromide (0.5M solution in toluene, 950 μL, 0.475 mmol) were added. The reaction mixture was stirred under N2 for 4 h. A second aliquot of catalyst (2 mg) and benzylzinc bromide (950 μL) were added and stirring maintained for 4 h. The reaction was quenched with water and extracted with EtOAc. The organic phase was dried (MgSO4), filtered and concentrated. The crude material was purified by column chromatography (EtOAc:petrol 1:1 to EtOAc 100%) to give the title compound (200 mg) as a pale yellow oil (ca. 50% pure by NMR, contaminated with NMP), used without further purification. MS: [M+H]+=393.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[S:8](N)([NH2:11])(=[O:10])=[O:9]>O1CCOCC1>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([S:8]([NH2:11])(=[O:10])=[O:9])[CH2:4][CH2:3]1
Reactant: NS(N)(=O)=O
Reactant: CN1CCNCC1
Solvent: C1COCCO1
Product: CN1CCN(S(N)(=O)=O)CC1

Procedure:
To a solution of 1-Methylpiperazine (1.58 g) in dioxane was added sulfamide (4.0 g) and the reaction mixture was then heated at reflux in dioxane for 18 h. The reaction mixture was then reduced in vacuo and the residue partitioned between EtOAc (100 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×100 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a white solid. Yield: 640 mg
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][N:24]=1)[C:5]([NH:7][C:8]1[S:9][CH:10]=[C:11]([C:13]2[C:18]([CH3:19])=[CH:17][C:16]([CH3:20])=[CH:15][C:14]=2[CH3:21])[N:12]=1)=[O:6].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O>CN1CCCC1=O>[C:14]1([CH3:21])[CH:15]=[C:16]([CH3:20])[CH:17]=[C:18]([CH3:19])[C:13]=1[C:11]1[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:22]=[CH:23][N:24]=[C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)[CH:3]=2)[S:9][CH:10]=1
Reactant: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(Cl)c3)n2)c(C)c1
Reactant: C1COCCN1
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(C)c(-c2csc(NC(=O)c3ccnc(N4CCOCC4)c3)n2)c(C)c1
Temperature: 150 °C
Reaction time: 16 h
Yield: 64.3 %

Procedure:
A mixture of 2-chloro-N-(4-mesitylthiazol-2-yl)isonicotinamide (500.0 mg, 1.4 mmol, 1.0 equiv) and morpholine (1.5 mL, 16.8 mmol, 12 equiv) in methylpyrrolidone (15.0 mL) was stirred at 150° C. for 16 h. The mixture was poured into icy H2O (20.0 mL), and the resultant solids were filtered to provide N-(4-mesitylthiazol-2-yl)-2-morpholinoisonicotinamide (358.6 mg, 0.90 mmol) as yellow solids in 63% yield: 1H NMR (DMSO-d6, 500 MHz) δ 8.30 (d, J=5.1 Hz, 2H), 7.50 (s, 1H), 7.22 (d, J=5.1 Hz, 2H), 7.10 (s, 1H), 6.92 (s, 2H), 3.70-3.73 (m, 4H), 3.53-3.55 (m, 4H), 2.26 (s, 3H), 2.05 (s, 6H); ESI-MS: m/z 409.3 (M+H)+.