Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]([CH2:21][N:22]1[C:26](=[O:27])C2=CC=CC=C2C1=O)[CH2:3][N:4]([CH:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].O.NN.[Br:36][C:37]1[CH:42]=[CH:41][C:40]([N:43]=C=O)=[CH:39][CH:38]=1.CO.C(Cl)(Cl)Cl>CCO>[Br:36][C:37]1[CH:42]=[CH:41][C:40]([NH:43][C:26](=[O:27])[NH:22][CH2:21][CH:2]([OH:1])[CH2:3][N:4]([CH:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:14][CH2:13][CH2:12]2)[CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[CH:39][CH:38]=1
Reactant: O=C(O)CCCN(CC(O)CN1C(=O)c2ccccc2C1=O)C1CCCc2ccccc21
Reactant: O=C=Nc1ccc(Br)cc1
Agent: NN
Solvent: CCO
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=C(O)CCCN(CC(O)CNC(=O)Nc1ccc(Br)cc1)C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.1 %

Procedure:
To a solution of 4[[2-hydroxy-(3-phthalimido)propyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (68 mg, 0.16 mmol) in EtOH (1 ml) was added hydrazine monohydrate (38 μl, 0.78 mmol), and the mixture was stirred at RT for 3 h. The reaction mixture was concentrated under vacuum to dryness, and the residue was suspended in CH2Cl2 (2 ml). To the suspension was added 4-bromophenyl isocyanate (47 mg, 0.24 mmol), and the mixture was stirred at RT for 40 h. The reaction mixture was adsorbed on a plate of silica gel and then developed with 10% methanol/chloroform to afford 4-[[3-(4-bromophenylureido)2-hydroxypropyl](1,2,3,4-tetrahydro-1-naphthyl)amino]butanoic acid (13 mg, 16%): MS(ES+) m/e 504 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 8.74 (s, 1H), 8.07 (br, 2H), 7.62 (d, J=7.6 Hz, 1H), 7.36 (m, 4H), 7.13-7.00 (m, 3H), 6.15 (m, 1H), 3.92 (m, 1H), 3.66-3.45 (m, 3H), 2.70 (m, 1H), 2.67 (m, 2H), 2.51 (m, 2H), 2.36 (m, 2H), 2.25 (m, 1H), 2.14 (m, 1H), 2.02 (m, 1H), 1.19 (m, 1H), 1.67-1.49 (m, 3H).
Reaction SMILES: CO.[O:3]([C:10]([N:12]1[CH2:17][CH2:16][C:15]([C:29]#[CH:30])([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[N+:26]([O-])=O)[CH2:14][CH2:13]1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl>O.[Fe]>[O:3]([C:10]([N:12]1[CH2:17][CH2:16][C:15]([O:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[NH2:26])([C:29]#[CH:30])[CH2:14][CH2:13]1)=[O:11])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Agent: [Fe]
Agent: Cl
Solvent: CO
Solvent: O
Product: C#CC1(Oc2ccc(F)cc2N)CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 32.9 %

Procedure:
To a stirred suspension of 735 ml of methanol and 51.7 g of 1-N-phenoxycarbonyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine was added a solution of 51 ml of concentrated hydrochloric acid in 206 ml of water. To the stirred mixture was added, in aliquots, 80.2 g of iron (reduced, electrolytic). The mixture was stirred 2 hr, heated to 45° for 1 hr and allowed to cool to room temperature. The mixture was poured into ice/water, extracted twice with dichloromethane, washed with saturated sodium chloride solution and dried over anhydrous potassium carbonate. The mixture was filtered and the filtrate was evaporated. The residue was purified by chromatography on a Waters Prep 500 High Pressure Liquid Chromatograph (1×500 cc silica gel:eluent: 0.5 methanol/dichloromethane). Concentration of the appropriate fractions provided an oil, which crystallized on standing to provide 15.7 g (33%) of product. Recrystallization from cyclohexane/ethyl acetate provided the analytical sample, mp 125°-127°.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[OH:26])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:14]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[O:26])[CH:20]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)c1cccc(-c2cccc(C(O)c3ccccn3)c2)c1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)c1cccc(-c2cccc(C(=O)c3ccccn3)c2)c1OCc1ccccc1

Procedure:
A solution of crude 10 (6.1 mmol) in dichloromethane (80 mL) was treated with manganese dioxide (85%, 8 g, 15 equiv.) and this suspension was stirred at reflux for 3 hr. The solids were filtered out and washed with ethyl acetate. The solvent was removed in a rotary evaporator and the residue was purified by chromatography on silica (80 g) with 5% ethyl acetate in heptane (1 L) and 7.5% ethyl acetate in heptane (3 L) to afford pure 11 (1.64 g, 60% over 2 steps).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH2:23][C:22](=[O:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:10][CH:9]=1.Cl[CH2:28][C:29]([N:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1)=[O:30]>CC(=O)CC>[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:23]=[C:22]([O:24][CH2:28][C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[O:30])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][C:20]=3[O:25][CH3:26])[N:15]=2)=[CH:12][CH:13]=1
Reactant: COc1cccc2c1C(=O)CC(c1ccc(C)cc1)=N2
Reactant: O=C(CCl)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COc1cccc2nc(-c3ccc(C)cc3)cc(OCC(=O)N3CCOCC3)c12
Temperature: 20 °C
Yield: 71 %

Procedure:
anhydrous potassium carbonate (2.28 g) is added to a stirred suspension of 2-(4-methylphenyl)-5-methoxy-4-quinolone (2.19 g) and 4-(2-chloroacetyl)morpholine (1.62 g) in 2-butanone (76 cc). The mixture is heated to reflux for 4 hours 20 minutes and cooled to room temperature (approximately 20° C.) and the solvent is evaporated off under reduced pressure. The residue is taken up with water and ethyl acetate and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated under reduced pressure. The residue obtained is chromatographed on silica gel, using a chloroform/acetone mixture (95:5 by volume). The solid collected is stirred in 40°-60° petroleum ether (50 cc). 4-{[2-(4-Methylphenyl)-5-methoxy-4-quinolyl]oxyacetyl}morpholine (2.3 g), m.p. 132° C., is thereby isolated.
Reaction SMILES: Cl.[CH3:2][C@@H:3]1[CH2:8][CH2:7][NH:6][CH2:5][C@@H:4]1[C:9]1[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1.[N:21]1([C:27](Cl)=[O:28])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1.C(Cl)Cl>[C:9]1([C@@H:4]2[C@H:3]([CH3:2])[CH2:8][CH2:7][N:6]([C:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[O:28])[CH2:5]2)[N:13]2[C:14]3[CH:20]=[CH:19][NH:18][C:15]=3[N:16]=[CH:17][C:12]2=[CH:11][N:10]=1
Reactant: O=C(Cl)N1CCCCC1
Reactant: C[C@@H]1CCNC[C@@H]1c1ncc2cnc3[nH]ccc3n12
Agent: Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: C[C@@H]1CCN(C(=O)N2CCCCC2)C[C@@H]1c1ncc2cnc3[nH]ccc3n12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 37.8 %

Procedure:
A round bottom flask was charged with 1-((3R,4R)-4-methylpiperidin-3-yl)-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine hydrochloride (0.050 g, 0.17 mmol, Example #5, Step J), TEA (0.10 mL, 0.69 mmol) in THF (1.6 mL). The reaction mixture was stirred for about 5 min at ambient temperature and then piperidine-1-carbonyl chloride (0.019 g, 0.13 mmol) was added. The reaction was heated at about 45° C. for about 18 h, cooled to ambient temperature, and concd under reduced pressure. The crude product was dissolved in DCM (5 mL) and washed with water (3 mL), dried over anhydrous MgSO4, filtered, and concd under reduced pressure. The material was purified by RP-HPLC (Table 1, Method f) to give ((3R,4R)-3-(6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)-4-methylpiperidin-1-yl)(piperidin-1-yl)methanone (0.018 g, 8%): LC/MS (Table 1, Method b) Rt=1.80 min; MS m/z 367 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH2:16])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1.[N:24]1[C:33]2[CH:32]=[CH:31][CH:30]=[C:29]([C:34](O)=[O:35])[C:28]=2[CH:27]=[CH:26][CH:25]=1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[C@H:14]([CH2:15][NH:16][C:34]([C:29]3[C:28]4[CH:27]=[CH:26][CH:25]=[N:24][C:33]=4[CH:32]=[CH:31][CH:30]=3)=[O:35])[CH2:13][C@H:12]3[C@@H:10]2[CH2:11]3)=[O:8])[N:6]=1
Reactant: NC[C@@H]1C[C@@H]2C[C@@H]2N1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2ncccc12
Product: Nc1nc(C(=O)N2[C@H](CNC(=O)c3cccc4ncccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl)-methanone with quinoline-5-carboxylic acid. LC-MS (basic): tR=0.75 min; [M+H]+=488.2.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9](=[N:36][OH:37])[CH2:10][O:11][CH:12]([CH:34]=[CH2:35])[CH2:13][O:14][C:15]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1(C=CC(O)=CC=1)O>C1(C)C=CC=CC=1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:10][O:11][C@H:12]([CH2:13][O:14][C:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[C@H:34]1[CH2:35][O:37][NH:36]2
Reactant: C=CC(COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCC(=NO)c1cccc(F)c1F
Agent: Oc1ccc(O)cc1
Solvent: Cc1ccccc1
Product: Fc1cccc([C@]23CO[C@H](COC(c4ccccc4)(c4ccccc4)c4ccccc4)[C@H]2CON3)c1F
Temperature: 112.5 °C
Reaction time: 13 h
Yield: 66.1 %

Procedure:
To a solution of 1-(2,3-Difluorophenyl)-2-(1-(trityloxy)but-3-en-2-yloxy)ethanone oxime (20.0 g, 0.0400 mol, 1.0 equiv.) in toluene (140 mL) was charged hydroquinone (0.0882 g, 0.008 mol, 0.2 equiv.). The reaction mixture was heated to reflux (110-115° C.) and held for 13 h. The reaction mixture was cooled to 20-25° C. and then concentrated under vacuum (T<45° C.). The solvents were chased with 2-propanol (100 mL). To the crude residue was charged isopropanol (140 mL) and the mixture was heated to 65-70° C. until a clear solution is formed. The solution was cooled to 0° C. at 10° C./hr and then held for 1 h. The resulting suspension was filtered and the solid was rinsed with cold 2-propanol (40.0). After drying the title compound was obtained as a powder (13.2 g). 1H NMR (500 MHz, DMSO) δ ppm 7.42-7.33 (m, 8H), 7.31 (t, J=7.6 Hz, 6H), 7.28-7.21 (m, 3H), 7.20-7.12 (m, 1H), 6.39 (s, 1H), 4.13 (d, J=8.2 Hz, 1H), 4.03 (s, 1H), 3.97 (s, 1H), 3.89 (d, J=9.2 Hz, 1H), 3.81-3.70 (m, 1H), 3.36-3.29 (m, 1H), 3.26 (dd, J=10.1, 6.0 Hz, 1H), 3.15 (dd, J=10.0, 3.5 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 150.74 (dd, JCF=246.4, 14.4 Hz), 148.66 (dd, JCF=248.3, 13.5 Hz), 144.09, 130.58, 128.67, 128.32, 127.48, 124.75, 124.45, 117.18 (d, JCF=17.0 Hz), 86.57, 84.91, 78.16, 76.81, 64.82, 56.46.
Reaction SMILES: [Cl:1][C:2]1[C:16]([Cl:17])=[CH:15][C:5]2[NH:6][C:7]([C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.Cl[CH2:19][CH:20]([OH:23])[CH2:21][OH:22].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[Cl:17][C:16]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]3([C:10]([F:13])([F:11])[F:12])[O:23][CH:20]([CH2:21][OH:22])[CH2:19][O:14]3)=[N:6][C:5]=2[CH:15]=1
Reactant: OCC(O)CCl
Reactant: O=C(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OCC1COC(c2nc3cc(Cl)c(Cl)cc3[nH]2)(C(F)(F)F)O1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
1-(5,6-DiChloro-1H-benzoimidazol-2-yl)-2,2,2-trifluoro-ethanone (503 mg), 3-chloro-1,2-propan-diol (393 mg) and potassium carbonate (491 mg) were dissolved in DMF (5 mL). The reaction mixture was stirred for 18 hrs at ambient temperature, then diluted with ethyl acetate (50 mL), washed with water (50 mL) and brine (2×20 mL). The extracts were dried over Na2SO4, filtered, concentrated, and purified by column chromatography (SiO2; 40% ethyl acetate/hexanes), followed by washing solid with CH2Cl2/hexanes to yield the title compound as an off-white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([OH:13])[C:10]2[CH:9]3[CH2:14][CH:6]([CH2:7][CH2:8]3)[C:5]=2[C:4]=1[OH:15].CCOC(C)=O>O.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:4](=[O:15])[C:5]2[CH:6]3[CH2:14][CH:9]([C:10]=2[C:11](=[O:13])[CH:12]=1)[CH2:8][CH2:7]3
Reactant: COc1cc(O)c2c(c1O)C1CCC2C1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: COC1=CC(=O)C2=C(C1=O)C1CCC2C1

Procedure:
To a vigorously stirred solution of NaIO4 (1.69 g, 7.89 mmol, Baker) in water (50 mL), there was added a solution of 1,2,3,4-tetrahydro-6-methoxy-1,4-methanonaphthalene-5,8-diol (52, 543 mg, 2.63 mmol) in CHCl3 (20 mL). The vigorously stirred reaction immediately became orange. The reaction was allowed to stir for 15 min at rt at which point TLC analysis (10% EtOAc, 90% CHCl3) showed the total consumption of the organic starting material and the formation of a yellow, higher Rf spot. The layers were separated and the aqueous portion extracted with CHCl3 (2×20 mL). The combined organic portion was washed with half saturated brine (30 mL), filtered through cotton and the solvent removed in vacuo. The residue was filtered through a plug of silica gel with CHCl3 elution. Solvent removal gave 53 as a yellow semisolid. Scraping this semisolid with a spatula resulted in a yellow powder. This was further dried in vacuo (470 mg, 88%, pure by TLC and 1H NMR); mp 106°-108° C.; 1H NMR (CDCl3) δ1.16 (m, 2H), 1.40 (d, J=9.0 Hz, 1H), 1.63 (d, J=8.7 Hz, 1H), 1.91 (m, 2H), 3.50 (m, 2H), 3.78 (s, 3H), 5.72 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2[CH2:10][CH2:11][CH2:12][C:8]=2[C:7]([C:13]2[N:18]=[C:17]([NH2:19])[C:16]([O:20]C)=[CH:15][N:14]=2)=[N:6]1.C(=O)([O-])[O-].[K+].[K+].C1(S)C=CC=CC=1.C(O)=O>CN1CCCC1=O>[NH2:19][C:17]1[C:16]([OH:20])=[CH:15][N:14]=[C:13]([C:7]2[C:8]3[CH2:12][CH2:11][CH2:10][C:9]=3[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:18]=1
Reactant: COc1cnc(-c2nn(Cc3ccccc3F)c3c2CCC3)nc1N
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: O=CO
Solvent: CN1CCCC1=O
Product: Nc1nc(-c2nn(Cc3ccccc3F)c3c2CCC3)ncc1O
Temperature: 190 °C
Reaction time: 0.5 h
Yield: 103 %

Procedure:
5.61 g of 2-[1-(2-fluorobenzyl)-1,4,5,6-tetrahydrocyclopenta[c]pyrazol-3-yl]-5-methoxypyrimidin-4-amine 1-4-2 (16.5 mmol, 1.00 eq) were dissolved in 680 mL of dry 1-methylpyrrolidin-2-one. 1.14 g of potassium carbonate (8.27 mmol, 0.5 eq.), and 3.40 mL benzenethiol (33.1 mmol, 2.0 eq.) were added. The mixture was stirred for 0.5 h at 190° C. bath temperature. Then the reaction mixture was partitioned between aqueous half saturated ammonium chloride solution and ethyl DCM/isopropanol (4:1). The organic layer was dried with magnesium sulfate and concentrated in vacuo. The purification of the residue by flash chromatography provided 6.60 g (17.0 mmol, 100%) of the target compound without formic acid. Further purification of 170 mg by HPLC resulted in analytically pure target compound: 53 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[C:5]([NH2:19])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[C:15]([F:18])([F:17])[F:16].[F:21][C:22]([F:30])([F:29])[C:23]([F:28])([F:27])[C:24](O)=O>>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=2[C:15]([F:17])([F:18])[F:16])=[CH:6][C:5]2[NH:19][C:24]([C:23]([F:28])([F:27])[C:22]([F:30])([F:29])[F:21])=[N:20][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(Cl)cc2C(F)(F)F)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: FC(F)(F)c1cc(Cl)ccc1-c1cc2[nH]c(C(F)(F)C(F)(F)F)nc2cc1Cl
Yield: 77 %

Procedure:
A solution of 4-chloro-5-[4-chloro-2-(trifluoromethyl)phenyl]benzene-1,2-diamine (100 mg, 0.31 mmol) in pentafluoropropanoic acid (5 ml) was stirred overnight at 80° C. in an oil bath and then quenched with ice-water (50 ml). The pH value of the solution was adjusted to 8 with saturated aqueous sodium carbonate and extracted with ethyl acetate ((50 ml×3). The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column with 10% ethyl acetate in petroleum ether to produce 5-chloro-6-[4-chloro-2-(trifluoromethyl)phenyl]-2-(pentafluoroethyl)-1H-1,3-benzodiazole as a off-white solid (129.8 mg, 77%).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18](=[O:24])[CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[O:12]1.C(=O)([O-])[O-].[K+].[K+]>CO>[O:24]=[C:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:17][CH2:16][CH:13]1[O:12][CH:11]([CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C:3]([OH:25])=[O:2])[CH2:15][CH2:14]1
Reactant: CCCCCC(=O)CCC1CCC(CCCCCCCC(=O)OC)O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CCCCCC(=O)CCC1CCC(CCCCCCCC(=O)O)O1

Procedure:
VIII (1.77 g, 0.00500 mole), methanol (20 ml), and 20% aqueous potassium carbonate (10 ml) were stirred and heated under reflux for 2.5 hours. The methanol was removed fron a water bath (60° C, 100 mm Hg). The residue was diluted with water (25 ml) and washed with ether (25 ml). The resulting clear solution was acidified to pH 5-6 with acetic acid. The emulsion being formed was extracted with ether (25 + 25 ml). The combined ethereal extracts were dried over sodium sulfate and evaporated from a water bath (60° C, 1 mm Hg). The yellowish, oily residue of IX (1.60 g, 94%) solidified by standing. M.p. 26°-28° C, nD25 1.4673.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][O:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:18][C:19]([OH:21])=O.N1C=CC=CC=1.[C:34]([C:38]1[CH:44]=[CH:43][C:42]([C:45](=[O:47])[NH2:46])=[CH:41][C:39]=1[NH2:40])([CH3:37])([CH3:36])[CH3:35]>C(Cl)Cl.C(OCC)C.C(Cl)Cl.C(OCC)C.CO.CN(C)C=O>[C:34]([C:38]1[CH:44]=[CH:43][C:42]([C:45](=[O:47])[NH2:46])=[CH:41][C:39]=1[NH:40][C:19](=[O:21])[CH2:18][CH:17]([C:10]1[CH:11]=[CH:12][C:13]([O:15][CH3:16])=[CH:14][C:9]=1[O:8][CH3:7])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)c1ccc(C(N)=O)cc1N
Reactant: CCCCCCC(CC(=O)O)c1ccc(OC)cc1OC
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CCCCCCC(CC(=O)Nc1cc(C(N)=O)ccc1C(C)(C)C)c1ccc(OC)cc1OC
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 86.4 %

Procedure:
0.31 ml (3.57 mmol) of oxalyl chloride and a catalyic amount of dimethyl-formamide were added, with ice-cooling, to a solution of 350 mg (1.19 mmol) of 3-(2,4-dimethoxyphenyl)nonanoic acid (prepared as described in Preparation 42B), in 7 ml of methylene chloride and the reaction temperature was raised to room temperature at once. The resulting mixture was then stirred for 50 minutes. The solvent and an excess of the reagent were removed by distillation under reduced pressure, and the resulting residue was dissolved in 7 ml of methylene chloride. 0.48 ml (5.95 mmol) of pyridine were added to the solution, followed by 206 mg (1.07 mmol) of 2-t-butyl-5-carbamoylaniline (prepared as described in Preparation 38), all with ice-cooling, and the resulting mixture was stirred at the same temperature for 30 minutes. At the end of this time, the reaction mixture was diluted with diethyl ether, and the diluted solution was washed with 1N aqueous hydrochloric acid, with a 0.5N aqueous solution of sodium hydroxide, with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by column chromatography through 25 g of silica gel using a gradient elution method, with mixtures of methylene chloride and methanol ranging from 100:2 to 100:4 by volume as the eluent, to give 433 mg (yield 86%) of the title compound as crystals, melting at 152°-153° C. (from methylene chloride-diethyl ether).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=1.ClC1[N:16]=[CH:15][C:14]([CH3:17])=CN=1>>[NH:16]1[CH2:15][CH:14]([C:2]2[N:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[N:3]=2)[CH2:17]1
Reactant: Cc1cnc(Cl)nc1
Reactant: Cc1cc(C)nc(Cl)n1
Product: Cc1cc(C)nc(C2CNC2)n1

Procedure:
Compound P15 was prepared according to the general procedure described for the synthesis of P12 in Preparation 12, except that 2-chloro-4,6-dimethylpyrimidine (the synthesis of 2-chloro-4,6-dimethylpyrimidine is described by G. Vlad & I. T. Horvath, J. Organic Chem., 2002, 67, 6550-6552) was used instead of 2-chloro-5-methylpyrimidine, to provide P15. Yield: 345 mg, 2.11 mmol, 43%. 1H NMR (400 MHz, CD3OD) δ 2.44 (s, 6H), 4.00 (m, 2H), 4.14 (m, 3H), 7.12 (s, 1H).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17]>[OH-].[Na+]>[C:1]([NH:10][C:11]1[NH:15][N:14]=[N:13][C:12]=1[C:16](=[O:18])[NH2:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)c1nn[nH]c1N
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1nn[nH]c1NC(=O)c1ccccc1

Procedure:
Benzoyl chloride (3.26 ml.) and 4N aqueous sodium hydroxide solution (8 ml.) were added alternately, in portions over 25 minutes, to a vigorously shaken, ice-cooled solution of 5-amino-4-carbamoyl-1H-1,2,3-triazole (1.27 g; prepared by the method of J. R. E. Hoover and A. R. Day, J. Amer. Chem. Soc., 1956, 78,5832) in 4N aqueous sodium hydroxide solution (15 ml.). The reaction mixture was extracted with diethyl ether, the aqueous layer cooled and acidified with concentrated hydrochloric acid, and the white precipitate filtered off and washed well with water. The crude solid was stirred in diethyl ether and then purified by dissolving in dilute aqueous sodium hydroxide solution, and reprecipitation by the addition of concentrated hydrochloric acid. The solid was filtered off, washed with water, and dried to give 5-benzamido-4-carbamoyl-1H-1,2,3-triazole (0.085 g.), m.p. 299° C. (with decomposition).
Reaction SMILES: [CH2:1]([C:3]1[C:8]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[C:21]([F:28])[CH:20]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2].[O:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O.C(#N)C>[CH2:1]([C:3]1[C:8]([C:9]#[C:10][C:11]2[CH:12]=[N:13][C:14]([NH:17][CH3:18])=[CH:15][CH:16]=2)=[C:7]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:38]3[CH2:37][CH2:36][N:35]([CH:32]4[CH2:33][CH2:34][O:29][CH2:30][CH2:31]4)[CH2:40][CH2:39]3)=[O:24])=[C:21]([F:28])[CH:20]=2)[CH:6]=[CH:5][N:4]=1)[CH3:2]
Reactant: CCc1nccc(-c2ccc(C(=O)O)c(F)c2)c1C#Cc1ccc(NC)nc1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CCc1nccc(-c2ccc(C(=O)N3CCN(C4CCOCC4)CC3)c(F)c2)c1C#Cc1ccc(NC)nc1

Procedure:
The title compound is synthesized according to general procedure GP5 starting from 100 mg (0.27 mmol) 4-[2-Ethyl-3-(6-methylamino-pyridin-3-ylethynyl)-pyridin-4-yl]-2-fluoro-benzoic acid (A-46) using 68 mg (0.40 mmoL) tetrahydro-pyran-4-yl piperazine, 101 mg (0.27 mmol) HATU and 50 μL DIPEA in 1.5 mL DMF. After completion of the reaction, the reaction mixture is filtered and the product is isolated from the obtained solution by RP-HPLC using a H2O/ACN-gradient. Yield: 59 mg (42%).
Reaction SMILES: [S:1]([C:5]1[N:6]([CH2:10][C:11]([O:13]CC)=[O:12])[CH:7]=[CH:8][N:9]=1)([CH3:4])(=[O:3])=[O:2]>S(=O)(=O)(O)O>[S:1]([C:5]1[N:6]([CH2:10][C:11]([OH:13])=[O:12])[CH:7]=[CH:8][N:9]=1)([CH3:4])(=[O:3])=[O:2]
Reactant: CCOC(=O)Cn1ccnc1S(C)(=O)=O
Agent: O=S(=O)(O)O
Product: CS(=O)(=O)c1nccn1CC(=O)O
Yield: 67.5 %

Procedure:
Ethyl (2-mesyl-imidazol-1-yl)-acetate (21.4 g.) in 4N sulphuric acid (50 cc.) is heated under reflux for 11/2 hours. A product crystallises on cooling. Crystallisation is completed by keeping the mixture in a bath of ice and water for 5 hours. After filtration, crystals (13.7 g.) which melt at 216- 217° C. are obtained. Recrystallisation from water (110 cc.) gives (2-mesylimidazol-1-yl)-acetic acid (12.7 g.), melting at 218- 219° C.