Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[C:3]([CH3:6])([CH3:5])[CH3:4].[OH-].[Na+].Cl[C:13]([O:15][CH3:16])=[O:14]>O1CCOCC1>[CH3:16][O:15][C:13]([NH:1][C@@H:2]([C:3]([CH3:6])([CH3:5])[CH3:4])[C:7]([OH:9])=[O:8])=[O:14]
Reactant: CC(C)(C)[C@H](N)C(=O)O
Reactant: COC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COC(=O)N[C@H](C(=O)O)C(C)(C)C
Temperature: 60 °C
Yield: 98 %

Procedure:
(L)-tert-Leucine (10 g, 0.076 mol) was dissolved in 1,4-dioxane (40 mL) and treated with 2M NaOH (125 mL, 3.2 equivalents) followed by dropwise addition of methyl chloroformate (11.2 mL, 1.9 equivalents) at 25° C. The mixture was heated at 60° C. for 22 hrs, cooled, and extracted twice with dichloromethane. The aqueous layer was separated, cooled in ice bath, and acidified with 4N HCl (60 mL). The mixture was extracted three times with ethyl acetate, and the organic layer was separated, dried with sodium sulfate, filtered, and the solvents were evaporated to give 14.1 g (98%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([S:10]([N:13]2[CH2:18][CH2:17][C:16]([F:20])([F:19])[CH2:15][CH2:14]2)(=[O:12])=[O:11])=[CH:5][C:6]=1[C:7]([NH2:9])=[O:8].[I-].ClC1C=CC=C[N+]=1C.[F:30][C:31]1[CH:39]=[CH:38][CH:37]=[CH:36][C:32]=1[C:33](O)=[O:34]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:19][C:16]1([F:20])[CH2:17][CH2:18][N:13]([S:10]([C:4]2[S:3][C:2]([NH:1][C:33](=[O:34])[C:32]3[CH:36]=[CH:37][CH:38]=[CH:39][C:31]=3[F:30])=[C:6]([C:7]([NH2:9])=[O:8])[CH:5]=2)(=[O:12])=[O:11])[CH2:14][CH2:15]1
Reactant: O=C(O)c1ccccc1F
Reactant: NC(=O)c1cc(S(=O)(=O)N2CCC(F)(F)CC2)sc1N
Agent: CN(C)c1ccncc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Product: NC(=O)c1cc(S(=O)(=O)N2CCC(F)(F)CC2)sc1NC(=O)c1ccccc1F

Procedure:
A solution of 2-Amino-5-(4,4-difluoro-piperidine-1-sulfonyl)-thiophene-3-carboxylic acid amide (53 mg, 0.18 mmol), TEA (125 μL, 0.90 mmol), DMAP (7 mg, 0.054 mmol), 2-Chloro-1-methylpyridinium iodide (60 mg, 0.23 mmol) and 2-fluorobenzoic acid (33 mg, 0.23 mmol) in DCM is stirred at 80° C. overnight. The mixture is then diluted with DCM and washed with aqueous NaHCO3. The organic phase is isolated evaporated, and the residue is purified by preparative chromatography to yield the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31]Cl)(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1.[NH2:33][C@H:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36]>>[NH2:1][C:2]1[C:7]([C:8]([C:10]2[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=2[O:17][CH3:18])=[O:9])=[CH:6][N:5]=[C:4]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([S:26]([CH2:29][CH2:30][CH2:31][NH:33][C@@H:34]([CH2:35][OH:36])[CH:37]([CH3:39])[CH3:38])(=[O:28])=[O:27])[CH2:22][CH2:21]2)[N:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCCl)CC2)nc1N
Product: COc1ccc(F)cc1C(=O)c1cnc(NC2CCN(S(=O)(=O)CCCN[C@@H](CO)C(C)C)CC2)nc1N

Procedure:
The compound was prepared from [4-amino-2-[1-(3-chloro-propane-1-sulfonyl)-piperidin-4-ylamino]-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone (Example 242) and (R)-2-amino-3-methyl-1-butanol (Aldrich) in an analogous manner as described in Example 227. HR-MS (ES, m/z) calculated for C25H38N6O5SF [(M+H)+] 553.2603, observed 553.2600.
Reaction SMILES: C[O:2][C:3](=[O:31])[C@@H:4]([O:28][CH2:29][CH3:30])[CH2:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:20]3[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=3)[S:18][CH:19]=2)=[CH:8][C:7]=1[CH3:27].[Li+].[OH-]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[S:18][CH:19]=[C:15]([CH2:14][O:13][C:9]3[CH:10]=[C:11]([CH3:12])[C:6]([CH2:5][C@H:4]([O:28][CH2:29][CH3:30])[C:3]([OH:31])=[O:2])=[C:7]([CH3:27])[CH:8]=3)[N:16]=2)=[CH:21][CH:22]=1
Reactant: CCO[C@@H](Cc1c(C)cc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)OC
Agent: [Li+]
Agent: [OH-]
Product: CCO[C@@H](Cc1c(C)cc(OCc2csc(-c3ccc(Cl)cc3)n2)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 10 d], (S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid methyl ester was treated with LiOH to obtain (S)-3-{4-[2-(4-chloro-phenyl)-thiazol-4-ylmethoxy]-2,6-dimethyl-phenyl}-2-ethoxy-propionic acid as light yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]([NH:18][C:19](=[O:27])[C:20]2[CH:25]=[CH:24][CH:23]=[N:22][C:21]=2[Cl:26])[CH:8]=[CH:9][C:10]=1[C:11]([F:17])([F:16])[C:12]([F:15])([F:14])[F:13].CCN(CC)CC.[CH3:35][S:36](Cl)(=[O:38])=[O:37]>C(Cl)Cl>[Cl:26][C:21]1[N:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([NH:18][C:7]1[CH:8]=[CH:9][C:10]([C:11]([F:16])([F:17])[C:12]([F:15])([F:14])[F:13])=[C:5]([O:4][CH2:3][CH2:2][NH:1][S:36]([CH3:35])(=[O:38])=[O:37])[CH:6]=1)=[O:27]
Reactant: NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)NCCOc1cc(NC(=O)c2cccnc2Cl)ccc1C(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 381 mg (0.93 mmol) N-[3-(2-amino-ethoxy)-4-pentafluoroethyl-phenyl]-2-chloro-nicotinamide in 10 ml CH2Cl2 at 0° C. was added 0.389 ml Et3N and 0.072 ml (0.93 mmol) methanesulfonylchloride. After 5 min, the reaction was stirred at RT for 30 min. The reaction was diluted with CH2Cl2, washed with brine, dried over Na2SO4, filtered, concentrated, and dried under vacuum, yielding the titled compound as a white foamy solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:18](=[O:19])[NH:17][C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:41][C:42]([N:44]([CH:53]([CH3:55])[CH3:54])[C:45]1[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=1)=[O:43]>CN(C)C=O>[CH2:1]([O:8][C:9]([NH:11][CH:12]1[C:18](=[O:19])[N:17]([CH2:41][C:42]([N:44]([CH:53]([CH3:55])[CH3:54])[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[O:43])[C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[C:14]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:13]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NC1N=C(c2cccnc2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: COc1ccc(N(C(=O)CBr)C(C)C)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(NC(=O)OCc3ccccc3)N=C(c3cccnc3)c3ccccc32)C(C)C)cc1
Reaction time: 0.17 h
Yield: 84.5 %

Procedure:
A solution of 1.000 g of 3-(benzyloxycarbonyl-amino)-5-pyridin-3-yl-1,3-dihydro-benzo[e][1,4]diazepin-2-one (2.591 mmol, Pat. App. WO 93/16999) in 7 mL dimethylformamide at 0° C. under nitrogen was treated with 5.44 mL (2.72 mmol) of potassium bis(trimethylsilyl)amide (0.5M in toluene). After stirring for 10 min., a solution of 0.779 g of 2-bromo-N-isopropyl-N-(4-methoxy-phenyl)-acetamide (2.72 mmol), prepared as in Intermediate 5, in 2 mL of dimethylformamide was added to the mixture. The reaction was stirred to ambient temperature over 2 hrs. and then quenched into a mixture of ethyl acetate, water and saturated aqueous brine. The phases were separated and the aqueous phase was back-extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous brine, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to a residue. The residue was purified on flash grade silica gel using 9:1 ethyl acetate/hexane. The appropriate fractions were combined, evaporated in vacuo to a foam and triturated with hexane. After evaporation of the hexane in vacuo, the residual solid was dried under high vacuum to provide 1.295 g of the title compound as a tan solid. 1H NMR (300 MHz, d6-DMSO) -- =8.70 (m, 2H), 8.56 (d, 1H, J=8.6), 7.92 (m, 1H), 7.71 (m, 1H), 7.52 (m, 2H), 7.32 (m, 9H), 7.07 (d, 2H, J=8.8), 5.19 (d, 1H, J=8.8), 5.08 (s, 2H), 4.71 (m, 1H), 4.27 (d, 1H, J=16.5), 4.12 (d, 1H, J=16.5), 3.81 (s, 3H), 0.95 (m, 6H); MS (ESI): [M+H]+ =592.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].Cl.O1[CH2:14][CH2:13][NH:12]C1=O>ClCCl.O1CCOCC1>[ClH:1].[NH2:12][CH2:13][CH2:14][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=1
Reactant: O=C1NCCO1
Reactant: Nc1cccc(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: NCCNc1cccc(Cl)c1
Temperature: 25 °C

Procedure:
To a solution of 3-chloroaniline (30 mL) in 500 mL of dichloromethane at 0° C. was added dropwise a solution of 4 N HCl in 1,4-dioxane (80 mL). The solution was warmed to room temperature, then concentrated to dryness in vacuo to provide a white powder. A mixture of this powder with 2-oxazolidinone (24.6 g) was heated under nitrogen atmosphere at 160° C. for 10 hours, during which the solids melted, and gas evolution was observed. The reaction was allowed to cool, forming the titled compound as a pale brown solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2].[F:20][CH2:21][CH2:22][CH2:23][CH2:24][NH2:25]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:25][CH2:24][CH2:23][CH2:22][CH2:21][F:20])=[CH:13][C:12]([F:17])=[CH:11][C:10]=2[O:18][CH3:19])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1Cl
Reactant: NCCCCF
Product: CCOC(=O)c1cnc2c(OC)cc(F)cc2c1NCCCCF

Procedure:
4-Chloro-6-fluoro-8-methoxy-quinoline-3-carboxylic acid ethyl ester (250 mg, 0.88 mmol) was treated with 4-fluoro-butylamine following general procedure B to afford 6-fluoro-4-(4-fluoro-butylamino)-8-methoxy-quinoline-3-carboxylic acid ethyl ester (175 mg). Thus obtained amino-ester was hydrolyzed to the corresponding acid using general procedure D and then transformed into the corresponding ethylamide (95 mg) following general procedure E. The above ethylamide (95 mg, 0.28 mmol) was subjected to reaction with methyl chloroformate according to general procedure F to furnish 3-ethyl-9-fluoro-1-(4-fluoro-butyl)-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (52 mg). LCMS: m/z 364 [M+1]+.
Reaction SMILES: C(O[C:6]([N:8](C)[CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:6][NH:8][CH2:9][CH2:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=1
Reactant: CCOC(=O)c1ccc(CCN(C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CCNC)cc1
Temperature: 22 °C
Reaction time: 3 h

Procedure:
To a solution of 0.907 g (2.95 mmol) of ethyl 4-(2-(tert-butoxycarbonyl(methyl)amino)ethyl)benzoate in 10 mL of DCM at 0° C. was added 2.0 mL (26 mmol) of trifluoroacetic acid (TFA). The reaction was warmed to 22° C., stirred for 3 h and the solvents were then evaporated. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1 N NaOH which had been saturated with NaCl. The aqueous layer was back-extracted with ethyl acetate (6×50 mL) and the combined organics were dried (Na2SO4) and evaporated to give 2c as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([NH2:8])[CH:7]=1.CCO[C:13]([S-:15])=[S:14].[K+].Cl>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:14][C:13]([SH:15])=[N:8][C:6]=2[CH:7]=1
Reactant: CCOC(=S)[S-]
Reactant: Nc1cc(Br)ccc1F
Agent: Cl
Agent: [K+]
Solvent: O
Product: Sc1nc2cc(Br)ccc2s1
Temperature: 140 °C
Yield: 95.2 %

Procedure:
To a solution of 5-bromo-2-fluorobenzenamine (200 mg, 1.28 mmol) in N-methyl-2-pyrrolidine (1.5 mL) was added potassium o-ethyl carbonodithioate (410 mg, 2.56 mmol). The mixture was heated at 140° C. for 2 h. The reaction mixture was poured into a large amount of water, acidified with concentrated hydrochloric acid, and filtered to give 5-bromo-benzothiazole-2-thiol 300 mg (95%).
Reaction SMILES: C([BH3-])#N.[Na+].[NH2:5][CH:6]1[CH:12]([OH:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]3[NH:18][C:19](=[O:20])[N:9]([C:10]=23)[CH2:8][CH2:7]1.CO.[CH3:23][C:24]([CH3:26])=O>>[CH:24]([NH:5][C@H:6]1[C@H:12]([OH:13])[C:11]2[CH:14]=[CH:15][CH:16]=[C:17]3[NH:18][C:19](=[O:20])[N:9]([C:10]=23)[CH2:8][CH2:7]1)([CH3:26])[CH3:23]
Reactant: NC1CCn2c(=O)[nH]c3cccc(c32)C1O
Reactant: CC(C)=O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3 g of sodium cyanoborohydride were added over 15 minutes at 0° to 5° C. to a mixture of 6 g of (6RS, trans) 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][1]-benzazepin-2(1H)-one, 60 ml of methanol and 30 ml of acetone and the mixture was stirred at room temperature for 3 hours and was evaporated to dryness under reduced pressure. The residue was added to 60 ml of water and the mixture was extracted with chloroform. The organic phase was dried and evaporated to dryness to obtain 3.6 g of (6RS,trans) 6-isopropylamino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][1]-benzazepin-2(1H)-one melting at ≃166° C. The latter was dissolved in 60 ml of ethanol and ethyl acetate saturated with hydrogen chloride was added thereto. The mixture was vacuum filtered to obtain 3.7 g of the corresponding hydrochloride melting at ≃270° C. The product was dissolved in hot methanol and ethyl acetate was added to obtain 3.3 g of the said product melting at ≃270° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[NH:22][C:21]3[C:20](=[O:23])[N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[N:17]([CH3:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1B(O)O.N1C=CC=CC=1>O1CCCC1.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:22]([C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[O:33][CH3:32])[C:21]3[C:20](=[O:23])[N:19]([CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[C:18](=[O:30])[N:17]([CH3:31])[C:16]=3[N:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(=O)Cn1c(=O)c2[nH]c(N3CCN(C(=O)OC(C)(C)C)CC3)nc2n(C)c1=O
Reactant: COc1ccccc1B(O)O
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCOC(=O)Cn1c(=O)c2c(nc(N3CCN(C(=O)OC(C)(C)C)CC3)n2-c2ccccc2OC)n(C)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
4-[1-(Ethoxycarbonylmethyl)-3-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylic acid tert-butyl ester, 2-methoxyphenyl boronic acid (60 mg), and copper (II) acetate (200 mg) were dissolved in anhydrous tetrahydrofuran (5 ml), and pyridine (0.2 ml) was added thereto. The reaction mixture was stirred at room temperature for 3 days, filtered through a short column packed with NH-silica gel, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain 18 mg of the title compound from a fraction eluted with hexane-ethyl acetate (1:1).
Reaction SMILES: [CH3:1][C:2]([CH3:4])=[O:3].[CH2:5]([OH:16])[C@H:6]([C@H:8]([C@@H:10]([C@@H:12]([CH2:14]O)[OH:13])[OH:11])[OH:9])[OH:7].[CH2:17](O)[C@H:18]([C@H:20]([C@@H]([C@@H](CO)O)O)O)O>[Cl-].[Zn+2].[Cl-].CC(C)=O>[CH3:1][C:2]1([CH3:4])[O:13][C@@H:12]([C@@H:10]([OH:11])[C@H:8]([OH:9])[C@@H:6]2[O:7][C:18]([CH3:20])([CH3:17])[O:16][CH2:5]2)[CH2:14][O:3]1
Reactant: CC(C)=O
Reactant: OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Cl-]
Agent: [Zn+2]
Product: CC1(C)OC[C@H]([C@@H](O)[C@H](O)[C@H]2COC(C)(C)O2)O1

Procedure:
In the preparation of the diketonide deriving from D-mannitol acetone is the ketone which is preferentially used. Then, the 1,2,5,6-diacetone D-mannitol is prepared by reacting acetone, to which solid zinc chloride has been added, with D-mannitol with stirring within a temperature range of from 0° C. to +50° C.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[CH:9][CH:8]=1.[CH3:14][C:15]([S:18]([N:20]=[C:21]1[CH2:24][O:23][CH2:22]1)=[O:19])([CH3:17])[CH3:16]>C1COCC1>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([C:21]2([NH:20][S:18]([C:15]([CH3:17])([CH3:16])[CH3:14])=[O:19])[CH2:24][O:23][CH2:22]2)=[CH:8][CH:9]=1
Reactant: CC(C)(C)S(=O)N=C1COC1
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)NC1(c2ccc(Br)cc2)COC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.7 %

Procedure:
A solution of n-butyllithium in hexanes (1.65M, 4.92 mL) was added dropwise to a solution of 1,4-dibromobenzene (2.05 g) in THF (25 mL) dropwise over the course of 30 min at −78° C. The resulting mixture was stirred at the same temperature for 1 h. To the mixture was added a solution of 2-methyl-N-oxetan-3-ylidenepropane-2-sulfinamide (1.02 g) in THF (5 mL) dropwise over the course of 30 min at −78° C. The reaction mixture was stirred for an additional 30 min. at −78° C. then allowed to warm to room temperature. After being stirred for 1 h at room temperature, the reaction mixture was quenched by addition of saturated ammonium chloride aqueous solution. The aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with saturated sodium bicarbonate solution then brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (50-100% ethyl acetate in hexanes then 5% methanol in ethyl acetate) gave the product (1.85 g, 96%). 1HNMR (CDCl3) 400 MHz δ: 7.55 (d, J=8.7 Hz, 2H), 7.27 (d, J=8.7 Hz, 2H), 5.16 (d, J=6.9 Hz, 1H), 5.06 (d, J=6.9 Hz, 1H), 5.02 (d, J=6.9 Hz, 1H), 4.94 (d, J=6.9 Hz, 1H), 4.05 (br s, 1H), 1.22 (s, 9H). LCMS: 332, 334 [M+H].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]2[C:8]1=[O:17].[C:18]1([CH:24]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[O:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:32]1([CH:24]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]3[C:11](=[O:12])[C:10]4=[CH:13][CH:14]=[CH:15][CH:16]=[C:9]4[C:8]3=[O:17])[CH2:28][CH2:27]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: c1ccc(C(OC2CCNCC2)c2ccccc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 15 h
Yield: 87.5 %

Procedure:
3.70 g of potassium phthalimide was dissolved in 20 ml of N,N-dimethylformamide; 5.4 ml of 1,5-dichloropentane was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (4:1). The desired fraction was collected to yield 4.68 g of N-(5-bromopentyl)phthalimide as an oily substance. 4.68 g of N-(5-bromopentyl)phthalimide and 4.25 g of 4-(diphenylmethoxy)piperidine were dissolved in 30 ml of N,N-dimethylformamide; 2.42 g of potassium carbonate was added, followed by stirring at room temperature for 15 hours. Ice water was added to the reaction mixture, followed by extraction with ethyl acetate; the extract was washed with saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate-triethylamine (50:50:1). The desired fraction was collected to yield 6.67 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide as an oily substance. 6.6 g of N-[5-[4-(diphenylmethoxy)piperidino]pentyl]phthalimide was dissolved in 30 ml of ethanol; 0.694 ml of hydrazine monohydrate was added, followed by thermal refluxing for 3 hours. After cooling, the mixture was concentrated under reduced pressure; ethyl acetate was added to the residue; the crystal precipitated was collected, dissolved in 15 ml of a 1 N aqueous solution of sodium hydroxide and 20 ml of water and extracted with ethyl acetate; the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the crystal obtained was collected to yield 3.29 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[CH2:9]O.[CH3:11][C:12]1[CH:17]=[C:16]([C:18]([CH3:20])=O)[CH:15]=[C:14]([CH3:21])[CH:13]=1.[OH-].[K+]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[N:1]=[C:18]([C:16]1[CH:17]=[C:12]([CH3:11])[CH:13]=[C:14]([CH3:21])[CH:15]=1)[CH:20]=[CH:9]2
Reactant: Nc1ccc(Br)cc1CO
Reactant: CC(=O)c1cc(C)cc(C)c1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: Cc1cc(C)cc(-c2ccc3cc(Br)ccc3n2)c1
Temperature: 25 °C

Procedure:
(2-Amino-5-bromophenyl)methanol (22 g, 109 mmol), 3,5-dimethylacetophenone (24.2 g, 163 mmol), RuCl2(PPh3)3 (1.05 g, 1.09 mmol), KOH (11.0 g, 196 mmol) were refluxed in 270 mL of toluene for 18 h. Water was collected from the reaction using a Dean-stark trap. The reaction mixture was allowed to cool to room temperature and filtered through a silica gel plug and eluted with 5% ethyl acetate in hexanes. The product was further purified by Kugelrohr distillation and crystallization from methanol.
Reaction SMILES: [F:1][C:2]([F:33])([C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[CH:12][N:13]=[C:14]2[NH:17][CH2:18][C:19]([NH:21][CH:22]2[CH2:25][N:24](C(OC(C)(C)C)=O)[CH2:23]2)=[O:20])=[CH:9][CH:8]=1)[C:3]([F:6])([F:5])[F:4].C(O)(C(F)(F)F)=O>ClCCl>[NH:24]1[CH2:25][CH:22]([NH:21][C:19](=[O:20])[CH2:18][NH:17][C:14]2[C:15]3[C:10](=[CH:9][CH:8]=[C:7]([C:2]([F:1])([F:33])[C:3]([F:6])([F:4])[F:5])[CH:16]=3)[CH:11]=[CH:12][N:13]=2)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)CNc2nccc3ccc(C(F)(F)C(F)(F)F)cc23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CNc1nccc2ccc(C(F)(F)C(F)(F)F)cc12)NC1CNC1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Into a 8 mL sealed tube, was placed a solution of tert-butyl 3-(2-[[7-(pentafluoroethyl)isoquinolin-1-yl]amino]acetamido)azetidine-1-carboxylate (as prepared in the previous step, 100 mg, 0.21 mmol, 1.00 equiv) in dichloromethane (5 mL), TFA (0.5 g). The resulting solution was stirred for 5 h at 0° C. The resulting mixture was concentrated under vacuum. The residue was washed with 3×5 mL of ether. This resulted in 0.12 g (crude) of N-(azetidin-3-yl)-2-[[7-(pentafluoroethyl)isoquinolin-1-yl]amino]acetamide as a white solid.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1>>[C:1]([N:23]1[CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)[CH2:25][CH2:24]1)(=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCC/C=C/C(=O)O
Reactant: Clc1ccc(N2CCNCC2)cc1
Product: CCCCCCC/C=C/C(=O)N1CCN(c2ccc(Cl)cc2)CC1

Procedure:
The same procedures as in Example 2 were carried out using (E)-2-decenoic acid and 1-(4-chlorophenyl)piperazine as starting raw materials, to produce an intended compound.