Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[Li]C(C)(C)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH:20]=[O:21]>C1COCC1>[S:1]1[C:5]([CH:20]([OH:21])[C:19]2[CH:18]=[C:17]([O:16][CH3:15])[C:24]([O:25][CH3:26])=[C:23]([O:27][CH3:28])[CH:22]=2)=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: c1ccc2sccc2c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cc3ccccc3s2)cc(OC)c1OC

Procedure:
a-(2-benzo[b]thienyl)-3,4,5-trimethoxybenzyl alcohol was prepared in the same manner as described in Example 40A. Reaction of benzo[b]thiophene (7.5 mmoles, 1.0 g), t-BuLi (1.7m, 9.7 mmoles, 5.7 mls) and 3,4,5-trimethoxybenzaldehyde (8.9 mmoles, 1.8 g) in THF (20 ml) yielded, after flash chromatography using 50% ethyl acetate/hexanes, 2.4 g (97%) of a yellow-white solid.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].C1(C)C=CC=CC=1.[F:12][C:13]1[CH:19]=[C:18]([S:20]([C:23]([F:28])([F:27])[CH:24]([F:26])[F:25])(=[O:22])=[O:21])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[CH:19]=[C:18]([S:20]([C:23]([F:27])([F:28])[CH:24]([F:25])[F:26])(=[O:22])=[O:21])[CH:17]=[CH:16][C:14]=1[N:15]=[C:1]=[O:2]
Reactant: O=C(Cl)Cl
Reactant: Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc(S(=O)(=O)C(F)(F)C(F)F)cc1F

Procedure:
To 4% phosgen-toluene solution was added 4.0 g of 2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)aniline, followed by heating under reflux for 3 hours. After the completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to give 2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl isocyanate as an oily material. In 50 ml of xylene was dissolved the oily material, and 1.5 of 2.6-difluorobenzamide was added to the solution, followed by heating under reflux for 20 hours. After the completion of the reaction, the reaction mixture was cooled to 0° C., and the crystals which separated out was recovered by filtration and recrystallized from acetone to give N-(2,6-difluorobenzoyl)-N'-[2-fluoro-4-(1,1,2,2-tetrafluoroethylsulfonyl)phenyl]urea (Compound No. 5) as crystals having a melting point of 186°-187° C. The melting point of the crystals did not descend in a mixed examination with the product of Example 4.
Reaction SMILES: C([N:9]=[C:10]=[S:11])(=O)C1C=CC=CC=1.C(O[C:15]([C:17]1[NH:18][CH:19]=[C:20]([Br:27])[C:21]=1[NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[O:16])C>C(Cl)Cl>[Br:27][C:20]1[C:21]2[N:22]([CH2:23][CH:24]([CH3:25])[CH3:26])[C:10](=[S:11])[NH:9][C:15](=[O:16])[C:17]=2[NH:18][CH:19]=1
Reactant: O=C(N=C=S)c1ccccc1
Reactant: CCOC(=O)c1[nH]cc(Br)c1NCC(C)C
Solvent: ClCCl
Product: CC(C)Cn1c(=S)[nH]c(=O)c2[nH]cc(Br)c21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Benzoyl isothiocyanate (0.034 g, 0.2 mmol) was added to a solution of 4-bromo-3-(isobutylamino)-1H-pyrrole-2-carboxylic acid ethyl ester (0.050 g, 0.17 mmol) in CH2Cl2 and the resulting mixture was stirred at r.t. for 1 h before it was concentrated in vacuo. The residue was dissolved in ammonia (7M in methanol, 1.5 mL) and stirred at 70° C. for 4 h. Additional ammonia (7M in methanol, 1 mL) was added and the mixture was stirred at 80° C. for 5 h. The mixture was cooled to r.t. and the precipitated product was filtered and washed with diethyl ether. After recrystallization with methanol the title compound (0.028 g, 55%) was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:17])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2.N1C=CC=CC=1.[Cl:24][CH2:25][C:26]1[S:27][CH:28]=[C:29]([C:31](Cl)=[O:32])[N:30]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([NH:17][C:31]([C:29]2[N:30]=[C:26]([CH2:25][Cl:24])[S:27][CH:28]=2)=[O:32])[C:5]2[C:9]([CH:10]=1)=[N:8][N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[CH:6]=2
Reactant: O=C(Cl)c1csc(CCl)n1
Reactant: Nc1cc(Br)cc2nn(C3CCCCO3)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1cc(Br)cc2nn(C3CCCCO3)cc12)c1csc(CCl)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.2 %

Procedure:
To 6-bromo-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (1.47 g) in DCM (20 ml) was added pyridine (1 ml). The reaction mixture was stirred for 5 minutes at room temperature before 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (1.21 g) in DCM (20 ml) was added dropwise over 10 minutes. The reaction mixture was stirred at room temperature for 18 hours. Saturated sodium bicarbonate solution (40 ml) was added and the reaction was stirred vigorously before the organic layer was separated using a hydrophobic frit. The aqueous layer was extracted with further DCM and the combined organic layers were evaporated to dryness. The residual solid was dried on a high vacuum line before triturating with cyclohexane to give the title compound (1.52 g).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[Br:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[N:37]=[C:38]=[O:39]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:38]([NH:37][C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=3[Br:30])=[O:39])[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: O=C=Nc1ccccc1Br
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)Nc1ccccc1Br

Procedure:
The title compound was prepared from [4-(3-amino-phenyl)-8-trifluoromethyl-quinolin-3-yl]-phenyl-methanone and 2-bromophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 587.8.
Reaction SMILES: [CH3:1]OCOC1C=CC=CC=1C(C1C=CC=CC=1)=O.[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O-:28])=[O:27])[C:21]=1[F:29].[Li+].[Br-].[Na+].S(Cl)(Cl)=O>>[Cl:19][C:20]1[CH:25]=[CH:24][N:23]=[C:22]([C:26]([O:28][CH3:1])=[O:27])[C:21]=1[F:29]
Reactant: O=C([O-])c1nccc(Cl)c1F
Reactant: COCOc1ccccc1C(=O)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: COC(=O)c1nccc(Cl)c1F
Temperature: 95 °C
Reaction time: 8 h

Procedure:
The title compound was prepared according to the procedure described in Org. Prep. and Proc. Int., 29 (1), 117-122 (1997). A suspension of lithium 4-chloro-3-fluoropicolinate (20.0 g, 136 mmol) and sodium bromide (28.0 g, 272 mmol, 2 eq) in thionyl chloride (99 mL, 1.36 mmol, 10 eq) was heated to reflux (95° C.) with an argon flush. The reaction was refluxed for 2 days then thionyl chloride (50 mL, 680 mmol, 5 eq) was added again and the reaction was refluxed for 3 more days. The mixture was then evaporated and the residue cooled down to 0° C. Methanol (300 mL) was cautiously added by portions and the mixture was stirred at 23° C. overnight. The reaction was then partitioned into ethyl acetate/sat. aq sodium carbonate and the aqueous phase was extracted with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered and concentrated. The residue was dissolved in boiling hexanes and the residual tar was decanted. The filtrate was evaporated to give the title material (24.36 g, 94%) as a solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.92 (3H, s), 8.01 (1H, t, J=5.1 Hz), 8.50 (1H, d, J=5.1 Hz). LC/MS (M+H)+: 190.
Reaction SMILES: [I:1][C:2]1[N:7]2[N:8]=[C:9]([S:19][CH3:20])[C:10]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[C:6]2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:24][CH:25]1[CH2:27][CH2:26]1.C(OCC)(=O)C>CN(C)C=O>[CH:25]1([CH2:24][N:11]([C:10]2[C:9]([S:19][CH3:20])=[N:8][N:7]3[C:2]([I:1])=[CH:3][CH:4]=[CH:5][C:6]=23)[C:12](=[O:18])[O:13][C:14]([CH3:16])([CH3:17])[CH3:15])[CH2:27][CH2:26]1
Reactant: BrCC1CC1
Reactant: CSc1nn2c(I)cccc2c1NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CSc1nn2c(I)cccc2c1N(CC1CC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl N-[7-iodo-2-methylthiopyrazolo[1,5-a]pyridin-3-yl]carbamate (600 mg) in N,N-dimethylformamide (6 mL) was added sodium hydride (60% in oil; 80 mg) with ice bath, and the reaction mixture was stirred for 30 minutes at room temperature. (Bromomethyl)cyclopropane (0.22 mL) was added to the reaction mixture at the same temperature, and stirring was continued for 1 hour at 40° C. After completion of the reaction, the reaction mixture was gradually added to ice, extraction was performed with ethyl acetate, and the organic extract was washed with water and brine. The organic extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to afford a crude product of tert-butyl N-cyclopropylmethyl-N-[7-iodo-2-(methylsulfanyl)pyrazolo[1,5-a]pyridin-3-yl]carbamate.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>CN(C)C=O>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)=[CH:18][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: OC1CCN(Cc2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 110.8 %

Procedure:
0.202 g (0.002 mol) of 4-hydroxypiperidine, 1.22 ml (0.0088 mol) of triethylamine and 0.43 g (0.0021 mol) of 4-chlorobenzyl bromide were dissolved in 5 ml of dimethylform-amide and stirred at room temperature for 2 hrs. The solvent was distilled off and the residue was taken up in dichloromethane and washed with saturated bicarbonate solution and sodium chloride solution. The organic phase was dried over sodium sulfate and concentrated. 0.50 g (100%) of 1-(4-chloro-benzyl)-piperidin-4-ol was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[CH:5]=[CH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH3:2].[CH2:15](O)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]C=C>CCOCC>[CH2:1]([O:3][C:4](=[O:14])/[CH:5]=[CH:6]/[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])[CH2:2][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:16]=[CH2:15]
Reactant: C=CCCCCCCCCO
Reactant: CCOC(=O)C=Cc1ccccc1O
Solvent: CCOCC
Product: C=CCCCCCCCCOC(=O)/C=C/c1ccccc1O
Temperature: 150 °C
Reaction time: 2.5 h
Yield: 21.5 %

Procedure:
A mixture of 5.0 g 3-(2-hydroxy-phenyl)-acrylic acid ethyl ester, 6.1 g dec-9-en-1-ol and 1.0 g tetraisopropyl-ortho-titanate was heated to 150° C. removing the ethanol formed. After stirring for 2.5 hours at this temperature, the reaction mixture was cooled, diluted with ether and washed with brine. The organic phase was dried and evaporated to dryness. The resulting oil was Kugelrohr-distilled, crystallized and recrystallized to yield 1.69 g of colourless crystals.
Reaction SMILES: C([C@H:8]1[C@@H:12]([OH:13])[CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[C@@H:9]1[C:24]([OH:26])=[O:25])C1C=CC=CC=1.C(O)(=[O:29])C>[Pd]>[OH:29][C@H:8]1[C@H:12]([OH:13])[CH2:11][NH:10][C@@H:9]1[C:24]([OH:26])=[O:25]
Reactant: CC(=O)O
Reactant: O=C(O)[C@@H]1[C@@H](Cc2ccccc2)[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: [Pd]
Product: O=C(O)[C@H]1NC[C@@H](O)[C@@H]1O
Reaction time: 48 h
Yield: 93.5 %

Procedure:
(2S, 3R, 4R)-3-benzyl-N-benzyloxycarbonyl-4-hydroxyproline (17) (523 mg, 1.95 mmol) was dissolved in glacial acetic acid (12 ml) containing palladium black (100 mg) and stirred under hydrogen at atmospheric pressure for 48 hours. The solution was filtered and the solvent removed. Purification by flash chromatography (CMAW) and ion exchange resin gave (2S, 3R, 4R)-3,4-dihydroxyproline (220 mg, 93.5%) as a white crystalline solid, m.p. 220°-245° C. decomposed without melting (lit.37 250° dec.), [α]20D -12.2° (c, 0.83 in water) [lit.37 [α]D25 -19° (c, 0.4 in water)]; νmax (KBr disc) 3260, 1615 (CO), 1370, 1270, 1075, 1050 and 760 cm-1 ; 1H NMR δ (D2O) 3.35 (1H, d, H-5, J5,5' 12.5 Hz); 3.44 (1H, dd, H-5', J4,5' 3.7 Hz); 3.90 (1H, s, H-2); 4.14 (1H, dt, H-4, J3,4 1.2 Hz); 4.36 (1H, bs, H-3). 13C NMR (D2O) δ 51.71 (t, C-5); 66.33 (d, C-2); 74.75 (d, C-4); 79.14 (d, C-3); 171.86 (s, C-1). m/z: 124 (100%), 104 (77%), 148 (M+H+, 75%), 84 (67%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([OH:14])=[C:8]([S:10]([OH:13])(=[O:12])=[O:11])[CH:9]=1)(=[NH:3])[NH2:2].[C:15](Cl)(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][C:15](=[O:22])[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:8]([S:10]([OH:13])(=[O:11])=[O:12])[CH:9]=1)(=[NH:2])[NH2:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: N=C(N)c1ccc(O)c(S(=O)(=O)O)c1
Solvent: c1ccncc1
Product: N=C(N)c1ccc(OC(=O)c2ccccc2)c(S(=O)(=O)O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 30 ml of dried pyridine, was added 3.0 g of 5-amidino-2-hydroxybenzenesulfonic acid. To the mixture, while being cooled in ice, was slowly added dropwise 2.0 g of benzoyl chloride. After the addition, the mixture was stirred overnight at room temperature. The insolubles deposited from the reaction mixture were separated by filtration, washed with pyridine, then with water, finally with acetone, and suspended in methanol. The insolubles were removed by filtration, and ethyl ether was added to the filtrate to precipitate a colorless solid. The solid was collected by filtration and recrystallized from a methanol-ethyl ether mixture to obtain 5-amidino-2-benzoyloxybenzenesulfonic acid in colorless solid form.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[CH2:15][CH2:16][F:17].C(N(CC)C(C)C)(C)C>C(#N)C>[C:4]([O:3][C:1]([N:8]1[CH2:9][CH2:10][N:11]([CH2:15][CH2:16][F:17])[CH2:12][CH2:13]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: FCCBr
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCF)CC1
Yield: 98.5 %

Procedure:
Heat a mixture of 1-boc-piperazine (4.08 g, 21.9 mmol), 1-bromo-2-fluoroethane (16.68 g, 0.131 mol) and N,N-diisopropyl ethyl amine (17.0 g, 0.131 mol) in acetonitrile (40 mL) to 50° C. for 16 hours and then heat to reflux for 7 additional hours. Cool the reaction to room temperature and remove the solvent in vacuo. Treat the residue with 1 N NaOH (25 mL) and extract twice with ethyl acetate. Dry the organic layer with Na2SO4 and purify the crude product on silica with a 0 to 10% Methanol in CH2Cl2 gradient to afford 5.01 g (99%) of 4-(2-fluoro-ethyl)-piperazine-1-carboxylic acid tert-butyl ester (Rf 0.36 (9/1 CH2Cl2/Methanol, I2 stain).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11]([OH:13])=O)=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH2:36].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>>[CH3:29][O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][NH:36][C:11]([C:9]1[CH:8]=[CH:7][C:6]2[N:2]([CH3:1])[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)=[N:4][C:5]=2[CH:10]=1)=[O:13]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCOCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCOCCNC(=O)c1ccc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Yield: 47 %

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid [2-(2-methoxy-ethoxy)-ethyl]-amide (44 mg) was prepared by following General Procedure F starting from 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (75 mg), 2-(2-methoxy-ethoxy)-ethylamine (24 mg), HBTU (84 mg), and DIEA (48 uL). LC/MS: m/z 511.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.40 (bs, 1H), 8.50 (t, 1H), 8.10 (s, 1H), 7.92 (s, 1H), 7.78 (d, 1H), 7.74 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.64 (s, 3H), 3.59-3.53 (m, 4H), 3.49-3.41 (m, 4H), 3.25 (s, 3H).
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([OH:28])=O)[NH:10][C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH2:44]([NH2:51])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50]>C(Cl)Cl>[C:12]1([C:11]2[N:10]=[C:9]([S:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]([NH:51][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:28])[NH:8][C:7]=2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reactant: CCCCCCCN
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCNC(=O)CCCCCCCSc1nc(-c2ccccc2)c(-c2ccccc2)[nH]1
Reaction time: 0.5 h
Yield: 33.5 %

Procedure:
Part A. To a solution of 8-(4,5-diphenyl-1H-imidazol-2-ylthio)octanoic acid (8.44 g, 0.02 mol) in methylene chloride (100 mL) at 0° was added, portionwise as a solid, dicyclohexylcarbodiimide (4.12 g, 0.02 mol), and the reaction mixture was stirred at 0° for 30 minutes. To this reaction mixture was added, dropwise, heptylamine (2.96 mL, 2.3 g, 0.02 mol) and the reaction mixture was stirred at reflux for 72 hours. The reaction mixture was cooled, and the solids were filtered and washed with chloroform. The filtrate was concentrated under vacuum and the residue was chromatographed with a gradient of 7:3 to 1:1 hexane-ethyl acetate. The resulting solid was recrystallized from acetonitrile and triturated with hexane to give 8-(4,5-diphenyl-1H-imidazol-2-ylthio)-N-heptyloctanamide (3.28 g, 0.0067 mol) as a white solid, mp 119°-120°. 1H NMR (DMSO-d6) δ12.5(s,1H), 7.8-7.1(m,10H), 3.2-2.9(m,4H), 2.0(t,2H,J=7Hz), 1.75-1.0(m,21H), 1.0-0.8(m,3H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:13]1[CH:28]=[CH:27][C:16]([CH2:17][N:18]([CH3:26])[CH2:19][C:20]([O:22]CC=C)=[O:21])=[CH:15][CH:14]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li+].[OH-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]([C:13]1[CH:14]=[CH:15][C:16]([CH2:17][N:18]([CH3:26])[CH2:19][C:20]([OH:22])=[O:21])=[CH:27][CH:28]=1)[S:9]([CH3:12])(=[O:11])=[O:10])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCOC(=O)CN(C)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(CC(=O)O)Cc1ccc(N(C(=O)OC(C)(C)C)S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89 %

Procedure:
To a solution of allyl 2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)-benzyl)(methyl)amino)acetate (0.390 g, 0.945 mmol) in THF (22 ml), LiOH 1N (0.945 ml, 0.945 mmol) was added, and the mixture was stirred at RT for 3 days. The mixture was diluted with water and washed twice with EtOAc. The aqueous phase was acidified with 0.189 ml of HCl 1N and frozen dry. The residue was dissolved in DCM/MeOH and transferred in a small container. 2-((4-(N-(tert-butoxycarbonyl)methylsulfonamido)-benzyl)(methyl)amino)acetic acid was obtained (0.313 g, 0.840 mmol, 89% yield, MS/ESI+ 373.2 [MH]+) and used without any further purification.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:11][C:12]2[N:16]([CH3:17])[C:15]3[CH:18]=[CH:19][C:20]([O:22][C:23]4[CH:28]=[CH:27][N:26]=[C:25]([C:29]([NH:31][CH3:32])=[O:30])[CH:24]=4)=[CH:21][C:14]=3[N:13]=2)=[O:10])=[CH:5][CH:4]=1.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>O1CCCC1>[CH3:32][NH:31][C:29]([C:25]1[CH:24]=[C:23]([O:22][C:20]2[CH:19]=[CH:18][C:15]3[N:16]([CH3:17])[C:12]([NH:11][C:9]([C:6]4[CH:7]=[CH:8][C:3]([CH2:2][N:37]5[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]5)=[CH:4][CH:5]=4)=[O:10])=[N:13][C:14]=3[CH:21]=2)[CH:28]=[CH:27][N:26]=1)=[O:30]
Reactant: CN1CCNCC1
Reactant: CNC(=O)c1cc(Oc2ccc3c(c2)nc(NC(=O)c2ccc(CCl)cc2)n3C)ccn1
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Oc2ccc3c(c2)nc(NC(=O)c2ccc(CN4CCN(C)CC4)cc2)n3C)ccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of [4-(2-{[4-(chloromethyl)phenyl]carbonylamino)-1-methylbenzimidazol-5-yloxy)(2-pyridyl)]-N-methylcarboxamide (1 eq) in tetrahydrofuran was added methylpiperazine (4 eq) and stirred at ambient temperature for 16 h. The reaction mixture was concentrated and purified on preparative chromatography to yield N-methyl {4-[1-methyl-2-({4-[(4-methylpiperazinyl)methyl]phenyl}carbonylamino)benzimidazol-5-yloxy](2-pyridyl)}carboxamide. MS: MH+=512.
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]=[O:10]>>[C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[C:3]=1[CH:9]=[O:10])[OH:2]
Reactant: C=O
Reactant: Oc1cccc(O)c1
Product: O=Cc1c(O)cccc1O

Procedure:
In the case of using RF-gel as carbon precursor, aqueous solutions containing 20 to 60 weight percent of inorganic template particles stabilized with surfactants specified in the step (a) are prepared, and the resulting aqueous solution is mixed with 30 to 70 weight percent aqueous solution of the mixture of resorcinol and formaldehyde (1:2 to 1:3 molar ratio) to produce mixtures with weight ratio of 1:1 to 1:20 (resorcinol-formaldehyde:inorganic template), followed by polymerizing at 20° C. to 95° C. to produce inorganic template/carbon precursor composites as specified in the step (a). In the case of commercial silica sol as template, resorcinol and formaldehyde can be polymerized without using catalyst, because weak basic property of the silica sol solution readily induces polymerization. In order to accelerate the specified polymerization reaction, catalyst such as sodium carbonate can be also added.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]1([CH3:15])[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1>>[C:4]1([CH3:5])[CH:3]=[CH:2][CH:7]=[CH:6][C:15]=1[C:8]1[CH:13]=[CH:12][C:11]([SH:14])=[CH:10][CH:9]=1
Reactant: Cc1ccc(S)cc1
Reactant: Ic1ccccc1
Product: Cc1ccccc1-c1ccc(S)cc1

Procedure:
The general procedure was used to convert iodobenzene and p-toluenethiol to the title product. Purification by flash chromatography (hexane as the eluent) gave the analytically pure product as a clear oil (388 mg, 97.0% yield). 1H NMR (300 MHz, CDCl3) δ 7.18 (dt, J=8.1, 2H; Ha, Ha′), 7.15–7.12 (m, 4H; He, He′, Hf, Hf′), 7.08 (m, 1H; Hg), 7.04–7.00 (d, J=7.34, 2H; Hc, Hc′), 2.22 (s, 3H; methyl protons). 13C NMR (75 MHz, CDCl3) δ 138.05 (C4), 137.62 (C1′), 132.77 (C2, C6), 131.76 (C1), 130.55 (C3, C5), 130.23 (C2′, C6′), 129.52 (C3′, C5′), 126.87 (C4′), 21.62 (C7). Anal. Calcd. for C13H12S: C, 77.95; H, 6.04; S, 16.01; Found C, 77.78; H, 6.01; S, 16.19.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[CH:5]=[C:4]([CH3:15])[N:3]=1.[Br:16][C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1>>[Br:16][C:17]1[CH:22]=[C:21]([C:2]2[N:7]=[C:6]([C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=3)[CH:5]=[C:4]([CH3:15])[N:3]=2)[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(-c2ccc(Cl)cc2)nc(Cl)n1
Reactant: OB(O)c1cccc(Br)c1
Product: Cc1cc(-c2ccc(Cl)cc2)nc(-c2cccc(Br)c2)n1

Procedure:
The title compound was prepared from 2-chloro-4-(4-chloro-phenyl)-6-methyl-pyrimidine (example A.11) (1.0 g, 4.18 mmol) and commercially available 3-bromo-benzeneboronic acid (1.09 g, 5.43 mmol) according to the general procedure IVb. Obtained as an off-white solid (0.5 g, 33%). MS (ISP) 361.0 [(M+H)+]; mp 123° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].CC1C=CC(S(O[CH2:31][CH2:32][F:33])(=O)=O)=CC=1.CCOC(C)=O>CN(C)C1C=CN=CC=1.C1COCC1>[F:33][CH2:32][CH2:31][N:17]1[CH2:18][CH2:19][N:14]([C:6]2[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=2)[CH2:15][CH2:16]1
Reactant: Cc1ccc(S(=O)(=O)OCCF)cc1
Reactant: O=[N+]([O-])c1cc(N2CCNCC2)cc(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cc(N2CCN(CCF)CC2)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
Mix (3-nitro-5-(trifluoromethyl)phenyl)piperazine (200 mg, 0.73 mmol), 2-fluoroethyl 4-methylbenzenesulfonate (320 mg, 1.46 mmol) and 4-dimethylaminopyridine (50 mg, 0.37 mmol) in THF (15 mL), stir at 90° C. overnight. TLC (EtOAc:PE=1:1) shows the reaction is complete. Concentrate under reduced pressure to give a residue, purify the residue by flash chromatography (silica gel, PE:EtOAc=1:1) to yield a white solid as the target compound (120 mg, 51%).