Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][CH:9]1[CH2:14][NH:13][CH2:12][CH2:11][N:10]1[C:15]1[C:24]2[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]3[CH:34]=[CH:33][N:32]=[CH:31][N:30]=3)(=[O:27])=[O:26])=[CH:22][CH:23]=2)[CH:18]=[CH:17][N:16]=1.CC(C)([O-])C.[Na+].[F:41][C:42]1[CH:47]=[CH:46][CH:45]=[C:44](I)[CH:43]=1>O1CCOCC1>[F:41][C:42]1[CH:43]=[C:44]([N:13]2[CH2:12][CH2:11][N:10]([C:15]3[C:24]4[C:19](=[CH:20][C:21]([S:25]([NH:28][C:29]5[CH:34]=[CH:33][N:32]=[CH:31][N:30]=5)(=[O:27])=[O:26])=[CH:22][CH:23]=4)[CH:18]=[CH:17][N:16]=3)[CH:9]([CH3:8])[CH2:14]2)[CH:45]=[CH:46][CH:47]=1
Reactant: Fc1cccc(I)c1
Reactant: CC1CNCCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O=C(O)C(F)(F)F
Product: CC1CN(c2cccc(F)c2)CCN1c1nccc2cc(S(=O)(=O)Nc3ccncn3)ccc12
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A vial was charged with 1-(2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide 2,2,2-trifluoroacetate (0.037 g, 0.074 mmol), ruphos palladium(ii) phenethylamine chloride (6.06 mg, 7.42 μmol), and sodium tert-butoxide (0.029 g, 0.297 mmol). Dioxane (0.742 ml) and 1-fluoro-3-iodobenzene (0.013 ml, 0.111 mmol) were added and the reaction was flushed with argon and stirred at 100° C. for one hour. The reaction was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 40 g, gradient elution 0-10% MeOH:DCM) to afford 1-(4-(3-fluorophenyl)-2-methylpiperazin-1-yl)-N-(pyrimidin-4-yl)isoquinoline-6-sulfonamide as a tan solid. 1H NMR (400 MHz, DMSO-d6) δ=8.64-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.97 (d, J=10.1 Hz, 1H), 7.68 (d, J=5.8 Hz, 1H), 7.24 (q, J=8.2 Hz, 1H), 7.05 (br. s., 1H), 6.87-6.76 (m, 2H), 6.56 (dt, J=1.9, 8.2 Hz, 1H), 4.02 (d, J=3.1 Hz, 1H), 3.61-3.44 (m, 3H), 3.29-3.22 (m, 1H), 1.08 (d, J=6.3 Hz, 5H). m/z (ESI) 479.2 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:3]1.[CH:23](OCC)=[O:24].[O-]CC.[Na+].Cl>C(O)C>[OH:24][CH:23]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:22])[CH3:21])=[CH:15][CH:14]=3)=[O:12])[CH:8]=2)[NH:3][C:2]1=[O:1]
Reactant: CCOC=O
Reactant: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)CC(=O)N3)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)c2ccc3c(c2)C(=CO)C(=O)N3)cc1
Temperature: 78 °C
Yield: 74.8 %

Procedure:
N-[4-(2-Oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.330 g, 1.12 mmol) and ethyl formate (0.269 mL, 3.37 mmol) were dissolved in anhydrous ethanol (3.80 mL). The resulting solution was treated in dropwise fashion with a 21 wt % solution of sodium ethoxide in ethanol (2.09 mL, 5.61 mmol). This reaction mixture was heated at 78° C. for 1 h, producing a black oil. Subsequently, the reaction mixture was cooled to room temperature, and then the reaction pH was adjusted to pH 1 with dropwise addition of 1M HCl(aq) causing the formation of a pale orange precipitate. The suspension was filtered yielding an orange solid as the pure N-[4-(3-Hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-5-carbonyl)-phenyl]-acetamide (0.272 g, 0.838 mmol, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[N:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O.[CH3:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[NH:26][CH2:25][CH2:24][CH2:23]2.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:3]=1[O:4][C:5]1[C:6]([C:7]([N:26]2[C:27]3[C:22](=[CH:21][C:20]([CH3:19])=[CH:29][CH:28]=3)[CH2:23][CH2:24][CH2:25]2)=[O:9])=[CH:10][CH:11]=[CH:12][N:13]=1
Reactant: O=C(O)c1cccnc1Oc1cc(Cl)ccc1Cl
Reactant: Cc1ccc2c(c1)CCCN2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc2c(c1)CCCN2C(=O)c1cccnc1Oc1cc(Cl)ccc1Cl
Temperature: 100 °C
Yield: 48.4 %

Procedure:
To a solution of 2-(2,5-dichloro-phenoxy)-nicotinic acid (42.6 mg, 0.15 mmol, 1.0 equiv) in anhydrous DMF (1 mL) was added 6-methyl-1,2,3,4-tetrahydro-quinoline (26.5 mg, 0.18 mmol, 1.2 equiv; [CAS RN 91-61-2]), N-ethyldiisopropylamine (97.0 mg, 131 μL, 0.75 mmol, 5.0 equiv; [CAS RN 7087-68-5]) and HATU (68.4 mg, 0.18 mmol, 1.2 equiv; [CAS RN 148893-10-1]). The reaction mixture was heated by microwave irradiation to 100° C. for 10 min. Removal of the solvent mixture under reduced pressure and purification by preparative (Xterra® PrepMSC 18, 5 μm, 19×50 mm column equipped with a Gilson Liquid Handler 215 autosampler, two Rainin Dynamax® SD-300 pumps, a Sedex ELSD 75 lightscatter and a Dionex UVD 340S UV detector) on reversed phase eluting with a gradient of acetonitrile/water provided 30 mg (49%) of the title compound. MS (ISP): 413.2 [M+H]+.
Reaction SMILES: C(O[C:6](=O)[N:7]([C:9]1[CH:10]=[N:11][C:12]([C:15](=[O:35])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C@:24]3([CH:32]([F:34])[F:33])[C@@H:30]4[C@@H:28]([CH2:29]4)[O:27][C:26]([NH2:31])=[N:25]3)[CH:18]=2)=[N:13][CH:14]=1)C)(C)(C)C.[ClH:37].O>O1CCOCC1>[ClH:37].[ClH:37].[NH2:31][C:26]1[O:27][C@H:28]2[C@@H:30]([C@:24]([C:19]3[CH:18]=[C:17]([NH:16][C:15]([C:12]4[N:13]=[CH:14][C:9]([NH:7][CH3:6])=[CH:10][N:11]=4)=[O:35])[CH:22]=[CH:21][C:20]=3[F:23])([CH:32]([F:34])[F:33])[N:25]=1)[CH2:29]2
Reactant: CN(C(=O)OC(C)(C)C)c1cnc(C(=O)Nc2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)nc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CNc1cnc(C(=O)Nc2ccc(F)c([C@@]3(C(F)F)N=C(N)O[C@@H]4C[C@@H]43)c2)nc1
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of tert-butyl(2-((3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)carbamoyl)pyrimidin-5-yl)(methyl)carbamate (0.06 g, 0.11 mmol) in 1,4-dioxane (2 mL) was treated with HCl (4.0M in 1,4-dioxane; 1 mL). The resulting suspension was treated with water (0.1 mL) resulting in a pale-yellow biphasic solution. The solution was stirred for 2 h, concentrated, and lyophilized from 1,4-dioxane to give N-(3-((1R,5S,6R)-3-amino-5-(difluoromethyl)-2-oxa-4-azabicyclo[4.1.0]hept-3-en-5-yl)-4-fluorophenyl)-5-(methylamino)pyrimidine-2-carboxamide dihydrochloride (0.05 g, 0.105 mmol, 93% yield) as a pale-yellow solid.
Reaction SMILES: O=C1CCC(=O)N1O[C:9]([C:11]1[O:15][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Br:22])=[N:13][C:12]=1[CH2:23][CH2:24][CH3:25])=[O:10].[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:36]=[CH:35][C:34]([NH2:37])=[CH:33][N:32]=1>>[CH3:26][O:27][CH2:28][CH2:29][N:30]([CH3:38])[C:31]1[N:32]=[CH:33][C:34]([NH:37][C:9]([C:11]2[O:15][C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[Br:22])=[N:13][C:12]=2[CH2:23][CH2:24][CH3:25])=[O:10])=[CH:35][N:36]=1
Reactant: CCCc1nc(-c2ccccc2Br)oc1C(=O)ON1C(=O)CCC1=O
Reactant: COCCN(C)c1ncc(N)cn1
Product: CCCc1nc(-c2ccccc2Br)oc1C(=O)Nc1cnc(N(C)CCOC)nc1

Procedure:
With a procedure similar to example 50 above, 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid {2-[(2-methoxy-ethyl)-methyl-amino]-pyrimidin-5-yl}-amide was prepared from 2-(2-bromo-phenyl)-4-propyl-oxazole-5-carboxylic acid 2,5-dioxo-pyrrolidin-1-yl ester and N-(2-methoxy-ethyl)-N-methyl-pyrimidine-2,5-diamine. LCMS calcd for C21H24BrN5O3 (m/e) 474, obsd 475 (M+H).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]21[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:16].[C:17](=O)([O:20]C)[O:18][CH3:19].[H-].[Na+]>CO>[O:16]=[C:10]1[C:2]2([CH2:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[C:17]([O:18][CH3:19])=[O:20]
Reactant: O=C1CCCCCC12Cc1ccccc1C2
Reactant: COC(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1CCCCC2(Cc3ccccc3C2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Example 19A (1.8 g, 8.40 mmol) in dimethyl carbonate (7.1 mL, 84 mmol) was treated with sodium hydride (60% dispersion in mineral oil, 0.672 g, 16.80 mmol) and a catalytic amount of MeOH (2 drops), then the mixture was heated at reflux. After 3 hours, the reaction was cooled to room temperature, and then it was quenched with 2N HCl. The mixture was extracted with ether, then the extracts were dried (Na2SO4) and evaporated. Purification by silica gel chromatography (10 to 25% EtOAc-hexane, eluant) afforded the title compound. 1H NMR (300 MHz, DMSO-d6) δ 7.10-7.21 (m, 4H), 4.25 (dd, J=11.1, 2.8 Hz, 1H), 3.57 (s, 3H), 3.51 (d, J=15.9 Hz, 1H), 3.15 (d, J=15.9 Hz, 1H), 3.00 (m, 1H), 2.60 (d, J=16.3 Hz, 1H), 2.09 (m, 1H), 1.90 (d, J=5.2 Hz, 2H), 1.72-1.85 (m, 2H), 1.44-1.56 (m, 2H), 1.02-1.15 (m, 1H). MS (DCI+) m/z 273 (M+H), 290 (M+NH4).
Reaction SMILES: [CH2:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH3:8][CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][Cl:11].S(=O)(=O)(O)O>C(Cl)(Cl)Cl>[CH2:1]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][CH:9]([CH3:8])[CH2:10][Cl:11])=[CH:14][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: C=CCCCCC
Reactant: CC(CCl)Cc1ccccc1
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Product: CCCCCCCc1ccc(CC(C)CCl)cc1
Reaction time: 14 h
Yield: 75 %

Procedure:
25 parts by weight of hept-1-ene are added dropwise at 10° C. to a mixture of 42 parts by weight of 2-methyl-3-phenylpropyl chloride and 20 parts by weight of 96% strength sulfuric acid. Stirring is continued at room temperature for 14 hours. The crude product is dissolved in CHCl3, and the solution is washed with ice water, dried over Na2CO3 and distilled. 50 parts by weight of 3-(4-heptylphenyl)-2-methyl-propyl chloride are obtained; boiling point 114° C.-7° C./0.1 mm Hg, yield 75%(based on 2-methyl-3-phenylpropyl chloride).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:18]([CH3:19])=[CH:17][C:10]2[N:11]=[C:12]([CH:14]3[CH2:16][CH2:15]3)[S:13][C:9]=2[C:8]=1[Br:20])(=O)=O.[CH2:23](C([Sn])=C(CCCC)CCCC)[CH2:24]CC.[Li+].[Cl-]>CN(C=O)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>[Br:20][C:8]1[C:9]2[S:13][C:12]([CH:14]3[CH2:16][CH2:15]3)=[N:11][C:10]=2[CH:17]=[C:18]([CH3:19])[C:7]=1[CH:23]=[CH2:24]
Reactant: Cc1cc2nc(C3CC3)sc2c(Br)c1OS(=O)(=O)C(F)(F)F
Reactant: CCCCC([Sn])=C(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: C=Cc1c(C)cc2nc(C3CC3)sc2c1Br

Procedure:
To a solution of 7-bromo-2-cyclopropyl-5-methylbenzo[d]thiazol-6-yl trifluoromethanesulfonate (16) (410 mg, 0.988 mmol) in DMF (4 ml), was added tributylvinyltin (0.43 ml, 1.47 mmol), LiCl (125 mg, 2.94 mmol) and PdCl2(PPh3)2 (70 mg, 0.096 mmol). The reaction mixture was reacted at 80° C. overnight. The reaction was cooled down, washed by saturated NaHCO3 solution, extracted by EtOAc. The organic phase was combined, dry over MgSO4, filtered, concentrated and purified by silica gel column, eluting by 0-50% EtOAc in hexanes.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][C:4]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1.CCN(CC)CC.[C:43](Cl)(=[O:45])[CH3:44]>C(Cl)Cl>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:43](=[O:45])[CH3:44])=[CH:5][C:4]=1[C:10]1[CH:34]=[C:33]([CH3:35])[C:13]2[N:14]=[C:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][N:28]4[CH2:32][CH2:31][CH2:30][CH2:29]4)=[CH:21][CH:20]=3)[N:16]=[N:17][C:12]=2[CH:11]=1
Reactant: Cc1cc(-c2cc(O)ccc2Cl)cc2nnc(Nc3ccc(OCCN4CCCC4)cc3)nc12
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Oc1ccc(Cl)c(-c2cc(C)c3nc(Nc4ccc(OCCN5CCCC5)cc4)nnc3c2)c1
Reaction time: 0.17 h
Yield: 80.8 %

Procedure:
To a solution of 4-chloro-3-{5-methyl-3-[4-(2-pyrrolidin-1-yl-ethoxy)-phenylamino]-benzo[1,2,4]triazin-7-yl}-phenol hydrochloride (1.0 equiv., 0.978 mmol) in DCM (30 mL) was added neat Et3N (10 equiv., 4.89 mmol) under an argon rich atmosphere and stirred for 10 minutes. Neat Acetyl chloride (1.2 equiv., 1.17 mmol) was added dropwise via syringe to the reaction mixture and allowed to stir at room temperature for 24 h. The reaction was quenched using saturated NaHCO3; the organics were dried over Na2SO4 and then concentrated down under reduced pressure. The resulting crude solid was then brought up in DCM and purified by flash chromatography using a solvent system of 85:10:5 (v/v/v) DCM/MeOH/Et3N. The fractions were concentrated under reduced pressure and precipitated out using 1:5 (v/v) DCM/hexanes to afford an orange solid (409.1 mg, 75% yield). 1H NMR (DMSO-d6): δ 1.68 (m, 4H), 2.29 (s, 3H), 2.51 (m, 4H), 2.63 (s, 3H), 2.78 (t, J=5.94 Hz, 2H), 4.07 (t, J=5.99 Hz, 2H), 6.99 (dd, J=7.05 Hz, 12.55 Hz, 2H), 7.27 (dd, J=5.90 Hz, 8.75 Hz, 1H), 7.41 (d, J=2.80 Hz, 1H), 7.67 (d, J=8.75 Hz, 1H), 7.85 (m, 1H), 7.93 (d, J=9.05 Hz, 2H), 8.17 (m, 1H), 10.83 (s, 1H). Rf=0.29 MS (ES+) m/z 520, LC retention time 2.57 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:26][C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.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:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:30]3[CH:31]=[CH:32][C:27]([Cl:26])=[CH:28][CH:29]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Reactant: OB(O)c1ccc(Cl)cc1
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: O
Product: CC(C)(C)OC(=O)N1CCc2cc(-c3ccc(Cl)cc3)ccc2C1
Temperature: 90 °C
Yield: 38.8 %

Procedure:
To a mixture of 6-trifluoromethanesulfonyloxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2 g, 5.25 mmol) and 4-chlorophenyl boronic acid (1.17 g, 7.5 mmol)in toluene (20 ml) was added a 2M sodium carbonate solution (7.5 ml). The reaction mixture was stirred under a nitrogen atmosphere, then tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.25 mmol) was added and the reaction mixture was heated at 90° C. for 18 h. After allowing to cool the reaction mixture was diluted with water (100 ml) and extracted with ethyl acetate (3×100 ml). The ethyl acetate extracts were combined, dried over magnesium sulphate, filtered and evaporated under reduced pressure to give an oil. Purification by flash chromatography using hexane/ethyl acetate as eluant gave the title compound as an oil (0.7 g, 39%); δH (CDCl3) 1.5 (9H, s, C(CH3)3), 2.89 (2H, t, J 8.3 Hz, CH2), 3.68 (2H, t, J 8.3 Hz, CH2), 4.61 (2H, s, CH2), and 7.15-7.5 (7H, m, ArH).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][C:10]1=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li][CH3:42]>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[O:12][C:10]1([OH:11])[CH3:42])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [Li]C
Solvent: C1CCOC1
Product: CC1(O)O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 96.2 %

Procedure:
18 g (33 mmol) of 21a was dissolved in 200 mL of anhydrous THF under nitrogen. Cooled to −78° C. 45 mL of MeLi (1.6 M, 72 mmol) was added by a syringe. After 1 hour at −78° C., the reaction was quenched by a solution of 7 g of NH4Cl in 200 mL of H2O. TLC showed no starting material left, while a new spot corresponding to the product appeared. The mixture was extracted by 3×150 mL of ethyl acetate, washed by brine, dried over Na2SO4. After evaporation, a thick pale yellow oil was obtained which was turned into a white solid (17.6 g, 95% yield) with a melting point of 92–93° C. 300 MHz 1H NMR(CDCl3) δ: 1.41 (s, 3H, CH3); 2.58 (s, 1H, OH); 3.35–3.38 (d, 1H); 3.65–3.72 (m, 3H); 3.93–3.99 (m, 2H); 4.50–4.95 (m, 8H, 4-CH2), 7.14–7.36 (m, 20H). 13C NMR (CDCl3) δ: 26.59, 68.81, 71.55, 73.42, 74.85, 75.58, 75.68, 78.42, 83.18, 83.63, 97.36, 127.58, 127.65, 127.74, 127.82, 127.84, 127.91, 128.28, 128.32, 128.36, 128.41, 137.87, 138.21, 138.25, 138.64.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[NH:20][CH2:19][C@@H:18]1[CH3:24])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)C=[CH:9][CH:8]=1.COC1C=C(C=CC=1)C(Cl)C1C2C(=CC=CC=2)[N:37]=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[CH:6]([N:17]1[CH2:22][C@@H:21]([CH3:23])[NH:20][CH2:19][C@@H:18]1[CH3:24])[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:37]=[CH:9][CH:8]=1
Reactant: COc1cccc(C(Cl)c2ccnc3ccccc23)c1
Reactant: COc1cccc(C(c2cccc3ccccc23)N2C[C@@H](C)NC[C@@H]2C)c1
Product: COc1cccc(C(c2ccnc3ccccc23)N2C[C@@H](C)NC[C@@H]2C)c1

Procedure:
The compound of this Example was prepared by following the synthesis procedure as described for compound 3, but substituting compound 2 for compound 27.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9]([NH2:12])(=[O:11])=[O:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22](Cl)(=[O:24])=[O:23])=[C:16]([O:26][CH3:27])[CH:15]=1>>[Cl:13][C:14]1[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[S:22]([NH:1][C:2]2[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=2[S:9]([NH2:12])(=[O:10])=[O:11])(=[O:23])=[O:24])=[C:16]([O:26][CH3:27])[CH:15]=1
Reactant: Cc1ccc(S(N)(=O)=O)c(N)c1
Reactant: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Cl
Product: COc1cc(Cl)ccc1/C=C/S(=O)(=O)Nc1cc(C)ccc1S(N)(=O)=O
Yield: 69 %

Procedure:
The title compound was synthesized as described for Example 194 a) in 69% yield, starting from 2-amino-4-methylbenzenesulfonamide and (E)-2-(4-chloro-2-methoxyphenyl)ethenesulfonyl chloride (1.5 equiv.). Purification by column chromatography, using chloroform/methanol (95:5) as the eluent.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:33]=[CH:32][C:12]([O:13][C:14]2[CH:15]=[CH:16][C:17]([N+:29]([O-])=O)=[C:18]([N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:19]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].O1CCCC1.C(OCC)(=O)C>[NH2:29][C:17]1[CH:16]=[CH:15][C:14]([O:13][C:12]2[CH:11]=[CH:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[CH:33][CH:32]=2)=[CH:19][C:18]=1[N:20]([CH3:28])[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24]
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(NC(=O)OC(C)(C)C)cc2)ccc1N
Yield: 101.2 %

Procedure:
In a similar manner to that described in Reference Example 7, a reaction was carried out using t-butyl N-[5-(4-t-butoxycarbonylaminophenoxy)-2-nitrophenyl]-N-methylcarbamate (27.7 g), palladium on carbon (10%, 1.07 g) and tetrahydrofuran/ethyl acetate=9/8 (170 ml) and the reaction mixture was purified to give the title compound (26.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:12]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[O:9][C:11]1[CH:16]=[C:15]([CH3:17])[N:14]=[C:13]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH:29]=[C:28]([CH3:30])[N:27]=[CH:26]3)=[C:21]([O:31][CH3:32])[CH:20]=2)[N:12]=1
Reactant: Oc1ccc(F)c(F)c1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3ccc(F)c(F)c3)n2)ccc1-n1cnc(C)c1
Yield: 81 %

Procedure:
The title compound was prepared in analogous manners as described in example 9) from 3,4-difluorophenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 81% yield as a pale-brown solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:16])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:23][S:24](Cl)(=[O:26])=[O:25]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][O:15][S:24]([CH3:23])(=[O:26])=[O:25])[CH2:12][CH2:13]1)=[O:16])([CH3:4])([CH3:2])[CH3:3]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CO)CC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](COS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Trans (4-hydroxymethyl-cyclohexyl)-carbamic acid tert-butyl ester (3.49 g, 15.0 mmol) in DCM (50 mL) was treated with pyridine (4.98 mL, 60.8 mmol). The mixture was cooled to 0° C. and methanesulfonyl chloride (2.36 mL, 30.4 mmol) was added dropwise over 5 minutes. The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated under vacuum. The residue was partitioned between ethyl acetate and water and the aqueous phase was extracted with ethyl acetate (×2). The combined organic extracts were washed with brine, dried with sodium sulfate and concentrated under vacuum. The residue was triturated with cyclohexane then dried under vacuum to give a white solid. Further purification by column chromatography on silica gel (eluting with 1:1 cyclohexane/ethyl acetate) gave 4.17 g (90%) of trans methanesulfonic acid 4-tert-butoxycarbonylamino-cyclohexylmethyl ester as a white solid. 1H NMR (400 MHz, CDCl3) δ: 4.37 (br s, 1H), 4.02 (d, 2H), 3.39 (br s, 1H), 3.00 (s, 3H), 2.11-2.00 (m, 2H), 1.91-1.81 (m, 2H), 1.77-1.64 (m, 1H), 1.43 (s, 9H), 1.18-1.05 (m, 4H).
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:42][CH:26]1[CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[CH:31][CH:30]=1.[OH-].[K+].Cl>O.O1CCOCC1>[OH:25][CH:26]([CH2:27][O:28][C:29]1[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[CH:31][CH:30]=1)[CH2:42][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)CCc1ccc(OCC2CO2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CCc1ccc(OCC(O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(2-ethoxycarbonylethyl)-phenoxy]-propane are added to 80 ml of dioxane/60 ml of water and adjusted to pH 14 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.