Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24](F)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:39]1([NH2:44])[CH2:43][CH2:42][CH2:41][CH2:40]1.O>CN1CCCC1=O>[CH2:1]([N:8]1[C:12]2[CH:13]=[C:14]([O:17][S:18]([C:21]3[CH:26]=[CH:25][C:24]([NH:44][CH:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:15]=[CH:16][C:11]=2[N:10]=[C:9]1[NH:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH3:38])[CH:30]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(F)cc4)cc3n2Cc2ccccc2)cc1OC
Reactant: NC1CCCC1
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1ccc(Nc2nc3ccc(OS(=O)(=O)c4ccc(NC5CCCC5)cc4)cc3n2Cc2ccccc2)cc1OC

Procedure:
A solution of 4-fluoro-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (151 mg) and cyclopentylamine (118 μl) in N-methylpyrrolidinone (1.5 ml) was heated at 110° C. in a sealed tube for 3 hours. The reaction mixture was allowed to cool then poured into water (30 ml) and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of ethyl acetate and heptane (1:1, v/v) to give 4-cyclopentylamino-benzenesulfonic acid 3-benzyl-2-(3,4-dimethoxy-phenylamino)-3H-benzoimidazol-5-yl ester (122 mg) as a brown solid. Mass spectrum: 599 [M+H]+, retention time=4.0 minutes.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:21]=[CH:20][N:19]=[C:18](Cl)[CH:17]=3)[N:10]=2)[CH:5]=[CH:6][C:7]=1[Cl:8].[C:23]([NH:27][S:28]([C:31]1[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([NH:27][S:28]([C:31]1[CH:32]=[CH:33][CH:34]=[C:35]([C:18]2[CH:17]=[C:16]([C:11]3[N:10]=[C:9]([C:4]4[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=4)[CH:14]=[C:13]([CH3:15])[N:12]=3)[CH:21]=[CH:20][N:19]=2)[CH:36]=1)(=[O:30])=[O:29])([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(Cl)c2)n1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1cc(-c2ccc(Cl)c(Cl)c2)nc(-c2ccnc(-c3cccc(S(=O)(=O)NC(C)(C)C)c3)c2)n1

Procedure:
3-{4-[4-(3,4-Dichloro-phenyl)-6-methyl-pyrimidin-2-yl]-pyridin-2-yl}-benzenesulfonic acid tert-butylamide was prepared from 4-(3,4-dichloro-phenyl)-2-(2-chloro-pyridin-4-yl)-6-methyl-pyrimidine (example E.63) (0.35 g, 1.0 mmol) and commercially available 3-(tert.-butylsulfamoyl)-phenylboronic acid (0.31 g, 1.2 mmol) according to the general procedure VI. Obtained as a light brown solid (0.54 g), which was subsequently deprotected.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1.C(N(C(C)C)CC)(C)C.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>O1CCOCC1>[NH2:1][C:2]1[N:3]=[C:4]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:5]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[O:8][C:6]=2[N:7]=1
Reactant: C1CNCCN1
Reactant: Nc1nc(Cl)c2nc(-c3ccc(F)cc3)oc2n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Nc1nc(N2CCNCC2)c2nc(-c3ccc(F)cc3)oc2n1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
To a solution of 5-amino-7-chloro-2-(4-fluorophenyl)-oxazolo[5,4-d]pyrimidine X (50 mg, 0.19 mmol) in dioxane (5 ml) was added diisopropylethylamine (0.28 mmol, 47 μL) and a piperazine derivative (0.28 mmol). The reaction was stirred at 70° C. for 6 hours after which the solvent was removed in vacuo. The resulting residue was purified by flash chromatography on silica, the mobile phase being a mixture of methanol and dichloromethane (in a ratio gradually ranging from 100% CH2Cl2 to 2% CH3OH in CH2Cl2), yielding the pure title compounds which were characterized by their mass spectra as indicated below:
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10](I)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Sn](C)(C)[C:20]1[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=1>COCCOC.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>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:20]2[O:21][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:23][CH:24]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc([Sn](C)(C)C)o1
Reactant: Ic1nn(Cc2ccccc2)c2ccccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2nn(Cc3ccccc3)c3ccccc23)o1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
A solution of methyl 5-bromofuranoate (0.75 g, 3.66 mmol), hexamethylditin (1.0 g, 3.05 mmol) and Pd(PPh3)4 (90 mg, 0.078 mmol) in DME (50 mL) was heated to reflux overnight. The initial amber coloured solution became black. The solution was allowed to cool and then filtered and concentrated under reduced pressure. The crude stannane was purified by passage through a plug of silica (1:9 EtOAc:cyclohexane) to give methyl 2-trimethylstannyl-5-furanoate (0.17 g, 19%): 1H-NMR (CDCl3); The low yield of the product may be due to its suspected volatility. Pd(PPh3)4 (9 mg, 0.008 mmol) was added to a solution of 1-benzyl-3-iodo-1H-indazole (0.13 g, 0.39 mmol) and methyl 2-trimethylstannyl-5-furanoate (0.17 g, 0.588 mmol) in DME (20 mL).and the mixture was heated to reflux overnight. The reaction mixture was allowed to cool to rt, filtered and concentrated under reduced pressure. Purification of the residue by chromatography on silica (3:7 EtOAc:cyclohexane) gave the product as a slightly contaminated yellow solid (88.6 mg, 69%).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[CH2:11]([O:18][C@@H:19]1[C@@:23]([CH2:43][O:44]S(C2C=CC(C)=CC=2)(=O)=O)([CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:41])[CH3:40])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[O:22][C@@H:21]([N:55]2[CH:62]=[C:61]([CH3:63])[C:59](=[O:60])[NH:58][C:56]2=[O:57])[C@@H:20]1O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)(O)[O-].[Na+]>O1CCCC1>[CH2:11]([O:18][C@@H:19]1[C@@:23]2([CH2:43][O:44][C@H:20]1[C@H:21]([N:55]1[CH:62]=[C:61]([CH3:63])[C:59](=[O:60])[NH:58][C:56]1=[O:57])[O:22]2)[CH2:24][O:25][Si:26]([C:39]([CH3:42])([CH3:40])[CH3:41])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@]2(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)O[C@@H](n3cc(C)c(=O)[nH]c3=O)[C@H](O)[C@@H]2OCc2ccccc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cn([C@@H]2O[C@@]3(CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)CO[C@@H]2[C@@H]3OCc2ccccc2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.9 %

Procedure:
In a stream of nitrogen, sodium bis(trimethylsilyl)amide (1.0 M in THF, 8.47 ml, 8.47 mmols) was added, under cooling with ice, to a tetrahydrofuran solution (30 ml) of Compound 36 (1.86 g, 2.42 mmols), and the mixture was stirred for 1 hour at room temperature. A saturated sodium bicarbonate solution (14 ml) was added to the reaction mixture, and then the solvent was distilled off under reduced pressure. After water was added to the residue, the mixture was extracted with chloroform. The organic phase was washed with a saturated sodium chloride solution, and then dried over sodium sulfate. The solvents were distilled off under reduced pressure, and the resulting crude product was purified by silica gel column chromatography (AcOEt-hexane, 2:3) to obtain a white powder, Compound 37 (1.42 g, 2.37 mmols, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:20][C:21](O)=[O:22])[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[C:54]1([CH:60]2[CH2:64][CH2:63][CH2:62][NH:61]2)[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:20][C:21](=[O:22])[N:61]2[CH2:62][CH2:63][CH2:64][CH:60]2[C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: COc1cccc(S(=O)(=O)N(CC(=O)O)c2ccc(Cl)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cccc(S(=O)(=O)N(CC(=O)N2CCCC2c2ccccc2)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of [(4-chlorophenyl)-(3-methoxy-benzenesulfonyl)-amino]-acetic acid (250 mg, 0.7 mmol) in dry dichloromethane (20 mL) were sequentially added EDCI (202 mg, 1.05 mmol), HOBT (142.4 mg, 1.05 mmol), and DIPEA (0.23 mL, 1.40 mmol). The reaction mixture was allowed to stir for 30 minutes under nitrogen at 25° C. 2-Phenyl-pyrrolidine (104 mg, 0.7 mmol) was added and the mixture was stirred at 25° C. for 12 h. The reaction mixture was diluted with dichloromethane (20 mL), washed with saturated aqueous ammonium chloride solution, saturated aqueous sodium bicarbonate solution and water. The organic layer was dried (Na2SO4) and evaporated under reduced pressure. The residue was purified by column chromatography over silica gel (30-40% ethyl acetate/hexane) to yield the title compound.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([NH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([OH:9])=[O:8])=[CH:10][CH:11]=1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: NCc1ccc(C(=O)O)cc1
Product: O=C(O)c1ccc(CNS(=O)(=O)c2ccc3ccccc3c2)cc1
Yield: 72 %

Procedure:
3.8 g (25 mmol) of 4-(aminomethyl)benzoic acid were reacted with 2-naphthalenesulfonyl chloride by the method of procedure 4b, affording 6.1 g (72%) of the product.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[C@H:3]([OH:20])[CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1.Cl[C:24]([O:26][C:27]1[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=1)=[O:25].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>ClCCCl>[C:24](=[O:25])([O:20][C@H:3]([CH2:4][N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)=[CH:8][CH:7]=[N:6]1)[C:2]([CH3:22])([CH3:21])[CH3:1])[O:26][C:27]1[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=1
Reactant: CC(C)(C)[C@H](O)Cn1nccc1-c1ccc(C(F)(F)F)cc1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: c1ccncc1
Product: CC(C)(C)[C@@H](Cn1nccc1-c1ccc(C(F)(F)F)cc1)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Yield: 90.7 %

Procedure:
To 562.0 mg (1.80 mmol) of (2S)-3,3-dimethyl-1-{5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}-2-butanol in 18 mL of 1,2-dichloroethane at room temperature was added 544.1 mg (2.70 mmol) of 4-nitrophenyl chloroformate. Then, 291.1 μL (3.60 mmol) of pyridine was added, and the solution was heated at reflux for 16 h. Saturated aqueous sodium bicarbonate was added, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with an ethyl acetate:hexanes solution (3:7) to give 779.7 mg (91%) of 4-nitrophenyl (1S)-2,2-dimethyl-1-({5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-1-yl}methyl)propyl carbonate. Rf=0.21 (3:7 ethyl acetate:hexanes); 1H-NMR (300 MHz, DMSO-d6): δ 8.29 (d, J=8 Hz, 2H), 7.87 (d, J=8 Hz, 2H), 7.73 (d, J=8 Hz, 2H), 7.63 (s, 1H), 7.33 (d, J=9 Hz, 2H), 6.52 (s, 1H), 4.71 (d, J=9 Hz, 1H), 4.64 (d, J=15 Hz, 1H), 4.33 (dd, J=15 Hz, J=10 Hz, 1H), 0.89 (s, 9H); ES-LCMS m/z 478 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[N:10]=1)[C:5]([OH:7])=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][CH:22]=1)[NH:19][CH2:18][CH2:17]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([N:19]2[C:20]3[C:16](=[CH:15][C:14]([F:13])=[CH:22][CH:21]=3)[CH2:17][CH2:18]2)=[O:7])[CH:8]=[C:9]([O:11][CH3:12])[N:10]=1
Reactant: Fc1ccc2c(c1)CCN2
Reactant: COc1cc(C(=O)O)cc(Cl)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1cc(C(=O)N2CCc3cc(F)ccc32)cc(Cl)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.50 g (2.7 mmol) 2-chloro-6-methoxyisonicotinic acid, 0.37 g (2.7 mmol) 5-fluoroindoline and 0.42 mL (3 mmol) TEA were in 10 mL DMF placed. 0.97 g (3.0 mmol) TBTU were added and the reaction mixture was 2 h stirred at RT. The substance was purified by HPLC. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [P:1]([O:13][CH2:14][C:15]([N:17]([CH2:22][C:23]1[CH:24]=[N:25][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][CH:49]4[CH2:51][CH2:50]4)=[O:47])=[CH:41][C:40]=3[F:52])[CH:30]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][O:20][CH3:21])=[O:16])([O:8]C(C)(C)C)([O:3]C(C)(C)C)=[O:2].Cl.O1CCOCC1>C(Cl)Cl>[P:1]([OH:8])([OH:3])([O:13][CH2:14][C:15]([N:17]([CH2:22][C:23]1[CH:24]=[N:25][C:26]([C:29]2[S:37][C:36]3[C:31](=[N:32][CH:33]=[CH:34][C:35]=3[O:38][C:39]3[CH:44]=[CH:43][C:42]([NH:45][C:46]([NH:48][CH:49]4[CH2:51][CH2:50]4)=[O:47])=[CH:41][C:40]=3[F:52])[CH:30]=2)=[CH:27][CH:28]=1)[CH2:18][CH2:19][O:20][CH3:21])=[O:16])=[O:2]
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)COP(=O)(OC(C)(C)C)OC(C)(C)C
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a stirred solution of 33 from the previous step in DCM (15 mL) was added a solution of 4M HCl in 1,4-dioxane (0.44 mL, 1.75 mmol). The reaction mixture (suspension) was stirred at RT for 1 h. The solid was collected by filtration, rinsed with DCM and dried under high vacuum. The residue was suspended in MeOH, concentrated and triturated with a minimum of methanol/water to afford the title compound 34 (136 mg, 0.21 mmol, 60% over 3 steps) as an off-white fluffy solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 8.71 (s, 1H), 8.58-8.48 (m, 2H), 8.37 and 8.33 (2 s, 1H), 8.29 and 8.24 (2d, J=8.2 Hz, 1H), 7.86-7.77 (m, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.1 Hz, 1H), 7.20 (bd, J=9.0 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 6.57 (d, J=2.5 Hz, 1H), 4.74-4.50 (m, 4H), 3.47 (bs, 4H), 3.24 and 3.21 (2s, 3H), 2.59-2.51 (m, 1H), 0.73-0.58 (m, 2H), 0.50-0.36 (m, 2H). MS (m/z): 646.7 (M+H).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23](=[O:25])[NH2:24])=[N:9][C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]1)[C:2]#[C:3][CH3:4].[ClH:39].C(OCC)(=O)C>CO>[ClH:39].[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH3:15])[C:10]([O:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[C:23]([NH2:24])=[O:25])=[N:9][C:8]=2[N:7]=[C:6]1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)[C:2]#[C:3][CH3:4]
Reactant: CC#CCn1c(N2CCN(C(=O)OC(C)(C)C)CC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CC#CCn1c(N2CCNCC2)nc2nc(Oc3ccccc3C(N)=O)n(C)c(=O)c21
Temperature: 25 °C
Reaction time: 4 h
Yield: 96 %

Procedure:
210 mg of t-butyl 4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was combined with 3.5 ml of methanol and 2.1 ml of 4N hydrochloric acid-ethyl acetate solution. After the mixture had been stirred at room temperature for 4 hours, the reaction solution was concentrated by flushing with nitrogen gas. The resulting residue was washed with ethanol and ethyl acetate to give 177 mg of the title compound (96%).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([O:12][CH3:13])[CH:8]=2)[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([Mg]Br)=[CH:18][CH:17]=1.C1COCC1>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.Cl>[CH3:13][O:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)[CH:3]=2)[CH:8]=1
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: COc1ccc([Mg]Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3c2)cc1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a mixture of 2-bromo-6-methoxynaphthalene (23.79 g, 100.3 mmol) and tetrakis(triphenylphosphine)palladium (5.8 g, 5 mmol) was added a solution of 4-methoxyphenylmagnesium bromide in THF (400 mL of 0.5 N solution, 200 mmol). The stirred solution was heated to reflux for 3 hr, cooled to RT, and stirred into 200 mL of 1 N HCl. The mixture was extracted with dichloromethane and filtered through a short silica plug with dichloromethane. The solvent was removed to yield a crude yellow solid which was further purified by silica chromatography (20-50% ethyl acetate-hexanes) to yield 25.68 g (97%) of the title compound as a white solid: mp 190° C.; 1H NMR (CDCl3): δ 3.86 (3H, s), 3.93 (3H, s), 7.01 (2H, d, J=8.57 Hz), 7.14-7.18 (2H, m), 7.63 (2H, d, J=8.50 Hz), 7.67 (1H, dd, J=1.68 Hz, J=8.73 Hz), 7.76-7.80 (2H, m), 7.91 (1H, d, J=0.94 Hz); MS (ESI) m/z265 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([NH2:20])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:19])([F:18])[F:17])=[CH:4][CH:3]=1.[C:21](O)(=[O:23])[CH3:22]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([NH:20][C:21](=[O:23])[CH3:22])[CH:11]=[N:12][C:13]=2[O:14][CH2:15][C:16]([F:17])([F:18])[F:19])=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1
Product: CC(=O)Nc1cnc(OCC(F)(F)F)c(-c2ccc(Cl)cc2)c1

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-(4-chloro-phenyl)-6-(2,2, 2-trifluoro-ethoxy)-pyridin-3-ylamine and acetic acid as starting materials, MS (LC/MS): 345.0 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:18]([O:20]CC)=[O:19])(=[O:3])[CH3:2].O1CCCC1.[OH-].[Na+]>C(O)C>[C:1]([NH:4][CH2:5][CH2:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[NH:9][C:8]=1[C:18]([OH:20])=[O:19])(=[O:3])[CH3:2]
Reactant: CCOC(=O)c1[nH]c2ccc(OC)cc2c1CCNC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2[nH]c(C(=O)O)c(CCNC(C)=O)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.4 %

Procedure:
To a mixture of ethyl 3-(2-acetamidoethyl)-5-methoxy-1H-indole-2-carboxylate (350 mg), tetrahydrofuran (5.00 mL), and ethanol (5.00 mL) was added a 1 M aqueous sodium hydroxide solution (2.00 mL), followed by stirring at room temperature for 1 hour. The solvent was evaporated under reduced pressure, and the obtained residue was dissolved in water and adjusted to be weakly acidic by the addition of 1 M hydrochloric acid. The precipitated solid was collected by filtration and then dried to obtain 3-(2-acetamidoethyl)-5-methoxy-1H-indole-2-carboxylic acid (300 mg) as a gray solid.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:25])(=[O:24])[NH2:23])[C:14]=1[S:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4].C(O)(=[O:28])C>OO>[CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([S:22](=[O:24])(=[O:25])[NH2:23])[C:14]=1[S:15]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:28])[C:9]([OH:11])=[O:10])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1Sc1ccccc1
Reactant: CC(=O)O
Agent: OO
Product: CCCCNc1cc(C(=O)O)cc(S(N)(=O)=O)c1S(=O)c1ccccc1

Procedure:
To a suspension of 3-n-butylamino-4-phenylthio-5-sulphamyl-benzoic acid (0.5 g) in acetic acid (5 ml), perhydrol (2.5 ml of 30% hydrogen peroxide in water) was added while stirring. The reaction mixture was stirred for an additional 24 hours at 30°C, after which the 3-n-butylamino-4-phenylsulphinyl-5-sulphamyl-benzoic acid was collected by suction and washed with aqueous acetic acid. After recrystallization from aqueous ethanol, the compound was obtained with a melting point of 203°-204°C (decomp.).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[CH:4][CH:3]=1.CCO[CH:12]=[C:13]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C(O)C>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Br)nc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: CCO
Product: CCOC(=O)C(=CNc1ccc(Br)nc1)C(=O)OCC
Yield: 88.8 %

Procedure:
6-bromopyridin-3-amine (40.3 g, 0.233 mol) and diethyl ethoxymethylene malonate (56.5 g, 0.261 mol) were added in 400 mL of ethanol, and reacted under reflux for 5 h, cooled and precipitated a solid. The reaction mixture was suction filtered and the resulting solid was washed with petroleum ether to give 71 g of a pale yellow solid.
Reaction SMILES: [C:1](#[N:10])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[NH2:11][OH:12]>C(O)C>[OH:12]/[N:11]=[C:1](\[NH2:10])/[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1
Reactant: COc1ccc(C#N)cc1
Reactant: NO
Solvent: CCO
Product: COc1ccc(/C(N)=N/O)cc1
Yield: 99 %

Procedure:
A solution of anisonitrile (300 mg, 2.25 mmol) and hydroxylamine (275 μL, 9.01 mmol) in ethanol (5.0 mL) was refluxed for 3 hours. The reaction was cooled and then concentrated in vacuo to give the product (370 mg, 99%), which immediately formed white crystals and was taken to the next step without further purification. A small quantity was purified by column chromatography over silica gel (Hex/EtOAc 1:8) to give the product (370 mg, 99%) as a white solid. 1H NMR (500 MHz, CDCL3) δ(ppm): 3.83 (3H, s), 4.86 (2H, bs), 6.91 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz). 13C NMR (125 MHz, CDCL3) δ(ppm): 55.5 (CH3), 114.2 (CH), 125.1, 127.4 (CH), 152.7, 161.2. MS (FAB+): 167 (MH+). HRMS for O8H10N2O2 (MH+): calculated: 167.0821; found 167.0803.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[C:11]([O:15][C:16](=[O:24])[NH:17][CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)([CH3:14])([CH3:13])[CH3:12].C(N(CC)CC)C>C(O)CCC>[C:11]([O:15][C:16](=[O:24])[NH:17][CH:18]1[CH2:23][CH2:22][N:21]([C:2]2[N:10]=[CH:9][N:8]=[C:7]3[C:3]=2[N:4]=[CH:5][NH:6]3)[CH2:20][CH2:19]1)([CH3:14])([CH3:12])[CH3:13]
Reactant: Clc1ncnc2nc[nH]c12
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CCN(c2ncnc3[nH]cnc23)CC1
Temperature: 100 °C
Yield: 77.8 %

Procedure:
To a mixture of 6-chloropurine (0.050 g, 0.323 mmol) and piperidin-4-yl carbamic acid tert-butyl ester (0.129 g, 0.646 mmol) in n-butanol (3.2 ml) was added triethylamine (0.225 ml, 1.617 mmol). After heating at 100° C. for 20 hours, solvent was removed and the resulting solid triturated with a DCM/methanol mix (3 ml/5 ml). Filtration gave the desired product as a white solid (0.080 g, 78%). LC/MS: (LCT) Rt 5.37 [M+H]+ 319.