Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:6]([CH2:9][OH:10])[CH2:7][OH:8])[CH2:2][CH2:3][CH2:4][CH3:5].[Br:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=1[F:21].CC1C=CC(S(O)(=O)=O)=CC=1>ClCCl>[Br:11][C:12]1[C:19]([F:20])=[CH:18][C:15]([CH:16]2[O:10][CH2:9][CH:6]([CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH2:7][O:8]2)=[CH:14][C:13]=1[F:21]
Reactant: O=Cc1cc(F)c(Br)c(F)c1
Reactant: CCCCCC(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: CCCCCC1COC(c2cc(F)c(Br)c(F)c2)OC1
Yield: 35.3 %

Procedure:
10.8 g (0.074 mol) of 2-pentylpropane-1,3-diol, 16.3 g of 4-bromo-3,5-difluorobenzaldehyde and 0.7 g of TsOH were dissolved in 74 cm3 of dichloromethane, and was refluxed for 3 hours on a hot water bath with a Dean-Stark trap applied to remove the water formed. The reactant was washed in water, the dichloromethane was removed, and the residue was recrystallized from a mixture of acetone and methanol to obtain 9.1 g (0.026 mol) of 2-(4'-bromo-3',5'-difluorophenyl)-5-pentyl-1,3-dioxane.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=3)[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH:17][CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:12]=3)=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH:18]1([NH:17][C:13]2[N:12]=[C:11]([C:10]3[C:9]([C:23]4[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=4)=[N:8][N:7]4[C:2]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[CH:3][CH:4]=[CH:5][C:6]=34)[CH:16]=[CH:15][N:14]=2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COCCN
Reactant: COc1ccc(-c2nn3c(Cl)cccc3c2-c2ccnc(NC3CCCC3)n2)cc1
Product: COCCNc1cccc2c(-c3ccnc(NC4CCCC4)n3)c(-c3ccc(OC)cc3)nn12
Temperature: 90 °C
Yield: 97.4 %

Procedure:
A mixture of 4-[7-chloro-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-3-yl]-N-cyclopentyl-2-pyrimidinamine (75 mg, 0.18 mmol) and 2-methoxyethylamine (5 mL, 58 mmol) was heated at 90° C. for 72 hours, then cooled and concentrated. Flash chromatography (1:1 to 1:3 hexanes-ethyl acetate) provided 3-[2-(cyclopentylamino)-4-pyrimidinyl]-N-(2-methoxyethyl)-2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridin-7-amine (80.4 mg, 98%) as an off-white solid. 1H NMR (CDCl3): δ 7.98 (d, 1 H), 7.81 (d, 1 H), 7.59 (d, 2 H), 7.31 (t, 1 H), 6.99 (d, 2 H), 6.35–6.29 (m, 2 H), 6.03 (d, 1 H), 5.15 (broad, 1 H), 4.38 (m, 1 H), 3.89 (s, 3 H), 3.72 (t, 2 H), 3.57 (q, 2 H), 3.43 (s, 3 H), 2.09 (m, 2 H), 1.80–1.53 (m, 6 H); MS m/z 459 (M+1).
Reaction SMILES: [OH-].[Na+].C(O)C.[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([C:31]([O:33]C)=[O:32])[CH:26]=4)[CH2:17][CH2:16]3)=[CH:12][CH:13]=[CH:14][C:7]1=2.Cl>ClCCl>[S:6]1[CH:10]=[CH:9][C:8]2[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH2:21][CH2:22][CH2:23][O:24][C:25]4[N:29]([CH3:30])[N:28]=[C:27]([C:31]([OH:33])=[O:32])[CH:26]=4)[CH2:19][CH2:20]3)=[CH:12][CH:13]=[CH:14][C:7]1=2
Reactant: COC(=O)c1cc(OCCCN2CCN(c3cccc4sccc34)CC2)n(C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: ClCCl
Product: Cn1nc(C(=O)O)cc1OCCCN1CCN(c2cccc3sccc23)CC1
Temperature: 25 °C
Reaction time: 96 h
Yield: 98 %

Procedure:
A 6N aqueous sodium hydroxide solution (2 ml) was added to an ethanol solution (10 ml) of methyl 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylate (1.62 g, 3.9 mmol) and the mixture was stirred at room temperature for 4 days. Then, 6N hydrochloric acid (2 ml) was added to the reaction solution under ice cooling and the solution mixture was stirred. Dichloromethane was added to the reaction solution and the precipitate was obtained by filtration. The filtrate was separated and the organic phase was concentrated under reduced pressure. The filter cake and the residue were combined, washed with water and dried to obtain 5-[3-(4-benzo[b]thiophen-4-yl-piperazin-1-yl)propoxy]-1-methyl-1H-pyrazole-3-carboxylic acid (1.53 g) as white powder.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:5]2[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]=2[O:3]1.[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=1>C(OCC)(=O)C>[F:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([NH:19][C:14]2[C:15]([CH3:18])=[C:16]([CH3:17])[C:4]3[O:3][C:2]([CH3:21])([CH3:1])[CH:6]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=4)[C:5]=3[C:13]=2[CH3:20])=[O:28])=[CH:25][CH:24]=1
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccccc1)C(C)(C)O2
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(F)cc1)C(c1ccccc1)C(C)(C)O2
Yield: 92 %

Procedure:
By using 2,2,4,6,7-pentamethyl-3-phenyl-2,3-dihydro-1-benzofuran-5-amine and 4-fluorobenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 92%. Melting point: 156-158° C. (Ethyl acetate)
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([C:22]#[N:23])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.Cl.[NH2:25][OH:26].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([C:22]([NH:25][OH:26])=[NH:23])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N=C(NO)c1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a mixture of 300 mg of (0.884 mmol) 8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-c]quinoline-2-carbonitrile (Example 84) and 245 mg (3.537 mmol) hydroxylamine hydrochloride in 7.5 ml DMF, a solution of 326 mg (3.08 mmol) sodium carbonate in 1.8 ml water is added by syringe within 2 min. The reaction mixture is heated at 70° C. for 4½ h. The cold solution is poured in ice-water and stirred for 1 h. The precipitate which is formed is filtered off and washed with water and ethanol. The compound is dried over night at 60° C. (high vacuum). mp: 265-267° C.; MS: 372 (M++1); HPLC: tret=80.43 min (Grad 1).
Reaction SMILES: C([O:3][C:4](=[O:31])[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:13]=2)[C:8]([NH:22][C:23]2[C:28]([CH3:29])=[CH:27][CH:26]=[CH:25][C:24]=2[CH3:30])=[N:7]1)C.[OH-].[Na+]>CO>[CH3:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([CH3:29])[C:23]=1[NH:22][C:8]1[C:9]2[C:14](=[CH:13][C:12]([NH:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:11][CH:10]=2)[N:6]([CH2:5][C:4]([OH:31])=[O:3])[N:7]=1
Reactant: CCOC(=O)Cn1nc(Nc2c(C)cccc2C)c2ccc(Nc3ccccc3)cc21
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cccc(C)c1Nc1nn(CC(=O)O)c2cc(Nc3ccccc3)ccc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 300 mg (0.72 mmol) of ethyl 2-(3-(2,6-dimethylphenylamino)-6-(phenylamino)-1H-indazol-1-yl)acetate 64 (Example 29) in MeOH (10 mL) was added 1 N NaOH solution (4 mL, 4 mmol). The mixture was stirred at room temperature for 8 hours before being concentrated under reduced pressure. The residue was extracted with DCM (5 mL×2) and neutralized with 3 N HCl solution to pH 2. The resulting yellow solid was filtered, washed with water and dried to give the title compound. 1H-NMR (DMSO-d6) δ 2.20 (s, 6H), 4.74 (s, 2H), 6.96 (t, J=7.2 Hz, 1H), 7.05-7.09 (m, 3H), 7.28 (t, J=7.7 Hz, 2H), 7.79 (d, J=7.9 Hz, 2H), 8.22 (s, 1H), 8.53 (s, 1H), 9.77 (s, 1H). Mass Spectrum (ESI) m/e=389 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[CH:30][C:6]([CH2:7][S:8][C@@H:9]2[CH2:13][N:12]([C:14]([O:16][CH2:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[O:15])[C@H:11]([C:27]([OH:29])=O)[CH2:10]2)=[CH:5][CH:4]=1.[OH:32][C@@H:33]([C@@H:43]([NH:51][C:52]([O:54][CH2:55][C:56]1[CH:61]=[CH:60][C:59]([N+:62]([O-:64])=[O:63])=[CH:58][CH:57]=1)=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:34][C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][NH:40][CH2:39]1)=[O:36]>O1CCCC1>[OH:32][C@@H:33]([C@@H:43]([NH:51][C:52]([O:54][CH2:55][C:56]1[CH:57]=[CH:58][C:59]([N+:62]([O-:64])=[O:63])=[CH:60][CH:61]=1)=[O:53])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:34][C:35]([NH:37][C@H:38]1[CH2:42][CH2:41][N:40]([C:27]([C@@H:11]2[CH2:10][C@H:9]([S:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:31][CH:30]=3)[CH2:13][N:12]2[C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])=[O:29])[CH2:39]1)=[O:36]
Reactant: O=C(C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccc([N+](=O)[O-])cc1)N[C@H]1CCNC1
Reactant: COc1ccc(CS[C@H]2C[C@@H](C(=O)O)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Solvent: C1CCOC1
Product: COc1ccc(CS[C@H]2C[C@@H](C(=O)N3CC[C@H](NC(=O)C[C@@H](O)[C@H](Cc4ccccc4)NC(=O)OCc4ccc([N+](=O)[O-])cc4)C3)N(C(=O)OCc3ccc([N+](=O)[O-])cc3)C2)cc1
Temperature: 30 °C
Reaction time: 0.5 h
Yield: 48.4 %

Procedure:
To a solution of (2S,4S)-4-(4-methoxybenzyl)thio-1-(4-nitrobenzyloxycarbonyl)-L-proline (2.23 g) in anhydrous tetrahydrofuran (50 ml), N,N'-carbonyldiimidazole (0.97 g) was added, followed by stirring at 30° C. for 30 minutes. To the reaction mixture, a solution of (3S)-3-[(3R,4S)-3-hydroxy-4-(4-nitrobenzyloxycarbonyl)amino-5-phenylpentanoylamino]pyrrolidine (2.28 g) in anhydrous tetrahydrofuran (50 ml) was added. The resulting mixture was treated in a similar manner to that described in Referential Example 18-(1), whereby 2.14 g of the title compound were obtained as a powder.
Reaction SMILES: [H-].[Na+].[CH2:3]([C:10]1[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=1[CH2:12][OH:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br.[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31]Br)[CH2:25]1)=[O:23])[CH3:20]>C1COCC1>[CH2:19]([O:21][C:22]([C@@H:24]1[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][CH2:31][O:13][CH2:12][C:11]2[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=2[CH2:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:25]1)=[O:23])[CH3:20]
Reactant: CCOC(=O)[C@@H]1CCCN(CCBr)C1
Reactant: OCc1ccccc1Cc1ccccc1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@@H]1CCCN(CCOCc2ccccc2Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 8.4 %

Procedure:
Sodium hydride (2.1 g, 53 mmol, 60% oil dispersion) was added portionwise to a stirred solution of 2-benzylbenzylalcohol (5.0 g, 25 mmol) in dry THF (125 ml) placed under an atmosphere of nitrogen. The mixture was heated at reflux for 1 h and then allowed to cool to ambient temperature within 30 minutes. (R)-1-(2-Bromoethyl)-3-piperidinecarboxylic acid ethyl ester hydrobromide (8.6 g, 25 mmol, EP 374801) was added and the mixture was stirred for 2 days at ambient temperature. The reaction mixture was diluted with THF (100 ml) and filtered. The solvent was evaporated in vacuo to give an oily residue which was purified by column chromatography (700 g, heptane/ethyl acetate=1/1) to give 0.8 g of (R)-1-(2-(2-benzylbenzyloxy)ethyl)-3-piperidinecarboxylic acid ethyl ester as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][NH:5][C:4]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14].[H-].[Na+].[C:20]([O:24][C:25]([N:27]1[CH2:31][CH2:30]OS1(=O)=O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>CN(C=O)C>[C:20]([O:24][C:25]([NH:27][CH2:31][CH2:30][N:5]1[CH:6]=[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:3]([O:2][CH3:1])=[C:4]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCOC(=O)c1c[nH]c(C(=O)OCC)c1OC
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(CCNC(=O)OC(C)(C)C)c(C(=O)OCC)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of diethyl 3-methoxy-1H-pyrrole-2,4-dicarboxylate (93 mmol) in DMF (340 ml) was added 60% NaH (140 mmol) in portions at 0° C. and the reaction mixture was stirred at 25° C. for 0.5 h. 2,2-Dioxo-[1,2,3]oxathiazolidine-3-carboxylic acid tert-butyl ester (93 mmol) was added at 0° C. and the mixture was allowed to warm to 25° C. and stirred for 21 h. The reaction was quenched with ethanol at 0° C. The solvent was evaporated under vacuum. Yield: 35 g (98% yield)
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[CH:12].[CH:13]1([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[C:23](I)[CH:22]=2)(=[O:20])=[O:19])[CH2:17][CH2:16][CH2:15][CH2:14]1>CC#N.C(N(CC)CC)C.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH2:9][CH2:10][C:11]#[C:12][C:23]1[CH:24]=[CH:25][CH:26]=[C:21]([S:18]([CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)(=[O:20])=[O:19])[CH:22]=1
Reactant: O=S(=O)(c1cccc(I)c1)C1CCCC1
Reactant: C#CCCOCCCCCCBr
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=S(=O)(c1cccc(C#CCCOCCCCCCBr)c1)C1CCCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 4-[(6-bromohexyl)oxy]-1-butyne (DE 3513885 A1) (288.9 mg) and 1-(cyclopentylsulfonyl)-3-iodobenzene (500 mg) in MeCN (20 ml) and triethylamine (345 μl) was treated with copper iodide (11.78 mg) and dichlorobis(triphenylphosphine)palladium(II) (43.4 mg) and stirred at room temperature for 3 h. The reaction mixture was partitioned between EtOAc and water, the organic phase was dried (MgSO4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE bond elut, gradient 0 to 40% diethyl ether in cyclohexane) to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[CH:20]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)[OH:21])=[CH:4][CH:3]=1>ClCCl.[O-2].[O-2].[Mn+4]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([S:16]([CH3:19])(=[O:17])=[O:18])=[CH:13][CH:14]=3)[CH:9]=[C:8]2[C:20]([C:22]2[S:23][CH:24]=[CH:25][N:26]=2)=[O:21])=[CH:27][CH:28]=1
Reactant: CS(=O)(=O)c1ccc2c(c1)cc(C(O)c1nccs1)n2Cc1ccc(F)cc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc2c(c1)cc(C(=O)c1nccs1)n2Cc1ccc(F)cc1
Reaction time: 0.5 h
Yield: 45.7 %

Procedure:
To a solution of the compound obtained in Example 27 (5) (110 mg) in dichloromethane (20 ml), manganese dioxide (900 mg) was added at 15 to 30° C. and the mixture was stirred for 30 minutes. The reaction solution was then filtered through Celite and concentrated under reduced pressure. The resulting residue was subjected to silica gel preparative thin-layer chromatography (hexane:ethyl acetate=1:1) to obtain 50 mg of the desired products as a yellow powder.
Reaction SMILES: [N:1]1([C:7]2[N:8]=[C:9]([CH2:14][C:15]([O-:17])=O)[NH:10][C:11](=[O:13])[CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Na+].[CH:19]1([O:24][C:25]2[CH:26]=[C:27]([CH:29]=[CH:30][CH:31]=2)[NH2:28])[CH2:23][CH2:22][CH2:21][CH2:20]1>>[CH:19]1([O:24][C:25]2[CH:26]=[C:27]([NH:28][C:15](=[O:17])[CH2:14][C:9]3[NH:10][C:11](=[O:13])[CH:12]=[C:7]([N:1]4[CH2:2][CH2:3][O:4][CH2:5][CH2:6]4)[N:8]=3)[CH:29]=[CH:30][CH:31]=2)[CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: Nc1cccc(OC2CCCC2)c1
Reactant: O=C([O-])Cc1nc(N2CCOCC2)cc(=O)[nH]1
Agent: [Na+]
Product: O=C(Cc1nc(N2CCOCC2)cc(=O)[nH]1)Nc1cccc(OC2CCCC2)c1
Yield: 67.8 %

Procedure:
The product is prepared according to the procedure described in Example 5, using 260 mg of sodium [4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate and 354 mg of 3-(cyclopentyloxy)aniline in place of the 2,4-difluoroaniline. 269 mg of N-[3-(cyclopentyloxy)phenyl]-2-[4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24]C1C=CC(C(F)(F)F)=CN=1.Cl[C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][N:37]=1>>[CH3:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[C:17]2[CH:18]=[N:19][N:20]([CH3:22])[CH:21]=2)=[O:9])[C@@H:3]1[CH2:23][NH:24][C:36]1[C:41]([C:42]([F:45])([F:44])[F:43])=[CH:40][CH:39]=[CH:38][N:37]=1
Reactant: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ccc(C(F)(F)F)cn2)c1
Reactant: FC(F)(F)c1cccnc1Cl
Product: Cc1ccc(-c2cnn(C)c2)c(C(=O)N2CCC[C@@H](C)[C@H]2CNc2ncccc2C(F)(F)F)c1

Procedure:
The title compound was synthesized following the same general protocol as described for ((2S,3R)-3-methyl-2-(((5-(trifluoromethyl)pyridin-2-yl)amino)methyl)piperidin-1-yl)(5-methyl-2-(1-methyl-1H-pyrazol-4-yl)phenyl)methanone in Example A1, using 2-chloro-3-(trifluoromethyl)pyridine. ESI-MS (m/z): 472 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=O)([O-:3])=[O:2].[CH2:12]([O:14][CH:15]([O:24][CH2:25][CH3:26])[C:16](=[O:23])[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH3:13].N1CCCCC1>C1C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH:7]=[C:17]([C:16]([CH:15]([O:14][CH2:12][CH3:13])[O:24][CH2:25][CH3:26])=[O:23])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([O-:3])=[O:2]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)CC(=O)C(OCC)OCC
Solvent: c1ccccc1
Solvent: C1CCNCC1
Product: CCOC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(=O)C(OCC)OCC
Yield: 113.7 %

Procedure:
A solution of 3-nitrobenzaldehyde (2.27 g), ethyl 4,4-diethoxyacetoacetate (3.28 g) and piperidine (0.2 ml) in benzene (15 ml) was refluxed under azeotropic dehydration for 3 hours. The resultant solution was washed three times with water and dried over magnesium sulfate. The solvent was removed from the reaction solution to give oily ethyl 2-(3-nitrobenzylidene)-4,4-diethoxyacetoacetate (6.0 g). The mixture of the compound obtained above and ethyl 3-aminocrotonate (1.94 g) was heated at about 95° to 100° C. for 7 hours and then at about 120° C. for 1.5 hours with stirring. After cooling, the resultant oil was extracted with ethyl acetate and the extract was washed with water and dried. The solvent was removed from the resultant solution to give an oil (7.8 g). The product was purified by column chromatography on silica gel with an eluent (benzene:ethyl acetate=20:1) to give the pure product of diethyl 2-methyl-4-(3-nitrophenyl)-6 -diethoxymethyl-1,4-dihydropyridine-3,5-dicarboxylate (4.65 g).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:8][C:9]=1[N:10]([CH:19]([CH3:21])[CH3:20])[C:11]([CH:13]1[CH2:17][CH:16]=[C:15]([CH3:18])[CH2:14]1)=[O:12])=[O:4].O[Li].O>>[CH:19]([N:10]([C:11]([CH:13]1[CH2:17][CH:16]=[C:15]([CH3:18])[CH2:14]1)=[O:12])[C:9]1[CH:8]=[C:7]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[S:6][C:5]=1[C:3]([OH:4])=[O:2])([CH3:21])[CH3:20]
Reactant: COC(=O)c1sc(-c2ccccc2)cc1N(C(=O)C1CC=C(C)C1)C(C)C
Agent: [Li]O
Solvent: O
Product: CC1=CCC(C(=O)N(c2cc(-c3ccccc3)sc2C(=O)O)C(C)C)C1
Yield: 62.5 %

Procedure:
Saponification of 3-[Isopropyl-(3-methyl-cyclopent-3-enecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid methyl ester (50 mg, 0.13 mmol) using LiOH.H2O (22 mg) as previously described furnished the 3-[Isopropyl-(3-methyl-cyclopent-3-enecarbonyl)-amino]-5-phenyl-thiophene-2-carboxylic acid (30 mg, 62.5% yield) as a solid.
Reaction SMILES: [N+:1]1([O-])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[C:2]=1[C:15]([O:17][CH3:18])=[O:16].P(Cl)(Cl)Cl>C(Cl)(Cl)Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[C:2]=1[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc2ccccc2[n+]([O-])c1C(=O)OC
Solvent: ClP(Cl)Cl
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc2ccccc2nc1C(=O)OC

Procedure:
A solution of N-oxide 3 (10 mM) and phosphorus trichloride (30 mM) in anhydrous chloroform (100 ml) was refluxed for 7 h. Solvent was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layer was dried over sodium sulphate and then evaporated under reduced pressure. The residue was recrystallized from isopropanol to provide the title dimethyl quinoline-2,3-dicarboxylate 7 as an off white (or light yellow) powder.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:13]([OH:15])=O)[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:16][NH:17][C@H:18]1[CH2:37][N:22]2[C:23]3[C:28]([C:29]([CH2:30][C:31]([O:33]CCC)=[O:32])=[C:21]2[CH2:20][CH2:19]1)=[CH:27][CH:26]=[CH:25][CH:24]=3>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:13]([N:17]([CH3:16])[C@H:18]3[CH2:37][N:22]4[C:23]5[C:28]([C:29]([CH2:30][C:31]([OH:33])=[O:32])=[C:21]4[CH2:20][CH2:19]3)=[CH:27][CH:26]=[CH:25][CH:24]=5)=[O:15])[CH2:9][CH2:10][CH2:11][CH2:12]2)=[CH:6][CH:7]=1
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)C[C@H](NC)CC2
Reactant: O=C(O)C1(c2ccc(F)cc2)CCCC1
Product: CN(C(=O)C1(c2ccc(F)cc2)CCCC1)[C@@H]1CCc2c(CC(=O)O)c3ccccc3n2C1

Procedure:
The title compound was prepared using analogous procedures described in Example 1 (Method A) from 1-(4-fluorophenyl)cyclopentanecarboxylic acid and propyl [(7R)-7-(methylamino)-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl]acetate. MS (+ESI) m/z: 449.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:20]([C:21]([NH2:23])=[O:22])=[CH:19][N:18]=[C:17]3[N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[CH:25]=[CH:26][C:16]=23)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36].[Cl-].[Na+]>CN(C)C(=O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:15]3[C:16]4[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:17]=4[N:18]=[CH:19][C:20]=3[C:21](=[O:22])[NH:23][C:35]2=[O:36])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Si](C)(C)CCOCn1ccc2c(NC3CCN(Cc4ccccc4)CC3)c(C(N)=O)cnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: C[Si](C)(C)CCOCn1ccc2c1ncc1c(=O)[nH]c(=O)n(C3CCN(Cc4ccccc4)CC3)c12
Temperature: 25 °C
Yield: 70.5 %

Procedure:
4-[(1-Benzylpiperidin-4-yl)amino]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridine-5-carboxamide (484 mg, 1.01 mmol) in N,N-dimethylacetamide (5 mL) was stirred with 1,1′-carbonyldiimidazole (486 mg, 3.00 mmol) at 120° C. for 3 hours. The reaction mixture was allowed to cool to room temperature and, after addition of saturated aqueous sodium chloride, extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=20/1 (v/v)) to give the title compound as a colorless solid (360 mg, yield 70%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]([NH2:18])=[S:17])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.Br[CH:20]1[CH2:25][CH2:24][CH2:23][CH:22]([C:26]2[CH:31]=[C:30]([F:32])[CH:29]=[C:28]([F:33])[CH:27]=2)[C:21]1=O>C(O)C>[F:32][C:30]1[CH:31]=[C:26]([CH:22]2[C:21]3[N:18]=[C:16]([NH:15][C:5]4[CH:6]=[CH:7][C:8]([N:9]5[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]5)=[C:3]([O:2][CH3:1])[CH:4]=4)[S:17][C:20]=3[CH2:25][CH2:24][CH2:23]2)[CH:27]=[C:28]([F:33])[CH:29]=1
Reactant: O=C1C(Br)CCCC1c1cc(F)cc(F)c1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(C)c1
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2cc(F)cc(F)c2)ccc1-n1cnc(C)c1
Temperature: 25 °C
Yield: 34 %

Procedure:
A suspension of [3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (68 mg, 0.26 mmol) and of crude 2-bromo-6-(3,5-difluoro-phenyl)-cyclohexanone (78 mg, 0.27 mmol) in ethanol (2 mL) was heated to reflux under an atmosphere of nitrogen for 2 days. After cooling to room temperature the solvent was evaporated under reduced pressure and the residue was purified by reversed preparative HPLC using acetonitril/water (0.1% formic acid) to yield the title compound (40 mg, 34%) as a yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm)=7.70 (s, 1H), 7.41 (s, 1H), 7.10 (d, 1H), 6.85 (s, 1H), 6.67-6.73 (m, 4H), 4.03 (m, 1H), 3.62 (s, 3H), 2.75 (m, 2H), 2.31 (s, 3H), 2.22 (m, 1H), 1.84 (m, 3H).