Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][C:15]=1[Br:24])[CH:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C(=O)([O-])O.[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[Br:24][C:15]1[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[C:19]2[C:14]=1[CH2:13][CH2:12][N:4]([CH:5]([CH2:9][CH2:10][CH3:11])[CH2:6][CH2:7][CH3:8])[C:3]2=[O:2]
Reactant: CCCC(CCC)N(CCc1ccc(C(F)(F)F)cc1Br)C(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CCC)N1CCc2c(Br)cc(C(F)(F)F)cc2C1=O
Reaction time: 15 h
Yield: 85.1 %

Procedure:
660 mg of methyl[2-(2-bromo-4-trifluoromethylphenyl)ethyl](1-propylbutyl)carbamate are dissolved under an inert atmosphere in 15 cm3 of dichloromethane at a temperature close to 10° C. 575 mg of 4-dimethylaminopyridine are added to the reaction mixture. 1.32 cm3 of trifluoromethanesulfonic anhydride in solution in 2 cm3 of anhydrous dichloromethane are poured into the reaction mixture over 5 min. The reaction mixture is kept stirring for 15 h at a temperature close to 20° C. 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate are added to the reaction medium. This stirring is continued for 30 min, then 20 cm3 of dichloromethane are added to the mixture. The organic phase is decanted then washed successively with 100 cm3 of a 0.1M aqueous solution of hydrochloric acid and 20 cm3 of a saturated aqueous solution of sodium hydrogen carbonate. Next, the organic phase is dried then concentrated using a rotary evaporator under reduced pressure (5 kPa). The residual solid is then purified by filtration through silica (silica 60—particle size 15-40 μm—eluent: 50% ethyl ethyl acetate/50% cyclohexane). The organic phase is concentrated under reduced pressure (5 kPa). 519 mg of 5-bromo-7-trifluoromethyl-2-(1-propylbutyl)-3,4-dihydroisoquinoline-1(2H)-one are obtained in the form of a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][C:8]([OH:10])=O)=[C:5]([CH3:11])[O:4][N:3]=1.CN(C=O)C.C(Cl)(C(Cl)=O)=O.[NH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[CH2:35][CH2:34][CH:33]([CH:36]([C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=3)[C:37]([N:39]([CH2:42][CH3:43])[CH2:40][CH3:41])=[O:38])[CH2:32][CH2:31]2)=[C:26]([F:50])[CH:25]=1>ClCCCl.O>[CH3:1][C:2]1[C:6]([CH2:7][C:8]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([N:30]3[CH2:35][CH2:34][CH:33]([CH:36]([C:44]4[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=4)[C:37]([N:39]([CH2:40][CH3:41])[CH2:42][CH3:43])=[O:38])[CH2:32][CH2:31]3)=[C:26]([F:50])[CH:25]=2)=[O:10])=[C:5]([CH3:11])[O:4][N:3]=1
Reactant: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(N)cc2F)CC1
Reactant: Cc1noc(C)c1CC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CC)C(=O)C(c1ccccc1)C1CCN(c2ccc(NC(=O)Cc3c(C)noc3C)cc2F)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
A mixture of (3,5-dimethyl-isoxazol-4-yl)-acetic acid (1.0 mmol) and DMF (0.050 mL) in DCE (10 mL) was treated with (COCl)2 (10 mmol), dropwise. The mixture was stirred at rt for 1 h and was concentrated. The residue was diluted with DCE (10 mL) and treated with 2-[1-(4-amino-2-fluoro-phenyl)-piperidin-4-yl]-N,N-diethyl-2-phenyl-acetamide (0.30 mmol) and TEA (2.0 mmol). After 16 h, the mixture was diluted with H2O (10 mL) and extracted. The organic layer was concentrated and the residue was purified by PTLC to provide the title compound (87 mg, 56%). MS (ESI): mass calcd. for C30H37FN4O3, 520.28; m/z found, 521.4 [M+H]+. 1H NMR (CDCl3): 7.40-7.20 (m, 6H), 6.96 (dd, J=8.6, 1.6, 1H), 6.83 (t, J=9.0, 1H), 3.50-3.10 (m, 9H), 2.70-2.60 (m, 1H), 2.52-2.42 (m, 1H), 2.38 (s, 3H), 2.30-2.20 (m, 4H), 2.08-1.98 (m, 1H), 1.50-1.15 (m, 3H), 1.15-1.03 (m, 6H).
Reaction SMILES: [S:1]1[C:9]2[CH:8]=[CH:7][NH:6][C:5](=O)[C:4]=2[CH:3]=[CH:2]1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:5]1[C:4]2[CH:3]=[CH:2][S:1][C:9]=2[CH:8]=[CH:7][N:6]=1
Reactant: O=c1[nH]ccc2sccc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1nccc2sccc12
Temperature: 100 °C
Reaction time: 4 h

Procedure:
5H-Thieno[3,2-c]pyridin-4-one (1.0 g, 6.62 mmol) is dissolved in 30 mL of phosphorous oxy chloride. The solution is heated to 100° C. After 4 hours, the solution is concentrated. The residue is dissolved in CH2Cl2. The resulting solution is washed with water and saturated NaCl. The organic layer is dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 40% CH2Cl2 /hexanes to 60% CH2Cl2 /hexanes. The title compound (1.0 g, 5.8 mmol) is obtained as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH:6]1[CH2:9][N:8]([C:10]2[N:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12](O)=[O:13])[CH2:7]1.Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[O:5][CH:6]1[CH2:7][N:8]([C:10]2[N:18]=[CH:17][C:16]([F:19])=[CH:15][C:11]=2[C:12]([NH:24][C:25]2([C:28]3[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=3)[CH2:27][CH2:26]2)=[O:13])[CH2:9]1
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(F)cnc1N1CC(Oc2cccc(Cl)c2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cnc3N3CC(Oc4cccc(Cl)c4)C3)CC2)cc1
Yield: 56.3 %

Procedure:
The title compound (D188) (12 mg) was prepared according to the experimental procedure described in Description 169 starting from 2-(3-(3-chlorophenoxy)azetidin-1-yl)-5-fluoronicotinic acid (D133) (14 mg, 0.043 mmol) and methyl 4-(1-aminocyclopropyl)benzoate hydrochloride (D7) (9.85 mg, 0.043 mmol).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][CH2:5][SH:6].[OH-].[Na+].Cl[C:10](Cl)(Cl)[CH2:11][N+:12]([O-:14])=[O:13].Cl>CO.C(Cl)Cl.O>[CH3:1][N:2]1[CH2:3][CH2:4][CH2:5][S:6][C:10]1=[CH:11][N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])CC(Cl)(Cl)Cl
Reactant: CNCCCS
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CN1CCCSC1=C[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
Into 40 ml of methanol were added 5.0 g of 1-methylamino-3-propanethiol and 1.0 g g of caustic soda, followed by stirring, to be completely dissolved therein. Then, the mixture was cooled to 0° C. While stirring the solution, a solution of 2.2 g of caustic soda dissolved in 25 ml of methanol and a solution of 3.5 g of 2,2,2-trichloro-1-nitroethane diluted in 20 ml of methanol were added at the same time dropwise slowly over 50 minutes, and the reaction was carried out for one hour. The reaction was exothermic and the liquid temperature was maintained at lower than 10° C. (about 8° C.). After the reaction, the reaction mixture was neutralized to pH 7 with 3 N aqueous hydrochloric acid, and then with addition of 60 ml of water, extraction with 50 ml of methylene chloride was repeated four times. The extracts were concentrated to give 3.27 g of tetrahydro-3-methyl-2-(nitromethylene)- 1,3-thiazine (yield: 94%).
Reaction SMILES: [Si]([O:8][C:9]1[C:18]([CH2:19][CH2:20][CH3:21])=[C:17]2[C:12]([C:13]([CH2:23][CH3:24])=[CH:14][C:15](=[O:22])[O:16]2)=[CH:11][CH:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:23]([C:13]1[C:12]2[C:17](=[C:18]([CH2:19][CH2:20][CH3:21])[C:9]([OH:8])=[CH:10][CH:11]=2)[O:16][C:15](=[O:22])[CH:14]=1)[CH3:24]
Reactant: CCCc1c(O[Si](C)(C)C(C)(C)C)ccc2c(CC)cc(=O)oc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCCc1c(O)ccc2c(CC)cc(=O)oc12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-tert-butyldimethylsilyloxy-4-ethyl-8-propylcoumarin (Step B; 117 mg, 0.3382 mmol) in five mL of tetrahydrofuran (THF) was added a 1.0M solution of tetrabutylammonium fluoride (0.51 mL, 0.51 mmol). The mixture was stirred at ambient temperature for five minutes and subsequently quenched by the addition of saturated ammonium chloride. The mixture was extracted several times with ethyl acetate and the combined organic extracts were dried over magnesium sulfate, filtered, concentrated in vacuo, and the crude residue was purified by flash chromatography on silica gel (gradient elution: 10% then 20% then 30% ethyl acetate/hexane) which yielded the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[NH:14][CH3:15].[N:16]([O-])=[O:17].[Na+]>Cl.O>[Cl:1][C:2]1[C:10](=[O:11])[C:9]2[N:8]([CH3:12])[N:7]=[CH:6][C:5]=2[C:4](=[O:13])[C:3]=1[N:14]([N:16]=[O:17])[CH3:15]
Reactant: CNC1=C(Cl)C(=O)c2c(cnn2C)C1=O
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CN(N=O)C1=C(Cl)C(=O)c2c(cnn2C)C1=O

Procedure:
6-Chloro-5-methylamino-1-methylindazole-4,7-dione (4.5 grams) in 30 % hydrochloric acid (50 milliliters was stirred at 0° C and treated dropwise with a solution of sodium nitrite (3.0 grams) in water (20 milliliters). After 1 hour the orange solid which had separated out was collected, washed with water and dried over silica gel to yield the desired product having a melting point of 124°-125° C (with decomposition).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C@H:17]([C@H:22]3[O:26]C(C)(C)[O:24][C:23]3=O)[CH2:18][CH:19]([CH3:21])[CH3:20])=[O:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[NH2:30][OH:31]>CC(O)C>[OH:31][NH:30][C:23](=[O:24])[C@H:22]([OH:26])[C@@H:17]([C:15]([N:12]1[CH2:11][CH2:10][N:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13]1)=[O:16])[CH2:18][CH:19]([CH3:20])[CH3:21]
Reactant: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)[C@H]3OC(C)(C)OC3=O)CC2)cc1
Reactant: NO
Solvent: CC(C)O
Product: COc1ccc(N2CCN(C(=O)[C@@H](CC(C)C)[C@@H](O)C(=O)NO)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55 %

Procedure:
To a suspension of (5R)-5-((1S)-1-{[4-(4-methoxyphenyl)piperazin-1-yl]carbonyl}-3-methylbutyl)-2,2-dimethyl-1,3-dioxolan-4-one (108 mg, 0.27 mmol) in iPrOH (4 mL) was added a 50% aqueous solution of hydroxylamine (80 μL) and the resulting mixture was stirred at RT for 2 hours. Then the white solid was filtered off, washed with water and dried under reduced pressure to give 56 mg (55%) of the title compound as a white powder. HPLC, Rt: 1.57 min (purity: 99.1%). LC/MS, M+(ESI): 380.2, M−(ESI): 378.2. 1H NMR (CD3OD, 300 MHz) δ 7.01 (d, J=9.1 Hz, 2H), 6.89 (d, J=9.1 Hz, 2H), 4.05 (d, J=6.8 Hz, 1H), 3.96 (m, 2H), 3.80 (m, 1H), 3.78 (s, 3H), 3.68 (m, 1H), 3.49 (m, 1H), 3.15-2.99 (m, 4H), 1.72 (m, 1H), 1.54 (m, 1H), 1.29 (m, 1H), 0.96 (d, J=6.5 Hz, 3H), 0.95 (d, J=6.4 Hz, 3H).
Reaction SMILES: CN(C=[N:5][S:6]([CH2:9][CH2:10][C:11]([CH3:16])([CH3:15])[CH2:12][CH2:13][OH:14])(=[O:8])=[O:7])C.Cl[C:18]1[C:19]([CH3:27])=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1>>[CH3:16][C:11]([CH3:15])([CH2:10][CH2:9][S:6](=[O:7])(=[O:8])[NH2:5])[CH2:12][CH2:13][O:14][C:18]1[C:19]([CH3:27])=[CH:20][C:21]2[N:22]([N:24]=[CH:25][N:26]=2)[N:23]=1
Reactant: Cc1cc2ncnn2nc1Cl
Reactant: CN(C)C=NS(=O)(=O)CCC(C)(C)CCO
Product: Cc1cc2ncnn2nc1OCCC(C)(C)CCS(N)(=O)=O

Procedure:
Using 5-(N,N-dimethylaminomethylene)aminosulfonyl-3,3-dimethyl-1-pentanol and 6-chloro-7-methyl[1,2,4]triazolo[1,5-b]pyridazine, the same reaction as in Example 6 was conducted to produce the title compound. m.p. 143°-144° C.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)[CH:8]=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[C:6]=1[OH:24])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].C(OCC)(=O)C>[NH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[CH:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:6]([OH:24])=[C:7]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:8]=2)=[CH:12][CH:13]=1
Reactant: [H][H]
Reactant: CC(C)(C)c1cc(-c2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)c1cc(-c2ccc(N)cc2)cc(C(C)(C)C)c1O
Reaction time: 16 h

Procedure:
A solution of 50 g. (0.152 mole) of 2,6-di(t-butyl)-4-(4'-nitrophenyl)phenol in 350 ml. of ethyl acetate is reduced with hydrogen gas at about 45 psig in a Paar apparatus using 10 percent palladium on charcoal as catalyst. The mixture is allowed to stand for about 16 hours, filtered, and the filtrate evaporated under vacuum. The residue is cooled, dissolved in ethanol and triturated with water. The resulting off-white solid is recrystallized from petroleum ether to provide 4-(4'-aminophenyl)-2,6-di(t-butyl)phenol, m.p. 113°-114.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C:5](=[CH:7][C:8](Cl)=[O:9])[C:4](=[O:11])[O:3]1.Cl.[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:18][NH:19][CH3:20].CCN(CC)CC>C(Cl)Cl>[Cl:14][C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([Cl:24])[CH:23]=1)[CH2:18][N:19]([CH3:20])[C:8](=[O:9])[CH:7]=[C:5]1[C:4](=[O:11])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: CNCc1cc(Cl)cc(Cl)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(Cc1cc(Cl)cc(Cl)c1)C(=O)C=C1OC(C)(C)OC1=O
Reaction time: 2 h
Yield: 98.8 %

Procedure:
To a stirred solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (0.96 g, 5 mmol) in CH2Cl2 (20 mL) was added a solution of 3,5-dichlorobenzyl-methylamine hydrochloride (1.133 g, 5 mmol) and Et3N (2 mL) in CH2Cl2 (25 mL). The addition flask was rinsed with CH2Cl2 (5 mL) and added to the reaction mixture. After 2 h, the reaction mixture was concentrated and the resulting residue was triturated with ether (100 mL), filtered and concentrated to give the desired product as a viscous brown oil (1.70 g, 100% yield). 1HNMR (300 MHz, CDCl3) δ: 7.30–7.27 (1H, m), 7.16 (1.5H, br s), 7.06 (0.5H, s), 6.17 (0.66H, s), 6.07 (0.34H, s), 4.59 (1.33H, s), 4.53 (0.67H, s), 3.03 (2H, s), 2.97 (1H, s), 1.74 (4H, s), 1.70 (2H,s).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[OH:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: OCCCCCCCCCCCCCCCCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=Cc1ccc(OCCCCCCCCCCCCCCCCO)cc1
Temperature: 25 °C

Procedure:
To a stirred solution of 4-hydroxy-benzaldehyde (0.24 g, 2mmol) and 1,16-dihydroxyhexadecane (0.51 g, 2 mmol), triphenylphosphine (0.53 g, 2 mmol) in dry THF (20 ml) at −15° C. under an argon atmosphere was added a solution of diisopropylazodicarboxylate (0.4 g, 2 mmol) in dry THF (7.5 ml) over a period of 40 minutes. The mixture was allowed to warm to room temperature overnight. The solvent was removed under reduced pressure, diethyl ether was added and the white solid formed was removed by filtration. The filtrate was evaporated to dryness and the residue purified by chromatography on a column of silica gel which was, eluted with petroleum ether (b.p. 40-60° C.):tetrahydrofuran (THF) (10:1 by volume) to yield the title compound which was used directly without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10](N)=[O:11])=[CH:9][N:4]2[N:3]=1.[OH-:14].[Na+].O>C(O)C>[CH3:1][C:2]1[CH:13]=[C:5]2[N:6]=[CH:7][C:8]([C:10]([OH:14])=[O:11])=[CH:9][N:4]2[N:3]=1
Reactant: Cc1cc2ncc(C(N)=O)cn2n1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1cc2ncc(C(=O)O)cn2n1
Temperature: 70 °C
Reaction time: 1 h
Yield: 63 %

Procedure:
2-Methylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid amide (475 mg) was dissolved in ethanol (5 ml), and 5 N sodium hydroxide solution (2 ml) was added thereto and stirred for 1 hour at 70° C. The reaction mixture was cooled to room temperature, water was added thereto, and the reaction mixture was washed with ethyl acetate. 2 N Hydrochloric acid was added to the aqueous phase until it became acidic, and precipitated crystals were collected by filtration and washed with water and n-hexane. The crystals were dried under reduced pressure to give the title compound (300 mg, Y.:63%) as white crystals.
Reaction SMILES: [OH:1][CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-])=O)[N:5]=[CH:4][N:3]1[CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>CCOC(C)=O.CO.[Pt]>[NH2:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]([OH:1])[N:3]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH:4]=[N:5]2
Reactant: CCCCCN1C=Nc2cccc([N+](=O)[O-])c2C1O
Agent: [Pt]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCN1C=Nc2cccc(N)c2C1O
Reaction time: 2 h
Yield: 74 %

Procedure:
4-hydroxy-5-nitro-3-pentyl-3,4-dihydroquinazoline (6a, 10.0 g, 38.0 mmol) was dissolved in EtOAc-MeOH mixed solvent (2:1, 150 ml) and 3% Pt—C (1.0 g) was added. Hydrogenation was carried out at room temperature under H2 atmosphere using a balloon. After 2 h, the reaction was stopped and the mixture was filtered. The filtrated was concentrated under reduced pressure and the obtaining residual oil was purified by a short silica gel (100 g) column chromatography (eluent: EtOAc/MeOH=20/1) to give 5-amino-4-hydroxy-3-pentyl-3,4-dihydroquinazoline (2a, 6.56 g, 74%); 1H NMR (270 MHz) δ (CD3OD) 0.88 (t, J=6.9 Hz, 3H), 1.23-1.41 (m, 4H), 1.63-1.74 (m, 2H), 3.26-3.35 (m, 1H), 3.51-3.62 (m, 1H), 6.15 (s, 1H), 6.47-6.51 (m, 1H), 6.55 (dd, J=1.0 and 7.9 Hz, 1H), 7.06 (t, J=7.9 Hz, 1H), 7.43 (s, 1H); MS (ES) m/z 234 (M+).
Reaction SMILES: C([N:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])C1C=CC=CC=1.C([O-])=O.[NH4+]>C(O)C.[Pd]>[NH:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1nccn1Cc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)c1ncc[nH]1

Procedure:
34.7 g (150.9 mmol) of ethyl 1-benzyl-1H-imidazole-2-carboxylate are dissolved in 1005 ml of ethanol, and 34 g of ammonium formate are added. The reaction mixture is heated under reflux for about 6 h. A total of 8 g of 10% palladium-on-carbon and 18 g of ammonium formate are thereby added in small portions. After cooling, the catalyst is filtered off and the filtrate is concentrated in vacuo. The product that crystallizes out during this operation is triturated with 80 ml of ice-water and collected by suction filtration.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14](O)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:20][CH:19]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2].[CH:31]1([NH2:37])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]([NH:37][CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)=[O:15])=[CH:11][CH:12]=2)[C@H:7]([NH:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)[CH2:6][C@@H:5]1[CH3:30])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(C(=O)O)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Reactant: NC1CCCCC1
Product: CC(=O)N1c2ccc(C(=O)NC3CCCCC3)cc2[C@H](Nc2ccc(N3CCOCC3)cc2)C[C@@H]1C
Yield: 87.5 %

Procedure:
Reactions and treatments were carried out in the same manner as in Example 110, using 82 mg of (2S,4R)-1-acetyl-2-methyl-4-[(4-morpholinophenyl)amino]-1,2,3,4-tetrahydroquinoline-6-carboxylic acid and 60 mg of cyclohexylamine. Thus, 86 mg (87%) of the title compound was obtained as a yellow amorphous substance.
Reaction SMILES: [N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([O:19]CC)=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(O)C.[OH-].[Na+]>O>[N:1]1[C:2]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:11]=2)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12
Reactant: CCOC(=O)Cc1ccc(-c2cn3ccccc3n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc(-c2cn3ccccc3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 49.1 %

Procedure:
A mixture of 5.2 g of ethyl 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetate, 20 ml of ethanol, 0.96 g of sodium hydroxide and 5 ml of water is stirred at room temperature for 10 minutes. The ethanol is distilled off under reduced pressure, and the residue is dissolved in water. The solution is adjusted to pH 6 by addition of dilute hydrochloric acid. The crystalline precipitate is filtered off, washed with water, and recrystallized from ethanol to give 2.3 g of 4-(imidazo[1,2-a]pyridin-2-yl)phenylacetic acid as colorless crystals melting at 217°-221°C with decomposition.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:15]3[N:16]=[CH:17][NH:18][C:14]=3[CH2:13][CH2:12][NH:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[F:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28](O)=[O:29])=[CH:22][CH:21]=1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>C(Cl)Cl>[F:19][C:20]1[CH:21]=[CH:22][C:23]([CH2:26][CH2:27][C:28]([N:11]2[CH2:12][CH2:13][C:14]3[NH:18][CH:17]=[N:16][C:15]=3[CH:10]2[C:7]2[CH:8]=[CH:9][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)=[O:29])=[CH:24][CH:25]=1
Reactant: CC(C)c1ccc(C2NCCc3[nH]cnc32)cc1
Reactant: O=C(O)CCc1ccc(F)cc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)c1ccc(C2c3nc[nH]c3CCN2C(=O)CCc2ccc(F)cc2)cc1
Yield: 33.3 %

Procedure:
A mixture of histamine dihydrochloride (1.85 g, 10.0 mmol), water (10 mL), potassium hydroxide (1.72 g, 30.0 mmol), ethanol (25 mL) and 4-isopropylbenzaldehyde (1.62 g, 10.91 mmol) was heated to reflux for 1.5 h. Ethanol was evaporated and the residue was diluted with water (40 mL). Extraction (5×25 mL DCM), washing of the combined extracts (2×50 mL brine) and drying (MgSO4) yielded 2.29 g (87%) of crude 4-(4-isopropylphenyl)-4,5,6,7-tetrahydro-imidazo[4,5-c]pyridine, which was used for the next synthetic step without further purification. This amine (0.48 g, 1.99 mmol) was dissolved in DCM (5 mL) and added to a 30 min old mixture of 3-(4-fluorophenyl)propionic acid (0.31 g, 1.84 mmol), HOBt (0.27 g, 1.20 mmol) and EDC (0.42 g, 12.19 mmol) in DCM (10 mL). After 18 h the mixture was washed with water (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography (silica gel, gradient elution with DCM/methanol). 0.24 g (33%) of the title amide was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]=[C:14]([Cl:16])[CH:15]=1)[C:5]([NH:7][NH:8][C:9](=[O:12])[CH2:10][Cl:11])=O>O=S(Cl)Cl>[Cl:11][CH2:10][C:9]1[O:12][C:5]([C:4]2[CH:3]=[C:2]([Cl:1])[CH:15]=[C:14]([Cl:16])[CH:13]=2)=[N:7][N:8]=1
Reactant: O=C(CCl)NNC(=O)c1cc(Cl)cc(Cl)c1
Solvent: O=S(Cl)Cl
Product: ClCc1nnc(-c2cc(Cl)cc(Cl)c2)o1
Yield: 122.7 %

Procedure:
Compound 6 (40 mg, 0.133 mmol) was stirred in SOCl2 at 55-60° C. under Ar atmosphere for 4.5 hours. TLC showed compound 6 had disappeared. The mixture was concentrated in vacuum to give crude product compound 7 as a yellow solid (43 mg). Yield: 100%.