Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:4]1.C(N(CC)CC)C.[C:29](=[S:31])=[S:30].[CH3:32]I>CS(C)=O>[OH:1][CH2:2][C@@H:3]1[CH2:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[C@H:5]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:4]1[C:29]([S:31][CH3:32])=[S:30]
Reactant: OC[C@@H]1Cc2c([nH]c3ccccc23)[C@H](c2ccccc2)N1
Reactant: CI
Reactant: S=C=S
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CSC(=S)N1[C@H](CO)Cc2c([nH]c3ccccc23)[C@@H]1c1ccccc1
Yield: 78.1 %

Procedure:
In the same manner as described in Example 13 by using (1RS, 3RS)-cis-3-hydroxymethyl-1-phenyl-1,2,3,4-tetrahydro-β-carboline (300 mg) [J.A.C.S., 102, 6976 (1980)], triethylamine (220 mg), CS2 (160 mg), methyl iodide (306 mg) and dimethylsulfoxide (6 ml), there is prepared the title compound (310 mg, 78%) as white powder.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[NH:8][C:7](=[O:15])[C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>C(#N)C>[N:20]1([CH2:26][CH2:27][CH:28]2[CH2:33][CH2:32][CH2:31][N:30]([C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7](=[O:15])[C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:29]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: O=C1Nc2ccccc2N(C(=O)Cl)c2ncccc21
Reactant: C1CCN(CCC2CCCNC2)CC1
Solvent: CC#N
Product: O=C1Nc2ccccc2N(C(=O)N2CCCC(CCN3CCCCC3)C2)c2ncccc21
Yield: 50 %

Procedure:
Prepared analogously to Example 4 from 11-(chlorocarbonyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepin-5-one and 3-[2-(1-piperidinyl)ethyl]piperidine in a yield of 50% of theory. Colourless crystals, m.p. 168°-169° C. (acetonitrile).
Reaction SMILES: [C:1]([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][C:13]=1[C:31]([F:34])([F:33])[F:32].[NH2:35][C@@H:36]([CH2:40][CH3:41])[C:37]([OH:39])=[O:38].C=O>CO.CC(O)=O.C(Cl)Cl>[CH3:1][N:35]([CH2:27][C:26]1[CH:29]=[CH:30][C:23]([C:20]2[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[CH3:5])=[C:13]([C:31]([F:32])([F:34])[F:33])[CH:14]=3)[O:22][N:21]=2)=[CH:24][CH:25]=1)[C@@H:36]([CH2:40][CH3:41])[C:37]([OH:39])=[O:38]
Reactant: CC[C@H](N)C(=O)O
Reactant: [BH3-]C#N
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1C(F)(F)F
Agent: C=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC[C@@H](C(=O)O)N(C)Cc1ccc(-c2noc(-c3ccc(-c4ccccc4C)c(C(F)(F)F)c3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (18 mg; 0.28 mmol) was added to a solution of 4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (Example 54, step 2, 103 mg; 0.25 mmol) and (S)-2-aminobutanoic acid (52 mg; 0.50 mmol) in a mixture of methanol (3 mL), DCM (3 mL) and acetic acid (38 μl). The mixture was stirred at room temperature overnight and was filtered through a frit under positive pressure. To the filtrate was added formaldehyde (37% aqueous solution; 204 mg, 2.51 mmol) followed by addition of AcOH until the pH was in the range of 3-4 (240 mL). To the resulting mixture was added sodium cyanoborohydride (79 mg, 1.26 mmol), the mixture stirred for 16 hours, the solvent removed in vacuo and the residue purified by reverse phase HPLC to give a white solid as the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.57-8.53 (1H, m), 8.52-8.48 (1H, m), 8.10 (2H, d, J=8.0 Hz), 7.67 (1H, d, J=7.9 Hz), 7.57 (2H, d, J=8.0 Hz), 7.40-7.35 (2H, m), 7.32-7.27 (1H, m), 7.18 (1H, d, J=7.5 Hz), 3.86 (1H, d, J=14.3 Hz), 3.72 (1H, d, J=14.3 Hz), 3.15 (1H, t, J=7.4 Hz), 2.24 (3H, s), 2.03 (3H, s), 1.76-1.60 (2H, m), 0.95 (3H, t, J=7.3 Hz). LC/MS (Method B): 510 (M+H)+. HPLC (Method D) Rt 3.39 min (Purity: 99.8%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([OH:6])=[O:5].O([C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:19][CH:18]=[CH:17][CH:16]=2)C1C=CC=CC=1.CCOCC>C1(O)C=CC=CC=1>[C:4]([CH2:3][CH2:2][NH:1][C:14]1[C:15]2[C:20]([N:21]=[C:22]3[C:27]=1[CH:26]=[CH:25][CH:24]=[CH:23]3)=[CH:19][CH:18]=[CH:17][CH:16]=2)([OH:6])=[O:5]
Reactant: c1ccc(Oc2c3ccccc3nc3ccccc23)cc1
Reactant: NCCC(=O)O
Solvent: Oc1ccccc1
Solvent: CCOCC
Product: O=C(O)CCNc1c2ccccc2nc2ccccc12
Temperature: 120 °C
Reaction time: 2 h

Procedure:
β-Alanine (1 g, 11.2 mmol) was added to a solution of 9-phenoxyacridine (2.7 g, 10 mmol) in phenol (15 g). The suspension was stirred at 120° C. for 2 h. The solution was cooled to room temperature and poured into ether whereby the product precipitated as a yellow-green solid. It was triturated with hot ethanol, filtered and then washed with ethanol, giving crude 9-(2-carboxyethyl)aminoacridine. Yield 1.9 g (71%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]=[C:4]([NH:9][C:10]23[CH2:19][CH:14]4[CH2:15][CH:16]([CH2:18][CH:12]([CH2:13]4)[CH2:11]2)[CH2:17]3)[N:3]=1.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[C:10]12([NH:9][C:4]3[N:3]=[C:2]([Cl:1])[CH:7]=[C:6]([N:20]4[CH2:24][CH2:23][CH2:22][CH2:21]4)[N:5]=3)[CH2:11][CH:12]3[CH2:13][CH:14]([CH2:15][CH:16]([CH2:18]3)[CH2:17]1)[CH2:19]2
Reactant: Clc1cc(Cl)nc(NC23CC4CC(CC(C4)C2)C3)n1
Reactant: C1CCNC1
Product: Clc1cc(N2CCCC2)nc(NC23CC4CC(CC(C4)C2)C3)n1

Procedure:
10 g (33.53 mmoles) of 4,6-dichloro-2-(1-adamantylamino)pyrimidine are added in small portions to 40 ml of pyrrolidine at a temperature below 10° C. under cooling and stirring. After addition the reaction mixture is stirred at room temperature for 1 hour, then evaporated. The residue is distributed between 150 ml of chloroform and 30 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 50 ml of water each, then dried and evaporated. The evaporation residue is recrystallized from ethyl acetate to give the title compound in a yield of 9.60 g (86%), m.p.: 178°-180° C.
Reaction SMILES: [F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[CH2:27][C:26]3[C:21](=[C:22]([NH:28][C:29]([CH:31]4[CH2:33][CH2:32]4)=[O:30])[CH:23]=[CH:24][CH:25]=3)[C:20]2=[O:34])[CH2:15][C:16](O)=[O:17])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:13])[F:12].[C:36](N1C=CN=C1)([N:38]1C=CN=[CH:39]1)=O.CNC.O>O1CCCC1>[F:1][CH:2]([F:35])[O:3][C:4]1[CH:5]=[C:6]([CH:14]([N:19]2[C:20](=[O:34])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][C:22]=3[NH:28][C:29]([CH:31]3[CH2:32][CH2:33]3)=[O:30])[CH2:27]2)[CH2:15][C:16](=[O:17])[N:38]([CH3:39])[CH3:36])[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([F:12])[F:13]
Reactant: O=C(O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CNC
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(=O)CC(c1ccc(OC(F)F)c(OC(F)F)c1)N1Cc2cccc(NC(=O)C3CC3)c2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 47.2 %

Procedure:
To a solution of 3-(3,4-bis-difluoromethoxy-phenyl)-3-[7-(cyclopropanecarbonyl-amino)-1-oxo-1,3-dihydro-isoindol-2-yl]-propionic acid (400 mg, 0.81 mmol) in tetrahydrofurane (10 ml) was added carbonyldiimidazole (200 mg, 1.21 mmol) at room temperature. The solution was stirred at room temperature for 2 hours. To the mixture was added dimethylamine in THF (0.8 ml, 1.6 mmol). The resulted mixture was stirred at room temperature for 3 hours. Water (20 ml) was added to the reaction mixture. The solvent was removed in vacuo. The resulted mixture was taken up in ethyl acetate (30 ml) and washed with water (20 ml). The organic layer was washed with saturated sodium bicarbonate solution (3×20 ml), water (20 ml), brine (20 ml) and dried over magnesium sulfate. The solvent was removed in vacuo. The resulted oil was stirred with ether overnight. The suspension was filtered to give a yellowish solid. The solid was purified by HPLC(CH3CN: Water=45:55) to give cyclopropanecarboxylic acid {2-[1-(3,4-bis-difluoromethoxy-phenyl)-2-dimethylcarbamoyl-ethyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-amide as a white solid (200 mg, 50%): mp, 158-160° C.; 1H NMR (CDCl3): δ 0.86-0.92 (m, 2H, cyclopropyl ring CH2), 1.08-1.12 (m, 2H, cyclopropyl ring CH2), 1.66-1.70 (m, 1H, cyclopropyl ring CH, 2.93 (s, 3H, NCH3), 3.04 (dd, J=5, 15 Hz, 1H, CHHCO), 3.10 (s, 3H, NCH3), 3.64 (dd, J=8, 15 Hz, 1H, CHHCO), 4.13 (t, J=15 Hz, 2H, CHHN), 5.56-5.62 (m, 1H, CHN), 6.51 (t, JH-F=75 Hz, 1H, OCF2H), 6.54 (t, JH-F=75 Hz, 1H, OCF2H), 7.01 (d, J=8 Hz, 1H, Ar), 7.23-7.36 (m, 3H, Ar), 7.44 (t, J=8 Hz, 1H, Ar), 8.43 (d, J=8 Hz, 1H, Ar), 10.52 (s, 1H, NHCO); 13C NMR (CDCl3): 8.22, 16.16, 35.58, 35.92, 37.27, 49.59, 53.83, 58.94, 111.0, 115.65, 117.64, 117.67, 119.90, 119.80, 121.66, 122.58, 125.64, 133.27, 138.05, 138.69, 141.49, 169.11, 169.81, 172.65; Anal. Calcd. for C25H25F4N3O5: C, 57.36; H, 4.81; N, 8.03. Found: C, 57.22; H, 4.76; N, 8.11.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][CH2:7][CH3:8])[CH3:5])[CH3:2].[CH2:9]([O:11][CH:12]=[CH:13]C)[CH3:10].[C:15]([O-])(O)=O.[Na+]>[Cl-].[Al+3].[Cl-].[Cl-]>[CH2:1]([O:3][CH:4]([O:6][CH2:7][CH3:8])[CH:5]([CH3:15])[CH:9]([O:11][CH2:12][CH3:13])[CH3:10])[CH3:2]
Reactant: O=C([O-])O
Reactant: CC=COCC
Reactant: CCOC(C)OCC
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: CCOC(C)C(C)C(OCC)OCC
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
236 g of acetaldehyde diethyl acetal (abbreviation: acetal) and 1 g of aluminum chloride are added in 500 ml of four necked bottle under protection of nitrogen, the solution is freezed to −10° C., and kept at −10° C.˜−5° C., a mixture of 118 g of acetaldehyde diethyl acetal and 86 g (0.945 mol) of ethyl-(1-propenyl)-ether is slowly dropped, and continue to stir it for 10 min after finishing dropping, and the end of reaction is detected by GC. A saturated NaHCO3 solution is added in the reaction to neutralize it to pH=7, and to layer, the oil layer is dried by anhydrous sodium sulfate after being washed by water, and heated to 50° C.; most of acetaldehyde diethyl acetal is recycled, to obtain 169.6 g of 1,1,3-triethoxy-2-methyl-butane by vacuum distillation, and its content is 97.2%, and its yield is 88%.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH3:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8].C(O[CH:15]=[C:16]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])C>>[CH3:10][O:9][C:7]([C:6]1[C:5]([CH3:11])=[CH:4][S:3][C:2]=1[NH:1][CH:15]=[C:16]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:8]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: COC(=O)c1c(C)csc1N
Product: CCOC(=O)C(=CNc1scc(C)c1C(=O)OC)C(=O)OCC

Procedure:
Reaction of methyl 2-amino-4-methylthiophene-3-carboxylate with diethyl ethoxymethylenemalonate in a manner similar to that used in Reference Example 10 yields diethyl (3-methoxycarbonyl-4-methylthienyl)aminomethylenemalonate as crystals melting at 105.5°-106°C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:9])[C:5]([OH:8])=[CH:6][CH:7]=1.CO[C:12](OC)([CH3:14])[CH3:13]>O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[O:8][C:12]([CH3:14])([CH3:13])[O:9][C:4]=2[CH:3]=1
Reactant: COC(C)(C)OC
Reactant: Oc1ccc(Br)cc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(C)Oc2ccc(Br)cc2O1
Yield: 63.3 %

Procedure:
To benzene (50 mL) in a 250 mL round bottom flask was added 4-bromobenzene-1,2-diol (1 g, 5.29 mmol), 2,2-dimethoxypropane (2.204 g, 21.16 mmol), and p-toluene sulfonic acid monohydrate (0.050 g, 0.265 mmol). The flask was fitted with a Dean-Stark trap and heated to reflux for 18 h. Upon cooling, the reaction mixture was transferred to a separatory funnel and washed with 2 N NaOH solution (100 mL) and saturated NaCl solution (100 mL). The organic layer was dried with MgSO4, filtered, and concentrated to yield 5-bromo-2,2-dimethylbenzo[d][1,3]dioxole as a dark brown oil (767 mg, 63%): 1H NMR (400 MHz, CDCl3) δ 6.91-6.85 (m, 2H), 6.62-6.57 (m, 1H), 1.66 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 146.81 (s), 144.25 (s), 123.64 (s), 121.02 (s), 112.05 (s), 109.40 (s), 108.46 (s), 25.83 (s); ESIMS m/z 230 ([M+H]+), 228 ([M−H]−).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[N:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:8]=2)[CH:3]=[CH:2]1.[Br:20]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Br:20][C:3]1[C:4]2=[N:5][CH:6]=[C:7]([C:10]([O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[O:11])[CH:8]=[C:9]2[NH:1][CH:2]=1
Reactant: O=C(OCc1ccccc1)c1cnc2cc[nH]c2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)c1cnc2c(Br)c[nH]c2c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
To a 0° C. solution of benzyl 1H-pyrrolo[3,2-b]pyridine-6-carboxylate (830 mg, 3.29 mmol) in N,N-dimethylformamide (19 mL) was added N-bromosuccinimide (609 mg, 3.42 mmol). The reaction was allowed to gradually warm to room temperature and stir over the weekend. The reaction was diluted with ethyl acetate and washed successively with saturated aqueous sodium thiosulfate, saturated aqueous sodium bicarbonate, water, and brine. The organics were dried over sodium sulfate, filtered, and concentrated to give the title compound (1.08 g, quantitative). +ESI (M+1+H) 333.0; 1H NMR (400 MHz, DMSO-d6, δ): 12.06 (br. s., 1 H), 8.99 (d, J=1.8 Hz, 1 H), 8.37 (d, J=2.0 Hz, 1 H), 8.14 (d, J=2.9 Hz, 1 H), 7.52 (m, 2 H), 7.41 (m, 3 H), 5.41 (s, 2 H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:14]1([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:6]([CH2:5][CH:4]([OH:13])[CH2:3][CH2:2][N:17]1[CH2:16][CH2:15][N:14]([C:20]2[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: N#Cc1ccc(N2CCNCC2)cc1
Product: N#Cc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-chloro-1-phenoxy-2-butanol and 4-(1-piperazinyl)benzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(N(CC)CC)C.Cl.[N:17]1([CH2:23][CH2:24][C:25]2[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]3=[C:27]([C:34](Cl)=[O:35])[N:26]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([NH:5][C:34]([C:27]2[N:26]=[C:25]([CH2:24][CH2:23][N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=23)=[O:35])[CH:6]=[CH:7][CH:8]=1
Reactant: Nc1cccc(Cl)c1
Reactant: O=C(Cl)c1nc(CCN2CCOCC2)n2ccccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(Nc1cccc(Cl)c1)c1nc(CCN2CCOCC2)n2ccccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.2 %

Procedure:
To a solution of 3-chloroaniline (0.060 mL, 0.54 mmol) and triethylamine (0.16 mL, 1.14 mmol) in CH2Cl2 (10 mL) was added 3-(2-morpholin-4-yl-ethyl)-imidazo[1,5-a]pyridine-1-carbonyl chloride hydrochloride (150 mg, 0.45 mmol). The mixture was stirred at ambient temperature for 1 h then washed with sat. aq. NaHCO3 (20 mL). The organic layer was separated and the aqueous layer was extracted with dichloromethane (20 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was chromatographed on silica to yield the title compound (61 mg, 35%). 1H NMR (DMSO-d6) δ 10.0 (1H), 8.45 (1H), 8.15 (2H), 7.81 (1H), 7.35 (1H), 7.20 (1H), 7.10 (1H), 6.94 (1H), 3.49 (4H), 3.26 (2H), 2.81 (2H), 2.44 (4H); m/z (M+H)=385.18.
Reaction SMILES: [CH:1]1([N:9]=[C:10]=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCOC(C)=O.CCCCCC.CC#[N:26]>>[CH:1]1([NH:9][C:10]([NH2:26])=[S:11])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: S=C=NC1CCCCCCC1
Reactant: CC#N
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: NC(=S)NC1CCCCCCC1
Reaction time: 72 h
Yield: 78.2 %

Procedure:
To a stirred solution of cyclooctyl isothiocyanate (7.26 g, 42.9 mmol) in 70 ml of CH3CN was added 8.5 ml of 15N NH4OH (130 mmol). The reaction progress was monitored by thin layer chromatography (TLC); 1/1 EtOAc/hexane. After 3 days, the reaction solution was concentrated, dissolved in 50 ml of ethyl acetate and washed with water (25 ml) and brine (aqueous saturated NaCl) (3×25 ml ea.). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica gel, 3/7 EtOAc/hexane) to yield 6.25 g (78.2%) of the desired thiourea. PMR(CDCl3)ppm 6.5 (bs, 1H), 6.00 (s, 2H), 4.35 (bs, 1/2H), 3.45 (bs, 1/2H), 2.1-1.3 (m, 14H). The melting point (MP) was 93°-95° C.
Reaction SMILES: [OH-].[Na+].[S:3](Cl)([C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1)(=[O:5])=[O:4].[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[NH:21][C:22]=2[CH:23]=1>O.C1(C)C=CC=CC=1>[Br:14][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26][CH2:25][CH2:24][C:20]=3[N:21]([S:3]([C:6]3[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=3)(=[O:5])=[O:4])[C:22]=2[CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CCCc2[nH]c3cc(Br)ccc3c2C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(S(=O)(=O)n2c3c(c4ccc(Br)cc42)CN(C(=O)OC(C)(C)C)CCC3)cc1
Reaction time: 18 h
Yield: 49.5 %

Procedure:
6 N NaOH (10 mL), TsCl (0.48 g, 2.5 mmol) and (Bu4NH)2SO4 (50% solution in water, 0.17 mL) were added to a solution of tert-butyl 8-bromo-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carboxylate (0.76 g, 2.1 mmol) in toluene (17 mL), and the resulting solution was stirred for 18 h. Additional TsCl (55 mg, 0.29 mmol) was added, and the reaction was stirred for 18 h. The solution was partitioned with H2O and the resulting layers were separated. The aqueous phase was extracted with EtOAc (2×20 mL). The combined organic extracts were washed with brine (25 mL), dried over Na2SO4 and concentrated to dryness under reduced pressure. Flash chromatography (40 g ISCO hexanes/EtOAC, 90:10 for 2 column volumes, increased to 50:50 over 12 column volumes and held for 4 column volumes) provided the title compound (0.54 g, 50%) as a white foam: 1H NMR (500 MHz, DMSO-d6) δ 8.24-8.20 (m, 1H), 7.64 (d, J=8.0 Hz, 2H), 7.51 (d, J=8.5 Hz, 1H), 7.46 (dd, J=8.5, 1.5 Hz, 1H), 7.37 (d, J=8.0 Hz, 2H) 4.44-4.40 (m, 2H), 3.56 (t, J=5.5 Hz, 2H), 3.20-3.18 (m, 2H), 2.31 (s, 3H), 1.86-1.84 (m, 2H), 1.29-1.03 (m, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:20]([OH:22])=O)[CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]1[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25][NH:24]1.OC1C2N=NNC=2C=CC=1.C(N(C(C)C)CC)(C)C.C(Cl)CCl>C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[NH:13][CH:12]=1)[C:20]([N:24]1[CH2:25][CH2:26][C:27]2[C:32](=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:23]1)=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: c1ccc2c(c1)CCNC2
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC(Cc1c[nH]c2ccccc12)C(=O)N1CCc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyloxycarbonyl-L-tryptophan (3.00 g, 9.9 mmol) and 1,2,3,4-tetrahydroisoquinoline (1.31 g, 9.9 mmol) were suspended in THF (20 ml). At a temperature of 0° C., hydroxybenzotriazole (1.33 g, 9.9 mmol), diisopropylethylamine (1.27 g, 9.9 mmol), and EDC (N-3-dimethylaminopropyl-N′-ethylcarbodiimide hydrochloride, 1.89 g, 9.9 mmol) were added. The reaction mixture was stirred overnight at r.t. The solvent was evaporated, the residue was taken up in ethyl acetate, washed with water, and dried (Na2SO4). After evaporation of the solvent, the title compound, MS: m/e=420.5 (M+H+), (2.90 g, 70%) was obtained by chromatographic purification of the residue (silica gel, MeOH, CH2Cl2).
Reaction SMILES: [NH2:1][C@H:2]([C:13]([OH:15])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>>[Cl:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH:2]([CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[C:13]([OH:15])=[O:14])=[O:22])=[CH:19][CH:18]=1
Reactant: N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Reactant: O=C(Cl)c1ccc(Cl)cc1
Product: O=C(NC(Cc1c[nH]c2ccccc12)C(=O)O)c1ccc(Cl)cc1
Yield: 79.2 %

Procedure:
By using 10 g of L-tryptophane and 9 g of 4-chlorobenzoyl chloride, and a method similar to that described in reference example 6, recrystallized from methanol-water there was obtained 13.3 g of 2-(4-chlorobenzoylamino)-3-(indol-3-yl)propionic acid in the form of colorless needle-like crystals. Melting point: 100°-102° C. [α]D25 -49.3° (C=1, methanol)
Reaction SMILES: O[CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C(Cl)(Cl)Cl>[Br:19][CH2:2][C:3]1[N:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][CH:4]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)/C=C/c1cccc(CO)n1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)/C=C/c1cccc(CBr)n1
Reaction time: 0.25 h
Yield: 88 %

Procedure:
To a solution prepared with t-butyl 3-(6-hydroxymethyl-pyridin-2-yl)-trans-acrylate (trans form, 2 g) described in Reference Example 10-(1) and carbon tetrabromide (4.23 g) in methylene chloride (20 mL) at ice temperature, triphenylphosphine (2.68 g) was added in small portions, and the mixture was stirred at the same temperature for 15 minutes. The reaction solution was transferred to a separating funnel, diluted with chloroform, washed with saturated aqueous sodium bicarbonate and brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by chromatography on silica gel (hexane-ethyl acetate=10:1) to give 2.23 g of t-butyl 3-(6-bromomethylpyridin-2-yl)-trans-acrylate as a light yellow powder.
Reaction SMILES: N1C=CC=CC=1.[CH3:7][C:8]1[C:13](=O)[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]=1[CH2:18][C:19]([CH3:21])=[CH2:20].[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([NH2:27])=[CH:25][CH:24]=1>ClCCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:22][C:23]1[CH:29]=[CH:28][C:26]([N:27]=[C:13]2[C:12]([CH3:15])=[C:11]([CH3:16])[C:10](=[O:17])[C:9]([CH2:18][C:19]([CH3:21])=[CH2:20])=[C:8]2[CH3:7])=[CH:25][CH:24]=1
Reactant: C=C(C)CC1=C(C)C(=O)C(C)=C(C)C1=O
Reactant: Nc1ccc(Cl)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCCl
Product: C=C(C)CC1=C(C)C(=Nc2ccc(Cl)cc2)C(C)=C(C)C1=O
Temperature: 90 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Titanium tetrachloride (2.42 ml, 22.1 mmol) was added dropwise to a solution of pyridine (7.13 ml, 88.2 mmol) in 1,2-dichloroethane (40 ml) and, after completion of addition, the reaction mixture was heated under reflux minutes in an argon atmosphere. After cooling of the reaction mixture, to the mixture was added a solution of 3,5,6-trimethyl-2-(2-methyl-2-propenyl)-1,4-benzoquinone (3.00 g, 14.7 mmol) and p-chloroaniline (5.62 g, 44.1 mmol) in 1,2-dichloroenhane (20 ml) and the mixture was stirred 90° C. for 45 minutes in an argon atmosphere. The reaction mixture was cooled and filtered through Cerite and the filtrate was washed with a saturated saline solution, dried and concentrated. The residue was purified by silica gel column chromatography (hexane-ethyl acetate, 93:7) to obtain the desired compound as oil (4.43 g, yield: 96.0%).