Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:24])[CH:5]([S:13]([C:16]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=1)(=[O:15])=[O:14])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)C>CO.[OH-].[Na+]>[CH3:23][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([CH:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:4]([OH:24])=[O:3])(=[O:15])=[O:14])=[CH:21][CH:20]=1
Reactant: CCOC(=O)C(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(S(=O)(=O)C(Cc2ccccc2)C(=O)O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a stirred solution of 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid ethyl ester (348 mg, 1 mmol) in methanol (25 ml), 10 N NaOH (10 ml) was added. The reaction mixture was stirred at room temperature for 48 hours. At the end, the reaction mixture was concentrated and carefully neutralized with dilute HCl. The residue obtained was extracted with chloroform washed well with water, dried and concentrated. The product obtained was purified by silica-gel column chromtography by eluting with ethyl acetate:methanol (95:5) to afford 2-(4-methoxy-benzenesulfonyl)-3-phenyl-propionic acid as a colorless oil. Yield: 250 mg, 89%; MS: 321 (M+H)+.
Reaction SMILES: ClC1N=C([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=4)=[N:11][C:10]=3[CH2:9]2)C=C(C)N=1.C(NC(NC1C=CC(C2N=C(N3CCOCC3)C3CCNCC=3N=2)=CC=1)=O)C.Cl[C:66]1[N:71]=[C:70]([Cl:72])[CH:69]=[C:68]([CH3:73])[N:67]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C>>[Cl:72][C:70]1[CH:69]=[C:68]([CH3:73])[N:67]=[C:66]([N:8]2[CH2:17][CH2:16][C:15]3[C:14]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[N:13][C:12]([C:24]4[CH:29]=[CH:28][C:27]([NH:30][C:31]([NH:33][CH2:34][CH3:35])=[O:32])=[CH:26][CH:25]=4)=[N:11][C:10]=3[CH2:9]2)[N:71]=1
Reactant: Cc1cc(Cl)nc(Cl)n1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2cc(C)nc(Cl)n2)C3)cc1
Agent: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCNC3)cc1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CCN(c2nc(C)cc(Cl)n2)C3)cc1

Procedure:
and 1-(4-(7-(2-chloro-6-methylpyrimidin-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (vz2): 1-Ethyl-3-(4-(4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (0.0506 g, 0.132 mmol) and 2,4-Dichloro-6-methylpyrimidine (0.0360 g, 0.221 mmol) were combined then added dry N,N-Dimethylformamide (0.910 mL, 11.8 mmol) followed by N,N-Diisopropylethylamine (0.0456 mL, 0.262 mmol). The reaction was microwaved on 200 watts, 120° C. for 30 minutes on a CEM microwave. The reaction mixture was concentrated, chromatographed through silica gel (4 g, 0-100% EtOAc in heptane), and then purified by HPLC. 1-(4-(7-(4-chloro-6-methylpyrimidin-2-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (vz1): 1H NMR (500 MHz, DMSO) δ 8.62 (s, 1H), 8.21 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.71 (s, 1H), 6.15 (t, J=5.6, 1H), 4.81 (s, 2H), 3.96 (s, 2H), 3.78-3.68 (m, 4H), 3.53-3.41 (m, 4H), 3.17-3.05 (m, 2H), 2.75 (t, J=5.2, 2H), 2.34 (s, 3H), 1.07 (t, J=7.2, 3H). LC/MS-m/z+509.2 (M+H)+; 1-(4-(7-(2-chloro-6-methylpyrimidin-4-yl)-4-morpholino-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)-3-ethylurea (vz2): 1H NMR (500 MHz, DMSO) δ 8.63 (s, 1H), 8.21 (d, J=8.8, 2H), 7.49 (d, J=8.8, 2H), 6.88 (s, 1H), 6.16 (t, J=5.6, 1H), 4.69 (s, 2H), 3.86 (s, 2H), 3.78-3.69 (m, 4H), 3.56-3.43 (m, 4H), 3.18-3.04 (m, 2H), 2.77 (d, J=4.6, 2H), 2.29 (s, 3H), 1.06 (t, J=7.2, 3H). LC/MS-m/z+509.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([C:7]2[O:12][C:11](=[O:13])[C:10]3[CH:14]=[C:15]([Cl:19])[CH:16]=[C:17]([CH3:18])[C:9]=3[N:8]=2)[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1.[CH3:27][NH2:28]>O1CCCC1>[Br:1][C:2]1[CH:6]=[C:5]([C:7]([NH:8][C:9]2[C:10]([C:11]([NH:28][CH3:27])=[O:13])=[CH:14][C:15]([Cl:19])=[CH:16][C:17]=2[CH3:18])=[O:12])[N:4]([C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][N:21]=2)[N:3]=1
Reactant: CN
Reactant: Cc1cc(Cl)cc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: C1CCOC1
Product: CNC(=O)c1cc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 60 °C

Procedure:
To a solution of 2-[3-bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazol-5-yl]-6-chloro-8-methyl-4H-3,1-benzoxazin-4one (i.e. the benzoxazinone product of Example 5, Step E) (0.20 g, 0.44 mmol) in tetrahydrofuran was added methylamine (2.0 M solution in THF, 0.514 mL, 1.02 mmol), and the reaction mixture was heated to 60° C. for 90 minutes and then cooled to room temperature. The tetrahydrofuran solvent was evaporated under reduced pressure, and the residual solid was triturated with ether, filtered, and dried to afford the title compound, a compound of the present invention, as a solid (40 mg), m.p. 162-164° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[CH:38](O)=[O:39]>ClCCl>[CH:38]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]4[O:21][CH2:20][O:19][C:17]4=[CH:18][C:13]=3[CH2:12][C:11]([CH3:22])=[N:10][N:9]=2)=[CH:4][CH:3]=1)=[O:39]
Reactant: O=CO
Reactant: CC1=NN=C(c2ccc(N)cc2)c2cc3c(cc2C1)OCO3
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CC1=NN=C(c2ccc(NC=O)cc2)c2cc3c(cc2C1)OCO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
3.0 g (10.2 mmol) of 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine were dissolved in 160 ml of dichloromethane and first 2.75 g (13.3 mmol) of dicyclohexylcarbodiimide, then 0.51 ml (13.3 mmol) of 100% formic acid were added and the reaction mixture was stirred for 2 hours at room temperature. The precipitated N,N'-dicyclohexylurea was filtered, the filtrate was exracted with 2×30 ml of 10% aqueous sodium carbonate solution, then with 2×30 ml of distilled water, the organic layer was dried and evaporated at reduced pressure. The residue was dissolved in ethyl acetate, filtered and evaporated under reduced pressure. The resulting raw product was recrystallized from 20 ml of 50% ethanol to yield 2.93 g (89.3%) of the aimed product, m.p. 152°-154° C. (slight decomp.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][C@@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:9]([OH:11])=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH:22]([N:35]1[CH2:38][CH:37]([C:39](=[N:41]O)[NH2:40])[CH2:36]1)([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[NH2:41]/[C:39](=[N:40]\[O:10][C:9]([C@H:8]([CH2:12][CH2:13][CH2:14][CH:15]1[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1)[CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:21])=[O:11])/[CH:37]1[CH2:38][N:35]([CH:22]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:36]1
Reactant: NC(=NO)C1CN(C(c2ccccc2)c2ccccc2)C1
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)C(=O)O/N=C(\N)C1CN(C(c2ccccc2)c2ccccc2)C1

Procedure:
Method as for preparation 2 using (2R)-2-(2-tert-butoxy-2-oxoethyl)-5-cyclohexylpentanoic acid (1.65 g, 5.51 mmol) and 1-benzhydryl-N′-hydroxy-3-azetidinecarboximidamide (preparation 34) (1.74 g, 6.17 mmol) as starting materials.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]2[N:6]([CH3:19])[C:7]([CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)=[N:8][C:4]=2[CH:3]=1.[CH3:22][N:23]([CH3:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.CC(O)=O.[OH-].[Na+]>C(Cl)Cl.O>[C:17]([C:14]1[CH:15]=[CH:16][C:11]([CH2:10][CH2:9][C:7]2[N:6]([CH3:19])[C:5]3[CH:20]=[CH:21][C:2]([NH:1][CH2:28][C:27]4[CH:30]=[CH:31][C:24]([N:23]([CH3:32])[CH3:22])=[CH:25][CH:26]=4)=[CH:3][C:4]=3[N:8]=2)=[CH:12][CH:13]=1)#[N:18]
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: Cn1c(CCc2ccc(C#N)cc2)nc2cc(N)ccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: O
Product: CN(C)c1ccc(CNc2ccc3c(c2)nc(CCc2ccc(C#N)cc2)n3C)cc1

Procedure:
5-amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole (1.0 g, 3.6 mmol) which is obtainable according to Example 2 (step c) and 4-dimethylamino-benzaldehyde (0.59 g, 3.0 mmol) in 25 mL of CH2Cl2 with 0.22 mL of AcOH are combined with Na[HB(OAc)3](2.2 g, 10.3 mmol) at ambient temperature with stirring. The mixture is stirred for 1 h at ambient temperature, covered with water, carefully acidified with conc hydrochloric acidaq and then made alkaline with 4N NaOH solution. The organic phase is separated off, dried and concentrated by evaporation. The product is chromatographed over silica gel (CH2Cl2/methanol=5/1) and crystallised from ethyl acetate.
Reaction SMILES: CCOCC.[Li].Br[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:14][N:15]1[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]1>C(Cl)Cl.O>[CH3:14][N:15]1[CH2:20][CH2:19][C:18]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:21])[CH2:17][CH2:16]1
Reactant: Brc1ccccc1
Reactant: CN1CCC(=O)CC1
Agent: [Li]
Solvent: O
Solvent: CCOCC
Solvent: ClCCl
Product: CN1CCC(O)(c2ccccc2)CC1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Anhydrous ether (1900 ml) is placed, under nitrogen, in a previously dried 5 liter 3-necked flask fitted with dropping funnel, reflux condenser and magnetic stirrer. Lithium (28.4 g, 4.1 g. at.) is added together with 20 ml bromobenzene (20 ml). The mixture is heated at reflux temperature until a reaction commences. Heating is discontinued and a total of 312 g. (2.0 moles) bromobenzene is added dropwise during 0.5 hour. The mixture is stirred for a further 3 hours and the remaining traces of lithium are removed. The solution is cooled to 0° C. and 1-methyl-4-piperidone (161 g, 1.42 moles) is added over a 0.5 hour period. The mixture is stirred for a further 2 hours at room temperature, cooled to 0° C. and water (500 ml) is added. The mixture is transferred to a separating funnel. Methylene chloride is added to redissolve the precipitate which formed and the aqueous layer is extracted with ether. The combined ether extracts are dried over Na2SO4, evaporated and crystallized from methylene chloride-pentane to give the title compound, mp 110°-112° C. (S. M. Elreain and J. C. Safranski, Jr., supra, reported bp 128°-130° C./0.9mm).
Reaction SMILES: [NH2:1][C:2]1[C:11]([CH3:12])=[C:10]([CH3:13])[CH:9]=[C:8]2[C:3]=1[N:4]=[C:5]([O:16][CH3:17])[C:6]([O:14][CH3:15])=[N:7]2.[CH2:18]([S:20](Cl)(=[O:22])=[O:21])[CH3:19].N1C=CC=CC=1.O>O1CCCC1>[CH3:15][O:14][C:6]1[C:5]([O:16][CH3:17])=[N:4][C:3]2[C:8](=[CH:9][C:10]([CH3:13])=[C:11]([CH3:12])[C:2]=2[NH:1][S:20]([CH2:18][CH3:19])(=[O:22])=[O:21])[N:7]=1
Reactant: COc1nc2cc(C)c(C)c(N)c2nc1OC
Reactant: CCS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: CCS(=O)(=O)Nc1c(C)c(C)cc2nc(OC)c(OC)nc12
Temperature: 20 °C
Reaction time: 3.5 h
Yield: 96.2 %

Procedure:
A mixture of 5-amino-2,3-dimethoxy-6,7-dimethylquinoxaline (from Preparation 2) (50 mg, 0.214 mmol), ethanesulphonyl chloride (138 mg, 1.07 mmol) and pyridine (87 μl, 1.07 mmol) in dry tetrahydrofuran (1 ml) was stirred at 20° C. for 3.5 hours. Additional portions of ethanesulphonyl chloride (138 mg, 1.07 mmol) and pyridine (87 ml, 1.07 mmol) were added and the mixture was stirred for a further 4 days. Water (0.6 ml) was added, and the mixture was stirred for 40 minutes. The mixture was partitioned between ethyl acetate (15 ml) and 2M hydrochloric acid (5 ml). The organic solution was washed with water (5 ml), saturated aqueous sodium bicarbonate (5 ml), dried (MgSO4), and concentrated under reduced pressure to give the title compound (67 mg, 96%) as a straw-coloured solid, m.p. 201°-203° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[CH:10][C:11]([C:21]([OH:23])=O)=[N:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.[NH2:24][N:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1.C(Cl)CCl>CN(C1C=CN=CC=1)C>[N:25]1([NH:24][C:21]([C:11]2[CH:10]=[N:9][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)=[C:13]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)[N:12]=2)=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: NN1CCCCC1
Reactant: O=C(O)c1cnc(-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)n1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Product: O=C(NN1CCCCC1)c1cnc(-c2ccc(Br)cc2)c(-c2ccc(Br)cc2)n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 5.2 %

Procedure:
To 5,6-Bis-(4-bromophenyl)-pyrazine-2-carboxylic acid (108 mg, 0.25 mmol) from Preparation A, step (b), DMAP (0.025 mmol, in 500 μl DCM), 1-aminopiperidine (0.25 mmol, in 1100 μl DCM), EDC (0.27 mmol, in 1100 μl DCM and cooled to 8° C.) were added. The reaction mixture was stirred at 25° C. for 20 h, then washed with saturated NaHCO3 solution, dried (MgSO4), filtered and evaporated. Semipreparatory HPLC (0.01% TEA in the buffered phase) gave the subtitle compound (6.7 mg, 5.4%).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][CH:4]([N:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:7](Cl)=[O:8])[CH3:5]>C1COCC1>[OH:2][NH:1][C:7](=[O:8])[N:6]([CH:4]([CH3:5])[CH3:3])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)N(C(=O)Cl)c1ccccc1
Reactant: NO
Solvent: C1CCOC1
Product: CC(C)N(C(=O)NO)c1ccccc1
Reaction time: 8 h
Yield: 75 %

Procedure:
A solution, of 50% aqueous hydroxylamine (16.8 g, 0.25 mol) was added dropwise to a solution of (1-methylethyl)phenylcarbamic chloride (20.0 g, 0.1 mol) in 200 mL of THF in an ice bath so that the reaction temperature was kept below 30° C. Precipitate began to form halfway through the addition. The resulting slurry was stirred overnight. The mixture was filtered, and the solids collected were first washed with water and then with hexane/ether. After air-drying, 14.56 g of the title compound was obtained. Its structure was confirmed by an analysis of the NMR spectra. The filtrate was stripped down to afford a residue which was washed sequentially with 1N HCl, water and hexane/ether to yield a second crop of the title compound (5.38 g) melting at 165-166° C. The combined yield was 100%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16][CH3:17])[N:10]3[N:9]=2)=[CH:4][CH:3]=1.ClC1C=CC=C(C(OO)=[O:33])C=1.CCCCCC.C(OCC)(=O)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)=[C:11]3[CH:12]=[CH:13][CH:14]=[C:15]([S:16]([CH3:17])=[O:33])[N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1cccc2c(-c3ccncn3)c(-c3ccc(F)cc3)nn12
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CS(=O)c1cccc2c(-c3ccncn3)c(-c3ccc(F)cc3)nn12
Reaction time: 1 h

Procedure:
To a stirred solution of 2-(4-fluorophenyl)-7-methylthio-3-(4-pyrimidinyl)pyrazolo[1,5-a]pyridine (Example 6, 0.246 g, 0.73 mmol) in chloroform (20 mL) was added, dropwise, a solution of of m-chloroperbenzoic acid (57–86%, 0.221 g, 0.73–1.1 mmol) in chloroform (10 mL). After 1 hour, the reaction was quenched by the addition of aqueous potassium carbonate (20 mL), and the organic phase was separated. The aqueous phase was further extracted with chloroform (2×20 mL) and the combined chloroform phases were dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and the solvent was evaporated to give a light brown solid. Chromatography on silica gel eluting with a hexane/ethyl acetate gradient (0–30% ethyl acetate) gave the title compound as the major product, 0.170 g (66%). 1H NMR (DMSO-d6): δ 3.11 (s, 3H), 7.13 (d, J=5.4 Hz, 1H), 7.33 (t, J=8.8 Hz, 2H), 7.50 (d, J=7.0 Hz, 1H), 7.63 (dd, J=5.7, 8.6 Hz, 2H), 7.76 (dd, J=7.4, 8.1 Hz, 1H), 8.50 (d, J=8.8 Hz, 1H), 8.60 (d, J=5.5 Hz, 1H), 9.20 (s, 1H); APESI+MS m/z 353 (M+1)−.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][CH:2]1[C:3]([OH:5])=[O:4].I[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO.Cl>CC(O)C.O.[Cu]I>[C:10]1([N:1]2[CH2:8][CH2:7][CH2:6][C@H:2]2[C:3]([OH:5])=[O:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Ic1ccccc1
Reactant: O=C(O)C1CCCN1
Agent: [Cu]I
Agent: Cl
Agent: O=P([O-])([O-])[O-]
Solvent: OCCO
Solvent: O
Solvent: CC(C)O
Product: O=C(O)[C@@H]1CCCN1c1ccccc1
Temperature: 85 °C
Reaction time: 24 h
Yield: 32.2 %

Procedure:
A mixture of D,L-proline (5.00 g, 43.4 mmol), iodobenzene (7.39 g, 36.2 mmol), copper(I) iodide (0.41 g, 2.17 mmol), K3PO4 (15.4 g, 72.4 mmol), and ethylene glycol (4.49 g, 72.4 mmol) in 2-propanol (36 mL) was stirred at 85° C. for 24 h under argon atmosphere. The reaction mixture was cooled to room temperature and diluted with water. The mixture was acidified with 6 M hydrochloric acid solution (pH 3), and extracted with diethyl ether (300 mL), and the extract was washed with water, and saturated brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to afford a light brown solid. This solid was triturated with ethyl acetate and washed with diisopropyl ether successively to give the title compound (2.23 g, 27%) as a yellow solid.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[CH:11][C:10]2[N:13]=[CH:14][N:8]3[C:9]=2[C:4]=1[CH2:5][CH:6]([N:15]([CH2:19][CH2:20][CH3:21])[CH2:16][CH2:17][CH3:18])[CH2:7]3>Br>[CH2:19]([N:15]([CH2:16][CH2:17][CH3:18])[CH:6]1[CH2:5][C:4]2[C:3]([OH:2])=[CH:12][CH:11]=[C:10]3[N:13]=[CH:14][N:8]([C:9]=23)[CH2:7]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1Cc2c(OC)ccc3ncn(c23)C1
Agent: Br
Product: CCCN(CCC)C1Cc2c(O)ccc3ncn(c23)C1

Procedure:
5,6-Dihydro-7-methoxy-N,N-dipropyl-4H-imidazo(4,5,1 -ij)quinolin-5 -amine (1.0 g) was heated at 130° C. in 48% hydrobromic acid for 2 hours. The solution was cooled and was then evaporated under reduced pressure. The solid thus obtained was crystallized from methanol: ether; mp 270° C.
Reaction SMILES: Cl.[CH:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH:12]([NH:14][CH:15]1[CH2:17][CH2:16]1)[CH3:13].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][O:28][C@@H:27]([C:31](O)=[O:32])[CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19].ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.C(N=C=NCCCN(C)C)C.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH:15]1([N:14]([CH:12]([C:3]2[CH:4]=[CH:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:2]=2)[CH3:13])[C:31]([C@@H:27]2[O:28][CH2:29][CH2:30][N:25]([C:23]([O:22][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:24])[CH2:26]2)=[O:32])[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](C(=O)O)C1
Reactant: CC(NC1CC1)c1ccc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(c1ccc2ccccc2c1)N(C(=O)[C@H]1CN(C(=O)OC(C)(C)C)CCO1)C1CC1
Temperature: 25 °C
Reaction time: 19 h
Yield: 59.9 %

Procedure:
To a solution of N-[1-(2-naphthyl)ethyl]cyclopropylamine hydrochloride (149 mg), (2R)-4-(tert-butoxycarbonyl)morpholine-2-carboxylic acid (208 mg) and 1-hydroxybenzotriazole (122 mg) in N,N-dimethylformamide (6 mL) was added diisopropylethylamine (0.125 μL), and the thereto was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2078 mg) under ice-cooling. The mixture was stirred at room temperature for 19 hours and then to the reaction solution was added 1-normal aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice, saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The residue was triturated with n-hexane-diethyl ether (5:1) to give tert-butyl (2R)-2-({cyclopropyl[1-(2-naphthyl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(163-1)] (153 mg) as a colorless powder.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.O1CCOCC1.CCN(C(C)C)C(C)C.[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:27]([S:34][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Reactant: SCc1ccccc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Nc1ccc(SCc2ccccc2)cc1[N+](=O)[O-]
Temperature: 80 °C
Yield: 88.2 %

Procedure:
A screw cap vial was charged with 4-bromo-2-nitroaniline (7.00 g, 32.3 mmol), xantphos (0.933 g, 1.613 mmol), tris(dibenzylideneacetone)dipalladium (0) (0.738 g, 0.806 mmol), 1,4-Dioxane (32.3 ml), and DIPEA (11.22 ml, 64.5 mmol). The vial was purged with Argon, sealed and heated to 80° C. for 10 minutes. The reaction was cooled to room temperature and benzyl mercaptan (4.01 ml, 33.9 mmol) was added and the reaction heated at 80° C. for 3 hours. The reaction was cooled to room temperature, diluted with water and extracted with DCM (3×). The combined organics were washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting material was concentrated, dissolved in minimal DCM and purified via column chromatography (silica gel 40 g, gradient elution 0 to 50% EtOAc:Heptane) to afford 4-(benzylthio)-2-nitroaniline (7.43 g, 28.5 mmol, 88% yield). m/z (ESI) 261.2 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([NH:6][S:7]([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8])([CH3:5])[C:3]#[CH:4].C([Mg]Br)C.[CH:21](=[O:29])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].O>C1COCC1>[OH:29][CH:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:4]#[C:3][C:2]([CH3:1])([NH:6][S:7]([C:10]1[CH:11]=[CH:12][C:13]([CH3:14])=[CH:15][CH:16]=1)(=[O:8])=[O:9])[CH3:5]
Reactant: CCCCCCCC=O
Reactant: C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Agent: CC[Mg]Br
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCC(O)C#CC(C)(C)NS(=O)(=O)c1ccc(C)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 75 %

Procedure:
In 2 ml of THF was dissolved 1.185 g (5 mmole) of 3-methyl-3-tosylamino-1-butyne, and a THF solution of ethylmagnesium bromide (12 mmole) was added thereto at room temperature, followed by refluxing for 1 hour. After cooling the solution to 0° C., a solution of 1.25 ml (8 mmole) of n -octanal in 3 ml of THF was added thereto, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed successively with a hydrochloric acid aqueous solution, a sodium hydrogencarbonate aqueous solution, and water, and then dried. The solvent was removed by distillation, and the residual oily substance was purified by column chromatography to obtain 1.37 g (percent yield: 75%) of 5-hydroxy-2-methyl-2-tosylamino-3-dodecyne.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:22][CH:21]=4)=[CH:16][CH:15]=3)[N:10]=2)=[CH:5][CH:4]=1)#[N:2].CC(O)=O.CCN(CC)CC.[N-:44]=[N+:45]=[N-:46].[Na+].Cl>O.CN(C=O)C>[NH:44]1[C:1]([C:3]2[CH:8]=[CH:7][C:6]([C:9]3[O:13][N:12]=[C:11]([C:14]4[CH:19]=[CH:18][C:17]([C:20]5[CH:25]=[CH:24][C:23]([O:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31])=[CH:22][CH:21]=5)=[CH:16][CH:15]=4)[N:10]=3)=[CH:5][CH:4]=2)=[N:2][N:46]=[N:45]1
Reactant: N#Cc1ccc(-c2nc(-c3ccc(-c4ccc(OCCCC(=O)O)cc4)cc3)no2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: O=C(O)CCCOc1ccc(-c2ccc(-c3noc(-c4ccc(-c5nnn[nH]5)cc4)n3)cc2)cc1
Temperature: 140 °C
Yield: 71.6 %

Procedure:
A mixture of 4-(4′-{5-[4-cyanophenyl]-[1,2,4]oxadiazol-3-yl}biphenyl-4-yloxy)butyric acid (3.17 g, 7.45 mmol), DMF (15 ml), AcOH (2.25 ml, 37.5 mmol), NEt3 (5.0 ml, 36 mmol), and NaN3 (2.89 g, 44.5 mmol) was stirred at 140° C. After 24 h water (150 ml) and concentrated hydrochloric acid (6 ml) were added. The product was isolated by filtration, washed with water, resuspended in MeCN (100 ml), heated to reflux (it did not dissolve completely), homogenized, and allowed to cool to room temperature. Filtration yielded 2.50 g (72%) of 4-(4′-{5-[4-(5-tetrazolyl)phenyl]-[1,2,4]oxadiazol-3-yl}biphenyl-4-yloxy)butyric acid as a solid.