Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[NH2:6].Cl[C:13](Cl)([O:15]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:24][O:25][C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][C:35]=1[O:36][CH3:37])[N:32]=[CH:31][CH:30]=[C:29]2[O:38][C:39]1[CH:44]=[CH:43][C:42]([NH2:45])=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:6][C:13]([NH:45][C:42]2[CH:41]=[CH:40][C:39]([O:38][C:29]3[C:28]4[C:33](=[CH:34][C:35]([O:36][CH3:37])=[C:26]([O:25][CH3:24])[CH:27]=4)[N:32]=[CH:31][CH:30]=3)=[CH:44][CH:43]=2)=[O:15])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: COc1ccc(N)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cc2)cc1OC
Yield: 39 %

Procedure:
3,4-Dimethoxyaniline (42 mg) was dissolved in toluene (5 ml), triphosgene (24 mg) was added, and the admixture was refluxed with heat for 22 minutes. 6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (52 mg) was added, and the admixture was refluxed with heat for 18 minutes. After the addition of aqueous sodium hydrogen carbonate, the reaction mixture was extracted 2 times with ethyl acetate, and the organic layer was then washed with brine and dried with anhydrous sodium sulfate. The solvent was removed by reduced-pressure distillation and the resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 15 mg of the title compound (yield: 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][C:3]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[N:25]=[C:26]=[O:27].CN(C)CCN>C(Cl)Cl.CCOC(C)=O>[N:14]1[CH:13]=[CH:12][C:11]([C:3]2[O:4][C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])=[CH:6][C:2]=2[NH:1][C:26]([NH:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:18]=2[Cl:17])=[O:27])=[CH:16][CH:15]=1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Reactant: CC(C)(C)c1cc(N)c(-c2ccncc2)o1
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(NC(=O)Nc2cccc(Cl)c2Cl)c(-c2ccncc2)o1
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
A solution of 3-amino-2-(4-pyridinyl)-5-tert-butylfuran (Method A2; 0.10 g, 0.46 mmol) and 2,3-dichlorophenyl isocyanate (0.13 g, 0.69 mmol) in CH2Cl2 was stirred at room temp. for 2 h, then was treated with 2-(dimethylamino)ethylamine (0.081 g, 0.92 mmol) and stirred for an additional 30 min. The resulting mixture was diluted with EtOAc (50 mL), then was sequentially washed with a 1 N HCl solution (50 mL), a saturated NaHCO3 solution (50 mL) and a saturated NaCl solution (50 mL), dried (Na2SO4), and concentrated under reduced pressure. The residue was purified using column chromatography (gradient from 10% EtOAc/90% hexane to 40% EtOAc/60% hexane) to give the desired compound as a white solid (0.12 g, 63%): mp 195-198° C.; TLC (60% EtOAc/40% hexane) Rf 0.47; 1H NMR (DMSO-d6) δ1.30 (s, 9H); 6.63 (s, 1H); 7.30-7.32 (m, 2H), 7.58 (dm, J=6.62 Hz, 2H), 8.16 (dd, J=2.57, 6.99 Hz, 1H), 8.60 (dm, J=6.25 Hz, 2H), 8.83 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO-d6) δ 28.5 (3C), 32.5, 103.7, 117.3 (2C), 119.8, 120.4, 123.7, 125.6, 128.1, 131.6, 135.7, 136.5, 137.9, 150.0 (2C), 152.2, 163.5; CI-MS m/z (rel abundance) 404 ((M+H)+, 15%), 406 ((M+H+2)+, 8%).
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[N:4][C:3]=1[C:20]([NH2:22])=[O:21].[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH2:33][C:34](OC)=O)[CH:28]=[CH:29][C:30]=1[O:31][CH3:32]>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[CH2:33][C:34]1[NH:22][C:20](=[O:21])[C:3]2[N:4]=[N:5][N:6]([CH:7]([CH:17]([OH:19])[CH3:18])[CH2:8][CH2:9][CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:2]=2[N:1]=1
Reactant: CC(O)C(CCCc1ccccc1)n1nnc(C(N)=O)c1N
Reactant: COC(=O)Cc1ccc(OC)c(OC)c1
Product: COc1ccc(Cc2nc3c(nnn3C(CCCc3ccccc3)C(C)O)c(=O)[nH]2)cc1OC

Procedure:
Analogously to the procedure of Example 29, the title compound is prepared from 10 mg (0.024 mmol) of 5-amino-1-[1-(1-hydroxy-ethyl)-4-phenyl-butyl]-1H-[1,2,3]triazole-4-carboxamide and 20 mg (0.107 mmol) of methyl 3,4-dimethoxyphenylacetate.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:3])[CH3:2].[NH2:28][C:29]1[C:30]([C:35]([NH:37][C:38]2[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=2)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=1>>[CH:1]([S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:28][C:29]2[C:30]([C:35]([NH:37][C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][N:39]=3)=[O:36])=[N:31][CH:32]=[CH:33][CH:34]=2)=[O:10])=[C:7]([O:14][CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:25])[CH3:26])=[O:22])[CH2:17][CH2:16]2)[CH:6]=1)([CH3:3])[CH3:2]
Reactant: CC(C)Sc1ccc(C(=O)O)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Product: CC(C)Sc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OC2CCN(C(=O)OC(C)(C)C)CC2)c1
Yield: 28 %

Procedure:
Using a procedure analogous to Example 1-G, 4-iso-propylthio-2-(1-t-butoxycarbonylpiperidin-4-yloxy)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the title compound as a glass (350 mg, 28%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH2:8][F:9])[C:3](=O)[CH2:4][S:5][CH3:6].Cl.[NH2:12][OH:13].C(N(CC)CC)C>C(O)C>[CH3:1][C:2]([CH3:10])([CH2:8][F:9])[C:3](=[N:12][OH:13])[CH2:4][S:5][CH3:6]
Reactant: CSCC(=O)C(C)(C)CF
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CSCC(=NO)C(C)(C)CF
Yield: 74.4 %

Procedure:
99 g (0.6 mol) of 3,3-dimethyl-4-fluoro-1-methylthiobutan -2-one, 46 g (0.66 mol) of hydroxylamine hydrochloride and 66.7 g (0.66 mol) of triethylamine in 300 ml of ethanol were heated under reflux for 6 hours. The solvent was then removed in vacuo, the residue was partitioned between methylene chloride and water and the methylene chloride phase was separated off and dried with sodium sulphate. After distilling off the solvent, the residue was distilled in vacuo. 80 g (75% of theory) of 3,3-dimethyl-4-fluoro-1-methylthio-2-hydroximino-butane of boiling point 133° C./13 mm Hg were obtained. ##STR31## 78 g (0.43 mol) of 3,3-dimethyl-4-fluoro-1-methylthio-hydroximinobutane were dissolved in 300 ml of methylene chloride, and 26 g (0.46 mol) of methyl isocyanate were added dropwise. During this addition, the temperature of the reaction solution rose to about 35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:6]([F:10])=[CH:7][C:8]=1[Cl:9])[NH2:5].Cl[C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>C(O)(C)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:12]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([N+:22]([O-:24])=[O:23])[CH:20]=3)[N:15]=[CH:14][N:13]=2)[C:6]([F:10])=[CH:7][C:8]=1[Cl:9]
Reactant: O=[N+]([O-])c1ccc2ncnc(Cl)c2c1
Reactant: Nc1cc(Cl)c(Cl)cc1F
Solvent: CC(C)O
Product: O=[N+]([O-])c1ccc2ncnc(Nc3cc(Cl)c(Cl)cc3F)c2c1

Procedure:
3,4-Dichloro-6-fluoroaniline (1 equivalent, prepared as described in U.S. Pat. No. 6,126,917) was reacted with 4-chloro-6-nitroquinazoline (3.5 equivalents, prepared by reacting 6-nitroquinazoline with thionyl chloride, according to known procedures), in iso-propylalcohol. After filtration, 4-[(3,4-dichloro-6-fluorophenyl)amino]-6-nitroquinazoline (compound 1) was obtained in 60% yield. m.p.=270–271° C.; MS (m/z): 353.2, 355.2 (M+); 1H-NMR: δ=6.97 (d, 1H), 7.345 (d, 1H), 7.885 (d, 1H), 8.405 (d, 1H), 8.554 (dd, 1H), 8.8 (d, 1H) ppm. HPLC conditions: C-18 column, 55% acetate buffer, PH=3.8/45% acetonitrile, flow=1 ml/min; r.t.=7.15 minutes.
Reaction SMILES: [OH-:1].[Na+].[OH:3][CH2:4][C:5]([CH3:9])([CH2:7][OH:8])[CH3:6].[N+:10]([C:13]1[CH:18]=[CH:17][C:16](Cl)=[CH:15][CH:14]=1)([O-:12])=[O:11]>CS(C)=O>[N+:10]([C:13]1[CH:18]=[CH:17][C:16]([O:3][CH2:4][C:5]([CH3:9])([CH3:6])[CH2:7][O:8][C:16]2[CH:17]=[CH:18][C:13]([N+:10]([O-:11])=[O:1])=[CH:14][CH:15]=2)=[CH:15][CH:14]=1)([O-:12])=[O:11]
Reactant: [OH-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Reactant: CC(C)(CO)CO
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(COc1ccc([N+](=O)[O-])cc1)COc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
140 g powdered sodium hydroxide were added in small portions with thorough stirring over a period of 3 hours to a solution of 104 g (1 mol) neopentyl glycol and 346.5 g (2.2 mols) 4-nitrochlorobenzene in 600 ml dimethylsulfoxide (DMSO). An internal temperature of 40°-50° C. was maintained by cooling with ice both during the addition and subsequently until the exothermic reaction abated. The reaction mixture was then stirred for 8 hours at 25° C. The product precipitated was filtered off under suction, washed first with water until neutral and then once with ethylacetate and then dried in vacuo at 90° C.
Reaction SMILES: C([N:4]1[CH2:9][C:8](=[O:10])[N:7]([C:11](=[O:13])[CH3:12])[CH2:6][C:5]1=[O:14])(=O)C.[C:15]([NH:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=O)=[CH:21][CH:20]=1)(=[O:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C.CCOC(C)=O>[C:11]([N:7]1[CH2:6][C:5](=[O:14])[NH:4][C:9](=[CH:23][C:22]2[CH:21]=[CH:20][C:19]([NH:18][C:15](=[O:17])[CH3:16])=[CH:26][CH:25]=2)[C:8]1=[O:10])(=[O:13])[CH3:12]
Reactant: CC(=O)Nc1ccc(C=O)cc1
Reactant: CC(=O)N1CC(=O)N(C(C)=O)CC1=O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(C=C2NC(=O)CN(C(C)=O)C2=O)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 56.2 %

Procedure:
1,4-Diacetyl-2,5-piperazinedione (10.0 g, 50 mmol), prepared by the published procedure mentioned in Reference Example 1, was stirred in DMF (40 ml) with 4-acetamidobenzaldehyde (8.24 g, 50 mmol) and triethylamine (7 ml, 50 mmol) and heated to 120° C. After 2% h the mixture was cooled to room temperature, diluted with EtOAc (100 ml) and stirred overnight. The solid formed was collected, washed with EtOAc and dried to give 8.46 g (56%) of a yellow solid.
Reaction SMILES: ClC1C2C(=CC=CC=2)[N:5]=[CH:4]C=1[NH-].Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][N:22]=2)[N:17]=[CH:16][C:15]=1[NH-:24].Cl.C(ON)C1C=CC=CC=1>>[NH:5]1[C:14]2[C:23]3[N:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=[CH:4]1
Reactant: [NH-]c1cnc2ccccc2c1Cl
Reactant: [NH-]c1cnc2cccnc2c1Cl
Agent: Cl
Agent: NOCc1ccccc1
Product: c1cnc2c(c1)ncc1nc[nH]c12

Procedure:
In step (2) of Reaction Scheme I, an N-(4-chloroquinolin-3-yl)amide or N-(4-chloro[1,5]naphthyridin-3-yl)amide of Formula XXI is reacted with O-benzylhydroxylamine hydrochloride to provide a benzyloxy substituted 1H-imidazo[4,5-c]quinoline or 1H-imidazo[4,5-c][1,5]naphthyridine of Formula XXII. The reaction can be carried out by combining a compound of Formula XXI and O-benzylhydroxylamine hydrochloride in an alcoholic solvent, such as isopropanol, and heating the resulting mixture.
Reaction SMILES: C(O[C:6]([N:8]1[CH:13]([C:14](=[O:30])[NH:15][C:16]2[CH:17]=[C:18]([Cl:29])[CH:19]=[C:20]3[C:28]=2[NH:27][C:26]2[CH:25]=[N:24][CH:23]=[CH:22][C:21]3=2)[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9]1)=O)(C)(C)C.C(OC(=O)[NH:39][CH:40](C=O)[CH:41]([CH3:43])[CH3:42])(C)(C)C>>[Cl:29][C:18]1[CH:19]=[C:20]2[C:28](=[C:16]([NH:15][C:14]([CH:13]3[CH2:12][O:11][C:10]([CH3:32])([CH3:31])[CH2:9][N:8]3[CH2:6][CH:40]([NH2:39])[CH:41]([CH3:43])[CH3:42])=[O:30])[CH:17]=1)[NH:27][C:26]1[CH:25]=[N:24][CH:23]=[CH:22][C:21]2=1
Reactant: CC(C)C(C=O)NC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Product: CC(C)C(N)CN1CC(C)(C)OCC1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12

Procedure:
Method C was followed, using 5-(6-chloro-9H-β-carbolin-8-ylcarbamoyl)-2,2-dimethyl-morpholine-4-carboxylic acid tert-butyl ester and the appropriate aldehyde, (1-formyl-2-methyl-propyl)-carbamic acid tert-butyl ester.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](F)=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[CH3:21][NH:22][CH3:23]>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([CH2:10][CH2:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16]([N:22]([CH3:23])[CH3:21])=[CH:15][CH:14]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)N1CCC(CCC(=O)c2ccc(F)cc2)CC1
Product: CC(=O)N1CCC(CCC(=O)c2ccc(N(C)C)cc2)CC1
Temperature: 100 °C
Reaction time: 6 h

Procedure:
A mixture consisting of 3.2 g of 1-acetyl-4-[2-(4-fluorobenzoyl)ethyl]piperidine and 10 ml of 50% aqueous dimethylamine solution was heated at 100° C. with stirring for 6 hours and then worked up in the same manner as Example 37 to give 1.6 g of colorless crystals melting at 158°-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH2:21][CH2:22]Cl)[N:9]=2)=[CH:4][CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C([O-])([O-])=O.[K+].[K+].CO.CCOC(C)=O>CC#N>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH2:13][N:14]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:16][C:11]=3[N:10]([CH2:20][CH2:21][CH2:22][N:34]3[CH2:33][CH2:32][N:31]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=4[F:24])[CH2:36][CH2:35]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1N1CCNCC1
Reactant: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCCl)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)N1CCc2c(c(-c3ccc(Cl)cc3)nn2CCCN2CCN(c3ccccc3F)CC2)C1
Temperature: 25 °C
Reaction time: 168 h
Yield: 40.3 %

Procedure:
1-[3-(4-Chloro-phenyl)-1-(3-chloro-propyl)-1,4,6,7-tetrahydro-pyrazolo[4,3-c]pyridin-5-yl]-ethanone (0.053 g, 0.15 mmol) was dissolved in CH3CN (0.5 mL) and a solution of 1-(2-fluorophenyl)piperazine (0.053 g, 0.30 mmol) in CH3CN (0.5 mL) was added, followed by K2CO3 (0.031 g, 0.22 mmol) and Bu4Nl (0.018 g, 0.05 mmol). The mixture was stirred at room temperature for 7 d. Preparative TLC (silica, 5% MeOH/EtOAc) afforded 30 mg (41%) of the title compound. MS (electrospray): exact mass calculated for C27H31ClFN5O, 495.22; m/z found, 496.3 [M+H]+. 1H NMR (500 MHz, CDCl3, a mixture of 1:1 rotamers): 7.60 (d, J=8.3 Hz, 1H), 7.54 (d, J=8.3 Hz, 1H), 7.39 (d, J=8.3 Hz, 1H), 7.35 (d, J=8.3 Hz, 1H), 7.06-6.90 (m, 4H), 4.77 (s, 1H), 4.60 (s, 1H), 4.10 (t, J=6.8 Hz, 2H), 3.92 (t, J=5.7 Hz, 1H), 3.74 (t, J=5.7 Hz, 1H), 3.08 (br s, 4H), 2.83 (t, J=5.6 Hz, 1H), 2.77 (t, J=5.7 Hz, 1H), 2.58 (br s, 4H), 2.41-2.38 (m, 2H), 2.19 (s, 1.5H), 2.13 (s, 1.5H), 2.10-2.07 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([Cl:9])=[CH:4][C:3]=1[S:10](Cl)(=[O:12])=[O:11].CN1C=CN=C1.[C:20]([O:28][CH2:29][C@@H:30]([OH:46])[C@@H:31]([O:37][C:38](=[O:45])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH2:32][CH:33]=[N:34][O:35][CH3:36])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(OCC)(=O)C>C(#N)C.O>[C:20]([O:28][CH2:29][C@@H:30]([O:46][S:10]([C:3]1[CH:4]=[C:5]([Cl:9])[C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])(=[O:12])=[O:11])[C@@H:31]([O:37][C:38](=[O:45])[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH2:32][CH:33]=[N:34][O:35][CH3:36])(=[O:27])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(Cl)cc1Cl
Reactant: CON=CC[C@H](OC(=O)c1ccccc1)[C@H](O)COC(=O)c1ccccc1
Agent: Cn1ccnc1
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: CON=CC[C@H](OC(=O)c1ccccc1)[C@@H](COC(=O)c1ccccc1)OS(=O)(=O)c1cc(Cl)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
5.51 g of 2,4,5-trichlorobenzenesulfonyl chloride and 2.14 mL of 1-methylimidazole were added to a solution of 6.65 g of (2R,3S)-2-hydroxy-5-(methoxyimino)pentane-1,3-diyl dibenzoate in 67 mL of acetonitrile at room temperature, and the obtained mixture was then stirred at room temperature for 2 hours. Thereafter, ethyl acetate and water were added to the reaction mixture. The organic layer was fractionated, and was then dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure. 20 mL of ethyl acetate and 30 mL of hexane were added to the obtained residue, and a solid was then removed by filtration. After that, the solvent was distilled away under reduced pressure, so as to obtain 8.97 g of (2R,3S)-5-(methoxyimino)-2-(((2,4,5-trichlorophenyl)sulfonyl)oxy)pentane-1,3-diyl dibenzoate in the form of a colorless oily product.
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:9]2[N:10]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:12]=[CH:13][C:8]=2[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4]1.[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[S:32]>>[I:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[NH:30][C:31]([N:17]1[CH2:18][CH2:19][N:14]([C:11]2[N:12]=[CH:13][C:8]3[C:6](=[O:7])[C:5]([C:20]([OH:22])=[O:21])=[CH:4][N:3]([CH2:2][CH3:1])[C:9]=3[N:10]=2)[CH2:15][CH2:16]1)=[S:32]
Reactant: S=C=Nc1ccccc1I
Reactant: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCNCC3)nc21
Product: CCn1cc(C(=O)O)c(=O)c2cnc(N3CCN(C(=S)Nc4ccccc4I)CC3)nc21

Procedure:
Pipemidic acid (25 mg, 0.0824 mmol) and 2-iodophenyl isothiocyanate (21.5 mg, 0.0824 mmol) were used. Purification on silica yielded compound 26 in Table 1, below (35 mg, 75%). 1H NMR (300 MHz, CDCl3) δ 9.36-9.30 (m, 1H), 8.69-8.65 (m, 1H), 7.89-7.82 (m, 1H), 7.62-7.55 (m, 1H), 7.41-7.32 (m, 1H), 7.00-6.92 (m, 1H), 4.40-4.01 (m, 10H), 1.53-1.44 (m, 3H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]1[C:15]2[C:10](=[CH:11][C:12]([NH:16][C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][C:25]=4[O:27][C@@H:28]([CH3:33])[C:29](OC)=[O:30])[N:20]=[CH:19][N:18]=3)=[CH:13][CH:14]=2)[CH:9]=[N:8]1.[CH3:34][NH2:35]>>[CH3:34][NH:35][C:29](=[O:30])[C@@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:2]1[S:1][CH:5]=[CH:4][N:3]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33]
Reactant: CN
Reactant: COC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Product: CNC(=O)[C@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4nccs4)c3)c12
Yield: 84 %

Procedure:
Using the same procedure as in Example 5, methyl (2S)-2-[(4-{[1-(1,3-thiazol-2-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (210 mg, 0.46 mmol) was reacted with methylamine to give the title compound as a white solid (178 mg, 84%); NMR Spectrum 1.66 (d, 3H), 2.68 (d, 3H), 5.16 (q, 1H), 6.04 (s, 2H), 7.01 (d, 1H), 7.37 (d, 1H), 7.66 (s, 1H), 7.72-7.80 (m, 4H), 8.21 (s, 1H), 8.39 (m, 1H), 8.54 (s, 1H), 8.56 (s, 1H), 10.70 (br s, 1H); Mass spectrum MH+ 460.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH2:6][O:7][CH2:8][CH:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[OH:10])[CH3:4].[C:21](OC(=O)C)(=[O:23])[CH3:22].C(N(CC)CC)C>N1C=CC=CC=1>[C:21]([O:10][CH:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH2:8][O:7][CH2:6][CH2:5][N:3]([CH3:2])[CH3:4])(=[O:23])[CH3:22]
Reactant: CN(C)CCOCC(O)c1cccc2ccccc12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CC(=O)OC(COCCN(C)C)c1cccc2ccccc12

Procedure:
2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethanol hydrochloride was reacted with acetic anhydride in pyridine in the presence of triethylamine to obtain oily 1-acetoxy-2-[2-(N,N-dimethylamino)ethoxy]-1-(1-naphthyl)ethane (compound No. 300).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([O:17]C)=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:14]([C:15]([OH:17])=[O:16])=[CH:13][N:12]3[CH:19]=[CH:20][N:21]=[C:11]3[C:10]=2[Cl:22])=[C:4]([Cl:23])[CH:3]=1
Reactant: COC(=O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cn2ccnc2c(Cl)c1Nc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of methyl 7-(4-bromo-2-chlorophenylamino)-8-chloroimidazo[1,2-a]pyridine-6-carboxylate (366 mg, 0.81 mmol) in a mixture of MeOH (30 ml) and THF (10 ml) was added 10 ml of 1M aq. NaOH solution and the solution was stirred for 18 hours at room temperature. The solvents were reduced in vacuo, and it was extracted using 1M HCl/EtOAc/THF. The organic layers were washed with brine and dried with Na2SO4, and the solvents were removed in vacuo to give the crude product which was used without further purification (200 mg, 62%). 1H-NMR (500 MHz, DMSO-D6): δ=9.33 (s, 1H), 8.11 (s, 1H), 7.69-7.68 (d, 1H), 7.35-7.33 (dd, 1H), 6.67-6.65 (d, br, 1H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:5]2=[CH:4][CH:3]=1.[Cl:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:18]([NH:20][NH2:21])=[O:19].CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]2[CH:8]=[C:9]([C:11]([NH:21][NH:20][C:18](=[O:19])[C:17]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:15]([Cl:14])[CH:16]=3)=[O:13])[NH:10][C:5]2=[CH:4][CH:3]=1
Reactant: NNC(=O)c1ccc(Cl)c(Cl)c1
Reactant: O=C(O)c1cc2nc(Cl)ccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NNC(=O)c1cc2nc(Cl)ccc2[nH]1)c1ccc(Cl)c(Cl)c1
Reaction time: 0.08 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[3,2-b]pyridine-2-carboxylic acid (Preparation 5, 20.0 mg, 0.10 mmol) in DMF (5 mL) was added 3,4-dichlorobenzoic acid hydrazide (23 mg, 0.11 mmol), DIPEA (19.5 μL, 0.11 mmol) and HOBt (14.0 mg, 0.10 mmol). The resulting solution was stirred for 5 min prior to the addition of EDCI (23 mg, 1.20 mmol). The reaction mixture was stirred for 16 hr at rt then partitioned between water (10 mL) and dichloromethane (20 mL) on a hydrophobic frit. The aqueous phase was extracted with a further portion of dichloromethane (30 mL) and the combined organics were concentrated in vacuo. Trituration of the resulting residue with ethyl acetate/dichloromethane gave the title compound. δH (d6 DMSO): 12.25 (1H, s), 10.83 (2H, d), 8.17 (1H, s), 7.55-7.97 (3H, m), 7.38 (1H, s), 7.26 (1H, d); m/z (ES+)=383 [M+H]+; RT=3.37 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:12][CH:11]=1.C(O)(=O)C.C1C(=O)N([Br:38])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[Br:38][C:18]1[S:17][C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:6]3[S:7][CH:8]=[CH:9][C:5]=3[CH2:4][C:3]([O:2][CH3:1])=[O:26])=[CH:11][CH:12]=2)=[C:20]([CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)Cc1ccsc1-c1ccc(-c2sccc2CC(=O)OC)cc1
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)Cc1ccsc1-c1ccc(-c2sc(Br)cc2CC(=O)OC)cc1
Temperature: 0 °C
Reaction time: 14 h

Procedure:
Intermediate R (1.13 g, 2.92 mmol) was dissolved in CHCl3 (5 ml), acetic acid (5 ml) was added and the solution was cooled to 0° C. NBS (0.53 g, 2.92 mmol) was added and the mixture was left to slowly reach ambient temperature. After 14 hrs, the reaction mixture was diluted with CH2Cl2 (20 ml), washed with water/brine (30:1-60 ml), dried with MgSO4 (s), filtered and evaporated to dryness to obtain the crude product. The residue was purified by flash chromatography using toluene/EtOAc 100:1→40:1) as eluent. Yield: 0.54 g (40%); off-white solid. 1H NMR (400 MHz, CDCl3): δ 3.63 (s, 2H), 3.69 (s, 2H), 3.73 (s, 3H), 3.74 (s, 3H), 7.06 (s, 1H), 7.09 (d, J 5.3 Hz, 1H), 7.30 (d, J 5.3 Hz, 1H), 7.45-7.48 (m, 2H), 7.51-7.54 (m, 2H).