Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)[CH3:2].[CH:11]([S:13]([F:16])(=[O:15])=[O:14])=[CH2:12].O>C(O)(C)C>[F:16][S:13]([CH2:11][CH2:12][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[CH:5]=1)(=[O:15])=[O:14]
Reactant: CCNc1cccc(C)c1
Reactant: C=CS(=O)(=O)F
Solvent: CC(C)O
Solvent: O
Product: CCN(CCS(=O)(=O)F)c1cccc(C)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
N-Ethyl-m-toluidine (66.5 g) (0.05 m) is dissolved in isopropyl alcohol (75 ml) and vinylsulfonyl fluoride (55 g 0.5) is added dropwise over 1.25 hr. The reaction exotherms to 38° C. and the reaction mixture is stirred for 1 hr. at ambient temperature and drowned into 500 ml of ice and water. The product is collected by filtration, washed with water, and dried in air. The product melts at 32°-34° C.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([NH:20][CH3:21])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[F:24][CH2:25][CH2:26][CH2:27]Br>CN(C=O)C>[I:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=[C:10]([C:18]([N:20]([CH3:21])[CH2:27][CH2:26][CH2:25][F:24])=[O:19])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Reactant: FCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCCF)C(=O)c1cc2ccccc2c(-c2cccc(I)c2)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 16.4 %

Procedure:
To a solution of 1-(3-iodophenyl)-N-methyl-3-isoquinolinecarboxamide (22 mg, 0.06 mmol) in DMF (4.6 mL) was added 60% NaH (16 mg, 0.39 mmol) in one portion. The mixture was stirred under Ar at room temperature for 15 min. Then, 3-fluoropropyl bromide (29 μl, 0.39 mmol) was added. After stirring at room temperature for 20 h, the mixture was quenched by adding H2O (5 mL). The mixture was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried (MgSO4), filtered. The filtrate was concentrated in vacuo. The residue was chromatographed (SiO2, 30% ethyl acetate/hexane, 0.035% Et3N), thereby affording a semisolid (4.4 mg, 37%). 1H NMR (CDCl3) d 2.04-2.24 (m, 2 H, CH2), 3.16, 3.18 (two s, total 3 H, N-methyl), 3.60-3.75 (m, 2 H, N--CH2), 4.25-4.70 (qt, J=67.8, 47.1, 5.7 Hz, 2 H, CH2F), 7.20-7.30 (m, 1 H, aromatic), 7.55-7.65 (m, 2 H, aromatic), 7.73 (t, J=7.2 Hz, 1 H, aromatic), 7.83 (d, J=7.8 Hz, 1 H, aromatic), 7.94 (d, J=8.4 Hz, 1 H, aromatic), 7.98-8.09 (m, 2 H, aromatic), 8.12 (s, 1 H, aromatic). HRMS calcd. for C20H18FIN2O: 448.0448. Found: 448.0461
Reaction SMILES: [NH2:1][CH2:2][C:3]1([F:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4]1.CCN(C(C)C)C(C)C.Cl[C:27]1[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=[C:29]([Cl:37])[N:28]=1>C1COCC1>[Cl:37][C:29]1[N:28]=[C:27]([NH:1][CH2:2][C:3]2([F:16])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:10])[CH2:4]2)[C:32]2=[N:33][CH:34]=[CH:35][N:36]=[C:31]2[CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(F)(CN)C1
Reactant: Clc1cc2nccnc2c(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCC(F)(CNc2nc(Cl)cc3nccnc23)C1
Yield: 26.8 %

Procedure:
tert-butyl 3-(aminomethyl)-3-fluoropiperidine-1-carboxylate (3.86 g, 16.6 mmol) and DIPEA (3.22 g, 24.9 mmol) were added to a solution of 5,7-dichloropyrido[3,4-b]pyrazine (3.32 g, 16.6 mmol) in THF (60 mL) and the mixture was refluxed overnight. The volatile components were evaporated and the residue was extracted with ethyl acetate. Ethyl acetate was washed with brine and dried. The solvent was removed in vacuo The crude residue was purified by silica-gel chromatography eluting with Hexane-50% EtOAc/Hexane (gradient) then C18 column to afford the subtitled compound as pale yellow solid 1.76 g. MS (m/z): 396 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][S:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Cl:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22]O)=[CH:20][CH:19]=1.[H+].[B-:27]([F:31])([F:30])([F:29])[F:28]>C(Cl)Cl>[F:28][B-:27]([F:31])([F:30])[F:29].[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([S+:7]([CH2:22][C:21]2[CH:24]=[CH:25][C:18]([Cl:17])=[CH:19][CH:20]=2)[CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: Clc1ccc(CSc2ccc(Cl)cc2)cc1
Reactant: OCc1ccc(Cl)cc1
Agent: F[B-](F)(F)F
Agent: [H+]
Solvent: ClCCl
Product: Clc1ccc(C[S+](Cc2ccc(Cl)cc2)c2ccc(Cl)cc2)cc1
Yield: 77.4 %

Procedure:
5.2 g (19.4 mmol) of 4-chlorophenyl 4-chlorobenzyl sulfide, 4.14 g (29.0 mmol) of 4-chlorobenzyl alcohol and 14.15 g (87 mmol) of hydrogen tetrafluoroborate (54% in diethyl ether) in 20 ml of methylene chloride are reacted as in Example 6a) to give 7.23 g (77.4% of theory) of 4-chlorophenylbis(4-chlorobenzyl)sulfonium tetrafluoroborate in the form of white-beige crystals of melting point 147°-148° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12](OC(=O)C)(=O)[CH3:13]>CC(O)C>[Cl:11][C:8]1[CH:9]=[CH:10][C:2]2[N:1]=[C:12]([CH3:13])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: CC(=O)OC(C)=O
Solvent: CC(C)O
Product: Cc1nc2ccc(Cl)cc2c(=O)o1
Temperature: 25 °C
Yield: 89 %

Procedure:
A mixture of 2-Amino-5-chlorobenzoic acid (90 g, 524 mmole) and acetic anhydride (160 ml) was heated to reflux under nitrogen for 3 hours. The reaction became a solution during heating. The reaction was cooled to room temperature. Some solid came out during this period of time. The reaction mixture was slurried with 1 L IPA and filtered. The solid was washed with more IPA (50 ml) and dried under vacuum at room temperature for 18 hours. Product was collected as solid (91 g, yield: 89%). 1H NMR (CDCl3): 8.14 (d, J=6 Hz, 1H), 7.73 (dd, J=21 Hz, 6 Hz, 1H), 7.50 (d, J=21 Hz, 1H), 2.47 (s, 3H).
Reaction SMILES: [I:1]Cl.[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[Si](CC)(CC)CC)[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.CO.C1COCC1.F[B-](F)(F)F.[Ag+]>[CH2:3]([O:10][CH2:11][C@H:12]([C:14]1[C:22]2[C:17](=[N:18][CH:19]=[C:20]([C:23]([CH3:29])([CH3:28])[C:24]([O:26][CH3:27])=[O:25])[CH:21]=2)[NH:16][C:15]=1[I:1])[CH3:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncc(C(C)(C)C(=O)OC)cc2c1[C@H](C)COCc1ccccc1
Reactant: ClI
Agent: [Ag+]
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C(C)(C)c1cnc2[nH]c(I)c([C@H](C)COCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 84 %

Procedure:
A solution of iodine monochloride (2.83 g, 17.4 mmol) in MeOH (25 mL) was added over approximately 0.5 h via pressure equalizing addition funnel to a vigorously stirred mixture of methyl (S)-2-[3-(2-benzyloxy-1-methylethyl)-2-triethylsilyl-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-methylpropanoate (6.00 g, 13.4 mmol) and silver tetrafluoroborate (3.39 g, 17.4 mmol) in MeOH/THF (1:2; 75 mL) at 0° C. After an additional 0.5 h, the reaction was quenched with 1M Na2S2O3, warmed to room temperature and filtered through celite® washing copiously with ethyl acetate. The filtrate was concentrated under reduced pressure, poured into 1M Na2S2O3 and extracted with ethyl acetate (×3). The combined organic extract was washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (25% ethyl acetate/hexanes as eluent) to give the title compound as a colourless solid (5.54 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH2:24])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:33]([NH:36][C:37]1[CH:42]=[CH:41][C:40]([S:43](Cl)(=[O:45])=[O:44])=[CH:39][CH:38]=1)(=[O:35])[CH3:34]>CN(C)C=O>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:24][S:43]([C:40]1[CH:39]=[CH:38][C:37]([NH:36][C:33](=[O:35])[CH3:34])=[CH:42][CH:41]=1)(=[O:45])=[O:44])[CH2:8][NH:9][C:10](=[O:23])[C:11]1[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:15][CH:16]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CCc1ccc(C(=O)NC[C@H](N)C(=O)OC(C)(C)C)cc1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)CCc1ccc(C(=O)NC[C@H](NS(=O)(=O)c2ccc(NC(C)=O)cc2)C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
0.123 g (0.35 mmol) of (2S)-2-amino-3-(4-(2-methoxycarbonyl-ethyl) -benzoylamino)-propionic acid tert-butyl ester was dissolved in 2 ml of dimethylformamide and treated with 0.196 ml (1.4 mmol) of triethylamine and 0.164 g (0.7 mmol) of 4-acetylamino-benzenesulfonyl chloride. The solution was stirred for 4 hours at room temperature. The solvent was removed in vacuo, the residue was dissolved in dichloromethane and the solution was washed three times with water. The organic phase was dried with sodium sulfate, filtered and the solvent was removed in vacuo. The residue was chromatographed on silica gel eluting with n-heptane/ethyl acetate (1/2). Yield 90 mg. MS (ES+): m/e=548 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]2[C:6]([CH3:14])=[CH:7][N:8]([CH:11]([CH3:13])[CH3:12])[C:9]=2[CH:10]=1.C1C(=O)N([Br:26])C(=O)C1.C(Cl)Cl>CN(C=O)C>[Br:26][C:7]1[N:8]([CH:11]([CH3:12])[CH3:13])[C:9]2[CH:10]=[C:2]([Cl:1])[CH:3]=[C:4]([C:15]([O:17][CH3:18])=[O:16])[C:5]=2[C:6]=1[CH3:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(Cl)cc2c1c(C)cn2C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)cc2c1c(C)c(Br)n2C(C)C
Reaction time: 18 h
Yield: 55.2 %

Procedure:
To a stirred solution of methyl 6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (2.5 g, 9.41 mmol) in DMF (25 mL) was added NBS (1.7 g, 9.55 mmol). The reaction was stirred for 18 h then evaporated to dryness under vacuum. The reaction was purified by silica gel chromatography (Analogix, SF40-80g, 0 to 5% EtOAc in hexanes) then (Analogix, SF25-60g, 25% CH2Cl2 in hexanes) to give the product methyl 2-bromo-6-chloro-1-isopropyl-3-methyl-1H-indole-4-carboxylate (1.79 g, 5.19 mmol, 55.2% yield) as a clear oil. 1H NMR (400 MHz, DMSO-d6) δ=7.98 (d, J=1.8 Hz, 1H), 7.41 (d, J=1.8 Hz, 1H), 5.05 (dt, J=6.7, 13.4 Hz, 1H), 3.89 (s, 3H), 2.22 (s, 3H), 1.57 (d, J=7.1 Hz, 6H). MS(ES)+ m/e 344.0 [M+H]+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O:21]CC)=[O:20])=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.O.[OH-].[Li+:26]>O1CCCC1.O.O1CCCC1>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][N:13]3[C:16]([C:19]([O-:21])=[O:20])=[CH:17][N:18]=[C:12]3[CH:11]=2)[CH2:3][CH2:2]1.[Li+:26]
Reactant: CCOC(=O)c1cnc2cc(OCCN3CCOCC3)ccn12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C([O-])c1cnc2cc(OCCN3CCOCC3)ccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 105.2 %

Procedure:
Ethyl 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate (1 g, 3.13 mmol) was dissolved in tetrahydrofuran/water (4:1, 0.5 M). Lithium hydroxide monohydrate (131 mg, 3.13 mmol) was added and the mixture stirred at ambient temperature overnight. The mixture was then further diluted with tetrahydrofuran and concentrated. The resulting material was dried under high vacuum for 6 hours to give lithium 7-(2-morpholinoethoxy)imidazo[1,2-a]pyridine-3-carboxylate as a pale yellow solid (979 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[C@H:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[C:26]([O:43][CH:44]([CH2:52][O:53][C:54](=[O:70])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])[CH2:45][S:46][CH2:47][CH2:48][C:49](O)=[O:50])(=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].O>N1C=CC=CC=1>[C:1]([O:5][C:6](=[O:25])[C@H:7]([CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[NH:8][C:9](=[O:17])[C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:49](=[O:50])[CH2:48][CH2:47][S:46][CH2:45][CH:44]([O:43][C:26](=[O:42])[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])[CH2:52][O:53][C:54](=[O:70])[CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH3:69])=[CH:14][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)O)OC(=O)CCCCCCCCCCCCCCC
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)c1ccc(N)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)OCC(CSCCC(=O)Nc1ccc(C(=O)N[C@@H](Cc2ccccc2)C(=O)OC(C)(C)C)cc1)OC(=O)CCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.1 %

Procedure:
To a solution of 4-arninobenzoylphenylalanine t-butyl ester (170 mg) in pyridine (5 ml), phospholic trichloride (0.022 ml) was added, followed by stirring at room temperature for 2 hours. After addition of 6,7-bis(palmitoyloxy)- 4-thiaheptanoic acid (164 mg) as obtained in Reference Example 4, the reaction mixture was stirred at room temperature for 24 hours. After addition of water, the reaction mixture was extracted with ethyl acetate. The extract was washed with a 5% aqueous solution of citric acid, a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield the title compound (208 mg, yield 86%) as a colorless wax-like substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][NH:7][N:6]=1)=[O:4].[C:13](=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.IC>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:13])[N:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])=[O:4]
Reactant: COC(=O)c1n[nH]cc1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1c([N+](=O)[O-])cnn1C
Reaction time: 0.5 h
Yield: 29.9 %

Procedure:
340 mg (1.99 mM) of 4-nitro-1H-pyrazole-3-carboxylic acid methyl ester was dissolved in 4 ml of N,N-dimethylformamide, to which 0.33 ml (2.19 mM) of iodomethane and 1.3 g (3.98 mM) of cesium carbonate were added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 110 mg (30%) of the title compound and 195 mg (53%) of the compound of Preparative Example 7.
Reaction SMILES: [NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([OH:13])=O)[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[CH:6][CH:5]=1.[NH:24]([CH3:49])[C@H:25]([C:29]([N:31]([CH3:48])[C@H:32]([C:45]([NH2:47])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([C:41]([CH3:44])([CH3:43])[CH3:42])[CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27].O>C1COCC1>[NH:1]([C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])[C@H:2]([C:11]([N:24]([CH3:49])[C@H:25]([C:29]([N:31]([CH3:48])[C@H:32]([C:45]([NH2:47])=[O:46])[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([C:41]([CH3:44])([CH3:42])[CH3:43])[CH:35]=1)=[O:30])[CH:26]([CH3:28])[CH3:27])=[O:13])[CH2:3][C:4]1[CH:5]=[CH:6][C:7]([F:10])=[CH:8][CH:9]=1
Reactant: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)C(C)C
Reactant: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)O)OCc1ccccc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(O)c(C(C)(C)C)c1)C(N)=O)N(C)C(=O)[C@H](Cc1ccc(F)cc1)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.9 %

Procedure:
To a solution of Z-Phe(4-F)—OH (1.09 g, 3.44 mmol), N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.04 g, 2.87 mmol) and CMPI (878 mg, 3.44 mmol) in THF (30 ml), TEA (0.96 ml, 6.88 mmol) was added under cooling with ice and stirred at room temperature overnight. The reaction mixture was mixed with water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated to remove the solvent under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: n-hexane:ethyl acetate=1:3) to give Z-Phe(4-F)-N-Me-Val-N-Me-Tyr(3-tBu)-NH2 (1.73 g, 91%).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[CH:21]=[C:20]([CH3:22])[C:15]([NH:16][C:17](=O)[CH3:18])=[CH:14][C:13]=2[CH3:23])=[C:7]([CH3:24])[CH:6]=1)(=O)[CH3:2].[CH3:25][C:26]1[CH:31]=CC(I)=[CH:28][CH:27]=1>>[CH3:24][C:7]1[CH:6]=[CH:5][C:1]([NH:4][C:5]2[C:10]([CH3:11])=[CH:9][C:8]([C:12]3[CH:21]=[C:20]([CH3:22])[C:15]([NH:16][C:17]4[CH:28]=[CH:27][C:26]([CH3:25])=[CH:31][CH:18]=4)=[CH:14][C:13]=3[CH3:23])=[C:7]([CH3:24])[CH:6]=2)=[CH:2][CH:8]=1
Reactant: CC(=O)Nc1cc(C)c(-c2cc(C)c(NC(C)=O)cc2C)cc1C
Reactant: Cc1ccc(I)cc1
Product: Cc1ccc(Nc2cc(C)c(-c3cc(C)c(Nc4ccc(C)cc4)cc3C)cc2C)cc1

Procedure:
According to the same manner as that described in Synthesis Example 1, 16.19 of N,N'-diacetyl-2,5,2',5'-tetramethylbenzidine was reacted with 21.8 g of 4-methyliodobenzene to give N,N'-bis(4-methylphenyl)-2,5,2',5'-tetramethylbenzidine. Further, 12.0 g of N,N'-bis(4-methylphenyl)-2,5,2',5'-tetramethylbenzidine was reacted with 13.0 g of 4-tert-butyliodobenzene according to the same manner as that described in Synthesis Example 1 to give N,N'-bis(4-methylphenyl)-N,N'-bis(4-tert-butylphenyl)-2,5,2',5'-tetramethylbenzidine of the formula (4-a) (9.0 g, yield: 27.1%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][NH2:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:10][O:11][C:12](=[O:24])[CH2:13][C:14]1[C:15]([CH2:20][C:21](O)=[O:22])=[CH:16][CH:17]=[CH:18][CH:19]=1>>[C:1]1([CH2:7][CH2:8][NH:9][C:21]([CH2:20][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH2:13][C:12]([O:11][CH3:10])=[O:24])=[O:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)Cc1ccccc1CC(=O)O
Reactant: NCCc1ccccc1
Product: COC(=O)Cc1ccccc1CC(=O)NCCc1ccccc1

Procedure:
This was prepared from benzeneethanamine and 1,2-benzenediacetic acid monomethyl ester by the method described in Example 6 (a), MS; m/e 311
Reaction SMILES: [CH2:1]([N:8]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>ClCCl>[CH2:24]([N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][CH2:10][CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16]1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCN(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(CN(CCC2CCNCC2)Cc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
tert-Butyl 4-(2-(dibenzylamino)ethyl)piperidine-1-carboxylate (5.0 g, 12.25 mmol, 1 eq) was dissolved in dichloromethane (100 ml) and cooled to 0° C. TFA (25 ml) was added dropwise at that temperature and then stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was concentrated under reduced pressure. The crude product was used in the next stage without being purified further.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[O:15]=[C:16]1[NH:21][C:20]2[CH:22]=[C:23]([CH:26]=O)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1.[N:28]1([C:34]2[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=2)[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>C1COCC1>[O:15]=[C:16]1[NH:21][C:20]2[CH:22]=[C:23]([CH2:26][N:31]3[CH2:32][CH2:33][N:28]([C:34]4[CH:39]=[CH:38][C:37]([S:40]([NH2:43])(=[O:42])=[O:41])=[CH:36][CH:35]=4)[CH2:29][CH2:30]3)[CH:24]=[CH:25][C:19]=2[O:18][CH2:17]1
Reactant: NS(=O)(=O)c1ccc(N2CCNCC2)cc1
Reactant: O=Cc1ccc2c(c1)NC(=O)CO2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: NS(=O)(=O)c1ccc(N2CCN(Cc3ccc4c(c3)NC(=O)CO4)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.4 %

Procedure:
Sodium triacetoxyborohydride (1.2 g, 5.9 mmol) is added to a solution of 3-oxo-3,4-dihydro-2H-benzo[1,4]-oxazine-6-carbaldehyde (0.5 g, 2.8 mmol) and 4-(piperazin-1-yl)-benzenesulfonamide (0.17 g, 3.1 mmol) in 20 mL of THF. The mixture is stirred at room temperature overnight. The reaction is quenched by addition of 50 mL of water, and the THF is removed under reduced pressure. The precipitate is collected by filtration and recrystallized from methanol to give 0.05 g (4% yield) of 4-[4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethyl)-piperazin-1-yl]-benzenesulfonamide; mp 150-153° C.
Reaction SMILES: [CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([NH2:12])[CH2:5][CH2:4]1.[C:13](Cl)(Cl)=[O:14]>>[CH3:1][O:2][CH:3]1[C:8]2[S:9][CH:10]=[CH:11][C:7]=2[CH:6]([N:12]=[C:13]=[O:14])[CH2:5][CH2:4]1
Reactant: O=C(Cl)Cl
Reactant: COC1CCC(N)c2ccsc21
Product: COC1CCC(N=C=O)c2ccsc21
Temperature: 25 °C
Reaction time: 7 h

Procedure:
A 1 g sample of 4,5,6,7-tetrahydro-7-methoxybenzo[b]thiophen-4-amine is added to 18 ml of 12.5% phosgene solution (benzene) in a nitrogen atmosphere at 20° C. After stirring at room temperature for an hour, the mixture is heated to 60° C and kept at this temperature for 7 hours. The mixture is cooled to room temperature and evaporated to dryness in vacuo to afford the crude 4,5,6,7-tetrahydro-7-methoxybenzo[b]thien-4-ylisocyanate.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2.[Br:16][CH2:17][CH2:18][CH2:19]Br.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Br:16][CH2:17][CH2:18][CH2:19][O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5]2
Reactant: BrCCCBr
Reactant: COC(=O)Cn1ccc2cc(O)ccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(OCCCBr)ccc21
Temperature: 25 °C
Reaction time: 6 h
Yield: 45.3 %

Procedure:
To a solution of methyl (5-hydroxy-1H-indol-1-yl)acetate (1.0 g, 4.87 mmol) (Example 9) in 35 mL DMF, was added 1,3-dibromopropane (5.90 g, 29.24 mmol) and Cs2CO3 (3.18 g, 9.75 mmol). The mixture was stirred at rt for 6 h, and then the solvent was evaporated under reduced pressure. The residue was suspended in EtOAc, filtered, and the filter cake was washed with EtOAc. The combined organic layers were dried, concentrated, and purified by column chromatography (0-10% EtOAc in hexane) to give 720 mg (45%) of the product containing minor impurities. This material was used in later steps with no further purification. 1H NMR (400 MHz, CDCl3) δ 7.18-7.10 (m, 2H), 7.05 (d, 1H), 6.94-6.85 (m, 1H), 6.50 (d, 1H), 4.80 (s, 2H), 4.18 (t, 2H), 3.75 (s, 3H), 3.65 (t, 2H), 2.40-2.30 (m, 2H).