Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH:5]([Cl:8])[CH2:6][CH3:7])=[O:3].N1C=CC=CC=1.[F:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[OH:22]>ClCCl.C(OCC)(=O)C>[F:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[O:22][C:2](=[O:3])[O:4][CH:5]([Cl:8])[CH2:6][CH3:7]
Reactant: CCC(Cl)OC(=O)Cl
Reactant: O[C@@H]1CCCC[C@H]1F
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCC(Cl)OC(=O)O[C@@H]1CCCC[C@H]1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1-Chloropropyl chloroformate [CAS No. 92600-20-9] (2.99 g) and pyridine (1.62 mL) were dissolved in dichloromethane (30 mL), and a solution of trans-2-fluorocyclohexanol [CAS No. 14365-32-3] (2.36 g) in dichloromethane was added dropwise thereto under ice-cooling. After stirring the resulting mixture overnight at room temperature, the reaction mixture was diluted with ethyl acetate, and sequentially washed with 1 N hydrochloric acid, water, and saturated aqueous sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate. The resulting mixture was filtered, and the filtrate obtained was concentrated under reduced pressure. The residue obtained was purified by silica gel column chromatography (mixed solvent of heptane-ethyl acetate) to obtain the captioned compound (2.731 g).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1.ClC1C=CC=C(C(OO)=[O:32])C=1>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[C:6]3[N:21]=[CH:20][N:19]=[CH:18][C:7]=3[CH2:8][N+:9]([O-:32])=[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])[C:4]=2[CH:3]=1
Reactant: Clc1ccc2c(c1)C(c1ccccc1Cl)=NCc1cncnc1-2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: [O-][N+]1=C(c2ccccc2Cl)c2cc(Cl)ccc2-c2ncncc2C1

Procedure:
A solution of 6.8 g (20 mmole) of 9-chloro-7-(2-chlorophenyl)-5H-pyrimido[5,4-d][2]benzazepine, 6 g (30 mmole) of 85% m-chloroperbenzoic acid in 200 ml of methylene chloride was stirred at room temperature for 4 hrs. The mixture was washed with an excess of ice cold dilute sodium hydroxide, dried over anhydrous sodium sulfate and filtered over hyflo. The filtrate was concentrated at reduced pressure to dryness. The residue was crystallized from a mixture of methylene chloride and ether to give a crude product, mp 228°-229° C. Recrystallization from a mixture of methylene chloride and ether gave the product, mp 216°-217° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(=[O:3])[CH3:2].C(Cl)(C([Cl:18])=O)=O>C1COCC1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([Cl:18])=[O:8])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CC(=O)Oc1ccccc1C(=O)Cl

Procedure:
To a solution of compound 2-acetoxybenzoic acid (1.0 g, 5.5 mmol) in THF (30 mL) was added (COCl)2 (0.8 ml, 9.1 mmol) at 0° C. The mixture was heated (reflux, 1.5 h) and concentrated under reduced pressure to afford 2-(chlorocarbonyl)phenyl acetate.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=2)[NH2:14])[CH3:10])[CH:5]=[N:4][CH:3]=1.[F:18][C:19]([F:30])([F:29])[C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](O)=[O:24].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.ClCCl>[Cl:1][C:2]1[N:7]=[C:6]([O:8][C@@H:9]([C:11]2[CH:12]=[C:13]([NH:14][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[C:20]([C:19]([F:18])([F:29])[F:30])[CH:21]=3)[CH:15]=[CH:16][CH:17]=2)[CH3:10])[CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: C[C@@H](Oc1cncc(Cl)n1)c1cccc(N)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](Oc1cncc(Cl)n1)c1cccc(NC(=O)c2cccc(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40.7 %

Procedure:
A mixture of (R)-3-(1-(6-chloropyrazin-2-yloxy)ethyl)aniline (160 mg, 0.64 mmol), 3-trifluoromethylbenzoic acid (183 mg, 0.96 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (246 mg, 1.28 mmol), 4-dimethylamino pyridine (4 mg, 0.032 mmol) and triethylamine (0.36 mL, 2.57 mmol) in dichloromethane (6 mL) was stirred at room temperature for 18 hours. After this time the mixture was diluted with dichloromethane (30 mL), washed successively with saturated aqueous sodium hydrogen carbonate (2×20 mL) and brine (20 mL), dried (Na2SO4) and concentrated under reduced pressure to give an orange oil which was purified by flash chromatography (silica, ethyl acetate/hexanes) to give (R)—N-(3-(1-(6-chloropyrazin-2-yloxy)ethyl)phenyl)-3-(trifluoromethyl)benzamide (110 mg, 30% over 2 steps) as a yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH2:19][CH2:20][C:21]2[S:22][CH:23]=[CH:24][N:25]=2)[NH:12][C:11]([CH2:26][C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH3:33])=[O:31].CCN=C=NCCCN(C)C.Cl.[N:46]1([CH2:52][C:53]2([C:59]#[N:60])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]2)[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>ClCCl>[C:59]([C:53]1([CH2:52][N:46]2[CH2:47][CH2:48][N:49]([C:27](=[O:28])[CH2:26][C:11]3[NH:12][C:13]([CH2:19][CH2:20][C:21]4[S:22][CH:23]=[CH:24][N:25]=4)=[C:14]([C:15]([O:17][CH3:18])=[O:16])[CH:9]([C:3]4[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=4[Cl:8])[C:10]=3[C:30]([O:32][CH3:33])=[O:31])[CH2:50][CH2:51]2)[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]1)#[N:60]
Reactant: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)O)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reactant: N#CC1(CN2CCNCC2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COC(=O)C1=C(CCc2nccs2)NC(CC(=O)N2CCN(CC3(C#N)CCCCC3)CC2)=C(C(=O)OC)C1c1c(Cl)cccc1Cl
Reaction time: 8 h

Procedure:
To a suspension of 2-[4-(2,6-dichlorophenyl)-3,5-bis(methoxycarbonyl)-6-[2-(1,3-thiazol-2-yl)ethyl]-1,4-dihydro-2-pyridinyl]acetic acid (511 mg/1.0 mmol) in dichloromethane (5 ml) was added water soluble carbodiimide (288 mg/1.5 mmol) followed by 1-(1-piperazinylmethyl)cyclohexanecarbonitrile (311 mg/1.5 mmol) at ambient temperature, and then the resulting solution was stirred overnight. The solution was diluted with dichloromethane (100 ml) and the resulting solution was washed with water (10 ml) and brine (10 ml) succesively. The solution was dried over magnesium sulfate, filtered and concentrated. The residue was purified by colum chromatography (NH2 gel/20 g/dichloromethane as eluent) to give a brown amorphous (731 mg/quant.).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([O:22][C:23]([N:25]([CH3:30])[CH2:26][C:27](O)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O>[C:18]([O:22][C:23]([N:25]([CH3:30])[CH2:26][C:27]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:28])=[O:24])([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: CN(CC(=O)O)C(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)CN(C)C(=O)OC(C)(C)C)C2
Yield: 69.7 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (2.3 g, 10 mmol) was dissolved in dimethylformamide (100 ml) while being cooled on ice. To the obtained mixture, N-tert-butoxycarbonyl-N-methylglycine (2.0 g, 11 mmol), WSC.HCl (2.0 g, 11.0 mmol), and HOBT (1.4 g, 11.0 mmol) were added, and the resultant mixture was stirred at room temperature overnight. The reaction mixture was subjected to distillation under reduced pressure. The resultant residue was extracted with chloroform after the pH was turned to acidic with HCl. The organic phase was washed with saturated aqueous NaCl solution, and dried. The solvent was distilled off under reduced pressure. The resultant residue was recrystallized from chloroform--methanol--ether. As a result, 2.8 g of the title compound was obtained as colorless powdery crystals (69.0%)
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH3:12].CCN(CC)CC.[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[CH:23].N#N>C1(C)C=CC=CC=1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:20][C:21]([CH3:25])([CH3:24])[C:22]#[C:23][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][CH3:12]
Reactant: CNc1ccc([N+](=O)[O-])cc1Br
Reactant: C#CC(C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: N#N
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: CNc1ccc([N+](=O)[O-])cc1C#CC(C)(C)C
Temperature: 70 °C
Yield: 88.8 %

Procedure:
To a solution of (2-bromo-4-nitro-phenyl)-methyl-amine (22.5 g, 97.4 mmol) in toluene (200 mL) and water (100 mL) were added Et3N (19.7 g, 195 mmol), Pd(PPh3)2Cl2 (6.8 g, 9.7 mmol), CuI (0.7 g, 3.9 mmol) and 3,3-dimethyl-but-1-yne (16.0 g, 195 mmol) successively under N2 protection. The mixture was heated at 70° C. for 3 hours and then cooled down to room temperature. The resulting mixture was extracted with EtOAc (100 mL×3). The combined organic extracts were dried over anhydrous Na2SO4 and evaporated under vacuum to give [2-(3,3-dimethyl-but-1-ynyl)-4-nitro-phenyl]-methyl-amine (20.1 g, 94%), which was used in the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 8.15 (d, J=2.4 Hz, 1H), 8.08 (dd, J=2.8, 9.2 Hz, 1H), 6.50 (d, J=9.2 Hz, 1H), 5.30 (brs, 1H), 3.00 (s, 3H), 1.35 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[NH:14][N:13]=[C:12]([C:18]3[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=3)[C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.[CH2:25](I)[CH3:26].C(OC(N1CCC2C(=C(C3C=CC(Cl)=CC=3)N(CC)N=2)CC1)=O)(C)(C)C>>[Cl:24][C:21]1[CH:20]=[CH:19][C:18]([C:12]2[C:11]3[CH2:10][CH2:9][NH:8][CH2:17][CH2:16][C:15]=3[N:14]([CH2:25][CH3:26])[N:13]=2)=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]nc(-c3ccc(Cl)cc3)c2CC1
Reactant: CCI
Agent: CCn1nc2c(c1-c1ccc(Cl)cc1)CCN(C(=O)OC(C)(C)C)CC2
Product: CCn1nc(-c2ccc(Cl)cc2)c2c1CCNCC2

Procedure:
The title compound (0.035 g) was prepared from 3-(4-chloro-phenyl)-4,5,7,8-tetrahydro-1H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 59, Step C; 0.1 g) using ethyl iodide (0.27 mL) in place of benzyl chloride. The reaction sequence also yielded 3-(4-chloro-phenyl)-2-ethyl-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester in the alkylation step. MS (ESI): exact mass calculated for C15H18ClN3, 275.12; found, m/z 276.1 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.39-7.34 (m, 4H), 7.11 (q, J=7.3 Hz, 2H), 3.38-3.36 (m, 2H), 3.27-3.24 (m, 2H), 3.15-3.13 (m, 2H), 2.94-2.92 (m, 2H), 1.30 (t, J=7.3 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])=[CH:4][CH:3]=1.Cl.C[CH2:17][O:18]CC.C(=O)(O)[O-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][CH:9]([CH:12]([CH3:14])[CH3:13])[C:10](=[NH:11])[O:18][CH3:17])=[CH:6][CH:7]=1
Reactant: CC(C)C(C#N)Nc1ccc(Cl)cc1
Reactant: CCOCC
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC(=N)C(Nc1ccc(Cl)cc1)C(C)C
Temperature: 0 °C

Procedure:
A solution of 3.86 g (20 mmol) of 2-(4-chlorophenylamino)-3-methylbutyronitrile in 10 ml of methanol is saturated at reflux with hydrogen chloride gas. When all of the starting nitrile has been consumed, most of the methanol and excess hydrogen chloride is removed in vacuo. Ether is added to precipitate the hydrochloride of methyl 2-(4-chlorophenyl)-3-methylbutanimidate, which is isolated by filtration under nitrogen. The white solid is added with vigorous stirring to an ice-cold mixture of ether and aqueous sodium bicarbonate. The aqueous layer is discarded and the ethereal layer is washed with cold water and dried over sodium sulfate. Filtration and concentration in vacuo gives methyl 2-(4-chlorophenylamino)-3-methylbutanimidate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:9][C:10]3[CH:16]=[C:15]([CH3:17])[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.[C:18](Cl)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C>C1COCC1>[CH3:17][C:15]1[CH:14]=[CH:13][C:11]2[N:12]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:18](=[O:25])[C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[CH:7][CH:6]=3)[S:9][C:10]=2[CH:16]=1
Reactant: Cc1ccc2nc(-c3ccc(N)cc3)sc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc2nc(-c3ccc(NC(=O)c4ccccc4)cc3)sc2c1
Yield: 85.8 %

Procedure:
Prepared as described in the Amide Coupling section using 2-(4-aminophenyl)-6-methylbenzothiazole (1.0 g, 4.16 mmol) and benzoyl chloride (0.58 g, 4.16 mmol) in dry THF (10 ml) containing triethylamine (0.46 g, 4.58 mmol) to give the title compound (1.23 g, 86%) as a colourless solid after work-up.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13](OS(C(F)(F)F)(=O)=O)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:34][C:35]1[CH:36]=[C:37]([CH:40]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:42]=1)[C:38]#[N:39]>>[CH3:1][O:2][C:3](=[O:33])[CH:4]([C:9]1[CH:10]=[C:11]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([F:31])([F:32])[F:30])=[CH:25][CH:24]=2)[CH:12]=[C:13]([C:41]2[CH:40]=[C:37]([C:38]#[N:39])[CH:36]=[C:35]([F:34])[CH:42]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:7])[CH3:8]
Reactant: CC1(C)OB(c2cc(F)cc(C#N)c2)OC1(C)C
Reactant: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(C(F)(F)F)cc2)c1
Product: COC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2cc(F)cc(C#N)c2)c1
Yield: 21 %

Procedure:
The title compound was prepared in 21% yield from 4-methyl-2-(5-trifluoromethanesulfonyloxy-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid methyl ester (prepared in Example 26, step (f)) and 3-fluoro-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzonitrile under the conditions described in Example 26, step (d).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:10]2[CH:11]=[C:12]([NH:16][S:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=2)=[O:9])=[CH:4][C:3]=1[CH2:26][NH:27][CH2:28][CH2:29][CH3:30].[N:31]#[C:32]Br>C(O)C>[NH2:31][C:32]1[N:27]([CH2:28][CH2:29][CH3:30])[CH2:26][C:3]2[C:2](=[CH:7][CH:6]=[C:5]([S:8]([C:10]3[CH:11]=[C:12]([NH:16][S:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)(=[O:19])=[O:18])[CH:13]=[CH:14][CH:15]=3)=[O:9])[CH:4]=2)[N:1]=1
Reactant: N#CBr
Reactant: CCCNCc1cc(S(=O)c2cccc(NS(=O)(=O)c3ccccc3)c2)ccc1N
Solvent: CCO
Product: CCCN1Cc2cc(S(=O)c3cccc(NS(=O)(=O)c4ccccc4)c3)ccc2N=C1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of N-[3-(4-amino-3-propylaminomethyl-benzenesulfinyl)-phenyl]-benzenesulfonamide (0.00090 mol) and cyanogen bromide (0.00094 mol) in ethanol (30 mL) was stirred overnight at room temperature, and then the solvent was evaporated. The residue was triturated under diisopropyl ether, and the solids were filtered off. The residue was converted into the free base with a NaOH solution. The mixture was extracted with CH2Cl2, but the product stayed in the aqueous layer so the mixture was desalted with NaCl to yield an oil. The solvent was decanted, and the remaining oil was triturated under CH3CN. The resulting solids were filtered off, washed with diisopropyl ether, and dried to yield the title compound as a solid.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:10][C:11](=[S:14])[NH:12][N:13]=2)=[C:5]([CH3:15])[CH:4]=1)[CH3:2].Br.Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][N:12]=[C:11]([S:14][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[N:10]=2)=[C:5]([CH3:15])[CH:4]=1)[CH3:2]
Reactant: BrCc1ccccn1
Reactant: CCc1ccc(-c2n[nH]c(=S)[nH]2)c(C)c1
Agent: Br
Product: CCc1ccc(-c2nc(SCc3ccccn3)n[nH]2)c(C)c1
Yield: 39 %

Procedure:
Prepared in a similar manner to example 1 using 5-(4-ethyl-2-methylphenyl)-2H-1,2,4-triazole-3(4H)-thione (example 10a) and 2-(bromomethyl)pyridine hydrobromide. Yield 39%. 1H NMR (300 MHz, dMSO): δ 1.17-1.22 (t, 3H), 2.46 (s, 3H), 2.60-2.64 (dd, 2H), 4.50 (s, 2H), 7.14-7.18 (m, 2H), 7.27-7.29 (m, 1H), 7.47-7.49 (d, 1H), 7.58 (bd, 1H), 7.72-7.77 (m, 1H), 8.50-8.51 (d, 1H). MS (M+H, 311).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:21]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: c1c[nH]cn1
Reactant: CCCCCCCCCCCCCCCCBr
Product: CCCCCCCCCCCCCCCCn1ccnc1

Procedure:
N-hexadecylimidazole was synthesized from imidazole and hexadecyl bromide with reference to the document (T. G. Traylor et al., J. Am. Chem. Soc., 115, 4808-4813 (1993)).
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([N+:11]([O-])=O)[C:5]=1[CH2:14][N:15]=[N+]=[N-].C(O)C>[Pd].C(O)(=O)C>[NH2:11][C:6]1[CH:7]=[C:8]([F:10])[CH:9]=[C:4]2[C:5]=1[CH2:14][NH:15][C:3]2=[O:2]
Reactant: COC(=O)c1cc(F)cc([N+](=O)[O-])c1CN=[N+]=[N-]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: Nc1cc(F)cc2c1CNC2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.86 g (7.32 mmol) of 2-(azidomethyl)-5-fluoro-3-nitrobenzoic acid methyl ester is added into 46 ml of ethanol and 3.4 ml of glacial acetic acid, and it is mixed with 256.6 mg of Pd/C. After stirring overnight at room temperature under hydrogen atmosphere, the catalyst is suctioned off with a glass-fiber filter, and the filtrate is evaporated to the dry state. The residue, 1.18 mg (97.5%) of the desired compound, is further used in crude form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH-].[K+].[CH2:13]([N:15]1[C:19]([CH:20]=[O:21])=[CH:18][C:17]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)=[N:16]1)[CH3:14]>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:20]([C:19]3[N:15]([CH2:13][CH3:14])[N:16]=[C:17]([NH:22][CH2:23][C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[CH:18]=3)=[O:21])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C=O
Reactant: Clc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCn1nc(NCc2ccc(F)cc2)cc1C(=O)c1c[nH]c2ncc(Cl)cc12
Reaction time: 0.83 h
Yield: 2.1 %

Procedure:
5-Chloro-1H-pyrrolo[2,3-b]pyridine (532, 0.068 g, 0.44 mmol) was combined with methanol (10 mL) and potassium hydroxide (0.16 g, 2.8 mmol). The: mixture was stirred for 50 minutes, then 2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazole-3-carbaldehyde (530, 0.100 g, 0.40 mmol, prepared as described in Example 47, Scheme 162, Step 5) was added and the reaction was stirred overnight at room temperature and then concentrated. Ethyl acetate was added and the mixture was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate the solvent was removed under reduced pressure. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (10-100%) in hexanes provided the desired compound (0.0033 g, 2%). MS (ESI) [M+H+]+=398.1.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)(=[O:10])=[O:9].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O>>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][NH:7][S:8]([C:11]1[CH:16]=[CH:15][C:14]([C:22]2[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=2[F:25])=[CH:13][CH:12]=1)(=[O:10])=[O:9]
Reactant: O=S(=O)(NCCCCCO)c1ccc(Br)cc1
Reactant: OB(O)c1ccc(F)cc1F
Product: O=S(=O)(NCCCCCO)c1ccc(-c2ccc(F)cc2F)cc1

Procedure:
Using a method analogous to that described in Example 40, 4-bromophenyl-sulfonic acid-(5-hydroxypentyl)-amide and 2,4-difluorophenyl boronic acid were reacted to give the title compound as a white solid. δC (CDCl3, 62.9 MHz): 22.7, 29.3, 31.9, 43.1, 62.5, 104.7 (t, J 25.8), 112.0 (dd, J 22.9 and 3.5), 127.3, 129.6, 131.5 (d, J 8.8), 131.5 (d, J 9.8), 139.1, 139.4, 159.8 (dd, J 252.0, 11.7) and 163.0 (dd, J 252.0, 11.7).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[F:5][C:6]1[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]([F:16])=[C:8](F)[C:7]=1[F:18].[F:19][C:20]1[C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:29])[C:23]([F:30])=[C:22](F)[C:21]=1[F:32].[CH2:33]([NH2:36])[CH2:34][NH2:35]>O.CN(C=O)C>[N:1]([C:8]1[C:7]([F:18])=[C:6]([F:5])[C:11]([C:12]([OH:14])=[O:13])=[C:10]([F:15])[C:9]=1[F:16])=[N+:2]=[N-:3].[N:1]([C:22]1[C:21]([F:32])=[C:20]([F:19])[C:25]([C:26]([OH:28])=[O:27])=[C:24]([F:29])[C:23]=1[F:30])=[N+:2]=[N-:3].[CH2:33]([NH2:36])[CH2:34][NH2:35]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)c1c(F)c(F)c(F)c(F)c1F
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: NCCN
Product: [N-]=[N+]=Nc1c(F)c(F)c(C(=O)O)c(F)c1F
Temperature: 60 °C
Reaction time: 8 h

Procedure:
Ethylene diamine (130 mg, 2.1 mmol) and triethylamine (510 mg, 5.0 mmol), together dissolved in 10 mL anhydrous ether is added to pentafluorobenzoyl chloride (1.2 g, 5.0 mmol) in 10 mL anhydrous ether. White precipitate is obtained and filtered off. The residue is washed with chloroform, then water and then filtered to recover ethylene diamine bis(pentafluorobenzoate) (III) as white needle crystals (yield, 100%). Sodium azide (270 mg, 4.2 mmol) in 1.7 mL water and 4.0 mL DMF is then reacted with III (870 mg, 2.0 mmol) in 20 mL DMF, and stirred overnight on a 60° C. hotplate. A white precipitate is obtained. The solution is reduced to half-volume by evaporation and the precipitate is filtered off (yield, 35%), dried and recrystallised from DMF to give ethylene diamine bis(4-azido-2,3,5,6-tetrafluorobenzoate) (IV) as white crystals. FTIR: 2129 (N3 asymmetric stretch), 1666 (C═O stretch), 1554, 1483, 1242 (N3 symmetric stretch), no acid OH band at 3000-3500.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH2:16][CH2:15]2)[CH2:10][CH2:9]1.[H][H]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[CH2:6][CH2:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([C@H:14]2[CH2:15][CH2:16][C@H:17]([CH2:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[CH2:18][CH2:19]2)[CH2:10][CH2:9]1
Reactant: Fc1ccc(C=C[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: Cc1ccccc1
Solvent: CCO
Product: Fc1ccc(CC[C@H]2CC[C@H]([C@H]3CC[C@H](CCC4OCCO4)CC3)CC2)cc1

Procedure:
A solution of 1 g of β-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]-4-fluorostyrene in 10 ml of toluene and 5 ml of ethanol is hydrogenated with 500 mg of 5 percent palladium-charcoal at room temperature and normal pressure until the hydrogen uptake comes to a standstill. The black suspension is subsequently filtered. Evaporation of the filtrate gives 1-[2-[trans-4-[trans-4-(2-(1,3-dioxolan-2-yl)ethyl)cyclohexyl]cyclohexyl]ethyl]-4-fluorobenzene.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:13]3[C:22]4[C:17](=[CH:18][CH:19]=[C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:29])=[O:28])[CH:21]=4)[CH2:16][CH2:15][NH:14]3)[CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH2:34]([N:36]=[C:37]=[O:38])[CH3:35]>>[ClH:2].[CH2:34]([NH:36][C:37]([N:14]1[CH2:15][CH2:16][C:17]2[C:22](=[CH:21][C:20]([O:23][CH2:24][CH2:25][NH:26][S:27]([CH2:30][CH2:31][CH2:32][CH3:33])(=[O:28])=[O:29])=[CH:19][CH:18]=2)[CH:13]1[C:9]1([C:6]2[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][CH:5]=2)[CH2:10][CH2:11][CH2:12]1)=[O:38])[CH3:35]
Reactant: CCCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)NCC2
Reactant: CCN=C=O
Agent: Cl
Product: CCCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(Cl)cc3)CCC1)N(C(=O)NCC)CC2
Yield: 23 %

Procedure:
The synthesis was performed according to example 33 (procedure 1), starting from butane-1-sulfonic acid (2-{1-[1-(4-chloro-phenyl)-cyclobutyl]-1,2,3,4-tetrahydro-isoquinolin-7-yloxy}-ethyl)-amide hydrochloride (example 16) and ethyl isocyanate instead of 1-propyl isocyanate. The product was obtained as a white solid (16.0 mg, 0.03 mmol, 23%).