Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N.[Br:21][C:22]1[CH:23]=[CH:24][C:25]2[S:29][C:28]([CH3:30])=[CH:27][C:26]=2[CH:31]=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:30][C:28]1[S:29][C:25]2[CH:24]=[CH:23][C:22]([Br:21])=[CH:31][C:26]=2[CH:27]=1
Reactant: Cc1cc2cc(Br)ccc2s1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: BrCc1cc2cc(Br)ccc2s1
Temperature: 0 °C
Reaction time: 0.02 h
Yield: 90.1 %

Procedure:
According to the procedure of S. Gronowitz, et al., Synth. Commin., 6, (7), 475 (1976), to a stirred, boiling partial solution of N-bromosuccinimide (17.63 g, 0.099 mol) in CCl4 (200 mL) was added 2,2'-azobis-(2-methylpropionitrile) (1.1 g, 0.007 mol). After one minute, a solution of 5-bromo-2-methylbenzthiophene (15.0 g, 0.066 mol) in CCl4 (100 mL) was added. The resulting mixture was heated at reflux for 2 hours and cooled to 0° C. The solid was filtered. The filtrate was concentrated to give 18.19 g (90%) of product as an orange solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:16]([C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)#[CH:17]>C(O)(C)C>[C:16]([C:18]1[CH:19]=[C:20]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)[CH:21]=[CH:22][CH:23]=1)#[CH:17]
Reactant: C#Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1cc2c(Cl)ncnc2cc1F
Solvent: CC(C)O
Product: C#Cc1cccc(Nc2ncnc3cc(F)c([N+](=O)[O-])cc23)c1
Temperature: 25 °C
Yield: 95 %

Procedure:
4-Chloro-7-fluoro-6-nitroquinazoline and 3-ethynylbenzenamine (234 mg, 2 mmol) was dissolved into isopropanol (5 mL) and refluxed for 3 h. After cooled to room temperature, the precipitate was filtered out and washed with water to give 0.59 g of N-(3-ethynylphenyl)-7-fluoro-6-nitroquinazolin-4-amine (95%).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([CH:17]=[CH:18][CH:19]3[CH2:24][CH2:23][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:21][CH2:20]3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>C1(C)C=CC=CC=1.C(O)C.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:6][CH2:7][CH:8]([C:11]2[CH:12]=[CH:13][C:14]([CH2:17][CH2:18][CH:19]3[CH2:20][CH2:21][CH:22]([CH2:25][CH2:26][CH3:27])[CH2:23][CH2:24]3)=[CH:15][CH:16]=2)[CH2:9][CH2:10]1)=[O:4]
Reactant: CCCC1CCC(C=Cc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Agent: [Pd]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCCC1CCC(CCc2ccc(C3CCC(C(=O)OC)CC3)cc2)CC1
Yield: 80.6 %

Procedure:
6.41 g (17.4 mmol) of 4-{4-[2-(4-propyl-cyclohexyl)-ethenyl]-phenyl}cyclohexane carboxylic acid methyl ester produced in Example 5-1 was dissolved in a mixture of toluene and ethanol (1:1 by volume %). 0.4 g of Pd/C was added to 200 mL of the resultant solution and reacted in hydrogenation reactor for 12 hours. After reaction, Pd/C was removed by filtration and concentrated under reduced pressure to obtain 5.2 g (80%) of 4-{4-[2-(4-propyl-cyclohexyl)-ethyl]-phenyl}-cyclohexane carboxylic acid methyl ester.
Reaction SMILES: [ClH:1].Cl.[CH:3]1([CH2:9][O:10][C:11]2[C:12]3[N:13]([C:17]([C:21]([NH:23][C@H:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)=[O:22])=[C:18]([CH3:20])[N:19]=3)[CH:14]=[CH:15][CH:16]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.N1C=CC=CC=1.[S:36](N)([NH2:39])(=[O:38])=[O:37].O>C(Cl)(Cl)Cl>[ClH:1].[NH2:39][S:36]([N:26]1[CH2:27][CH2:28][CH2:29][C@H:24]([NH:23][C:21]([C:17]2[N:13]3[CH:14]=[CH:15][CH:16]=[C:11]([O:10][CH2:9][CH:3]4[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]4)[C:12]3=[N:19][C:18]=2[CH3:20])=[O:22])[CH2:25]1)(=[O:38])=[O:37]
Reactant: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCNC1
Reactant: NS(N)(=O)=O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(OCC3CCCCC3)cccn2c1C(=O)N[C@H]1CCCN(S(N)(=O)=O)C1
Temperature: 25 °C
Yield: 68.9 %

Procedure:
To 200 mg of 8-(cyclohexylmethoxy)-2-methyl-N-[(3S)-piperidin-3-yl]imidazo[1,2-a]pyridine-3-carboxamide dihydrochloride were added 5 ml of pyridine and 217 mg of sulfamide, followed by heating to reflux for 4 hours. After leaving to be cooled at room temperature, to the reaction mixture were added water and chloroform to carry out a layer separation operation. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography. The obtained solid was suspended in ethyl acetate, and 120 μl of a 4 M hydrogen chloride/ethyl acetate solution was added thereto. The resulting solid was collected by filtration and dried to obtain 151 mg of N-[(3S)-1-(aminosulfonyl)piperidin-3-yl]-8-(cyclohexylmethoxy)-2-methylimidazo[1,2-a]pyridine-3-carboxamide hydrochloride.
Reaction SMILES: [NH:1]([C:22]([O:24]C(C)(C)C)=O)[C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].Cl.CCOC(C)=O.C1C=CC2N(O)N=NC=2C=1.[N:46]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][C@H:52]([OH:53])[CH2:51][C@H:47]1C(O)=O.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[N:46]1([C:55]([O:57][C:58]([CH3:61])([CH3:60])[CH3:59])=[O:56])[CH2:54][C@H:52]([OH:53])[CH2:51][C@H:47]1[C:22]([NH:1][C@H:2]([C:7]([NH:9][CH2:10][C:11]([NH:13][O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)=[O:12])=[O:8])[CH2:3][CH:4]([CH3:5])[CH3:6])=[O:24]
Reactant: CC(C)C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C)C(=O)NCC(=O)NOCc1ccccc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 56.2 %

Procedure:
To Boc-Leu-Gly-NHOBzl (3.89 g; 9.89 mmol) obtained in Example 1 (C) was added under ice cooling 4.5N-HCl/AcOEt (30 ml), and the solution was brought back to room temperature. The reaction was carried out for 1 hour. The solvent was distilled off under reduced pressure and the residue was dissolved in THF (100 ml). The solution was cooled with a coolant at -20° C. After TEA (1.40 ml; 10.0 mmol) was added dropwise, HOBt (1.22 g; 9.03 mmol) and Boc-Hyp-OH (1.99 g; 8.60 mmol) were added and DCC (2.31 g; 11.2 mmol) dissolved in THF (10 ml) was added dropwise. The reaction was carried out for 1 hour at -10° C. and overnight in a refrigerator. Insolubles were filtered off and the solvent was then distilled off under reduced pressure. The residue was dissolved in AcOEt and the solution was washed successively with water, 1N-HCl, water, 10% Na2CO3 and water and then dried over anhydrous MgSO4. The solvent was distilled off under reduced pressure and the residue was recrystallized from AcOEt to give Boc-Hyp-Leu-Gly-NHOBzl (2.45 g; 56%) as colorless crystals. m.p. 168°-173° C., specific rotation [α]D28 -50.8 (c= 1.0, EtOH).
Reaction SMILES: [CH2:1]1[CH:5]2[CH:6]3C=CC([CH:4]2[CH:3]=[CH:2]1)C3.C[SiH:12]([Cl:14])[Cl:13].CCCCCCCCCCCCCCCC>C1(C)C=CC=CC=1>[CH:5]1([CH2:6][SiH:12]([Cl:14])[Cl:13])[CH2:4][CH2:3][CH:2]=[CH:1]1
Reactant: C1=CC2C3C=CC(C3)C2C1
Reactant: C[SiH](Cl)Cl
Solvent: CCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: Cl[SiH](Cl)CC1C=CCC1
Reaction time: 1 h
Yield: 781.2 %

Procedure:
As described in Example 2, 1.49 g (0.0113 mol) of dicyclopentadiene, 10.79 g (0.0902 mol) of methyldichlorosilane, 5 mL of toluene and 2 mL of hexadecane were placed in a reactor. The reactor was sealed and the reaction was performed at 250° C. for 1 hour. Products were subject to simple vacuum distillation, thereby providing a mixture (15.99 g) of (2-cyclopentenyl)methyldichlorosilane (1.2 g, 29%), unreacted methyldichlorosilane, toluene and hexadecane.
Reaction SMILES: [CH:1]([C:3]1[C:18]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]CC)=[O:11])=[O:2].[OH-].[K+]>C(O)C>[CH:1]([C:3]1[C:18]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[O:2]
Reactant: CCOC(=O)CCCCOc1cccc(OCc2ccccc2)c1C=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=Cc1c(OCCCCC(=O)O)cccc1OCc1ccccc1
Reaction time: 5 h

Procedure:
A mixture of ethyl 5-(2-formyl-3-benzyloxyphenoxy)pentanoate (3.61 g, 0.01 M), potassium hydroxide (1.19 g, 0.021 M) and ethanol (40 ml) were stirred at 50°-60° C. for 5 hours. The ethanol was then removed in vacuo, the residue dissolved in water (50 ml) and the solution extracted with ether (2×80 ml). The aqueous layer was then acidified by the addition of 2 N aqueous hydrochloric acid and the product extracted with ether (3×50 ml), and the combined extracts washed with water to neutrality, dried, and concentrated in vacuo to give 5-(2-formyl-3-benzyloxyphenoxy) pentanoic acid, 3.0 g, 91% as a yellow oil which crystallised on standing. The crude solid was crystallised from benzene/petroleum spirit 30°-40° C. to give pale cream crystals m.p. 110° C.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:7][CH:6]=2.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[N:4][C:5]3[C:10]([N:11]=2)=[CH:9][C:8]([C:12]([N:14]([O:16][CH3:17])[CH3:15])=[O:13])=[CH:7][CH:6]=3)=[CH:21][CH:20]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CON(C)C(=O)c1ccc2ncc(Cl)nc2c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CON(C)C(=O)c1ccc2ncc(-c3ccc(Cl)cc3)nc2c1
Temperature: 80 °C
Yield: 61 %

Procedure:
A mixture of 3-chloro-N-methoxy-N-methylquinoxaline-6-carboxamide (5 g, 0.02 mol, 1.0 eq.), (4-chlorophenyl)boronic acid (3.43 g, 0.022 mol, 1.1 eq.) Pd(dppf)2C12 (816 mg, 0.001 mol, 0.05 eq.) and Na2CO3 (4.24 g, 0.04 mol, 2.0 eq.) in dioxane and water (90 mL/10 mL) was heated at 80° C. for 4 hs under N2 protection, then cooled and concentrated. The resulting residue was purified by flash column chromatography (PE/EA=4/1, v/v) to afford 3-(4-chlorophenyl)-N-methoxy-N-methylquinoxaline-6-carboxamide (4 g, 61.0%).
Reaction SMILES: Cl[CH2:2][C:3](=[CH2:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6].CN(C)C=O.[Br-:20].[Na+]>BrCBr>[Br:20][CH2:2][C:3](=[CH2:14])[CH2:4][S:5]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=[O:7])=[O:6]
Reactant: [Br-]
Reactant: C=C(CCl)CS(=O)(=O)c1ccccc1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: BrCBr
Product: C=C(CBr)CS(=O)(=O)c1ccccc1
Temperature: 100 °C
Reaction time: 16 h
Yield: 37250.8 %

Procedure:
A solution of crude (2-chloromethyl-prop-2-ene-1-sulfonyl)-benzene (186 g, assumed 0.80 mmol) in a mixture of dibromomethane (400 ml) and of dimethylformamide (800 ml) was stirred at room temperature during the addition of sodium bromide (82 g, 0.80 mmol). The resulting suspension was stirred at 100° C. for 16 hours, then cooled to room temperature and concentrated in vacuo. The crude material was dissolved in of ethyl acetate (750 ml) and the resulting solution was washed with water (750 ml) and brine (750 ml), dried (anhydrous magnesium sulfate) and concentrated in vacuo. The crude product was recrystallised from isopropyl ether to give (2-bromomethyl-prop-2-ene-1-sulfonyl)-benzene (82 g, 37%). Mass spectrum 276 [M+H]+.
Reaction SMILES: FC1C=C(C(C)(C)CC(O)(C(F)(F)F)C=O)C2OCCC=2C=1.NC1C=CC=C2C=1C=CN=C2.[F:34][C:35]1[CH:36]=[C:37]([C:44]([CH3:65])([CH3:64])[CH2:45][C:46]([OH:63])([C:59]([F:62])([F:61])[F:60])[CH:47]=[N:48][C:49]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:50]=2[CH:51]=[CH:52][N:53]=[CH:54]3)[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1.[BH4-].[Na+]>>[F:34][C:35]1[CH:36]=[C:37]([C:44]([CH3:65])([CH3:64])[CH2:45][C:46]([OH:63])([C:59]([F:60])([F:62])[F:61])[CH2:47][NH:48][C:49]2[CH:58]=[CH:57][CH:56]=[C:55]3[C:50]=2[CH:51]=[CH:52][N:53]=[CH:54]3)[C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1
Reactant: CC(C)(CC(O)(C=Nc1cccc2cnccc12)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(F)cc2c1OCC2
Agent: Nc1cccc2cnccc12
Agent: [BH4-]
Product: CC(C)(CC(O)(CNc1cccc2cnccc12)C(F)(F)F)c1cc(F)cc2c1OCC2

Procedure:
Analogously to Example 1, 4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentanal is converted with 5-aminoisoquinoline into 5-[4-(5-fluoro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-trifluoromethyl-pentylidenamino]isoquinoline, which is reduced with sodium borohydride to the product.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[Al+3].[Cl-].[Cl-].[Cl-].[C:11]1([C:17]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[O:18][CH2:19][C:20](=[CH2:24])[CH2:21]C#N)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[OH-:37].[Na+]>CCOCC>[C:31]1([C:17]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[O:18][CH2:19][C:20](=[CH2:24])[CH2:21][OH:37])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: C=C(CC#N)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [OH-]
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: CCOCC
Product: C=C(CO)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 0.25 h
Yield: 65 %

Procedure:
To a solution of LiAlH4 (119 mg; 2.98 mmol) in dry ether (5 mL), AlCl3 (400 mg; 2.94 mmol) was added carefully at 0° C. and the mixture was stirred for 15 min. Then a solution of 12 (829 mg; 2.44 mmol) in dry ether (9 mL) was added and the reaction was stirred at 0° C. for 3 h. After that 10% aqueous NaOH (10 mL) was added to quench the reaction. The organic layer was separated and washed by saturated aqueous NaHCO3 and NaCl respectively, and dried over anhydrous K2CO3. After evaporation of the solvent, the residue was purified by flash column chromatography over silica gel using CH3OH—CH2Cl2 (1:205) as the eluent to afford 10 as colorless oil (545 mg; 65% yield): 1H NMR (400 MHz, CDCl3) δ 7.41-7.48 (m, 6H, six of ArH), 7.26-7.33 (m, 6H, six of ArH), 7.19-7.26 (m, 3H, three of ArH), 5.33 (s, 1H, one of C═CH2), 4.96 (s, 1H, one of C═CH2), 3.53 (s, 2H, Ph3COCH2), 2.70 (m, 2H, CH2CH2NH2) 2.18 (t, J=6.7 Hz, 2H, CH2CH2NH2), 2.06 (br s, 2H, NH2); 13C NMR (100 MHz, CDCl3) δ 143.6, 143.4, 128.1, 127.4, 126.5, 111.3, 86.5, 66.1, 39.8, 37.4; HRMS (FAB+) calcd for C24H26ON (M+H+): 344.2014. found: 344.2017, (11).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1.Cl.[CH3:27]O>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23]([O:25][CH3:27])=[O:24])=[CH:19][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCC(=O)O)cc2)cc1
Reactant: CO
Agent: Cl
Product: COC(=O)CCc1ccc(-c2ccc(CCN3CCC[C@H]3C)cc2)cc1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To (R)-3-(4′-(2-(2-methylpyrrolidin-1-yl)ethyl)biphenyl-4-yl)propanoic acid (14.0 mg, 0.041 mmol, see Example 1.46 for preparation) was added 1.25M hydrogen chloride in methanol (0.996 mL, 1.245 mmol). The reaction was stirred at 60° C. for 2 h. The resulting mixture was concentrated and triturated with acetonitrile to give the title compound. LCMS m/z=352.4 [M+H]+; 1H NMR (400 MHz, CD3CN) δ ppm 1.24 (d, J=6.9 Hz, 0.5H), 1.56 (d, J=6.4 Hz, 2.5H), 1.76-1.90 (m, 1H), 1.99-2.14 (m, 2H), 2.23-2.38 (m, 1H), 2.68 (t, J=7.6 Hz, 2H), 2.97 (t, J=7.6 Hz, 2H), 3.00-3.21 (m, 3H), 3.30-3.41 (m, 2H), 3.45-3.55 (m, 1H), 3.65 (s, 3H), 3.69-3.80 (m, 1H), 7.33 (d, J=8.1 Hz, 2H), 7.40 (d, J=8.2 Hz, 2H), 7.58 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.2 Hz, 2H).
Reaction SMILES: Cl.[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:13][CH:12]([NH2:14])[CH2:11]2)=[N:5][CH:6]=[CH:7][CH:8]=1.CCN(CC)CC.[C:22]1([CH3:32])[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)Cl>[Br:2][C:3]1[C:4]([O:9][CH:10]2[CH2:11][CH:12]([NH:14][S:28]([C:25]3[CH:26]=[CH:27][C:22]([CH3:32])=[CH:23][CH:24]=3)(=[O:30])=[O:29])[CH2:13]2)=[N:5][CH:6]=[CH:7][CH:8]=1
Reactant: NC1CC(Oc2ncccc2Br)C1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)NC2CC(Oc3ncccc3Br)C2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
To a solution of 3-((3-bromopyridin-2-yl)oxy)cyclobutanamine hydrochloride (243 mg, 1 mmol) in dry DCM (10 mL) was added Et3N (1 mL). The reaction mixture was cooled to 0° C. with an ice bath, and p-toluenesulfonyl chloride (380 mg, 2 mmol) was added dropwise. After 1 hour, the reaction mixture was warmed to room temperature, and stirred overnight. Then the reaction mixture was washed with brine, dried over Na2SO4, filtered, and concentrated under vacuum to give the crude product. The crude product was purified by flash chromatography on silica gel (20% to 45% EtOAc in petroleum ether) to give N-(3-((3-bromopyridin-2-yl)oxy)cyclobutyl)-4-methylbenzenesulfonamide (318 mg, 0.8 mmol, yield 80%). ESI-MS (M+1): 397 calc. for C16H17BrN2O3S 396.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:5][N:6]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9][CH:8]([NH:17]C(=O)OC(C)(C)C)[C:7]1=[O:25].[ClH:30]>O1CCOCC1>[ClH:30].[NH2:17][CH:8]1[C:7](=[O:25])[N:6]([CH2:5][C:4]2[CH:3]=[C:2]([F:1])[CH:28]=[C:27]([F:29])[CH:26]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CSc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Agent: Cl
Solvent: C1COCCO1
Product: NC1CSc2ccccc2N(Cc2cc(F)cc(F)c2)C1=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
520 mg of 53 (1.24 mmol) are taken up in a 25 ml round-bottomed flask and 10 ml of a solution of hydrogen chloride in dioxane (4M) are added. The mixture is stirred for 3 hours at room temperature under argon. After evaporating off the solvent, 470 mg of amine 54 are obtained in hydrochloride form, which product is used directly in the following step.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH2:6][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])[C:3]([OH:5])=[O:4].C1(N=C=NC2CCCCC2)CCCCC1.[Br:38][CH2:39][CH2:40]O>ClCCl>[CH3:1][C:2]([CH3:22])([CH2:6][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])[C:3]([O:5][CH2:40][CH2:39][Br:38])=[O:4]
Reactant: CCCCCCCCCCCCCCCCC(C)(C)C(=O)O
Reactant: OCCBr
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: CCCCCCCCCCCCCCCCC(C)(C)C(=O)OCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 34.3 %

Procedure:
500 mg (1.6 mmol) of 2,2-Dimethyl-octadecanoic acid (Roth, Bruce D. et al., J. Med. Chem. 1992, 35(9), 1609-17) were dissolved in anhydrous dichloromethane (10 ml), and 350 mg (1.8 mmol) of dicyclohexylcarbodiimide (DCC), and 140 μl (2 mmol) of 2-bromoethanol were added thereto, followed by stirring of the mixture at room temperature overnight. The reaction mixture was purified using a silica gel column (elution by hexane-ethyl acetate (7:1) solvent mixture) to obtain 230 mg of 2-(2,2-dimethyloctadecanoyloxy)ethyl bromide to be used below.
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([OH:17])(=O)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:20])=O>CN(C=O)C>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([Cl:20])(=[O:17])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reaction time: 6 h

Procedure:
The sulphonic acid (2a) was dissolved in an excess of thionyl chloride (30 mL), a catalytic amount of DMF (cat) was added, and the resulting mixture was stirred for 6 h at reflux. The solvent was evaporated and the residue dissolved in Et20 (40 mL). The ether solution was washed with 5% aqueous NaOH (3×40 mL) and water (6×40 mL), dried over anhydrous MgSO4, filtered, and concentrated in vacuo. After drying in high vacuum overnight, the pure product was obtained as a white solid. Yield 63%: 2.09 g, 7.44 mmol, (light yellow syrup). 1H-NMR (CDCl3): δ 7.44 (d, 3J=9.1 Hz, 2H, ArH), 7.38 (d, 3J=9.1 Hz, 2H, ArH), 7.19 (t, 1H, ArH), 7.12 (d, 3J=9.1 Hz, 2H, ArH), 6.98 (d, 3J=9.1 Hz, 2H, ArH)
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[C:10](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][C:28]([N:30](OC)[CH3:31])=O)[C:21](=[O:34])[CH2:20]2)=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14].CC(C)=O.C(OC(N1CCN(CCC=O)C(=O)C1)=O)(C)(C)C.N1C[CH2:61][CH2:60][CH2:59][CH2:58]1.B.N1C=CC=CC=1.C(O)(=O)C>ClCCCl.C(O)C>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:15]=[CH:16]/[C:17]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][CH2:27][CH2:28][N:30]3[CH2:31][CH2:61][CH2:60][CH2:59][CH2:58]3)[C:21](=[O:34])[CH2:20]2)=[O:18])[CH:11]=[CH:12][C:13]=1[Cl:14]
Reactant: C1CCNCC1
Reactant: CON(C)C(=O)CCCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CC1=O
Agent: B
Agent: CC(C)(C)OC(=O)N1CCN(CCC=O)C(=O)C1
Agent: [Al+3]
Solvent: c1ccncc1
Solvent: CCO
Solvent: ClCCCl
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCN(CCCCN2CCCCC2)C(=O)C1
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 53.2 %

Procedure:
Lithium aluminum hydride solution (1 M in tetrahydrofuran, 0.13 ml, 0.13 mmol) was added dropwise at −30° C. to a solution of 4-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-2-oxo-piperazin-1-yl}-N-methoxy-N-methyl-butyramide (intermediate 5; 54 mg, 0.13 mmol), then after 10 min the reaction mixture was, cooled to −75° C. and acetone (161 mg, 2.8 mmol) was added. The homogeneous solution was allowed to reach room temperature over 16 h, then partitioned between water and ethyl acetate. The organic layer was washed with brine, dried (MgSO4), and evaporated. The crude aldehyde intermediate (4-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-2-oxo-piperazin-1-yl}-butyraldehyde) and piperidine (10 mg, 0.12 mmol) were dissolved in 1,2-dichloroethane, then a freshly prepared solution of pyridine borane complex (8 M in pyridine, 30 μl, 0.33 mmol) and acetic acid (22 mg, 0.37 mmol) in ethanol (1 ml) was added dropwise at room temperature. The reaction mixture was stirred overnight, then volatile material was removed by rotary evaporation. The residue was purified by chromatography (SiO2; CH2Cl2/MeOH/NH4OH 90:10:0.25) to afford the title compound (28 mg, 51%). Light yellow gum, MS (ISP)=438.2 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[F:25][C:26]([F:39])([O:30][C:31]1[CH:32]=[C:33]([CH2:37]Br)[CH:34]=[CH:35][CH:36]=1)[CH:27]([F:29])[F:28].O>COCCOC>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:22])[CH:16]([CH2:37][C:33]2[CH:34]=[CH:35][CH:36]=[C:31]([O:30][C:26]([F:25])([F:39])[CH:27]([F:28])[F:29])[CH:32]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: FC(F)C(F)(F)Oc1cccc(CBr)c1
Reactant: CCOC(=O)CC(=O)c1ccc(OCc2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(=O)c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 3-(1,1,2,2-tetrafluoroethoxy)toluene (27.8 g, 133 mmol) in ethyl acetate (250 ml) were added N-bromosuccinimide (26.1 g, 147 mmol) and 2,2′-azobis(isobutyronitrile) (440 mg, 2.67 mmol), and the mixture was heated under reflux for 5 hrs. After concentration of the reaction solution, crystals were filtered with hexane and the filtrate was concentrated to give 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene. To a solution of ethyl 3-[4-(benzyloxy)phenyl]-3-oxopropanoate (37.8 g, 127 mmol) in 1,2-dimethoxyethane (250 ml) was added sodium hydride (60% in oil, 5.07 g, 127 mmol) under ice-cooling, and the mixture was stirred at room temperature for 30 min. To the reaction solution was dropwise added a solution of 3-(1,1,2,2-tetrafluoroethoxy)-α-bromotoluene prepared earlier in 1,2-dimethoxyethane (50 ml), and the mixture was stirred overnight at room temperature. The reaction solution was poured into water (500 ml), and the mixture was extracted with ethyl acetate (500 ml×2). The extract was washed with water and saturated brine, dried (anhydrous magnesium sulfate) and evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1-1:1) and recrystallized from ethyl acetate-hexane to give the objective substance (43.4 g, 68%).