Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2].[N+:16]([C:19]1[CH:24]=[CH:23][C:22](O)=[CH:21][CH:20]=1)([O-:18])=[O:17]>>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:22]2[CH:23]=[CH:24][C:19]([N+:16]([O-:18])=[O:17])=[CH:20][CH:21]=2)[CH2:6][C@@H:5]1[CH3:15])(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: CC(=O)N1c2ccccc2[C@H](O)C[C@@H]1C
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc([N+](=O)[O-])cc2)C[C@@H]1C
Yield: 72.4 %

Procedure:
[Step 1] Reactions and treatments were carried out in the same manner as in Step 2 of Example 117, using 102.6 g of (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline instead of ethyl (2S,4R)-1-acetyl-4-hydroxyl-2-methyl-1,2,3,4-tetrahydroquinoline-6-carboxylate, and using 4-nitrophenol instead of benzoic acid. Thus, 118.2 mg (72.4%) of (2S,4R)-1-acetyl-2-methyl-4-(4-nitrophenoxy)-1,2,3,4-tetrahydroquinoline was obtained as a pale yellow amorphous substance.
Reaction SMILES: Cl.[CH3:2][C:3]1([CH3:31])[C:7]([CH3:9])(O)[C:6]2[C:10]([CH3:30])=[C:11]([N:16]3[CH2:21][CH2:20][N:19]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=4)[CH2:18][CH2:17]3)[C:12]([CH3:15])=[C:13]([CH3:14])[C:5]=2[O:4]1>C(#N)C>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([N:19]2[CH2:20][CH2:21][N:16]([C:11]3[C:12]([CH3:15])=[C:13]([CH3:14])[C:5]4[O:4][C:3]([CH3:2])([CH3:31])[C:7](=[CH2:9])[C:6]=4[C:10]=3[CH3:30])[CH2:17][CH2:18]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(C)(O)C(C)(C)O4)CC2)cc1
Agent: Cl
Solvent: CC#N
Product: C=C1c2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2OC1(C)C
Reaction time: 6 h
Yield: 92.3 %

Procedure:
A solution of 10% hydrochloric acid (5 ml) was added to a solution of 1-(2,2,3,4,6,7-hexamethyl-3-hydroxy-2,3-dihydro-1-benzofuran-5-yl)-4-(4-methoxyphenyl)piperazine (1.70 g, 4.14 mmol) obtained in Reference Example 26 in acetonitrile (15 ml) at room temperature and the mixture was stirred for 6 hours. The resulting mixture was concentrated under reduced pressure, and the residue was made to basic with 10% aqueous potassium carbonate. The aqueous layer was extracted with ethyl acetate. The organic extract was washed with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and the residue was crystallized from ethanol to obtain 1.50 g (yield 92%) of the title compound. mp. 134–136° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[C:17]2[C:12](=[N:13][CH:14]=[N:15][C:16]=2[NH:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[CH:28]=3)=[C:21]([O:34][CH3:35])[CH:20]=2)[NH:11][N:10]=1)(=O)=O.[NH:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[CH2:26][O:25][C:22]1[CH:23]=[CH:24][C:19]([NH:18][C:16]2[N:15]=[CH:14][N:13]=[C:12]3[NH:11][N:10]=[C:9]([O:8][CH2:7][CH2:6][N:36]4[CH2:40][CH2:39][CH2:38][CH2:37]4)[C:17]=23)=[CH:20][C:21]=1[O:34][CH3:35]
Reactant: C1CCNC1
Reactant: COc1cc(Nc2ncnc3[nH]nc(OCCOS(C)(=O)=O)c23)ccc1OCc1cccc(F)c1
Product: COc1cc(Nc2ncnc3[nH]nc(OCCN4CCCC4)c23)ccc1OCc1cccc(F)c1
Yield: 30 %

Procedure:
The procedure described in Example 55 was repeated using 2-{[4-({4-[(3-fluorobenzyl)oxy]-3-methoxyphenyl}amino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]oxy}ethyl methanesulfonate (prepared as described in Example 22) and pyrrolidine to give the title compound in 30% yield; NMR Spectrum: 1.66 (s, 4H), 2.55 (s, 4H), 2.88 (t, 2H), 3.80 (s, 3H), 4.42 (t, 2H), 5.11 (s, 2H), 7.00 (d, 1H), 7.16 (m, 2H), 7.29 (m, 2H), 7.38 (d, 1H), 7.45 (q, 1H), 8.25 (s, 1H), 8.52 (s, 1H); Mass Spectrum: 479 (MH+).
Reaction SMILES: Cl.[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH2:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3].[Cl:15][C:16]1[CH:36]=[CH:35][C:19]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[C:23]([CH3:33])=[C:22]2[CH3:34])=[CH:18][C:17]=1[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40]>>[CH:2]([O:5][C:6]1[CH:7]=[C:8]([C@@H:12]([NH:14][C:30]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([CH2:20][C:19]2[CH:35]=[CH:36][C:16]([Cl:15])=[C:17]([CH:18]=2)[O:37][C@@H:38]([CH3:43])[C:39]([O:41][CH3:42])=[O:40])[C:22]([CH3:34])=[C:23]3[CH3:33])=[O:31])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([CH3:4])[CH3:3]
Reactant: CC(C)Oc1cccc([C@H](C)N)c1
Reactant: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl
Agent: Cl
Product: COC(=O)[C@H](C)Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(OC(C)C)c4)ccc32)ccc1Cl

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropoxyphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and (S)-1-(4-chloro-3-((1-methoxy-1-oxopropan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.BrCC1CCCCO1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]>>[N:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][N:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]2([C:36]3[C:32]4=[N:33][O:34][N:35]=[C:31]4[CH:30]=[CH:29][C:28]=3[O:27][CH2:26]2)[C:18]1=[O:37]
Reactant: BrCc1ccccn1
Reactant: O=C1Nc2ccccc2C12COc1ccc3nonc3c12
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccccn2)c2ccccc2C12COc1ccc3nonc3c12

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 2-(bromomethyl)pyridine to replace 2-(bromomethyl)tetrahydro-2H-pyran, and spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(pyridin-2-ylmethyl)spiro[furo[3,2-e][2,1,3]benzoxadiazole-8,3′-indol]-2′(1′H)-one was obtained (81%) as a colorless solid: mp 180-182° C.; 1H NMR (300 MHz, CDCl3) δ8.63-8.59 (m, 1H), 7.84 (d, J=9.6 Hz, 1H), 7.77-7.70 (m, 1H), 7.57 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.6 Hz, 1H), 7.28-7.16 (m, 3H), 7.04 (ddd, J=7.5, 7.5, 0.9 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 5.45 (d, J=16.2 Hz, 1H), 5.28 (d, J=9.6 Hz, 1H), 5.01 (d, J=9.6 Hz, 1H), 4.92 (d, J=16.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ176.1, 163.0, 155.1, 149.4, 148.3, 144.9, 142.2, 137.3, 129.8, 129.7, 123.7, 123.67, 122.8, 121.9, 121.6, 119.4, 110.1, 107.0, 82.0, 57.4, 46.5; MS (ES+) m/z 371.0 (M+1).
Reaction SMILES: [C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=O.[C:12](#[N:16])[CH2:13][C:14]#[N:15].N1CCCCC1>C(O)CCC>[C:1]1([CH3:11])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[CH:9]=[C:13]([C:12]#[N:16])[C:14]#[N:15]
Reactant: N#CCC#N
Reactant: Cc1cc(C)c(C=O)c(C)c1
Solvent: CCCCO
Solvent: C1CCNCC1
Product: Cc1cc(C)c(C=C(C#N)C#N)c(C)c1
Temperature: -20 °C
Reaction time: 5 h

Procedure:
In analogy to the methods described by M. Boehringer et al., WO 03/068748, a solution of 25 g (169 mmol) of mesitaldehyde (2,4,6-trimethylbenzaldehyde) and 13.5 g (204 mmol) of malononitrile in 70 mL of n-butanol was stirred at room temperature for 1 h and then treated dropwise with 0.4 mL of piperidine, resulting in a color change and precipitation. After 5 h, the mixture was cooled in a freezer (−20° C.) for 10 min and then filtered. The solid was washed three times with cold n-butanol and then dried to give the title compound as a white solid. LC-MS 197 (M+1). This material has been reported as being made by a similar procedure [A. M. Shestapalov et al., Chem. Heterocycl. Compd. (Engl. Transl. of Khim. Geterotsikl. Soedin.), 38, 1345 (2002)].
Reaction SMILES: FC(F)(F)C([N:5]([C@@H:13]1[CH2:15][C@H:14]1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:6][CH:7]1[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33]>C(#N)C>[C:16]1([C@@H:14]2[CH2:15][C@H:13]2[NH:5][CH2:6][CH:7]2[CH2:8][CH2:9][N:10]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:11][CH2:12]2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)CN1CCC(CN[C@@H]2C[C@H]2c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 4 h
Yield: 24.8 %

Procedure:
To the solution of 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (200 mg, 0.613 mmol, Example 11b) in acetonitrile (5 mL) was added potassium carbonate (254 mg, 1.838 mmol) followed by tert-butyl 2-bromoacetate (155 mg, 0.797 mmol). The reaction mixture was stirred at 80° C. for 4 hours. The suspension was filtered and evaporated. The oil was suspended in 2 mL of dioxane and 2 mL of 1 M NaOH. The solution was stirred for 1 hour, then injected on preparatory HPLC (5 to 30% AcCN: H2O with 0.1% formic acid modifier). The fractions were collected. The combined fractions were neutralized with NH4OH and extracted with ethyl acetate. The organic layer was separated, washed with brine, dried, filtered and evaporated till dryness. tert-butyl 2-(4-(((trans-2-phenylcyclopropyl)amino)methyl)piperidin-1-yl)acetate (55 mg, 0.152 mmol, 24.75% yield) was isolated as colorless oil. 1H NMR (400 MHz, METHANOL-d4) δ 7.20-7.31 (m, 2H), 7.09-7.17 (m, 1H), 6.99-7.09 (m, 2H), 3.12 (s, 2H), 2.91-3.03 (m, 2H), 2.62 (d, J=7.07 Hz, 2H), 2.28-2.36 (m, 1H), 2.11-2.23 (m, 2H), 1.92 (ddd, J=3.28, 5.87, 9.28 Hz, 1H), 1.68-1.83 (m, 2H), 1.52-1.63 (m, 1H), 1.44-1.52 (m, 9H), 1.31 (qd, J=3.92, 12.34 Hz, 2H), 1.08 (dt, J=4.86, 9.47 Hz, 1H), 1.02 (dt, J=5.59, 7.26 Hz, 1H); LC-MS Rt=0.58 min; MS (ESI): 345.3 [M+H]+.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][CH2:3]1.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([O:10][C:11]([CH3:12])([CH3:14])[CH3:13])=[O:15])[CH2:4][CH2:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCC(O)CC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCC(OS(C)(=O)=O)CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.8 %

Procedure:
tert-Butyl (4-hydroxycyclohexyl)carbamate (2.5 g, 11.61 mmol) and TEA (3.23 ml, 23.22 mmol) was dissolved in DCM (50 ml) and cooled to 0° C. with an icebath. Methansulfonyl chloride (1.17 ml, 15.10 mmol) was added dropwise and the icebath was removed. After stirring at rt for 2 h the reaction mixture was washed with water (200 ml), dried over Na2SO4, filtered and evaporated. The residue was purified by silica gel column chromatography using a 70:30 mixture of heptane:EtOAc to give the title compound (1.8 g, 53%) as 50:50 mixture of cis and trans isomers. 1H-NMR (CDCl3, 500 MHz): δ 4.91-4.83 (m, 1H), 4.67-4.56 (m, 1H), 4.53-4.31 (m, 2H), 3.58-3.36 (m, 2H), 3.00 (ds, 6H), 2.17-1.98 (m, 6H), 1.88-1.78 (m, 2H), 1.77-1.50 (m, 6H), 1.43 (ds, 18H), 1.33-1.18 (m, 2H); 13C-NMR (CDCl3, 125 MHz): δ 155.4, 79.9, 78.1, 48.2, 39.0, 38.9, 31.3, 30.8, 30.0, 28.6, 27.7.
Reaction SMILES: Cl.[C:2]([CH2:4][S:5]C(=N)N)#[N:3].C[O-].[Na+].[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35](/[C:37](=[N:43]/[O:44][CH2:45][CH2:46]I)/[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[C:12]([NH:31][C:32]1[S:33][CH:34]=[C:35](/[C:37](=[N:43]/[O:44][CH2:45][CH2:46][S:5][CH2:4][C:2]#[N:3])/[C:38]([O:40][CH2:41][CH3:42])=[O:39])[N:36]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#CCSC(=N)N
Reactant: CCOC(=O)/C(=N\OCCI)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OCCSCC#N)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: -35 °C
Yield: 88.7 %

Procedure:
In 10 ml of dimethylformamide is suspended 0.976 g of S-cyanomethylisothiourea hydrochloride prepared according to the method described in Japanese Published Unexamined Patent Application No. 50-154279. Under cooling at -35° C. and stirring, 2.73 g of 28% (w/w) sodium methylate solution is added dropwise, after which the mixture is stirred at -40° C. to -35° C. for 10 minutes. Then, a solution of 3.94 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-iodoethoxyimino)acetate in 10 ml of dimethylformamide is added at the same temperature. The mixture is stirred at or below -30° C. for 5 minutes and then under ice-cooling for 4 hours. The reaction mixture is poured into 400 ml of ice-water and extracted with ethyl acetate. The extract is washed with aqueous sodium chloride solution, dried over magnesium sulfate and concentrated under reduced pressure. To the solid residue is added a mixture of ether-petroleum ether (1:1) and the mixture is filtered to give 3.18 g of ethyl 2-(2-tritylaminothiazol-4-yl)-(Z)-2-(2-cyanomethylthioethoxyimino)acetate as light yellow crystals.
Reaction SMILES: [C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)#[N:2].[OH-:21].[Na+]>S(=O)(=O)(O)O.O>[C:1]([C:3]([C@H:16]1[CH2:20][CH2:19][NH:18][CH2:17]1)([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:21])[NH2:2]
Reactant: N#CC(c1ccccc1)(c1ccccc1)[C@H]1CCNC1
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: NC(=O)C(c1ccccc1)(c1ccccc1)[C@H]1CCNC1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
3 3-(R)-(-)-(1-cyano-1,1-diphenylmethyl)pyrrolidine (9.2 g--see Preparation 9(B)) was dissolved in 95% sulphuric acid (80 ml) and the mixture was heated at 80° C. for 4 hours and then at 90° C. for 1 hour. Ice (1 kg) was added and the mixture was basified (pH 12) by the addition of a cold solution of sodium hydroxide (120 g) in water (100 ml). The mixture was extracted with dichloromethane (4×100 ml) and the combined extracts were dried (MgSO4) then concentrated in vacuo to give a foam which was purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield, 4.5 g, [α]25D +16 9° (c 1.0, CH2Cl2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][C:7](=[O:15])[C:6]=2[CH:16]=1.C(O)C>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:11][C:10]3=[CH:12][CH:13]=[CH:14][N:9]3[CH2:8][CH:7]([OH:15])[C:6]=2[CH:16]=1
Reactant: O=C1Cn2cccc2Sc2ccc(Cl)cc21
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: OC1Cn2cccc2Sc2ccc(Cl)cc21
Yield: 88 %

Procedure:
The titre compound was obtained starting from 9b (112 mg, 0.45 mmol) using the procedure described above: 88% yield; melting point 118-119° C. (ethanol); IR (CHCl3) 3300 cm−1; 1H NMR (CDCl3) δ7.48 (d, 1H, J=2.1 Hz); 7.32 (d, 1H, J=8.0 Hz), 7.15 (dd, 1H, J=8.1, 2.1 Hz), 6.88 (m, 1H), 6.34 (m, 1H), 6.11 (m, 1H), 5.02 (m, 1H), 4.85 (dd, 1H, J=13.9, 1.9 Hz), 4.29 (dd, 1H, J=13.9, 6.6 Hz), 2.10 (dd, 1H, J=9.6 Hz). Anal. (C12H10CINOS): C, H, N.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:6][CH2:7][C:8](Br)=[O:9].C(N(CC)CC)C>ClCCl>[Br:6][CH2:7][C:8]([N:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:9]
Reactant: O=C(Br)CBr
Reactant: C1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CBr)N1CCCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 67.3 %

Procedure:
A mixture of pyrrolidine (1.7 g, 24 mmol), bromoacetyl bromide (4.6 g, 24 mmol) and triethylamine (2.02 g, 20 mmol) in dichloromethane (40 mL) was stirred at room temperature for 4 hours. The precipitate was filtered off and the residue was concentrated to give 3.1 g of 2-bromo-1-pyrrolidin-1-yl-ethanone as a light brown solid.
Reaction SMILES: C1(O[C:8](=[O:21])[NH:9][C:10]2[C:11]([O:19][CH3:20])=[N:12][C:13]([CH3:18])=[C:14]([CH2:16][CH3:17])[CH:15]=2)C=CC=CC=1.[C:22]([C:25]1[CH:30]=[CH:29][C:28]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[CH:27][CH:26]=1)(=[O:24])[CH3:23]>>[CH2:16]([C:14]1[CH:15]=[C:10]([NH:9][C:8]([N:34]2[CH2:33][CH2:32][N:31]([C:28]3[CH:27]=[CH:26][C:25]([C:22](=[O:24])[CH3:23])=[CH:30][CH:29]=3)[CH2:36][CH2:35]2)=[O:21])[C:11]([O:19][CH3:20])=[N:12][C:13]=1[CH3:18])[CH3:17]
Reactant: CCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Product: CCc1cc(NC(=O)N2CCN(c3ccc(C(C)=O)cc3)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)carbamate and 1-(4-acetylphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7](Br)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4].[CH3:11][O:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:1][C:2]1[CH:8]=[C:7]([C:17]2[CH:16]=[CH:15][CH:14]=[C:13]([O:12][CH3:11])[CH:18]=2)[CH:6]=[C:5]([F:10])[C:3]=1[NH2:4]
Reactant: Nc1c(F)cc(Br)cc1F
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(-c2cc(F)c(N)c(F)c2)c1
Yield: 79.6 %

Procedure:
The title compound (992 mg) was prepared from 2,6-difluoro-4-bromo aniline (1.1 g, 5.3 mmol) and 3-methoxyphenylboronic acid (1.04 g, 6.8 mmol) as a pale-yellow liquid. 1H-NMR (δ ppm, CDCl3+DMSO-d6, 400 MHz): 7.21-7.20 (m, 1H), 6.99-6.89 (m, 3H), 6.87-6.83 (m, 1H), 6.74-6.68 (m, 1H), 3.97 (bs, 2H), 3.69 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[N+:10]([CH2:13][C:14](OCC)=[O:15])([O-:12])=[O:11].N1CCCCC1>C1(C)C(C)=CC=CC=1>[N+:10]([C:13]1[C:14](=[O:15])[NH:1][C:2]2[C:3]([CH:4]=1)=[CH:6][CH:7]=[CH:8][CH:9]=2)([O-:12])=[O:11]
Reactant: Nc1ccccc1C=O
Reactant: CCOC(=O)C[N+](=O)[O-]
Solvent: Cc1ccccc1C
Solvent: C1CCNCC1
Product: O=c1[nH]c2ccccc2cc1[N+](=O)[O-]
Temperature: 150 °C
Yield: 50.8 %

Procedure:
2-Aminobenzaldehyde (1.75 g, 14.5 mmol) was dissolved in xylene (87.5 mL). To this, ethyl 2-nitroacetate (6.43 mL, 58.0 mmol) and piperidine (1.58 mL, 16.0 mmol) were added and the mixture was stirred with heat at 150° C. for 1.5 hours and successively stirred with cooling in an ice bath for 0.5 hour. The precipitate was collected by filtration and dried under reduced pressure. Thus, 3-nitroquinolin-2(1H)-one (1.40 g, yield: 51%) was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH2:13](O)[CH2:14][OH:15].C1C=CC=CC=1>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:7]2[O:15][CH2:14][CH2:13][O:8]2)[CH:9]=1
Reactant: O=Cc1cc(Cl)ccc1[N+](=O)[O-]
Reactant: OCCO
Solvent: O
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(Cl)cc1C1OCCO1
Yield: 94.9 %

Procedure:
Prepared as described by D. E. O'Brien et al, J. Het. Chem., 7, 102 (1970) as follows. A mixture of 5-chloro-2-nitrobenzaldehyde (18.3 g, 0.1 mole), ethylene glycol (7.0 g, 0.11 mole) p-toluenesulfonic acid (0.5 g) and benzene (850 mL) was stirred and refluxed with continuous removal of water via a Dean and Stark trap for 24 hours. The solvent was removed, the residue dissolved in dichloromethane and filtered through a plug of silica gel (6" deep). Evaporation of the solvent afforded 2-(5-chloro-2-nitrophenyl)-1,3-dioxolane (21.8 g, 97%) as an oil.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([C:25]2[S:26][CH:27]=[CH:28][C:29]=2[NH2:30])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:31]=[C:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]1[CH2:42][C:43](O)=[O:44]>>[O:31]=[C:32]1[CH2:41][CH2:40][C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]1[CH2:42][C:43]([NH:30][C:29]1[CH:28]=[CH:27][S:26][C:25]=1[C:23]1[N:22]=[CH:21][N:20]([C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:24]=1)=[O:44]
Reactant: Nc1ccsc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: O=C(O)CN1C(=O)CCc2ccccc21
Product: O=C(CN1C(=O)CCc2ccccc21)Nc1ccsc1-c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1

Procedure:
The title compound was prepared from 2-(1-trityl-1H-imidazol-4-yl)thiophen-3-amine and 2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetic acid using protocol B (269 mg, 32%). Method [7] Retention time 9.32 min by HPLC (MH+ 595).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[N:11][N:12]([CH2:14][C:15]3[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=3)[C:18](O)=[O:19])[CH:13]=2)=[CH:5][CH:4]=1)#[N:2].[C:24]([O:28][C:29](=[O:41])[NH:30][C@@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH2:38])[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29](=[O:41])[NH:30][C@@H:31]1[CH2:40][CH2:39][C:34]2[N:35]=[C:36]([NH:38][C:18](=[O:19])[C:17]3[CH:21]=[CH:22][CH:23]=[C:15]([CH2:14][N:12]4[CH:13]=[C:9]([C:6]5[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=5)[N:10]=[N:11]4)[CH:16]=3)[S:37][C:33]=2[CH2:32]1)([CH3:27])([CH3:25])[CH3:26]
Reactant: N#Cc1ccc(-c2cn(Cc3cccc(C(=O)O)c3)nn2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCc2nc(N)sc2C1
Product: CC(C)(C)OC(=O)N[C@@H]1CCc2nc(NC(=O)c3cccc(Cn4cc(-c5ccc(C#N)cc5)nn4)c3)sc2C1

Procedure:
React 3-[4-(4-cyano-phenyl)-[1,2,3]triazol-1-ylmethyl]-benzoic acid and ((R)-2-amino-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester under TBTU coupling conditions as described in Example 1 to give ((R)-2-{3-[4-(4-cyano-phenyl)-1,2,3-triazol-1-ylmethyl]-benzoylamino}-4,5,6,7-tetrahydro-benzothiazol-6-yl)-carbamic acid tert-butyl ester
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:9][C:7](=[O:8])[CH2:6][C:4](=[O:5])[O:3]1.[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1>>[Cl:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:6]2[C:7](=[O:8])[O:9][C:2]([CH3:10])([CH3:1])[O:3][C:4]2=[O:5])=[CH:14][CH:13]=1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=Cc1ccc(Cl)cc1
Product: CC1(C)OC(=O)C(=Cc2ccc(Cl)cc2)C(=O)O1

Procedure:
Prepared from Meldrum's acid and 4-chlorobenzaldehyde by Cope-Knoevenagel reaction.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH:26]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]([CH2:39][CH:40]=O)[C:34](=[O:42])[CH:33]=[CH:32]2)([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:40][CH2:39][N:35]4[C:36]5[C:31](=[CH:30][C:29]([CH:26]([CH3:28])[CH3:27])=[CH:38][CH:37]=5)[CH:32]=[CH:33][C:34]4=[O:42])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: CC(C)c1ccc2c(ccc(=O)n2CC=O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)c1ccc2c(ccc(=O)n2CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c1
Temperature: 25 °C
Yield: 44 %

Procedure:
To 4 mL of a chloroform solution containing 0.62 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.41 g of (6-isopropyl-2-oxoquinolin-1(2H)-yl)acetaldehyde and 40 μL of acetic acid were added, then, to the reaction mixture, 0.57 g of sodium triacetoxyborohydride was added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.44 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(6-isopropyl-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.