Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.[C:15]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[N+](C1C=CC=CC=1)([O-])=O.S(=O)(=O)(O)O>C1(C)C(C)=CC=CC=1.[Pd]>[CH:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:10][CH:9]=2)=[CH:3][CH:2]=1
Reactant: Nc1ccc(Nc2ccccc2)cc1
Reactant: O=C1CCCCC1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1C
Solvent: O=[N+]([O-])c1ccccc1
Product: c1ccc(Nc2ccc(Nc3ccccc3)cc2)cc1

Procedure:
To a 500 ml, 3-necked round bottom flask were added 92 g (500 mmole) p-aminodiphenylamine, 61 ml (600 mmole) cyclohexanone, 82 ml (800 mmole) nitrobenzene, 120 ml xylene solvent and 1.0 g of 5% palladium on carbon catalyst (0.05 g Pd). Using essentially the procedure of Example 1 the reaction was (A) carried out without acid and then again (B) in the presence of 3 millimoles of sulfuric acid. Reaction (B) provided about 40% (mole) more yield of DPPD over reaction (A) after 7 hours at reflux.
Reaction SMILES: [CH2:1]([C:5]1[N:9]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:7][C:6]=1[C:24](Cl)=[O:25])[CH2:2][CH2:3][CH3:4].[NH2:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.CCN(CC)CC>C(Cl)Cl>[CH2:1]([C:5]1[N:9]([C:10]2[CH:11]=[CH:12][C:13]([Cl:16])=[CH:14][CH:15]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[Cl:23])=[N:7][C:6]=1[C:24]([NH:27][N:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:25])[CH2:2][CH2:3][CH3:4]
Reactant: NN1CCCCC1
Reactant: CCCCc1c(C(=O)Cl)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1c(C(=O)NN2CCCCC2)nc(-c2ccccc2Cl)n1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.3 %

Procedure:
To a solution of 5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-1H-imidazole-4-carbonyl chloride (227 mg, 0.56 mmol) in CH2Cl2 (5 mL), were added 1-aminopiperidine (113 mg, 1.12 mmol) and Et3N (234 μL, 1.68 mmol). The solution was stirred overnight at rt, and then the solvents were evaporated under reduced pressure. The residue was purified by preparative reversed-phase HPLC, using 20 to 100% MeCN in water as gradient, to provide 125 mg (48%) of 5-butyl-2-(2-chlorophenyl)-1-(4-chlorophenyl)-N-(1-piperidinyl)-1H-imidazole-4-carboxamide as a white powder. 1H NMR (400 MHz, CDCl3) δ 7.49-7.27 (m, 8 H), 2.93 (t, 2 H), 2.82 (bs, 4 H), 1.77-1.71 (m, 4 H), 1.46-1.37 (m, 4 H), 1.25-1.20 (2 H), 0.79 (t, 3 H). LC-MS m/z 471.33 (MH+), retention time 2.88 min (method 2).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C(N(CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([C:14]([F:13])([F:24])[F:25])[CH:16]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)c1cccc(C(F)(F)F)c1
Yield: 71.5 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 3-(trifluoromethyl)benzoic acid (347 mg, 1.83 mmol), BOP-Cl (465 mg, 1.83 mmol), and triethylamine (0.606 mL, 4.35 mmol) in DCM (5 mL) was processed as described in Example 62, Step A, to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-(trifluoromethyl)benzamide (250 mg, 71% yield) as a solid.
Reaction SMILES: [C:1]1([N:7]2[C:11]3=[N:12][C:13]([Cl:27])=[N:14][C:15]([NH:16][C@@H:17]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:18]O)=[C:10]3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)(Cl)=O>C(Cl)(Cl)Cl>[C:1]1([N:7]2[C:11]3[N:12]=[C:13]([Cl:27])[N:14]4[CH2:18][C@H:17]([CH2:20][C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=5)[N:16]=[C:15]4[C:10]=3[CH:9]=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OC[C@H](Cc1ccccc1)Nc1nc(Cl)nc2c1cnn2-c1ccccc1
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClC1=Nc2c(cnn2-c2ccccc2)C2=N[C@@H](Cc3ccccc3)CN12
Reaction time: 8 h
Yield: 56 %

Procedure:
1.037 g of the above product (S)-β-[(1-phenyl-6-chloro-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino]benzenepropanol was then dissolved in 25 ml CHCl3. Next, 1.38 ml thionyl chloride was added and the reaction was allowed to stir overnight. It was then placed in a freezer at -28° C. After 5 hours the precipitate was filtered and collected washing with cold CHCl3. The white solid was dried in a vacuum oven at 70° C. for 24 hours to yield 550 mg of (S)-2,7-dihydro-7-phenyl-2-(phenylmethyl)-5-chloro-3H-imidazo[1,2-c]pyrazolo-[4,3-e]pyrimidine (56%).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5][CH2:6][CH2:7][C:8]1([C:13]([O:15]CC)=O)[S:12][CH2:11][CH2:10][S:9]1)#[N:4]>O1CCOCC1.O>[O:15]=[C:13]1[CH:5]([C:3]#[N:4])[CH2:6][CH2:7][C:8]21[S:9][CH2:10][CH2:11][S:12]2
Reactant: CCOC(=O)C1(CCCC#N)SCCS1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: N#CC1CCC2(SCCS2)C1=O
Temperature: 100 °C

Procedure:
A mixture of NaH (60%, 31.8 mg, 0.79 mmol) and ethyl 2-(3-cyanopropyl)-1,3-dithiolane-2-carboxylate (171.5 mg, 0.66 mmol) in dioxane (5 mL) was heated at 100° C. overnight. The mixture was diluted with H2O and then extracted with ethyl acetate (×2). The combined organic layers were washed with brine, dried with Na2SO4, and evaporated to afford crude 6-oxo-1,4-dithiaspiro[4.4]nonane-7-carbonitrile: LCMS tR=1.67 Min (5 min run, UV254nm), Mass calculated for, M+213.0, observed LC/MS m/z 214.1 (M+H).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[O:7][CH2:6][C:5]([CH2:17][OH:18])([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])[CH2:4][O:3]1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1.[Cl-].[NH4+].O>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:19])[O:3][CH2:4][C:5]([CH2:8][N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[N+:14]([O-:16])=[O:15])([CH2:17][O:18][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH2:6][O:7]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC1(C)OCC(CO)(Cn2ccnc2[N+](=O)[O-])CO1
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OCC2(Cn3ccnc3[N+](=O)[O-])COC(C)(C)OC2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.2 %

Procedure:
100 mg (0.369 mmol equivalents) of 2,2-dimethyl-5-hydroxymethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-1,3-dioxane was dissolved in 4.0 mL of pyridine and cooled to 0° C., 77.3 mg (0.406 mmol equivalents) of p-toluenesulfonyl chloride was then added thereto, and the mixture was stirred at room temperature (25° C.) for 1 hours. After completion of the reaction, a saturated aqueous solution of ammonium chloride and water were added thereto, and the mixture was extracted three times with ethyl acetate. The combined ethyl acetate layers were washed with water and brine, then dried with anhydrous magnesium sulfate and subsequently concentrated under vacuum, and the obtained crude product was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (v/v)=1/1) to give 115 mg (0.270 mmol equivalents) of 2,2-dimethyl-5-[(2-nitro-1H-imidazol-1-yl)methyl]-5-(p-toluenesulfonyloxymethyl)-1,3-dioxane.
Reaction SMILES: [C:1]1(=[O:12])[O:7][C:5](=[O:6])[C:4]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:3]2[CH2:2]1.[Cl-].[Al+3].[Cl-].[Cl-].[CH2:17]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>>[CH2:17]([C:24]1[CH:25]=[CH:26][C:27]([C:1](=[O:12])[CH2:2][C:3]2[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=2[C:5]([OH:7])=[O:6])=[CH:28][CH:29]=1)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: O=C1Cc2ccccc2C(=O)O1
Reactant: CCCCCCCc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCCCCCCc1ccc(C(=O)Cc2ccccc2C(=O)O)cc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of homophthalic anhydride (40 g, 0.24 mole), aluminum chloride (48 g, 0.36 mole) and heptylbenzene (400 ml) is heated (90° C. for 90 minutes). The reaction mixture is poured into a mixture of ice water (800 ml) and concentrated hydrochloric acid (200 g) and stirred overnight. The product is extracted with ether (3×300 ml). The extracts are combined, dried over magnesium sulfate, filtered and evaporated. The residue is crystallized from heptane to provide 2-(4-n-heptylphenacyl)benzoic acid (10.4 g) as a white crystalline solid, m.p. 128°-131° C.
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH:13][CH2:14][CH:15]([CH2:17][OH:18])[OH:16].C1C=CC=CC=1.[F:25][C:26]1[CH:27]=[C:28]([N:39]2[CH2:43][C@H:42]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:41][C:40]2=[O:49])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:37][CH2:36][C:35](=O)[CH2:34][CH2:33]1>O>[F:25][C:26]1[CH:27]=[C:28]([N:39]2[CH2:43][C@H:42]([CH2:44][NH:45][C:46](=[O:48])[CH3:47])[O:41][C:40]2=[O:49])[CH:29]=[CH:30][C:31]=1[N:32]1[CH2:33][CH2:34][C:35]2([O:16][CH:15]([CH2:17][OH:18])[CH2:14][O:13]2)[CH2:36][CH2:37]1
Reactant: OCC(O)CO
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC(=O)CC3)c(F)c2)C(=O)O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)OCC(CO)O4)c(F)c2)C(=O)O1
Temperature: 25 °C
Yield: 84 %

Procedure:
Para-toluenesulfonic acid monohydrate (299 mg) and glycerol (0.21 ml) were added successively to a benzene suspension (10 ml) of 500 mg of the (S)-N-{3-[3-fluoro-4-(4-oxo-piperidin-1-yl)-phenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (Compound No. 7) which was synthesized in Example 3, and the mixture was heated under reflux for 4 h, with water being removed continuously by means of a water separator. After the reaction mixture was cooled to room temperature, a saturated aqueous sodium hydrogencarbonate solution was added and the mixture was stirred. Thereafter, the solution was extracted with methylene chloride and the organic layer was washed with water and brine and dried over anhydrous sodium sulfate. The solvent was evaporated under vacuum and the residue was purified by silica gel column chromatography (solvent: chloroform/methanol=50/1-25/1) to afford the title compound (510 mg) in a yield of 84%.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:29])[CH3:28])[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Cl[C:41]([O:43][CH2:44][CH3:45])=[O:42]>C(Cl)(Cl)Cl>[CH2:1]([O:8][C:9](=[O:30])[C@H:10]([CH:27]([CH3:28])[CH3:29])[N:11]([C:41]([O:43][CH2:44][CH3:45])=[O:42])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[C:25]#[N:26])=[CH:17][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OCc1ccccc1
Reactant: CCOC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)N(Cc1ccc(-c2ccccc2C#N)cc1)[C@H](C(=O)OCc1ccccc1)C(C)C

Procedure:
10.0 g of N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-valine benzyl ester are dissolved in 150 ml of chloroform and treated with 8.2 ml of diisopropylethylamine at 0°. 2.4 ml of ethyl chloroformate are added and the mixture is heated to reflux for 3 hours. The reaction mixture is washed with 0.1M hydrochloric acid and brine, dried and concentrated. Amorphous product. TLC (system N3) Rf : 0.45.
Reaction SMILES: Cl.[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:39]([O:41][CH2:42][CH3:43])=[O:40]>ClCCl.C(O)C>[C:2]1([N:8]([CH2:32][CH2:33][C:34]([O:36][CH3:37])=[O:35])[C:9]([C:11]2[CH:31]=[CH:30][C:14]3[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]4[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:39]([O:41][CH2:42][CH3:43])=[O:40])=[CH:22][CH:21]=4)=[N:17][C:13]=3[CH:12]=2)=[O:10])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: COC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OC)c4ccccc4)ccc3n2C)cc1
Yield: 62 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-phenyl-N-(2-methoxycarbonylethyl)-amide-hydrochloride and ethyl chloroformate. Yield: 62% of theory, C30H32N6O5 (556.6) Rf value: 0.51 (silica gel; dichloromethane/ethanol=19:1) ##EQU63##
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[C:4]([O:39][CH3:40])[CH:3]=1.C(N(CC)CC)C.[C:48](Cl)(=[O:50])[CH3:49]>C1COCC1>[C:48]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([CH:11]2[NH:15][CH:14]([CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])[C:13]3([C:28]4[C:23](=[CH:24][C:25]([Cl:29])=[CH:26][CH:27]=4)[NH:22][C:21]3=[O:30])[CH:12]2[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[C:32]=2[F:38])=[O:10])=[C:4]([O:39][CH3:40])[CH:3]=1)(=[O:50])[CH3:49]
Reactant: CC(=O)Cl
Reactant: COc1cc(N)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cc(NC(C)=O)ccc1NC(=O)C1NC(CC(C)(C)C)C2(C(=O)Nc3cc(Cl)ccc32)C1c1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-amino-2-methoxy-phenyl)-amide (17 mg, 0.029 mmol) and triethylamine (4 mg, 0.044 mmol) in THF (2 mL) was acetyl chloride (2.3 mg, 0.029 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated. The residue was partitioned between ethyl acetate and water. The organic layer, was separated, and aqueous layer was extracted with ethyl acetate. The combined organic extract was washed with water, brine, dried over MgSO4, and concentrated to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetylamino-2-methoxy-phenyl)-amide as a off white solid (17 mg, 93%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=1.ClC1N=CC(OC2CCN(C)CC2)=CN=1.[F:30][C:31]1([F:77])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([O:47]CC4C=CC(OC)=CC=4)[CH2:44][C:43]([CH3:58])([CH3:57])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:75])([F:74])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1>>[F:77][C:31]1([F:30])[CH2:36][CH2:35][CH:34]([C:37]2[C:46]3[CH:45]([OH:47])[CH2:44][C:43]([CH3:57])([CH3:58])[CH2:42][C:41]=3[N:40]=[C:39]([CH:59]3[CH2:64][CH2:63][N:62]([C:2]4[N:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([F:14])([F:13])[F:12])=[CH:4][N:3]=4)[CH2:61][CH2:60]3)[C:38]=2[CH:65]([F:76])[C:66]2[CH:71]=[CH:70][C:69]([C:72]([F:74])([F:75])[F:73])=[CH:68][CH:67]=2)[CH2:33][CH2:32]1
Reactant: FC(F)(F)CCOc1cnc(Cl)nc1
Reactant: COc1ccc(COC2CC(C)(C)Cc3nc(C4CCNCC4)c(C(F)c4ccc(C(F)(F)F)cc4)c(C4CCC(F)(F)CC4)c32)cc1
Agent: CN1CCC(Oc2cnc(Cl)nc2)CC1
Product: CC1(C)Cc2nc(C3CCN(c4ncc(OCCC(F)(F)F)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1

Procedure:
Reactions similar to those of Reference Example 29 and Example 38 were performed except for using 2-chloro-5-(3,3,3-trifluoropropoxy) pyrimidine, which was prepared by a method similar to that of Reference Example 31, instead of 2-chloro-5-[(1-methylpiperidin-4-yl)oxy]pyrimidine, and from 150 mg (222 μmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-5-[(4-methoxybenzyl)oxy]-7,7-dimethyl-2-(piperidin-4-yl)-5,6,7,8-tetrahydroquinoline, which was prepared by a method similar to that of Reference Example 10, 85 mg of the title compound was obtained as a white solid (yield: 51%).
Reaction SMILES: Cl.[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]=[C:21]([S:22][CH3:23])[N:16]3[CH:15]=2)[CH2:11][C@@H:10]([O:24][Si](C(C)(C)C)(C)C)[CH2:9]1)=[O:7])[CH:3]=[CH2:4].C(=O)([O-])O.[Na+].C(OCC)(=O)C>C(#N)C>[CH2:2]([O:5][C:6]([N:8]1[C@H:12]([CH2:13][C:14]2[S:18][C:17]3=[CH:19][N:20]=[C:21]([S:22][CH3:23])[N:16]3[CH:15]=2)[CH2:11][C@@H:10]([OH:24])[CH2:9]1)=[O:7])[CH:3]=[CH2:4]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1Cc1cn2c(SC)ncc2s1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1Cc1cn2c(SC)ncc2s1
Reaction time: 0.5 h
Yield: 99.5 %

Procedure:
Concentrated hydrochloric acid (1.3 ml) is added to a solution of 1.37 g of (3R,5S)-1-allyloxycarbonyl-3-t-butyldimethylsilyloxy-5-(5-methylthioimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine in 15 ml of acetonitrile under ice cooling, and the mixture is stirred for 30 min. The reaction mixture is neutralized with a saturated sodium hydrogencarbonate solution, and ethyl acetate is added, followed by extraction three times. The extract is washed three times with semi-saturated saline and dried over magnesium sulfate. The solvent is removed by evaporation to give 1.03 g of (3R,5S)-1-allyloxycarbonyl-3-hydroxy-5-(5-methylthioimidazo[5,1-b]thiazol-2-yl)methylpyrrolidine. This compound is dissolved in 18 ml of THF, 1.53 g of triphenylphosphine and 0.92 ml of diethyl azodicarboxylate are added thereto at −17° C., and the mixture is stirred for 30 min. Further, 0.7 ml of thiobenzoic acid is added thereto, and the mixture is stirred at about −20° C. for 40 min. The solvent is removed by evaporation, and the residue is purified by column chromatography on Sephadex LH-20 (dichloromethane:methanol=1:1) to give 1.06 g of the title compound as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH:12]=[CH:11][N:10]=[CH:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1.[H][H]>FC(F)(F)C(O)=O.[Pt]=O>[CH3:1][C:2]1[N:3]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:4]2[C:13]3[CH2:12][CH2:11][NH:10][CH2:9][C:8]=3[N:7]=[C:6]([NH2:14])[C:5]=2[N:15]=1
Reactant: Cc1nc2c(N)nc3cnccc3c2n1CC(C)C
Reactant: [H][H]
Agent: O=[Pt]
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c(N)nc3c(c2n1CC(C)C)CCNC3

Procedure:
A catalytic amount of platinum oxide was added to a solution of 2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine (0.1 g, 0.4 mol) in trifluoroacetic acid. The reaction mixture was reduced on a Parr apparatus at 50 psi (3.5 Kg/cm2) hydrogen pressure overnight. The reaction mixture was filtered and washed with methanol to remove the catalyst, and the filtrate was concentrated under vacuum. The residue was combined with dichloromethane and aqueous sodium bicarbonate was added until the mixture was basic. The dichloromethane layer was separated, and the aqueous layer was extracted three times with dichloromethane (100 mL). The combined dichloromethane extracts were dried over magnesium sulfate and concentrated under vacuum. The resulting residue was recrystallized from toluene to provide 6,7,8,9-tetrahydro-2-methyl-1-(2-methylpropyl)-1H-imidazo[4,5-c][1,7]naphthyridin-4-amine as a solid, m.p. 226-230° C. Analysis: Calculated for C14H21N5+1.75H2O: % C, 57.81; % H, 8.49; % N, 24.07; Found: % C, 57.89; % H, 8.04; % N, 23.45.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH3:7])[C:3]=1[C:8]#[N:9].CN(C)[CH:12]=[CH:13][C:14]([C:16]1[CH:17]=[CH:18][C:19]([Cl:27])=[C:20]([N:22]([CH3:26])[C:23](=[O:25])[CH3:24])[CH:21]=1)=O.C(OCC)(=O)C>C(O)(=O)C>[Cl:27][C:19]1[CH:18]=[CH:17][C:16]([C:14]2[N:6]3[N:5]=[C:4]([CH3:7])[C:3]([C:8]#[N:9])=[C:2]3[N:1]=[CH:12][CH:13]=2)=[CH:21][C:20]=1[N:22]([CH3:26])[C:23](=[O:25])[CH3:24]
Reactant: Cc1n[nH]c(N)c1C#N
Reactant: CC(=O)N(C)c1cc(C(=O)C=CN(C)C)ccc1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(=O)N(C)c1cc(-c2ccnc3c(C#N)c(C)nn23)ccc1Cl
Yield: 72.6 %

Procedure:
A mixture of 0.055 g (0.43 mmol) of 5-amino-3-methyl-1H-pyrazole-4-carbonitrile and 0.120 g (0.43 mmol) of N-[5-(3-dimethylamino-acryloyl)-2-chloro-phenyl]-N-methyl-acetamide in 12 mL of glacial acetic acid was refluxed for 1.5 hours and then the solvent was removed by reduced pressure distillation. To the resulting residue were added 15 mL of dichloromethane and 10 mL of saturated sodium bicarbonate solution. The two layers were separated, and the aqueous layer was washed with 10 mL of dichloromethane. The organic layers were washed with 10 mL of water and dried over magnesium sulfate. The dichloromethane layer was evaporated to dryness to yield an oil which, in the presence of ethyl acetate, gave 106 mg of N-{2-chloro-5-[3-cyano-2-methyl-pyrazolo[1,5-a]pyrimidin-7-yl]-phenyl}-N-methyl-acetamide as a solid (yield 73%).
Reaction SMILES: ClC1C=C(C[CH2:9][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH2:32]([S:39]CC(O)=O)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH2:32]([S:39][CH2:9][CH2:10][N:11]([C@H:25]1[CH2:26][CH2:27][C@H:28]([CH3:31])[CH2:29][CH2:30]1)[C:12](=[O:24])[NH:13][C:14]1[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Reactant: O=C(O)CSCc1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: C[C@H]1CC[C@H](N(CCSCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl-cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using benzylsulfanyl-acetic acid and (2-aminothiazol-5-ylsulfanyl)acetic acid ethyl ester.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([O:20]COC)=[CH:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1.Cl.O>C(O)(C)C>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][N:15]3[CH:24]=2)=[CH:8][CH:7]=1
Reactant: COCOc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: Oc1ccc2nc(-c3ccc(OCCCF)cc3)cn2c1
Yield: 47.1 %

Procedure:
1.18 g (corresponding to 3.57 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-methoxymethoxyimidazo[1,2-a]pyridine was dissolved in 29 mL of isopropyl alcohol, and 0.59 mL of conc. hydrochloric acid was added thereto. Then, the mixture was refluxed for 23 hours. After the reaction solution was cooled, the solution was poured into water, and extracted twice by a salting-out extraction procedure using chloroform with addition of sodium chloride. The combined chloroform layer was dried over anhydrous magnesium sulfate. The resulting crude product was purified by silica gel column chromatography (elution solvent: chloroform/methanol=10/1), to obtain 481 mg (corresponding to 1.68 mmol) of 2-[4′-(3″-fluoropropoxy)phenyl]-6-hydroxyimidazo[1,2-a]pyridine (hereinafter referred to as Compound 2) (FIG. 3, Step 10).