Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([O:13][CH2:14][C@H:15]2[CH2:19][CH2:18][CH2:17][N:16]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)#[N:2].CN1C(=O)CCC1.[NH:34]([C:36](OCC)=[O:37])[NH2:35]>CCOC(C)=O>[O:37]=[C:36]1[NH:34][N:35]=[C:1]([C:3]2[N:4]=[C:5]([O:13][CH2:14][C@H:15]3[CH2:19][CH2:18][CH2:17][N:16]3[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:6]3[C:11]([CH:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[NH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(C#N)cc2ccccc12
Reactant: CCOC(=O)NN
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1nc(-c2n[nH]c(=O)[nH]2)cc2ccccc12
Temperature: 175 °C

Procedure:
To a crude reaction mixture containing (R)-tert-butyl 2-(((3-cyanoisoquinolin-1-yl)oxy)methyl)pyrrolidine-1-carboxylate (0.749 g) was added NMP (2 mL) and ethyl hydrazinecarboxylate (0.883 g, 8.48 mmol). The reaction mixture was heated at 175° C. overnight and was subsequently cooled, diluted with EtOAc, and washed with saturated aqueous NH4Cl followed by water. The organic layer was separated and concentrated to give the title compound, which was used without further purification.
Reaction SMILES: C([NH:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH:13]1[CH2:15][CH2:14]1)(=O)C.[ClH:16]>C(O)C.O>[ClH:16].[NH2:4][C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[CH:7][C:6]=1[CH:13]1[CH2:14][CH2:15]1
Reactant: CC(=O)Nc1ccc(C#N)cc1C1CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: N#Cc1ccc(N)c(C2CC2)c1
Reaction time: 12 h

Procedure:
A mixture of 2.39 g of the product of step A dissolved in 45 ml of ethanol with 36 ml of water and 5 ml of concentrated HCl is stirred for 12 hours under reflux. The ethanol is evaporated off under vacuum, and the precipitate is filtered off, washed with 1 ml of water and dried under vacuum to obtain 1.5 g of the expected product.
Reaction SMILES: C([O:4][C@H:5]([CH2:10]Br)[CH2:6][C:7]([OH:9])=[O:8])(=O)C.[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13]>O>[CH2:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:13].[O:4]1[CH2:10][C@@H:5]1[CH2:6][C:7]([OH:9])=[O:8]
Reactant: CC(=O)O[C@H](CBr)CC(=O)O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(O)C[C@H]1CO1
Reaction time: 2 h

Procedure:
To a 2 l of three-necked flask equipped with thermometer, pH meter and mechanical stirrer were charged distilled water (1 l), (S)-3-acetoxy-4-bromobutyric acid (90 g, 0.4 mol) and triethylamine (12 g, 1.2 mol). The reaction mixture was stirred at 0˜5° C. for 2 hours to afford (S)-3,4-epoxybutyric acid triethylamine salt. Over 99% of conversion was detected by NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:61]=[CH:60][C:5]([O:6][CH2:7][C:8]2[N:9]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][N:37](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[CH2:36]3)[C:10]3[C:15]([C:16]=2[C:17](=[O:31])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([N:25]4[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]4)[CH2:21][CH2:20]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:4][CH:3]=1.C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]2[N:9]([CH2:32][CH2:33][CH2:34][CH:35]3[CH2:40][CH2:39][CH2:38][NH:37][CH2:36]3)[C:10]3[C:15]([C:16]=2[C:17](=[O:31])[CH2:18][N:19]2[CH2:24][CH2:23][CH:22]([N:25]4[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]4)[CH2:21][CH2:20]2)=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:60][CH:61]=1
Reactant: O=C(CN1CCC(N2CCCCC2)CC1)c1c(COc2ccc(Cl)cc2)n(CCCC2CCCN(C(c3ccccc3)(c3ccccc3)c3ccccc3)C2)c2ccccc12
Solvent: O=CO
Solvent: ClCCl
Product: O=C(CN1CCC(N2CCCCC2)CC1)c1c(COc2ccc(Cl)cc2)n(CCCC2CCCNC2)c2ccccc12
Reaction time: 1 h

Procedure:
Under an argon atmosphere (RS) 2-[(4-chlorophenoxy)methyl]-1-[3-(1-tritylpiperidin-3-yl)propyl]-3-[[4-(piperidin-1-yl)piperidin-1-yl]acetyl]-1H-indole (0.0162 g, 0.0194 mmol) was dissolved in 0.2 ml methylene chloride. The reaction vessel was then placed in an ice bath and formic acid (0.073 ml, 0.194 mmol) was slowly added. The resulting mixture was stirred for about one hour over ice. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for two additional hours and then an additional 5.0 equivalents of formic acid were added, followed by stirring at room temperature.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[CH:6][N:7]([CH:9]2[CH2:12][CH:11]([OH:13])[CH2:10]2)[CH:8]=1)([O-:3])=[O:2].CCN(CC)CC.[C:21]1([CH3:31])[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1>C(Cl)Cl>[N+:1]([C:4]1[N:5]=[CH:6][N:7]([C@H:9]2[CH2:10][C@H:11]([O:13][S:27]([C:24]3[CH:25]=[CH:26][C:21]([CH3:31])=[CH:22][CH:23]=3)(=[O:29])=[O:28])[CH2:12]2)[CH:8]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cn(C2CC(O)C2)cn1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](n3cnc([N+](=O)[O-])c3)C2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-(4-nitro-imidazol-1-yl)-cyclobutanol (Preparation 4, Step 1; 4 g, 22 mmol) was treated with Et3N (7.7 mL, 55 mmol) in methylene chloride (150 mL) followed by p-toluenesulfonyl chloride (TsCl) (5 g, 26.4 mmol) and 4-N,N-dimethylaminopyridine (DMAP) (268 mg, 2.2 mmol). The resulting mixture was stirred at room temperature for 24 h. Analysis by thin layer chromatography showed two new spots. The reaction mixture was diluted with methylene chloride and was washed with water (1×) and brine (1×). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. Purification by silica gel chromatography (1:1 to 2:1 hexanes-ethyl acetate) allowed for separation of the trans and cis diastereomers. The first spot to elute (high Rf) was the trans-isomer, trans-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.7 g, 37% yield); 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.77 (m, 2H), 7.44 (d, J=1.7 Hz, 1H), 7.36 (dd, J=0.5, 8.0 Hz, 2H), 5.034 (m, 1H), 4.94 (m, 1H), 2.9 (m, 2H), 2.7 (m, 2H); MS (AP/CI): 338.1 (M+H)+. The second spot to elute was the cis-isomer, cis-toluene-4-sulfonic acid 3-(4-nitro-imidazol-1-yl)-cyclobutyl ester (2.9 g, 39% yield); 1H NMR (400 MHz, CDCl3) δ 7.8 (m, 3H), 7.43 (d, J=1.4 Hz, 1H), 7.36 (dd, J=0.6, 8.5 Hz, 2H), 4.74 (m, 1H), 4.30 (m, 1H), 3.05 (m, 2H), 2.6–2.5 (m, 2H), 2.45 (s, 3H); MS (AP/CI): 338.1 (M+H)+. Relative configurations were determined by the measurement of nuclear Overhauser effects.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[CH2:8]([O:15][C@@H:16]1[C@@H:29]([OH:30])[C@@H:28]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C@@H:27]([CH2:39][OH:40])[O:26][C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CO>N1C=CC=CC=1>[CH2:8]([O:15][C@@H:16]1[C@@H:29]([OH:30])[C@@H:28]([O:31][CH2:32][C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[C@@H:27]([CH2:39][O:40][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])[O:26][C@H:17]1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)C(=O)OC[C@H]1O[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](O)[C@H]1OCc1ccccc1
Reaction time: 1.17 h
Yield: 90.2 %

Procedure:
Under nitrogen gas atmosphere, pivaloyl chloride (4.2 ml, 35.7 mmol) was added to a solution of Compound 13 (7.3 g, 16.2 mmol) in pyridine (50 ml) at 0° C., and the mixture was stirred for 70 minutes. Methanol was added to the reaction mixture, and the mixture was stirred for 40 minutes, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (toluene:ethyl acetate=6:1) to obtain Compound 14 (7.81 g, 90%).
Reaction SMILES: [NH2:1][C:2]1[C:9]([NH2:10])=[CH:8][CH:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([F:20])([F:19])[F:18])[CH2:12]2)[C:3]=1[C:4]#[N:5].[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:32][CH2:31]2)=[O:29])=[CH:24][C:23]=1[N:39]=[C:40]=S.C(Cl)CCl>CN(C=O)C>[Cl:21][C:22]1[CH:38]=[CH:37][C:25]([CH2:26][NH:27][C:28]([C:30]2([C:33]([F:36])([F:35])[F:34])[CH2:31][CH2:32]2)=[O:29])=[CH:24][C:23]=1[NH:39][C:40]1[NH:10][C:9]2[CH:8]=[CH:7][C:6]([N:11]3[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([F:20])([F:18])[F:19])[CH2:12]3)=[C:3]([C:4]#[N:5])[C:2]=2[N:1]=1
Reactant: O=C(NCc1ccc(Cl)c(N=C=S)c1)C1(C(F)(F)F)CC1
Reactant: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc(N)c1N
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: N#Cc1c(N2CCCC(C(F)(F)F)C2)ccc2[nH]c(Nc3cc(CNC(=O)C4(C(F)(F)F)CC4)ccc3Cl)nc12

Procedure:
The title compound was prepared in analogy to Example 71 using 2,3-diamino-6-(3-trifluoromethyl-piperidin-1-yl)benzonitrile (115 mg, 0.40 mmol), N-(4-chloro-3-isothiocyanatobenzyl)-1-(trifluoromethyl)cyclopropane carboxamide (135 mg; 0.40 mmol), EDC (77 mg, 0.40 mmol) and DMF (3 mL).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=O)[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.CN.[C:19]([BH3-])#[N:20].[Na+].C(O)(=O)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:20][CH3:19])[CH2:9][N:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1
Reactant: [BH3-]C#N
Reactant: O=C(CN1CCOCC1)c1cccc(Br)c1
Agent: CN
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CNC(CN1CCOCC1)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 100.3 %

Procedure:
To a solution of 1-(3-bromophenyl)-2-(4-morpholinyl)ethanone (7.8 g, 27.0 mmol) in THF (50 mL) was added methylamine (100 mL, 200 mmol, 2M solution in THF). After stirring for 15 min at room temperature, sodium cyanoborohydride (3.40 g, 54 mmol) was added followed by acetic acid (2 mL). The resultant mixture was stirred at RT for 5 days. The mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (200 mL) and washed with 5% NaHCO3 (200 mL) and brine (200 mL). The organic layer was dried (MgSO4) and concentrated to give [1-(3-bromophenyl)-2-(4-morpholinyl)ethyl]methylamine as yellow oil (8.10 g, 100%) which solidified after standing at room temperature. MS (ESI): 299.6 [M+H]+.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[C:16]([O:20][C:21]([NH:23][C@H:24]([C:31]([OH:33])=O)[CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)=[O:22])([CH3:19])([CH3:18])[CH3:17].[C:34]([O:38][C:39](=[O:42])[CH2:40][NH2:41])([CH3:37])([CH3:36])[CH3:35]>C(OCC)(=O)C.C(O)(=O)C>[C:34]([O:38][C:39](=[O:42])[CH2:40][NH:41][C:31](=[O:33])[C@H:24]([CH2:25][C:26]1[N:27]=[CH:28][S:29][CH:30]=1)[NH:23][C:21]([O:20][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:22])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)CN
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cscn1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=O)[C@H](Cc1cscn1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 110.2 %

Procedure:
Dicyclohexyl carbodiimide (226 mg) was added to a solution of 273 mg of Nα -t-butoxycarbonyl-β-(4-thiazolyl)-L-alanine and 132 mg of glycine t-butylester in 5 ml of ethyl acetate at 0° C. The reaction solution was stirred at 0° C. for 0.5 hour, then at ambient temperature for 18 hours. 4 drops of glacial acetic acid was then added to the reaction mixture and the mixture filtered. The filtrate was concentrated under vacuum to provide 426 mg of the title compound as an oil.
Reaction SMILES: [CH:1]([CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)=O.[CH2:18]([O:21][CH2:22]C[C@H]1CC[C@H](C2C=CC(C#N)=CC=2)CC1)[CH:19]=[CH2:20]>>[CH2:18]([O:21][CH2:22][CH2:1][CH2:3][C@H:4]1[CH2:9][CH2:8][C@H:7]([C:10]2[CH:17]=[CH:16][C:13]([C:14]#[N:15])=[CH:12][CH:11]=2)[CH2:6][CH2:5]1)[CH:19]=[CH2:20]
Reactant: N#Cc1ccc([C@H]2CC[C@H](CC=O)CC2)cc1
Reactant: C=CCOCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Product: C=CCOCCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1

Procedure:
The compound (iii) of Example 7 was subjected to the procedures of (ii), (iii), (iv) and (v) of Example 7 in this order to obtain the captioned compound. M.P.: 12.0° C.,N-I point: 5.9° C.
Reaction SMILES: [Cl:1][CH2:2][C:3]([OH:5])=O.Cl.[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].Cl.CN(C)CCCN=C=NCC.CN1CCOCC1>C(Cl)Cl>[Cl:1][CH2:2][C:3]([N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[O:5]
Reactant: O=C(O)CCl
Reactant: CCNCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)C(=O)CCl
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.5 %

Procedure:
To a solution of chloroacetic acid (10 g, 0.11 mol) in methylene chloride (530 ml) at 0° C. was added diethylamine HCl (15.3 g, 0.14 mol), 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride (26.4 g, 0.14 mol) and 4-methyl morpholine (29 ml, 0.27 mol). After the reaction stirred 1 hour at 0° C., the reaction was stirred at room temperature for 4 hours. The reaction mixture was then washed with water, 1N hydrochloric acid (until the aqueous phase was colorless) and saturated sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated to give the title A compound as a yellow oil (9.3 g).
Reaction SMILES: [N:1]1([C:7]2[C:8]3[N:9]([N:13]=[C:14]([NH2:16])[N:15]=3)[CH:10]=[CH:11][CH:12]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]2)[CH:19]=1.C(Cl)Cl>C(Cl)Cl.CO>[CH3:17][C:18]1[N:23]=[CH:22][N:21]=[C:20]([N:24]2[CH2:29][CH2:28][CH:27]([NH:16][C:14]3[N:15]=[C:8]4[C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[CH:12][CH:11]=[CH:10][N:9]4[N:13]=3)[CH2:26][CH2:25]2)[CH:19]=1
Reactant: Cc1cc(N2CCC(=O)CC2)ncn1
Reactant: Nc1nc2c(N3CCOCC3)cccn2n1
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(N2CCC(Nc3nc4c(N5CCOCC5)cccn4n3)CC2)ncn1

Procedure:
Prepared in analogy to example 1h, starting from 8-morpholin-4-yl-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine and 1-(6-methylpyrimidin-4-yl)piperidin-4-one (see example 93b). The title compound was obtained as a white solid (yield: 34%) after column chromatography on silica gel using a gradient from methylene chloride to methylene chloride/methanol 19:1 (v/v) as eluent.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:17](O)[CH2:18][OH:19].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][C:13]3([O:19][CH2:18][CH2:17][O:16]3)[CH2:14][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: OCCO
Reactant: O=C1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(N2CCC3(CC2)OCCO3)cc1
Yield: 67.3 %

Procedure:
A mixture of 1-(4-nitrophenyl)-4-piperidone (0.6 g, 2.7 mmol), ethylene glycol (0.3 mL, 5.4 mmol) and p-toluenesulfonic acid (0.1 g in toluene (20 mL) was heated at reflux in a Dean-Stark apparatus until no more water accumulation occurred. The reaction was evaporated to dryness and the residue partitioned between ethyl acetate and water. The organic layer was separated and washed with water then brine and dried over sodium sulfate. Concentration under reduced pressure afforded 8-(4-nitrophenyl)-1,4-dioxa-8-aza-spiro[4,5]decane (0.48 g, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16](O)=[O:17])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:16](=[O:17])[C:15]1[CH:14]=[CH:13][C:12]([S:9](=[O:11])(=[O:10])[NH:8][C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C:21]([F:22])([F:23])[F:24])[CH:4]=2)=[CH:20][CH:19]=1)[CH3:27]
Reactant: CCOC(=O)CN
Reactant: O=C(O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNC(=O)c1ccc(S(=O)(=O)Nc2ccc(F)c(C(F)(F)F)c2)cc1

Procedure:
Under the conditions of Example 2(a), 3.633 g (10 mmol) of 4-[N-(4-fluoro-3-trifluoromethylphenyl)sulfamoyl]benzoic acid, 1.396 g (10 mmol) of glycine ethyl ester hydrochloride, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is chromatographed on silica gel. The title compound is eluted with ethyl acetate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:15]([C:22]1[CH:27]=[CH:26][C:25]([Mg]Br)=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C1C=CC(OC2C=CC(Br)=CC=2)=CC=1.[Cl-].[NH4+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([C:25]2[CH:26]=[CH:27][C:22]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:23][CH:24]=2)([OH:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Br[Mg]c1ccc(Oc2ccccc2)cc1
Agent: Brc1ccc(Oc2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(Oc3ccccc3)cc2)CC1
Yield: 45 %

Procedure:
To an 100 ml tetrahydrofuran solution of 3.5 g of N-tert-butoxycarbonyl-4-piperidone, a 35 ml of 4-phenoxyphenyl magnesium bromide prepared from 4-bromodiphenyl ether (0.6 mol/l tetrahydrofuran solution) was dropwise added under ice cooling and the resultant mixture was stirred for 1 hour. To the reaction mixture was added a 30 ml of saturated aqueous ammonium chloride solution. The product was extracted with ether. The extract was washed with saturated saline, dried, filtered, then concentrated under reduced pressure to give a residue, which was then purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to give N-tert-butoxycarbonyl-4-(4-phenoxyphenyl)-4-piperidinol in an amount of 2.92 g (yield 45%).
Reaction SMILES: CO[C:3]([C:5]1([CH3:26])[CH2:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([Cl:18])[CH:14]=3)[NH:9][C:8]=2[CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=2)[NH:6]1)=[O:4].[Br:27][CH2:28][CH2:29][N:30]=[C:31]=[O:32]>CC(=O)CC>[Br:27][CH2:28][CH2:29][N:30]1[C:31](=[O:32])[N:6]2[CH:7]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([OH:25])[CH:20]=3)[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[CH2:17][C:5]2([CH3:26])[C:3]1=[O:4])=[CH:14][C:13]([Cl:18])=[CH:12][CH:11]=4
Reactant: COC(=O)C1(C)Cc2c([nH]c3ccc(Cl)cc23)C(c2cccc(O)c2)N1
Reactant: O=C=NCCBr
Solvent: CCC(C)=O
Product: CC12Cc3c([nH]c4ccc(Cl)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Temperature: 80 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a suspension of 1.66 g (5.39 mmol) (1RS,3SR)-6-Chloro-1-(3-hydroxy-phenyl)-3-methyl-2,3,4,9-tetrahydro-1H-beta-carboline-3-carboxylic acid methyl ester in 20 ml 2-butanon are added 490 μl 2-bromoethyl isocyanate. After heating the mixture to reflux for 4 h, additional 490 μl 2-bromoethyl isocyanate are added and the mixture is heated to reflux over night. The solvent is removed at reduced pressure and the residue is dissolved in 20 ml dimethyl formamide. The mixture is stirred at 80° C. for 15 h. The solvent is removed at reduced pressure and the residue is dissolved in ethyl acetate. Water is added and the organic layer is dried with magnesium sulfate. The solvent is removed at reduced pressure and the residue is suspended in a mixture of toluene and ethyl acetate (4:1). The suspension is filtered. 1.35 g (62%) of the title compound are obtained as the precipitate. m.p.: 262-264° C., MS: m/z (MH+)=488.0/490.0
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:17]([O:20][CH2:21][CH2:22]Cl)[CH2:18][CH3:19].O>CN(C)C=O>[CH2:17]([O:20][CH2:21][CH2:22][O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH3:19]
Reactant: CCCOCCCl
Reactant: O=C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOCCOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.6 %

Procedure:
To a solution of 4-hydroxybenzoic acid (3.04 g) and anhydrous potassium carbonate (5.52 g) in N,N-dimethylformamide (20 ml) was added 2-propyloxyethyl chloride (2.94 g), and the mixture was stirred at room temperature overnight, and then stirred at 80° C. for 8 hours. To a reaction solution was added water, and then the mixture was extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, successively, dried and concentrated under reduced pressure to give the title compound (5.21 g; crude).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[N:5]=[C:4]2[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][C:3]=12.[N:17]#[C:18][NH2:19]>C(O)(=O)C.C(O)C>[C:18]([N:14]1[CH2:15][CH2:16][C:3]2[C:4](=[N:5][C:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:11]=3[C:2]=2[CH3:1])[CH2:12][CH2:13]1)(=[NH:17])[NH2:19]
Reactant: N#CN
Reactant: Cc1c2c(nc3ccccc13)CCNCC2
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1c2c(nc3ccccc13)CCN(C(=N)N)CC2

Procedure:
5 gm (23.6 millimols) of 1,2,4,5-tetrahydro-11-methyl-3H-azepino[4,5-b]quinoline were dissolved in 2.7 ml of glacial acetic acid and 20 ml of ethanol, and the solution was stirred at room temperature with 1.12 gm (26.6 millimols) of cyanamide for 72 hours. Thereafter, the product which had crystallized out was dissolved in water and reprecipitated with sodium hydroxide. Yield: 0.6 gm, 10% of theory; m.p. 140° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([CH:11]=[O:12])=[CH:5][N:4]=1.Cl([O-])=[O:14].[Na+].O.P([O-])(O)(O)=O.[Na+].O>C(O)(C)(C)C>[CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[C:6]([C:11]([OH:14])=[O:12])=[CH:5][N:4]=1
Reactant: COc1ncc(C=O)c(OC)n1
Reactant: [O-][Cl+][O-]
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Product: COc1ncc(C(=O)O)c(OC)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2,4-Bis(methyloxy)-5-pyrimidinecarbaldehyde (commercially available from Toronto, 1.400 g, 8.33 mmol) at 0° C. in t-Butanol (14.00 mL) an aqueous solution (7 mL) of Sodium chlorite (1.807 g, 19.98 mmol) was added over 25 min and sodium dihydrogen phosphate hydrate (3.64 g, 23.33 mmol). The yellow mixture obtained was warmed to 25° C. and after 6 h 14 mL of t-Butanol, 7 mL of water, and Sodium chlorite (2.26 g, 25 mmol) were added. The reaction mixture was stirred at room temperature overnight. After 24 h, the mixture was evaporated in vacuo, and the crude material purified by SPE 25 g cartridge eluting with DCM/MeOH 8:2 to recover 1 g of title compound.
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH2:28])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11].[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl>[CH2:8]([C:12]1[N:13]([CH2:25][CH2:26][CH2:27][NH:28][S:30]([CH3:29])(=[O:32])=[O:31])[C:14]2[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[N:17]=[CH:16][C:15]=2[N:24]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CCCCc1nc2cnc3ccccc3c2n1CCCN
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCc1nc2cnc3ccccc3c2n1CCCNS(C)(=O)=O
Reaction time: 8 h
Yield: 74.1 %

Procedure:
Triethylamine (1.1 g, 10.6 mmol) was added with stirring to a solution of 3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propylamine (2.00 g, 7.08 mmol) in dichloromethane (˜150 mL). Methanesulfonyl chloride (892 mg, 7.79 mmol) was added and the reaction was stirred under nitrogen overnight. The reaction mixture was washed with aqueous 1% sodium bicarbonate solution (3×50 mL). The aqueous washes were extracted with dichloromethane (2×20 mL). The organics were combined, dried over magnesium sulfate and then concentrated under reduced pressure to provide 1.89 g of N-[3-(2-butyl-1H-imidazo[4,5-c]quinolin-1-yl)propyl]methanesulfonamide as a light brown solid.