Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:24])[F:23])=[C:17]([O:25][CH:26]3[CH2:28][CH2:27]3)[CH:16]=2)=[C:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([O:38]C(C)(C)C)=[O:37])[CH:31]=2)[C:12]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:11]1[CH:48]=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH2:1]([O:8][CH2:9][N:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH:22]([F:23])[F:24])=[C:17]([O:25][CH:26]3[CH2:28][CH2:27]3)[CH:16]=2)=[C:13]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([OH:38])=[O:37])[CH:31]=2)[C:12]([C:43]([O:45][CH2:46][CH3:47])=[O:44])=[C:11]1[CH:48]=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(Cc2cccc(C(=O)OC(C)(C)C)c2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)c1c(Cc2cccc(C(=O)O)c2)c(-c2ccc(OC(F)F)c(OC3CC3)c2)n(COCc2ccccc2)c1C=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 106.1 %

Procedure:
To 25 ml of dichloromethane solution containing 1.24 g (1.84 mmol) of ethyl 1-benzyloxymethyl-4-(3-tert-butoxycarbonylbenzyl)-5-(3-cyclopropoxy-4-difluoromethoxyphenyl)-2-formyl-1H-pyrrol-3-carboxylate obtained in Reference example 41-(c) was added 5 ml of trifluoroacetic acid, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and azeotropic dehydration with toluene was further carried out, and then the residue was dried under reduced pressure to obtain 1.21 g of the title compound as a yellowish oil substantially quantitatively.
Reaction SMILES: [C:1]([C:4]1[S:8][CH:7]=[C:6]([C:9]2[C:13]3[C:14]([O:18]C)=[N:15][CH:16]=[CH:17][C:12]=3[N:11]([C@@H:20]3[CH2:25][CH2:24][C@H:23]([NH:26]C(=O)OC(C)(C)C)[CH2:22][CH2:21]3)[N:10]=2)[CH:5]=1)(=[O:3])[NH2:2].[I-].[Na+].Cl[Si](C)(C)C.FC(F)(F)C(O)=O>C1COCC1.C(#N)C>[NH2:26][C@@H:23]1[CH2:24][CH2:25][C@H:20]([N:11]2[C:12]3[CH:17]=[CH:16][NH:15][C:14](=[O:18])[C:13]=3[C:9]([C:6]3[CH:5]=[C:4]([C:1]([NH2:2])=[O:3])[S:8][CH:7]=3)=[N:10]2)[CH2:21][CH2:22]1
Reactant: COc1nccc2c1c(-c1csc(C(N)=O)c1)nn2[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: NC(=O)c1cc(-c2nn([C@H]3CC[C@@H](N)CC3)c3cc[nH]c(=O)c23)cs1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (cis-4-(3-(5-carbamoyl-3-thienyl)-4-methoxy-1H-pyrazolo[4,3-c]pyridin-1-yl)cyclohexyl)carbamate (33.0 mg) in a mixed solvent of acetonitrile (2 ml) and THF (1 ml) were added sodium iodide (26.2 mg) and chloro(trimethyl)silane (0.089 ml), and the mixture was stirred at 50° C. for 1 hr. Trifluoroacetic acid (2 mL) was added thereto, and the mixture was stirred at 50° C. for additional 2 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (basic silica gel, ethyl acetate/methanol) to give the title compound (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:9][CH3:10])=[C:6]([NH2:8])[CH:7]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18](Cl)(=[O:20])=[O:19])=[CH:14][C:13]=1[CH3:22]>>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([S:18]([NH:8][C:6]2[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[S:9][CH3:10])(=[O:20])=[O:19])=[CH:14][C:13]=1[CH3:22]
Reactant: Cc1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: CSc1ccc(Cl)cc1N
Product: CSc1ccc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C)c1
Yield: 59.6 %

Procedure:
Following General Procedure B, the title compound (205 mg, 59%) was prepared from 5-chloro-2-methylsulfanyl-phenylamine (165 mg, 0.95 mmol) and 4-chloro-3-methyl-benzenesulfonyl chloride (215 mg, 0.95 mmol).
Reaction SMILES: Br[C:2]1[N:10]([CH3:11])[C:9]2[C:8](=[O:12])[N:7]3[CH2:13][CH2:14][N:15]=[C:6]3[N:5]([CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[C:4]=2[N:3]=1.[CH3:24][CH:25]([CH3:28])[CH2:26][NH2:27]>C(O)C>[Cl:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][N:5]2[C:4]3[N:3]=[C:2]([NH:27][CH2:26][CH:25]([CH3:28])[CH3:24])[N:10]([CH3:11])[C:9]=3[C:8](=[O:12])[N:7]3[CH2:13][CH2:14][N:15]=[C:6]23)=[CH:18][CH:19]=1
Reactant: CC(C)CN
Reactant: Cn1c(Br)nc2c1C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1
Solvent: CCO
Product: CC(C)CNc1nc2c(n1C)C(=O)N1CCN=C1N2Cc1ccc(Cl)cc1

Procedure:
A mixture of the product of Procedure 46, 1.0 g. (0.0025 mole) and 0.37 g. (0.005 mole) of 2-methylpropylamine in 20 ml. of ethanol is refluxed for 16 hrs. The desired product precipitated as the hydrobromide salt which was collected and mixed with dilute aqueous sodium hydroxide to convert it into the free base form, m.p. 185°-187°.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4]([C:6]1[S:10][C:9]([N:11]=CN(C)C)=[N:8][CH:7]=1)=[O:5]>Cl>[NH2:11][C:9]1[S:10][C:6]([C:4]([C:3]2[CH:16]=[CH:17][CH:18]=[CH:19][C:2]=2[Cl:1])=[O:5])=[CH:7][N:8]=1.[Cl:1][C:2]1[CH:19]=[CH:18][CH:17]=[CH:16][C:3]=1[C:4](=[O:5])[CH3:6]
Reactant: CN(C)C=Nc1ncc(C(=O)c2ccccc2Cl)s1
Agent: Cl
Product: CC(=O)c1ccccc1Cl
Product: Nc1ncc(C(=O)c2ccccc2Cl)s1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
The crude N′-[5-(2-chloro-benzoyl)-thiazol-2-yl]-N,N-dimethyl-formamidine was dissolved in 10% HCl (150 mL) and heated to 70° C. for 4 hours. The precipitate was filtered, washed with ether, and then suspended in a 10% sodium carbonate solution (250 mL). The suspension was stirred for 1 hour and the precipitate was filtered, washed with ether, and dried in air to give (2-amino-thiazol-5-yl)-(2-chloro-phenyl)-methanone as a brown solid (8.5 g, 36 mmol, 55% from 1-(2-chloro-phenyl)-ethanone). 1H NMR (400 MHz, DMSO-d6) δ 7.27 (s, 1H), 7.41-7.58 (m, 4H), 8.37 (s, 2H). ESI-MS m/z calc. 238.0, found; 239.3 (M+1)
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].[CH2:7]([NH:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[CH2:14][N:13]1[CH2:27][CH3:28])=[O:11])[CH3:8]>C(Cl)Cl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[CH2:7]([NH:9][C:10]([C@@H:12]1[CH2:16][C@H:15]([S:17][CH2:18][C:19]2[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=2)[CH2:14][N+:13]1([CH2:27][CH3:28])[CH3:6])=[O:11])[CH3:8]
Reactant: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)CN1CC
Reactant: COS(=O)(=O)F
Solvent: ClCCl
Product: CCNC(=O)[C@@H]1C[C@H](SCc2ccc(OC)cc2)C[N+]1(C)CC
Product: O=S(=O)([O-])F
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
233 μl of methyl fluorosulfonate were added, whilst ice-cooling, to a solution of 910 mg of (2S, 4S)-2-ethylcarbamoyl-1-ethyl-4-(4-methoxybenzylthio)pyrrolidine dissolved in 35 ml of dry methylene chloride, and the mixture was stirred at room temperature for 3.5 hours. At the end of this time, the solvent was removed by distillation under reduced pressure, and the residue was washed by decantation with diethyl ether and dried under reduced pressure, to afford 1.20 g of the title compound as a pale brown oil.
Reaction SMILES: [CH2:1]([C:6]1[N:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][N:16]2C(OC(C)(C)C)=O)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:6]1[N:11]=[CH:10][C:9]([NH:12][C:13]([C@@H:15]2[CH2:24][C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][NH:16]2)=[O:14])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2C(=O)OC(C)(C)C)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCc1ccc(NC(=O)[C@@H]2Cc3ccccc3CN2)cn1
Reaction time: 1.5 h

Procedure:
The crude product from step 1 was dissolved in methylene chloride (6.4 mL) and treated with trifluoroacetic acid (3.6 mL). After stirring for 1.5 hours the reaction was concentrated and the residue was partitioned between methylene chloride and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a gray-green solid.
Reaction SMILES: C1(C[C:5]2([Cl:17])[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[CH:6]2[CH2:12][C:13](=[N:15][OH:16])[NH2:14])CC1.[C:18]1([CH2:24][C:25](Cl)=[O:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])O.[Na+].[C:33]1([CH3:39])[CH:38]=[CH:37]C=CC=1>>[CH:38]1([CH2:37][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:24][C:25]([NH:14][C:13](=[N:15][OH:16])[CH2:12][C:6]2[C:7]([Cl:11])=[CH:8][CH:9]=[CH:10][C:5]=2[Cl:17])=[O:26])[CH2:33][CH2:39]1
Reactant: NC(CC1C(Cl)=CC=CC1(Cl)CC1CC1)=NO
Reactant: Cc1ccccc1
Reactant: O=C(Cl)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=C(Cc1ccccc1CC1CC1)NC(Cc1c(Cl)cccc1Cl)=NO
Temperature: 100 °C

Procedure:
5.0 g (18 mmol) of 0-cyclopropylmethyl (2,6-dichlorophenyl)acetamidoxime in 40 ml of toluene were heated to 85° C and admixed with 3.9 g (25 mmol) of phenylacetyl chloride. The mixture was heated at 100° C. for 5 h, cooled, poured into aqueous sodium hydrogen carbonate solution (pH 7) and extracted three times with toluene. The combined extracts were washed with water, dried over sodium sulfate and concentrated under reduced pressure. The crude product (5.6 g) was purified by silica gel chromatography using cyclohexane/ethyl acetate. M.p. 134–135° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([O:36]C)=[C:23]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH:24]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:6][C:5]=1[CH3:38])([CH3:3])[CH3:2].C[Si](Cl)(C)C.[I-].[Na+]>CC#N>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[C:23]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:22](=[O:36])[NH:21][CH:20]=3)[CH:16]=[CH:15][N:14]=2)=[O:12])=[CH:6][C:5]=1[CH3:38])([CH3:3])[CH3:2]
Reactant: COc1ncc(-c2ccnc(C(=O)Nc3ccc(C(C)C)c(C)c3)c2)cc1NC(=O)OCc1ccccc1
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: Cc1cc(NC(=O)c2cc(-c3c[nH]c(=O)c(NC(=O)OCc4ccccc4)c3)ccn2)ccc1C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.7 %

Procedure:
To a solution of benzyl (2′-((4-isopropyl-3-methylphenyl)carbamoyl)-6-methoxy-[3,4′-bipyridin]-5-yl)carbamate (216 mg, 0.42 mmol) in MeCN (50 mL) was added trimethylsilylchloride (0.18 mL, 2.1 mmol), sodium iodide (317 mg, 2.10 mmol), and the mixture was stirred at RT for 1.5 h. The precipitate was then collected by filtration. This solid was dissolved in a mixture of MeCN (1 mL) and water (50 mL) and then added to a solution of saturated aq. NaHCO3 (10 mL). The suspension was then stirred for 30 min, filtered and dried to afford benzyl (2′-((4-isopropyl-3-methylphenyl)carbamoyl)-6-oxo-1,6-dihydro-[3,4′-bipyridin]-5-yl)carbamate (210 mg, 99% yield) as a yellow solid: MS (ES) m/z 497 (M+H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[CH2:7][CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2].S([O-])([O-])(=O)=[O:17].[Mg+2].[Mn]([O-])(=O)(=O)=O.[K+].O>CC(C)=O>[C:1]([NH:4][C:5]1[CH:14]=[C:13]([F:15])[CH:12]=[C:11]2[C:6]=1[C:7](=[O:17])[CH2:8][CH2:9][CH2:10]2)(=[O:3])[CH3:2]
Reactant: O=S(=O)([O-])[O-]
Reactant: CC(=O)Nc1cc(F)cc2c1CCCC2
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(F)cc2c1C(=O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a-solution of the compound obtained in (6) above (9.46 gm) in 420 ml of acetone was added 42 ml of 15% aqueous solution of magnesium sulfate. After cooling to 0° C., 21.7 gm of potassium permanganate was added to the mixture, a bit at a time. The mixture was stirred for 50 minutes at 0° C. and for 1 hour at room temperature. Upon addition of 1 l of water, the reaction product was extracted 3 times with chloroform. The chloroform layer was washed with water and saturated brine in this order, and dried over anhydrous-sodium sulfate. The solvent was evaporated and the residue was subjected to silica gel column chromatography using hexane-ethyl acetate (3:1) as an eluant to obtain fractions containing the target compound. The fractions were concentrated to obtain 7.98 gm of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][C:15]3=[N:18][C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=3)[O:22][CH2:23][C:24]([O:26][CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[B-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][CH2:14][CH:15]3[NH:18][C:19]3[CH:20]=[C:21]([CH:30]=[CH:31][CH:32]=3)[O:22][CH2:23][C:24]([O:26][CH:27]([CH3:28])[CH3:29])=[O:25])=[CH:10][CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)OC(=O)COc1cccc(N=C2CCCc3ccc(-c4cccc(F)c4)cc32)c1
Agent: CC(=O)O[B-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: CC(C)OC(=O)COc1cccc(NC2CCCc3ccc(-c4cccc(F)c4)cc32)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 36.4 %

Procedure:
To a solution of isopropyl 2-(3-((7-(3-fluorophenyl)-3,4-dihydronaphthalen-1(2H)-ylidene)amino)phenoxy)acetate (25 mg, 0.057 mmol) and methanol (2 mL) was added sodium triacetoxyborohyride (12 mg, 0.057 mmol) at 0° C. The solution was stirred for 4 hours at room temperature. The reaction was quenched with saturated aqueous NaHCO3 (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. The resulting crude residue was purified by combiflash (4 g column, hexanes→100% ethyl acetate/hexanes, gradient) to afford 9 mg (36%) of isopropyl 2-(3-((7-(3-fluorophenyl)-1,2,3,4-tetrahydronaphthalen-1-yl)amino)phenoxy)acetate.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][CH2:12][OH:13])[C:3]=1[F:14].[ClH:15].N([O-])=O.[Na+]>C(O)(=O)C>[Cl:15][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[C:4]([CH2:11][CH2:12][OH:13])[C:3]=1[F:14]
Reactant: Cl
Reactant: Nc1ccc([N+](=O)[O-])c(CCO)c1F
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(Cl)c(F)c1CCO
Reaction time: 0.5 h
Yield: 83 %

Procedure:
7.33 g (37 mmol) of the compound (124) obtained in Reference Example 6 was added to 60 ml of 6N hydrochloric acid, and while cooling on ice, 15 ml of aqueous solution containing 2.95 g (43 mmol) of sodium nitrite was dropped to the solution through 5 minutes. The solution was stirred for 30 minutes as was. Then, 20 ml of concentrated hydrochloric acid and 20 ml of acetic acid were added to the solution, and the solution was stirred for 1 hour. While cooling on ice, 35 ml of concentrated hydrochloric acid solution containing 6.20 g (63 mmol) of cuprous chloride was dropped to the solution through 40 minutes, and the solution was stirred for 3 hours as was. The solution was extracted with 300 ml of ethyl acetate, and after drying over magnesium sulfate, the solvent was removed by distillation. The residue was separated by the column chromatography (silica gel 100 g, eluent solvent; chloroform: methanol=50:1) to obtain 6.69 g of the subject compound (125) in a 83% yield.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[CH:7]=1.BrC1C=NC2N(C=C(CC3C=C4C(=CC=3)N=CC=C4)N=2)C=1.C([Sn](CCCC)(CCCC)[C:48]([O:50]CC)=[CH2:49])CCC>O1CCOCC1.CCOC(C)=O.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>[N:18]1[C:19]2[C:14](=[CH:13][C:12]([CH2:11][C:8]3[N:6]4[CH:7]=[C:2]([C:48](=[O:50])[CH3:49])[CH:3]=[N:4][C:5]4=[N:10][CH:9]=3)=[CH:21][CH:20]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Brc1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Brc1cnc2nc(Cc3ccc4ncccc4c3)cn2c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)c1cnc2ncc(Cc3ccc4ncccc4c3)n2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 6-((6-bromoimidazo[1,2-a]pyrimidin-3-yl)methyl)quinoline and 6-(6-bromo-imidazo[1,2-a]pyrimidin-2-ylmethyl)quinoline (mixture, 250 mg, 0.737 mmol), PdCl2(PPh3)2 (51.7 mg, 0.074 mmol) and tributyl(1-ethoxyvinyl)stannane (399 mg, 1.106 mmol) in 5 mL of 1,4-dioxane was heated at 80° C. for 12 h under N2. The reaction mixture was diluted with EtOAc, washed with water. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in HOAc and 3 N HCl and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure and the residue was dissolved in CH2Cl2, washed with sat. aqueous NaHCO3 and brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography in silica gel eluting with a EtOAc/MeOH gradient to afford the title compound as a yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 8.97 (d, 1H), 8.84 (d, 1H), 8.67 (d, 1H), 8.04-7.99 (m, 2H), 7.74 (s, 1H), 7.53-7.51 (m, 1H), 7.34 (dd, 1H), 7.19 (s, 1H), 4.44 (s, 2H), 2.49 (s, 3H).
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10]C)[C:4]=1[NH2:5])C.Cl[CH2:13][CH:14]=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>>[CH3:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:3]([CH3:1])[C:4]=1[NH:5][CH2:13][CH:14]=[O:15]
Reactant: O=CCCl
Reactant: CCc1cccc(CC)c1N
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: Cc1cccc(C)c1NCC=O
Temperature: 150 °C

Procedure:
2,6-Diethylaniline (100 grams), the dimethyl acetal of 2-chloroacetaldehyde (37.5 grams) and sodium carbonate (31.8 grams) were charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. The reaction mixture was heated at 150°C for a period of about 30 hours. After this time the mixture was filtered and the filtrate was distilled to yield the desired product the dimethyl acetal of 2-(2,6-dimethylanilino)acetaldehyde having a boiling point of 120°C at 1 mm of Hg pressure.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N+:19]([O-])=O)=[CH:15][C:14]=1[Cl:22])[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Ni]>[C:1]([O:5][C:6]([N:8]([CH3:9])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][C:14]=1[Cl:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCOc1ccc([N+](=O)[O-])cc1Cl)C(=O)OC(C)(C)C
Agent: [Ni]
Product: CN(CCOc1ccc(N)cc1Cl)C(=O)OC(C)(C)C

Procedure:
The product was obtained analogously to Intermediate product 29b starting from 4.19 g (12.7 mmol) N-tert.butoxycarbonyl-N-methyl-[2-(2-chloro-4-nitro-phenoxy)-ethyl]-amine by hydrogenation with 500 mg Raney nickel at 3 bar.
Reaction SMILES: CO[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)C(OC1CC3N(C(=O)N(C)CCCCC=CC4C(C(O)=O)(NC3=O)C4)C1)=NC=C2.Cl[C:39]1[N:40]=[C:41]([O:51][CH:52]2[CH2:69][CH:68]3[N:54]([C:55](=[O:81])[N:56]([CH3:80])[CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH:62][CH:63]4[C:65]([C:71]([NH:73][S:74]([CH:77]5[CH2:79][CH2:78]5)(=[O:76])=[O:75])=[O:72])([NH:66][C:67]3=[O:70])[CH2:64]4)[CH2:53]2)[C:42]2[C:47]([CH:48]=1)=[CH:46][C:45]([O:49][CH3:50])=[CH:44][CH:43]=2>>[C:3]1([C:39]2[N:40]=[C:41]([O:51][CH:52]3[CH2:69][CH:68]4[N:54]([C:55](=[O:81])[N:56]([CH3:80])[CH2:57][CH2:58][CH2:59][CH2:60][CH:61]=[CH:62][CH:63]5[C:65]([C:71]([NH:73][S:74]([CH:77]6[CH2:79][CH2:78]6)(=[O:75])=[O:76])=[O:72])([NH:66][C:67]4=[O:70])[CH2:64]5)[CH2:53]3)[C:42]3[C:47]([CH:48]=2)=[CH:46][C:45]([O:49][CH3:50])=[CH:44][CH:43]=3)[CH:4]=[CH:5][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(Cl)cc2c1
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)O)CC5C=CCCCCN(C)C(=O)N4C3)nccc2c1
Product: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)C6CC6)CC5C=CCCCCN(C)C(=O)N4C3)nc(-c3ccccc3)cc2c1

Procedure:
The title product 56 was prepared from 17-(6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo[13.3.0.04,6]octadec-7-ene-4-carboxylic acid (55) following the same procedures described for the preparation of N-[17-(3-chloro-6-methoxyisoquinolin-1-yloxy)-13-methyl-2,14-dioxo-3,13,15-triaza-tricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](cyclopropyl)sulfonamide (43, Example 11): m/z=688.
Reaction SMILES: [CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11]([OH:13])=O)[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2].C(N(CC)C(C)C)(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[NH2:45][C:46]1[CH:51]=[CH:50][C:49]([N:52]2[CH:57]=[CH:56][CH:55]=[CH:54][C:53]2=[O:58])=[CH:48][C:47]=1[F:59]>C(#N)C>[CH2:1]([O:3][C:4]([C@@H:6]1[C@@H:10]([C:11](=[O:13])[NH:45][C:46]2[CH:51]=[CH:50][C:49]([N:52]3[CH:57]=[CH:56][CH:55]=[CH:54][C:53]3=[O:58])=[CH:48][C:47]=2[F:59])[CH2:9][N:8]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: Nc1ccc(-n2ccccc2=O)cc1F
Reactant: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H]1CN(C(=O)OC(C)(C)C)C[C@@H]1C(=O)Nc1ccc(-n2ccccc2=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Compound 7a (1.85 g; 6 mmol) is suspended in acetonitrile (20 ml) and N,N-diisopropyl ethyl amin (1.65 ml; 10 mmol) is added at 25° C. BOP-CL (2.46 g; 10 mmol) is added as a solid and after stirring for 30 min at 25° C. 1-(4-amino-3-fluoro-phenyl)-1H-pyridin-2-one (1.45 g; 7 mmol) is added to the reaction mixture. The mixture is stirred for 4 d at 25° C., evaporated to dryness and dissolved in ethyl acetate (200 ml). The organic phase is washed with 2 N HCl (50 ml), with 10% aqueous Na2CO3 solution, water and brine and dried over Na2SO4. The organic phase is filtered and the filtrate is evaporated to dryness. The crude product is purified by silica gel chromatography. Yield: 1.77 g (58.1%), ESI-MS: m/z=472 [M−H]−
Reaction SMILES: C(C1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#N.[OH-].[K+].[C:14]([OH:17])(=[O:16])[CH3:15]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:15]=1[C:14]([OH:17])=[O:16]
Reactant: CC(=O)O
Reactant: COc1cccc(N)c1C#N
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(N)c1C(=O)O

Procedure:
Fifty-four grams (0.364 mol) of the product prepared in (a) are refluxed with 800 ml of a 25% aqueous solution of potassium hydroxide for 16 hours. After cooling, the reaction solution is adjusted to a pH of 6 by the addition of acetic acid and then extracted several times, each time with one-half liter of ethyl acetate. The combined extracts are dried with sodium sulfate, and the ethyl acetate is distilled off. The residue is purified by column chromatography [silica gel; ethylene chloride/acetone (19:1)]. The uniform fractions are concentrated to dryness.
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH2:20][CH3:21])[C:14](Cl)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[OH:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:25][CH:24]=1>>[C:1]12([C:11]3[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=3[CH2:20][CH3:21])[C:14]([O:22][C:23]3[CH:24]=[CH:25][C:26]([C:27]([O:29][CH2:30][CH:31]=[CH2:32])=[O:28])=[CH:33][CH:34]=3)=[O:15])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C=CCOC(=O)c1ccc(O)cc1
Reactant: CCc1ccc(C(=O)Cl)cc1C12CC3CC(CC(C3)C1)C2
Product: C=CCOC(=O)c1ccc(OC(=O)c2ccc(CC)c(C34CC5CC(CC(C5)C3)C4)c2)cc1
Yield: 70.5 %

Procedure:
In a manner analogous to Example 9(e), by reacting 2.35 g (8.1 mmoles) of 3-(1-adamantyl)-4-ethylbenzoyl chloride with 1.44 g (8.1 mmoles) of allyl 4-hydroxybenzoate, 2.54 g (71% yield) of the expected ester having a melting point of 111°-113° C. are obtained.