Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:17]([C:21]1[NH:22][C:23]2[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=2[N:25]=1)[C:18]([NH2:20])=[NH:19].[OH-].[Na+]>CO.O>[N:25]1[C:24]2[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=2[NH:22][C:21]=1[N:17]=[C:18]1[NH:20][C:7]2([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:20][C:18](=[N:17][C:21]3[NH:25][C:24]4[CH:26]=[CH:27][CH:28]=[CH:29][C:23]=4[N:22]=3)[NH:19][C:8]2([C:10]2[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=2)[NH:19]1
Reactant: N=C(N)Nc1nc2ccccc2[nH]1
Reactant: O=C(C(=O)c1ccncc1)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: c1ccc(C23NC(=Nc4nc5ccccc5[nH]4)NC2(c2ccncc2)NC(=Nc2nc4ccccc4[nH]2)N3)cc1

Procedure:
Following the procedure of Example 1, 1 -phenyl-2-(4-pyridinyl)ethanedione (500 mg, 2.42 mmol) and 2-guanidinobenzimidazole (1.0 g, 6.0 mmol) in methanol (10 mL) was treated with a solution of sodium hydroxide (40 mg, 1.0 mmol) in 1 mL of water. The title compound was isolated as pale yellow crystals (45 mg, 3% yield). 1H NMR (300 MHz, d6 -DMSO) δ 11.5 (br s, NH, 1 H), 1 1.0 (br.s, NH, 1H), 10.0 (br s, NH, 1 H), 8.6 (br s, NH, 1 H), 8.4 (m, 2 H), 7.4-6.8 (m, 15H); MS (ESI) m/z 526 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[C:6]([CH:9]=1)[CH2:7][NH2:8].FC(F)(F)C[O:29][C:30](=O)[NH:31][C:32]1[N:33]([CH3:41])[N:34]=[C:35]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:36]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C>[C:37]([C:35]1[CH:36]=[C:32]([NH:31][C:30]([NH:8][CH2:7][C:6]2[CH:9]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:10][C:11]2[CH:25]=[CH:24][C:14]3[C:15]([CH2:18][N:19]4[CH2:20][CH2:21][CH2:22][CH2:23]4)=[N:16][O:17][C:13]=3[CH:12]=2)=[O:29])[N:33]([CH3:41])[N:34]=1)([CH3:40])([CH3:38])[CH3:39]
Reactant: NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Reactant: Cn1nc(C(C)(C)C)cc1NC(=O)OCC(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nc(C(C)(C)C)cc1NC(=O)NCc1cc(F)ccc1Oc1ccc2c(CN3CCCC3)noc2c1
Temperature: 85 °C
Yield: 39 %

Procedure:
5-Fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzylamine, (6v) (50 mg, 0.15 mmol), (5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trifluoro-ethyl ester (a), (68 mg, 0.21 mmol) and diisopropylethylamine (0.038 mL, 0.22 mmol) were combined in DMF (1.5 mL) and heated at 85° C. for 3 hours. The reaction was cooled and concentrated in vacuo and purified by column chromatography (silica, 4% MeOH/CH2Cl2/0.5% Et3N) to provide 1-(5-tert-butyl-2-methyl-2H-pyrazol-3-yl)-3-[5-fluoro-2-(3-pyrrolidin-1-ylmethyl-benzo[d]isoxazol-6-yloxy)-benzyl]-urea (7v) (30 mg, 39%). 1H NMR (400 MHz, CDCl3) δ 7.79 (d, J=8.6 Hz, 1H), 7.16 (d, J=8.6 Hz, 1H), 7.03-6.80 (m, 4H), 6.11 (s, 1H), 5.93 (s, 1H), 5.25 (t, J=8.6 Hz, 1H), 4.38 (d, J=6.3 Hz, 2H), 3.99 (s, 2H), 3.67 (s, 3H), 2.61 (s, 4H), 1.81 (s, 4H), 1.26 (s, 9H); MS (APCI+) m/z 521 (M+H) detected; HPLC (5 to 95%) 2.61 min.
Reaction SMILES: C(OC(=O)[NH:10][C:11]1[C:12](=[O:25])[N:13]([CH2:21][CH2:22][CH2:23][CH3:24])[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1)C1C=CC=CC=1.[C:27]([OH:30])(=[O:29])[CH3:28]>CO.[Pd]>[C:27]([OH:30])(=[O:29])[CH3:28].[NH2:10][C:11]1[C:12](=[O:25])[N:13]([CH2:21][CH2:22][CH2:23][CH3:24])[C:14]2[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=2[CH:20]=1
Reactant: CCCCn1c2c(cc(NC(=O)OCc3ccccc3)c1=O)CCCC2
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCn1c2c(cc(N)c1=O)CCCC2
Reaction time: 1.5 h
Yield: 76.4 %

Procedure:
(1-Butyl-2-oxo-1,2,5,6,7,8-hexahydroquinolin-3-yl)carbamic acid benzyl ester (6-007) (100 mg, 0.28 mmol) was dissolved in methanol (7 mL), and to the reaction mixture were added acetic acid (16 μL, 0.28 mmol) and palladium on carbon (10%, 30 mg), and the reaction mixture was stirred vigorously under hydrogen atmosphere for 1.5 h. Palladium on carbon was filtered off, and the filtrate was concentrated under reduced pressure, and the crystalloid residue was recrystallized from hexane to give 3-amino-1-butyl-5,6,7,8-tetrahydro-1H-quinolin-2-one acetic acid salt (6-001-01) (60 mg, 76%) as a white crystal.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH2:6]([C:8]([CH2:20][CH3:21])([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)[OH:9])[CH3:7].C(N(CC)CC)C.O1CCCC1>O>[C:1]([O:9][C:8]([C:10]12[CH2:19][CH:14]3[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]3)[CH2:11]1)[CH2:17]2)([CH2:6][CH3:7])[CH2:20][CH3:21])(=[O:4])[CH:2]=[CH2:3]
Reactant: CCC(O)(CC)C12CC3CC(CC(C3)C1)C2
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: C=CC(=O)OC(CC)(CC)C12CC3CC(CC(C3)C1)C2
Temperature: 25 °C
Reaction time: 6 h
Yield: 72 %

Procedure:
A total of 15 mmole of acryloyl chloride was added dropwise to a mixture of 10 mmole of the above-prepared α, α-diethyl-1-adamantanemethanol, 20 mmole of triethylamine and 40 ml of tetrahydrofuran over about 30 minutes. After the completion of addition, the resulting mixture was stirred at room temperature for 6 hours. After the addition of water, the reaction mixture was concentrated, and the concentrate was subjected to column chromatography on a silica gel to thereby yield the title compound in a yield of 72%.
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:4]([N+:13]([O-])=O)=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2.O.NN>CO.[Ni]>[CH3:1][NH:2][C:3]1[C:4]([NH2:13])=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[N:6]2
Reactant: CNc1ccc2nccnc2c1[N+](=O)[O-]
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CNc1ccc2nccnc2c1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 102.3 %

Procedure:
To a solution of N-methyl-5-nitroquinoxaline-6-amine (1.3 g, 6.4 mmol) in MeOH (100 mL) was added hydrazine hydrate (1.27 g, 25.5 mmol) and Raney Ni (0.2 g). The mixture was stirred at room temperature for 1 h. The mixture was then filtered, and the filtrate was concentrated under reduce pressure to give N6-methylquinoxaline-5,6-diamine as a black solid (1.14 g, yield 100%). ESI MS: m/z 175.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][OH:17].[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.CO>CN(C)C=O.O>[Br:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][C:5]([O:12][CH2:13][O:14][CH3:15])=[CH:4][C:3]=1[CH2:16][O:17][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: BrCc1ccccc1
Reactant: COCOc1cc(CO)c(Br)c(OCOC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: COCOc1cc(COCc2ccccc2)c(Br)c(OCOC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
The above-obtained [2-bromo-3,5-bis(methoxymethoxy)phenyl]methanol (3.5 g, 11 mmol) was dissolved in N,N-dimethylformamide (20 mL) and cooled to 0° C. The obtained solution was added with 60% sodium hydride-oil dispersion (0.59 g, 15 mmol) and benzyl bromide (2.0 mL, 17 mmol), followed by stirring at a room temperature for 1 hour. The reaction mixture was added with methanol and water and extracted with chloroform 3 times. The organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=20/1 to 10/1) to obtain 2-bromo-1-(benzyloxymethyl)-3,5-bis(methoxymethoxy)benzene (3.2 g, 70%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[C:8]=1[CH3:9])(=[O:3])[CH3:2].[ClH:16].[N:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[N:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.[CH2:29]=O>C(O)C>[ClH:16].[CH3:9][C:8]1[N:7]([C:10]2[N:15]=[CH:14][CH:13]=[CH:12][N:11]=2)[N:6]=[CH:5][C:4]=1[C:1](=[O:3])[CH2:2][CH2:29][N:26]1[CH2:25][CH2:24][N:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][N:17]=2)[CH2:28][CH2:27]1
Reactant: C=O
Reactant: CC(=O)c1cnn(-c2ncccn2)c1C
Reactant: c1ccc(N2CCNCC2)nc1
Agent: Cl
Solvent: CCO
Product: Cc1c(C(=O)CCN2CCN(c3ccccn3)CC2)cnn1-c1ncccn1
Yield: 29.5 %

Procedure:
606 mg of 4-acetyl-1-(2-pyrimidinyl)-5-methylpyrazole was dissolved in 60 ml of ethanol and 490 mg of 2-pyridylpiperazine hydrochloride and 270 mg of paraformaldehyde were added thereto. The obtained mixture was heated under reflux for 24 hours. Further, 100 mg of paraformaldehyde was added and the obtained mixture was heated under reflux for 60 hours. Then the ethanol was almost halved by evaporation and the precipitate was filtered. To the precipitate was added chloroform. Next, it was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate followed by evaporation. The residue was purified by silica gel column chromatography (silica gel 50 g, chloroform:methanol=50:1-40:1). Then the obtained product was converted into hydrochloride by adding 1N hydrochloric acid and recrystallized from ethanol to thereby give 300 mg of the title compound.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].CN(C=O)C.[CH3:11][O:12][CH2:13][CH2:14][C:15]1[S:16][CH:17]=[CH:18][C:19]=1[CH3:20]>>[CH3:11][O:12][CH2:13][CH2:14][C:15]1[S:16][C:17]([S:1]([Cl:5])(=[O:3])=[O:2])=[CH:18][C:19]=1[CH3:20]
Reactant: COCCc1sccc1C
Reactant: O=S(=O)(Cl)Cl
Solvent: CN(C)C=O
Product: COCCc1sc(S(=O)(=O)Cl)cc1C
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Sulfuryl chloride (0.26 g, 1.9 mmol) was added dropwise to a stirred solution of dry DMF (0.14 ml, 1.9 mmol) at 0° C. under an argon atmosphere resulting in the formation of a white solid. After 15 min, 2-(2-methoxy-ethyl)-3-methyl-thiophene (250 mg, 1.6 mmol) was added and the mixture was warmed to 100° C. and the melt was further stirred for 45 min. Crushed ice was added and the reaction mixture was extracted with ethyl acetate (2×) and the combined organic extracts were washed with water, brine, dried (magnesium sulfate. dihydrate), filtered and concentrated under reduced pressure. The crude solid was purified over silica gel (ethyl acetate/n-heptane): light yellow oil, 220 mg, GC-MS (EI): M=254.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[S:26]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:38]([CH:45]=O)=[CH:37]1)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:45]/[C:38]3[C:39]4[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=4)[N:36]([S:26]([C:29]4[CH:30]=[CH:31][C:32]([CH3:33])=[CH:34][CH:35]=4)(=[O:28])=[O:27])[CH:37]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C(=O)OC(C)(C)C)CC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.697 g, 2.00 mmol) obtained in Example A16, Step 1 in methanol (10 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.599 g, 2.00 mmol) synthesized in Step 1 and piperidine (0.0170 g, 0.200 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({6-hydroxy-3-oxo-2-[(1-tosyl-1H-indol-3-yl)methylene]-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.470 g, 37%).
Reaction SMILES: [OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[Br:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]=[C:20]=[O:21]>>[OH:1][C:2]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][C:3]=1[NH:4][C:20]([NH:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[Br:12])=[O:21]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccccc1Br
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccccc1Br
Yield: 46.5 %

Procedure:
N-(2-Hydroxy-4-nitrophenyl)-N'-(2-bromophenyl)urea was prepared from 2-hydroxy 4-nitro aniline (500 mg, 3.24 mmol) and 2-bromophenyl isocyanate (3.24 mmol) according to the procedure in General Method B. The product was purified by dilution with methylene chloride and precipitation with hexanes. Filtering afforded the title compound(530 mg, 47%). EI-MS m/z 350(M-H)-
Reaction SMILES: C([O:9][CH2:10][C:11]1[CH:15]=[C:14]([C@H:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[O:17]2)[S:13][C:12]=1[Cl:55])(=O)C1C=CC=CC=1>C1COCC1.CO.O>[Cl:55][C:12]1[S:13][C:14]([C@H:16]2[C@H:21]([O:22][CH2:23][C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)[C@@H:20]([O:30][CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C@H:19]([O:38][CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C@@H:18]([CH2:46][O:47][CH2:48][C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[O:17]2)=[CH:15][C:11]=1[CH2:10][OH:9]
Reactant: O=C(OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: OCc1cc([C@@H]2O[C@H](COCc3ccccc3)[C@@H](OCc3ccccc3)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)sc1Cl
Temperature: 25 °C
Reaction time: 5 h
Yield: 99.1 %

Procedure:
To a solution of benzoate 36 (4.5 g, 5.80 mmol) in THF/MeOH/H2O (30 mL/10 mL/10 mL) was added LiOH monohydrate (0.73 g, 17.4 mmol) at room temperature. The mixture was stirred at room temperature for 5 hours. The mixture was extracted with EtOAc/aq. saturated NH4Cl solution (100 mL/100 mL). The organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield the title compound 37 (3.86 g, 99%), which was carried on to the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[C:5]([OH:10])=[C:4]([O:11][CH3:12])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O>O.S(OC)(OC)(=O)=O>[CH3:9][O:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[C:4]([O:11][CH3:12])[C:5]=1[O:10][CH3:19]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(Br)cc(OC)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1cc(Br)cc(OC)c1OC
Temperature: 10 °C
Yield: 78.8 %

Procedure:
A mixture of 74 g (0.32 mol) of 4-bromo-2,6-dimethoxy-phenol 17 and 32 g (0.8 mol) of NaOH in 850 ml of H2O was cooled to 10° C. and 45 ml (0.48 mmol) of dimethyl sulfate was added. The mixture was refluxed for 3 h and an equal amount of dimethyl sulfate (total 0.96 mol) was then added. The mixture was refluxed for another 3 h. Upon cooling overnight, the gray product solidified and was filtered off and dissolved in 1.2 l of ether. The ether solution was filtered to remove insoluble impurity and washed sequentially with 5% NaOH solution (200 ml), water (2×200 mL), and brine (200 mL). The ether phase was dried over Na2SO4 to give a off-white solid, which was recrystallized in hexane (300 ml) to give 62.3 g (79%) of 18.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)[CH2:2][CH2:3][CH3:4].[Cl:14][C:15]1[CH:23]=[CH:22][C:18]([C:19](Cl)=[O:20])=[C:17]([O:24][CH3:25])[CH:16]=1.ClC1C=CC(C(O)=O)=C(OC)C=1.S(Cl)(Cl)=O>>[CH2:1]([C:5]1[O:6][C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[C:9]=1[C:19](=[O:20])[C:18]1[CH:22]=[CH:23][C:15]([Cl:14])=[CH:16][C:17]=1[O:24][CH3:25])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1cc2ccccc2o1
Reactant: COc1cc(Cl)ccc1C(=O)Cl
Agent: COc1cc(Cl)ccc1C(=O)O
Solvent: O=S(Cl)Cl
Product: CCCCc1oc2ccccc2c1C(=O)c1ccc(Cl)cc1OC

Procedure:
Acylation of 13.1 g. (0.075 mol.) of 2-n-butylbenzofuran with 15.4 g. (0.075 mol.) of 4-chloro-2-methoxybenzoic acid chloride, prepared from 4-chloro-2-methoxybenzoic acid and thionyl chloride as previously described, according to the procedure of Example 10 gave 2-n-butyl-3-(4'-chloro-2'-methoxybenzoyl)benzofuran. Demethylation as previously described gave 2-n-butyl-3-(4'-chloro-2'-hydroxybenzoyl)benzofuran.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH2:14][NH2:15])=[CH:4][CH:3]=1.CO[CH:18]1[CH2:22][CH2:21][CH:20](OC)O1>C(O)(=O)C>[ClH:1].[Cl:1][C:2]1[C:7]2[CH2:8][CH2:9][N:10]([CH3:13])[CH2:11][CH2:12][C:6]=2[C:5]([CH2:14][N:15]2[CH:18]=[CH:22][CH:21]=[CH:20]2)=[CH:4][CH:3]=1
Reactant: COC1CCC(OC)O1
Reactant: CN1CCc2c(Cl)ccc(CN)c2CC1
Solvent: CC(=O)O
Product: CN1CCc2c(Cl)ccc(Cn3cccc3)c2CC1
Product: Cl
Temperature: 115 °C

Procedure:
A solution of 9-chloro-2,3,4,5-tetrahydro-3-methyl-1H-3-benzazepine-6-methanamine (0.75 g, 3.4 mmol) in acetic acid (6.5 ml) was treated with 2,5-dimethoxy-tetrahydrofuran (0.44 ml, 3.4 mmol) and heated to 115° C. for 1 hour. The mixture was quenched with ice water, basified with 20% sodium hydroxide and extracted with ethyl acetate. The organic phase was washed, dried and concentrated. The residue was triturated with ethyl ether and the residue chromatographed on silica gel eluted with methanol-methylene chloride (3:97) to give 6-chloro-2,3,4,5-tetrahydro-3-methyl-9-(1H-pyrrol-1-ylmethyl)-1H-3-benzazepine hydrochloride; mp 219°-223° C.
Reaction SMILES: [NH2:1][C:2]1[N:23]=[C:5]2[CH:6]=[C:7]([C:14]3[CH:15]=[N:16][C:17]([N:20]([CH3:22])[CH3:21])=[N:18][CH:19]=3)[CH:8]=[C:9]([C:10]([NH:12][NH2:13])=[O:11])[N:4]2[N:3]=1.[C:24](Cl)(=[O:29])[CH2:25][CH:26]([CH3:28])[CH3:27]>C1COCC1.O1CCOCC1>[CH3:27][CH:26]([CH3:28])[CH2:25][C:24]([NH:13][NH:12][C:10]([C:9]1[N:4]2[N:3]=[C:2]([NH2:1])[N:23]=[C:5]2[CH:6]=[C:7]([C:14]2[CH:19]=[N:18][C:17]([N:20]([CH3:21])[CH3:22])=[N:16][CH:15]=2)[CH:8]=1)=[O:11])=[O:29]
Reactant: CC(C)CC(=O)Cl
Reactant: CN(C)c1ncc(-c2cc(C(=O)NN)n3nc(N)nc3c2)cn1
Solvent: C1COCCO1
Solvent: C1CCOC1
Product: CC(C)CC(=O)NNC(=O)c1cc(-c2cnc(N(C)C)nc2)cc2nc(N)nn12

Procedure:
The product of Step 2 (0.11 g, 0.35 mmol) was combined with isovaleryl chloride (0.04 mL, 0.35 mmol) and 5 mL of a 1:1 solution of THF/dioxane in a tube. The mixture was microwaved at 130° C. for five minutes. The reaction mixture was cooled, then the solid was collected by filtration to give 2-amino-7-(2-dimethylamino-pyrimidin-5-yl)-[1,2,4]triazolo[1,5-a]pyridine-5-carboxylic acid N′-(3-methyl-butyryl)-hydrazide. MS (APCI+): m/z 398.1.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C@@H:6]([CH2:10][C:11]#[CH:12])[C:7]([OH:9])=[O:8].[O:13](C(OC(C)(C)C)=O)[C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=O.[C:28]([O-])(O)=O.[Na+]>CO.C(OCC)(=O)C>[CH3:18][C:17]([O:16][C:14]([NH:5][C@@H:6]([CH2:10][C:11]#[CH:12])[C:7]([O:9][CH3:28])=[O:8])=[O:13])([CH3:20])[CH3:19]
Reactant: O=C([O-])O
Reactant: C#CC[C@H](N)C(=O)O
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: C#CC[C@H](NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 73 %

Procedure:
Thionylchloride (16 ml, 26 g, 221 mmol) was added dropwise to a cooled (0° C.) solution of (2S)-2-amino-4-pentynoic acid (5.0 g, 44.18 mmol, commercially) in methanol (dry, 100 ml). After stirring the mixture at room temperature for 5.5 hrs the solvent was evaporated and the residue was taken up in 1,4-dioxane (100 ml) and aqueous saturated NaHCO3 solution (50 ml). Then BOC2O (10.1 g, 46.4 mmol) was added and the mixture was stirred overnight at room temperature. Ethyl acetate and aqueous NaHCO3 solution were added. The separated organic layer was washed with bicarbonate solution, dried (Na2SO4), filtrated and evaporated. The resulting crude material was purified by chromatography on silica gel using ethyl acetate/cyclohexanes (1:100 to 3:7) to afford the title compound (7.35 g, 73%); MS: (ES/+) m/z: 250 [MNa]+, C11H17NO4 requires 227. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 7.3 (d, 1H), 4.1 (m, 1H), 2.9 (s, 1H), 2.6-2.5 (m, 2H), 1.4 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH2:27])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[C:32]([CH3:37])[CH:31]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:38]1[CH:43]=C[CH:41]=[CH:40][CH:39]=1.ClC(Cl)([O:47]C(=O)OC(Cl)(Cl)Cl)Cl.C1(N)CC1>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:28])=[C:24]([NH:27][C:43]([NH:38][CH:39]3[CH2:41][CH2:40]3)=[O:47])[CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:30]1[CH:31]=[C:32]([CH3:37])[CH:33]=[C:34]([CH3:36])[CH:35]=1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(N)c(Cl)cc3[nH]c2=O)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: c1ccncc1
Agent: NC1CC1
Solvent: CCOC(C)=O
Product: Cc1cc(C)cc(-c2c(OCC[C@@H]3CCCCN3C(=O)OC(C)(C)C)c3cc(NC(=O)NC4CC4)c(Cl)cc3[nH]c2=O)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-2-{2-[6-amino-7-chloro-3-(3,5-dimethylphenyl)-2-oxo-1,2-dihydro-quinolin-4-yloxy]-ethyl}-piperidine-1-carboxylic acid tert-butyl ester (700 mg in 13 mL dry methylene chloride) at 0° C. was added 0.33 mL pyridine followed by 158 mg triphosgene and the mixture allowed to stir at 0° C. for 1 hour. At this time 0.46 mL of cyclopropylamine was added via syringe and the reaction mixture warmed to room temperature. After 2 hours, the mixture was diluted with 200 mL ethyl acetate and washed with saturated ammonium chloride (100 mL) and brine (100 mL). The organic portion was dried over magnesium sulfate then concentrated in vacuo. The crude product was purified by crystallization from ethyl acetate to give the title compound (615 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[CH:9]2)=[CH:4][CH:3]=1.[C:18]([NH:23][C:24](=[O:29])[O:25][CH:26]([CH3:28])[CH3:27])(=[O:22])/[CH:19]=[CH:20]/[CH3:21]>C(#N)C.O.O.O.O.O.O.[N+]([O-])([O-])=O.[Y+3].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O>[CH3:21][CH:20]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:10]=[CH:9]2)=[CH:6][CH:7]=1)[CH2:19][C:18]([NH:23][C:24]([O:25][CH:26]([CH3:27])[CH3:28])=[O:29])=[O:22]
Reactant: C/C=C/C(=O)NC(=O)OC(C)C
Reactant: CCOC(=O)c1cn(-c2ccc(N)cc2)cn1
Agent: O=[N+]([O-])[O-]
Agent: [Y+3]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1cn(-c2ccc(NC(C)CC(=O)NC(=O)OC(C)C)cc2)cn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 31 %

Procedure:
A mixture of ethyl 1-(4-aminophenyl)-1H-imidazole-4-carboxylate (for a preparation see intermediate 85) (9.4 g, 40.6 mmol), 1-methylethyl (2E)-2-butenoylcarbamate (for a preparation see intermediate 49) (6.96 g, 40.6 mmol), and yttrium nitrate hexahydrate (1.56 g, 4.06 mmol) in dry acetonitrile (200 mL) was stirred at 60° C. for 48 h then cooled to room temperature and concentrated in vacuo. The residue was suspended in AcOEt (250 mL) and the organic phase was washed with water (×2) then brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 60-100% AcOEt in Hexanes followed by 0 to 5% methanol in AcOEt) gave ethyl 1-(4-{[1-methyl-3-({[(1-methylethyl)oxy]carbonyl}amino)-3-oxopropyl]amino}phenyl)-1H-imidazole-4-carboxylate (5 g, 12.42 mmol, 31%) as a colourless gum.