Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)=O)(C)(C)C.C(N(CC)CC)C.[F:22][C:23]([F:35])([F:34])[C@@:24]([O:29][Si](C)(C)C)([CH3:28])[C:25](Cl)=[O:26]>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:25](=[O:26])[C@:24]([OH:29])([CH3:28])[C:23]([F:35])([F:34])[F:22])[CH2:13][CH2:14]1
Reactant: C[C@@](O[Si](C)(C)C)(C(=O)Cl)C(F)(F)F
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@](O)(C(=O)N1CCC(N)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-t-butyloxycarbonylaminopiperidine (Method C, 8.0 g, 40.0 mmol) and triethylamine (8.5 ml), 60 mmol) in DCM (200 ml) was added a solution of (S)-3,3,3-trifluoro-2-trimethylsilyloxy-2-methylpropanoyl chloride (J. Med. Chem., 1999, 42, 2741-2746) (10.0 g, 41.3 mmol) in DCM (5 ml). The resultant mixture was stirred at ambient temperature overnight, the DCM evaporated, the residue taken up in EtOAc (150 ml), washed with saturated citric acid solution, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was dissolved in methanol (25 ml), treated with saturated hydrogen chloride in methanol (100 ml), stirred at ambient temperature overnight and evaporated to dryness. The residue was recrystallized from methanol/EtOAc to give the title compound as the hydrochloride salt (7.5 g, 27.2 mmol). Mp: 245-246° C.; NMR: 1.45 (m, 2H), 1.5 (s, 3H), 1.95 (m, 2H), 3.25 (m, 1H), 4.4 (m, 2H), 4.65 (m, 2H), 7.15 (s, 1H), 8.2 (s, 3H); m/z (+ve ESP) 241 (M+H)+.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:32])=[O:31])[N:18]=3)=[CH:15][N:16]=[C:11]2[N:10](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:12]2=[N:13][C:14]([C:17]3[C:25]4[C:20](=[CH:21][C:22]([F:26])=[CH:23][CH:24]=4)[N:19]([CH2:27][CH2:28][CH2:29][S:30]([CH3:33])(=[O:31])=[O:32])[N:18]=3)=[CH:15][N:16]=[C:11]2[NH:10][CH:9]=1)=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)NC(=O)c1c[nH]c2ncc(-c3nn(CCCS(C)(=O)=O)c4cc(F)ccc34)nc12
Reaction time: 2 h
Yield: 71.5 %

Procedure:
To a stirred solution of N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5-trityl-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (55 mg, 0.077 mmol) in dichloromethane (2 mL) was added drop-wise trifluoroacetic acid (2 mL) at room temperature and the reaction mixture was stirred for 2 hours. The solvent was removed under reduced pressure. The residue was triturated with MeOH then decanted and dried and dried to give N-tert-butyl-2-(6-fluoro-1-(3-(methylsulfonyl)propyl)-1H-indazol-3-yl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxamide (26 mg, 72%) as a white solid. LCMS: (M+H)+=473; (M+Na)+=495; 1H NMR (300 MHz, DMSO): δ 12.84 (s, 1H), 9.09 (s, 1H), 8.51-8.46 (m, 1H), 8.38 (s, 1H), 7.93 (s, 1H), 7.74 (d, 1H, J=9.9 Hz), 7.18 (t, 1H, J=9.0 Hz), 4.63 (t, 2H, J=6.6 Hz), 3.22 (t, 2H, J=7.8 Hz), 2.99 (s, 3H), 2.33 (t, 2H, J=7.4 Hz), 1.52 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([NH2:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]([NH:16][C:17]1([C:20](O)=[O:21])[CH2:19][CH2:18]1)=[O:15]>>[Br:1][C:2]1[CH:11]=[CH:10][C:5]2[CH:6]([NH:9][C:20]([C:17]3([NH:16][C:14](=[O:15])[C:13]([F:12])([F:23])[F:24])[CH2:18][CH2:19]3)=[O:21])[CH2:7][O:8][C:4]=2[CH:3]=1
Reactant: O=C(NC1(C(=O)O)CC1)C(F)(F)F
Reactant: NC1COc2cc(Br)ccc21
Product: O=C(NC1(C(=O)NC2COc3cc(Br)ccc32)CC1)C(F)(F)F

Procedure:
In analogy to the procedure described for the preparation of intermediate A-1 [B] and A-1 [C], (rac)-6-bromo-2,3-dihydro-benzofuran-3-ylamine has been coupled with 1-(2,2,2-trifluoroacetamido)cyclopropanecarboxylic acid (intermediate A-1 [A]) to give 1-(2,2,2-trifluoro-acetylamino)-cyclopropanecarboxylic acid ((rac)-6-bromo-2,3-dihydro-benzofuran-3-yl)-amide, which was subsequently reacted with 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) to yield the title compound as light brown solid. MS: 439.2 (M−H−).
Reaction SMILES: [CH2:1]([C:3]1[CH:15]=[C:14]([CH:16]=O)[CH:13]=[CH:12][C:4]=1[O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH3:2].[CH2:18]([NH2:22])[CH2:19][CH2:20][CH3:21]>C(O)C>[CH2:18]([NH:22][CH2:16][C:14]1[CH:13]=[CH:12][C:4]([O:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:3]([CH2:1][CH3:2])[CH:15]=1)[CH2:19][CH2:20][CH3:21]
Reactant: CCCCN
Reactant: CCOC(=O)COc1ccc(C=O)cc1CC
Solvent: CCO
Product: CCCCNCc1ccc(OCC(=O)OCC)c(CC)c1
Reaction time: 0.5 h
Yield: 56.4 %

Procedure:
To a solution of ethyl (2-ethyl-4-formylphenoxy)acetate (0.52 g, 2.2 mmol) in anhydrous ethanol (10 mL) was added butylamine (0.26 mL, 2.6 mmol). The resulting solution was stirred at room temperature under N2 for 18 h over 4A molecular sieves. The reaction was quenched by cautious addition of sat. NaHCO3 aq. (30 mL) and the mixture stirred for 30 mins. The mixture was then extracted EtOAc (2×100 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated in vacuo. Purification by SPE (SCX, 20 g) conditioning the cartridge with ethanol and then loading the compound and washing with CH2Cl2, then ethanol before eluting the title compound using 10% NH3 in ethanol, evaporation of the 10% NH3 in ethanol extract afforded the title compound as a pale yellow oil (0.364 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[NH2:13][CH2:14][CH2:15][C:16]1[CH:28]=[CH:27][C:19]([O:20][CH2:21][C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=1>N1C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([NH:13][CH2:14][CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[CH:27][CH:28]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1ccc(CCN)cc1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)NCCc2ccc(OCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 10.35 g. (50 mMol) 4-methoxybenzenesulphonyl chloride and 50 ml. pyridine is added dropwise at 0°-10° C. in the course of 5 minutes to a solution of 11.2 g. (50 mMol) ethyl 4-(2-aminoethyl)-phenoxyacetate in 125 ml. anhydrous pyridine. The reaction mixture is allowed to warm up to ambient temperature and then kept at 60° C. for 45 minutes. Subsequently, the reaction mixture is evaporated to half its volume in a vacuum, then poured into ice-water and acidified with hydrochloric acid. The precipitated viscous mass is dissolved in toluene and the toluene phase successively extracted with dilute hydrochloric acid, an aqueous solution of sodium bicarbonate and water. After drying over anhydrous calcium chloride, the solution is evaporated in a vacuum and the residue triturated with some diethyl ether, crystallization thereby takes place. The product is filtered off with suction and recrystallized from a very small amount of diethyl ether. There are thus obtained 13.0 g. (66% of theory) ethyl 4-[2-(4-methoxybenzenesulphonylamino)-ethyl]-phenoxyacetate; m.p. 82°-83° C.
Reaction SMILES: Cl[CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4].[Na+].[I-:14]>CC(C)=O>[I:14][CH2:2][C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[OH:4]
Reactant: [I-]
Reactant: O[C@@H](CCl)c1ccc(Cl)cc1Cl
Agent: [Na+]
Solvent: CC(C)=O
Product: O[C@@H](CI)c1ccc(Cl)cc1Cl
Temperature: 25 °C

Procedure:
(R)-2-Chloro-(2′,4′-dichlorophenyl)-1-ethanol (1.95 g, 8.65 mmol) was dissolved in 60 mL of anhydrous acetone (4A molecular sieves). Then NaI (7 g, 46.70 mmol) was added to the solution and the solution refluxed for 3 hours under nitrogen. Upon cooling to room temperature, the solution was poured into 160 mL of hexanes/ethyl acetate (3:1), and filtered to remove excess NaI which had precipitated. The filtrate was evaporated to dryness in vacuo, and the residue treated with ether and decanted from the solid NaI. Upon removal of ether, the product was obtained as white solid. Yield: 2.40 g (88%).
Reaction SMILES: [CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([O:14]C)=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1.[OH-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]1([CH3:32])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:12]([OH:14])=[O:13])[CH:9]=2)[NH:4][CH:3]1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([S:22](=[O:31])(=[O:30])[NH:23][CH:24]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25]2)[CH:17]=1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(S(=O)(=O)NC3CCN(C)C3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CN1CCC(NS(=O)(=O)c2cccc(C3Nc4ccc(C(=O)O)cc4CC3(C)C)c2)C1
Yield: 29.1 %

Procedure:
To a stirred solution of methyl 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylate (140 mg, 0.31 mmol) in methanol/tetrahydrofuran (5 mL/5 mL) was added 1N sodium hydroxide (4.59 mL). The resultant mixture was heated to reflux for 2.5 h. Organic solvent was removed and the residue was dissolved in water. The aqueous layer was acidified to pH=4. The precipitates were filtered, and dissolved in tetrahydrofuran, dried over anhydrous magnesium sulfate. Anhydrous magnesium sulfate was removed, and after evaporation, the residue was treated with ethyl acetate to afford 40 mg of 3,3-dimethyl-2-(3-(N-(1-methylpyrrolidin-3-yl)sulfamoyl)phenyl)-1,2,3,4-tetrahydroquinoline-6-carboxylic acid. (Yield: 29%). MS (ESI+APCI) M+1=444.2.
Reaction SMILES: [Br-].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][N+:4]=1[CH:10]([C:12](=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH3:11]>CO>[F:9][C:6]1[CH:7]=[CH:8][C:3]2[N:4]([C:10]([CH3:11])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:2]=2)[CH:5]=1
Reactant: CCOC(=O)C(=O)C(C)[n+]1cc(F)ccc1N
Agent: [Br-]
Solvent: CO
Product: CCOC(=O)c1nc2ccc(F)cn2c1C
Temperature: 25 °C

Procedure:
A solution of compound 5-C (5.35 g, 16.7 mmol) in MeOH (75 mL), was heated at reflux for 6 hours. The solution was cooled to rt, and the solvent was evaporated in vacuo. The residue was dissolved in water and made basic with aqueous NaHCO3, to give a solid precipitate. The solid was collected by filtration, dissolved into EtOAc, and dried over sodium sulfate. The solvent was evaporated in vacuo to give compound 5-D as a pale pink solid (3.4 g, 92%). 1H-NMR (CDCl3): δ 7.82-7.86 (m, 1H), 7.64-7.68 (m, 1H), 7.15-719 (m, 1H), 4.47 (q, J=7.1 Hz, 2H), 2.78 (s, 3H), 1.46 (t, J=7.1 Hz, 3H); MS: m/z 223.0 (MH+)
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[CH:20]=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[N:18]=[C:17]([Cl:25])[N:16]=2)[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)C.Cl.O1CCOCC1>[ClH:25].[ClH:25].[Cl:25][C:17]1[N:18]=[C:19]([NH:21][C:22](=[O:24])[CH3:23])[CH:20]=[C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[N:16]=1
Reactant: CC(=O)Nc1cc(NC2CCN(C(=O)OC(C)(C)C)CC2)nc(Cl)n1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: CC(=O)Nc1cc(NC2CCNCC2)nc(Cl)n1

Procedure:
A solution of 4-(6-acetylamino-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.27 mmol) in ethanol (2 mL) and 4 M HCl in dioxane (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 270.0 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]4[CH2:28][CH2:29][N:24]([CH3:23])[CH2:25][CH2:26]4)=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CN1CCNCC1
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CN1CCN(CCCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 1-Methylpiperazine were converted to yield 3-(4-Bromo-phenyl)-6-[4-(4-methyl-piperazin-1-yl)-butoxy]-benzo[d]isothiazole as white solid, MS: 460(MH+, 1Br).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)[N:21]([CH2:36][C:37](O)=[O:38])[C:20]3=[O:40])[CH2:10][CH:9]1[CH3:41])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:42]([NH2:45])([CH3:44])[CH3:43].CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][N:11]([C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][CH:26]=2)[N:23]=[C:22]([C:27]2[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=2)[N:21]([CH2:36][C:37](=[O:38])[NH:45][CH:42]([CH3:44])[CH3:43])[C:20]3=[O:40])[CH2:10][CH:9]1[CH3:41])=[O:7])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)N
Reactant: COc1cc(-c2nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)CC(C)(C)C4)cc3c(=O)n2CC(=O)O)ccc1F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(-c2nc3ccc(N4CC(C)N(C(=O)OC(C)(C)C)CC(C)(C)C4)cc3c(=O)n2CC(=O)NC(C)C)ccc1F
Yield: 56 %

Procedure:
4-[3-Carboxymethyl-2-(4-fluoro-3-methoxyphenyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2,6,6-trimethylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (200 mg, 0.352 mmol), isopropylamine (208 mg, 299 uL, 3.52 mmol), 1-propanephosphonic acid cyclic anhydride (336 mg, 320 uL, 0.528 mmol) and DIPEA (135 mg, 186 uL, 1.06 mmol) were stirred at room temperature in DCM (15 mL) for 2 h. NaHCO3 (aq.) (15 mL) was added, the organic layer separated, dried (Na2SO4) and evaporated under reduced pressure. Crude product was purified by chromatography on silica gel with a gradient of DCM to DCM:MeOH (4:1, v/v) as eluent to afford 4-[2-(4-fluoro-3-methoxyphenyl)-3-(isopropylcarbamoylmethyl)-4-oxo-3,4-dihydroquinazolin-6-yl]-2,6,6-trimethylperhydro-1,4-diazepine-1-carboxylic acid tert-butyl ester (120 mg, 0.197 mmol, 56%).
Reaction SMILES: Br[CH2:2][CH2:3][C@H:4]([NH:10][O:11][Si](C(C)(C)C)(C)C)[C:5]([O:7][CH2:8][CH3:9])=[O:6].CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-]>C1COCC1>[O:11]1[CH2:2][CH2:3][C@@H:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[NH:10]1
Reactant: CCOC(=O)[C@H](CCBr)NO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)[C@@H]1CCON1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.6 %

Procedure:
To a solution of ethyl (2S)-4-bromo-2-({[tert-butyl(dimethyl)silyl]oxy}amino)butanoate (870 mg, 2.556 mmol) in THF (25 mL) was added tetrabutylammoniumfluoride trihydrate (887 mg, 2.812 mmol) and the mixture was stirred at rt for 1 h. The solvents were evaporated and the residue was purified by flash chromatography (DCM/EtOAc 9:1, then 4:1) to give ethyl (3S)-isoxazolidine-3-carboxylate (340 mg, 91%) as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[O:12]1[CH2:17][CH2:16][CH:15]([CH:18]([C:21]2[CH:22]=[N:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=2)[CH2:19][NH2:20])[CH2:14][CH2:13]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:19][CH:18]([CH:15]1[CH2:16][CH2:17][O:12][CH2:13][CH2:14]1)[C:21]1[CH:22]=[N:23][C:24]([C:27]([F:30])([F:28])[F:29])=[CH:25][CH:26]=1)=[O:6]
Reactant: NCC(c1ccc(C(F)(F)F)nc1)C1CCOCC1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: O=C(NCC(c1ccc(C(F)(F)F)nc1)C1CCOCC1)c1cccc(Cl)c1Cl

Procedure:
From 2,3-dichlorobenzoic acid and 2-(tetrahydro-2H-pyran-4-yl)-2-(6-(trifluoromethyl)pyridin-3-yl)ethanamine. LCMS (MH+): m/z=447.0, tR (minutes, Method E)=0.70
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)[OH:4].O=[C:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:32]=[CH:31][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:21][CH:20]=1.C1C=CC=CC=1.[BH4-].[Na+]>CO>[CH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:13]=[CH:14][C:5]=1[CH:3]([OH:4])[CH2:2][NH:1][CH:16]([CH3:33])[CH2:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[S:28][C:27](=[O:29])[NH:26][C:25]2=[O:30])=[CH:31][CH:32]=1
Reactant: NCC(O)c1ccc2ccccc2c1
Reactant: CC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: CC(COc1ccc(CC2SC(=O)NC2=O)cc1)NCC(O)c1ccc2ccccc2c1

Procedure:
A procedure similar to that described in Preparation 10, below, was followed, but using 520 mg of 2-amino-1-(2-naphthyl)ethanol [prepared as described in Preparation 8], 650 mg of 5-[4-(2-oxopropoxy)benzyl]thiazolidine-2,4-dione [prepared as described in Preparation 9], 150 ml of benzene, 100 ml of absolute methanol and 1.25 g of sodium borohydride, to give the title compound in crude form. This crude product was then purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and ethanol as the eluent, to give 490 mg of the title compound melting at between 115° C. and 145° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]2=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]2[C:6]1=[O:15].[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)=[C:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:19][CH:18]=1>>[F:36][C:33]1[CH:34]=[CH:35][C:30]([C:23]([C:20]2[CH:19]=[CH:18][C:17]([F:16])=[CH:22][CH:21]=2)=[C:24]2[CH2:29][CH2:28][N:27]([CH2:2][CH2:3][CH2:4][N:5]3[C:9](=[O:10])[C:8]4=[CH:11][CH:12]=[CH:13][CH:14]=[C:7]4[C:6]3=[O:15])[CH2:26][CH2:25]2)=[CH:31][CH:32]=1
Reactant: Fc1ccc(C(=C2CCNCC2)c2ccc(F)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC(=C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Yield: 97 %

Procedure:
The title compound was prepared in a yield of 97% in a similar manner to that described in Preparation 1' by reacting N-(3-bromopropyl)phthalimide and 4-[bis(4-fluorophenyl)methylene]piperidine.
Reaction SMILES: C([S:4][CH2:5][CH:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:19]([O:21]C)=[O:20])[NH:8][C:7]1=[O:23])(=O)C.O.[OH-].[Li+].Cl>>[SH:4][CH2:5][CH:6]1[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][S:11][CH2:10][C@@H:9]([C:19]([OH:21])=[O:20])[NH:8][C:7]1=[O:23]
Reactant: COC(=O)[C@@H]1CSCCCCCCCC(CSC(C)=O)C(=O)N1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: O=C1N[C@H](C(=O)O)CSCCCCCCCC1CS
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Methyl (3R)-6-(acetylthiomethyl)-5-oxo-1-thia-4-azacyclotridecane-3-carboxylate (Isomer B) (0.16 g, 0.44 mmol) is partially dissolved in nitrogen degassed tetrahydrofuran (10 ml) and water (5 ml). Lithium hydroxide monohydrate (0.056 g, 1.33 mmol) is added and the mixture is stirred at room temperature for 3 hours. The mixture is poured into 1N hydrochloric acid and extracted with ethyl acetate (2×50 ml). The combined organic layers are washed with brine (1×50 ml), dried (Na2SO4) and the solvent is evaporated to give (3R)-6-mercaptomethyl-5-oxo-1-thia-4-azacyclotridecane-3-carboxylic acid (Isomer B), m.p. 169°-173° C.; the more active NEP inhibiting isomer.
Reaction SMILES: [F:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][C@@H:8]([NH2:10])[CH3:9])=[C:4]([C:13]([F:16])([F:15])[F:14])[CH:3]=1.[Si:17]([O:24][CH2:25][CH:26]=O)([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Si:17]([O:24][CH2:25][CH2:26][NH:10][C@@H:8]([CH3:9])[CH2:7][O:6][C:5]1[CH:11]=[CH:12][C:2]([F:1])=[CH:3][C:4]=1[C:13]([F:14])([F:15])[F:16])([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:19])[CH3:18]
Reactant: C[C@H](N)COc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: C[C@@H](COc1ccc(F)cc1C(F)(F)F)NCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S)-1-[4-fluoro-2-(trifluoromethyl)phenoxy]propan-2-amine (C7) (785 mg, 3.31 mmol) in dichloromethane (15 mL) was added {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (577 mg, 3.31 mmol). After 2 hours, sodium triacetoxyborohydride was added portion-wise. The reaction mixture was allowed to stir at room temperature overnight, then taken up in dichloromethane and washed with saturated aqueous sodium bicarbonate solution and water. The organic layer was concentrated in vacuo, then purified via silica gel chromatography (Gradient: 0 to 7% methanol in ethyl acetate) to afford the title compound as a clear liquid. Yield: 466 mg, 1.18 mmol, 36%. LCMS m/z 396.2 (M+1). 1H NMR (400 MHz, CDCl3) δ 0.07 (s, 6H), 0.90 (s, 9H), 1.19 (d, J=6.4 Hz, 3H), 2.73-2.86 (m, 2H), 3.11-3.19 (m, 1H), 3.74 (dd, J=5.6, 5.4 Hz, 2H), 3.92 (d, J=5.5 Hz, 2H), 6.94 (dd, J=9.0, 4.0 Hz, 1H), 7.15-7.21 (m, 1H), 7.29 (dd, J=8.4, 3.1 Hz, 1H).
Reaction SMILES: CS([Cl:5])(=O)=O.[CH3:6][O:7][C:8]1[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=[C:10]([CH2:20]O)[CH:9]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][CH2:20][C:10]1[CH:9]=[C:8]([O:7][CH3:6])[C:17]2[C:12](=[C:13]([O:18][CH3:19])[CH:14]=[CH:15][CH:16]=2)[CH:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(CO)cc2c(OC)cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(CCl)cc2c(OC)cccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 88.9 %

Procedure:
A solution of 3.92 g of methanesulphonyl chloride in 20 ml of methylene chloride was added dropwise to a solution, cooled to -10° C., of 7.7 g (35.3 mmol) of (4,8-dimethoxy-naphthalen-2-yl)-methanol and 4.4 g (38.8 mmol) of triethylamine in 50 ml of methylene chloride. The reaction mixture was stirred at room temperature for 18 hours. For the working-up, the mixture was extracted with 50 ml of ice-cold sodium hydrogen carbonate solution and the aqueous phase was separated and back-extracted with 25 ml of methylene chloride. The combined organic phases were dried over sodium sulphate and subsequently evaporated under reduced pressure. For purification, the residue was filtered over a layer of silica gel using methylene chloride as the eluent. There were obtained 7.2 g of 2-chloromethyl-4,8-dimethoxy-naphthalene as a beige solid; MS: 296 (M)+.
Reaction SMILES: [N+:1]([C:4]1[NH:5][CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:11][Si:12]([CH3:19])([CH3:18])[CH2:13][CH2:14][O:15][CH2:16]Cl>C1COCC1>[N+:1]([C:4]1[N:5]([CH2:16][O:15][CH2:14][CH2:13][Si:12]([CH3:19])([CH3:18])[CH3:11])[CH:6]=[CH:7][N:8]=1)([O-:3])=[O:2]
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=[N+]([O-])c1ncc[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ccnc1[N+](=O)[O-]
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 92.7 %

Procedure:
A suspension of 2-nitroimidazole (0.885 g, 7.8 mmol) and sodium hydride (60% dispersion in mineral oil, 0.440 g, 11.0 mmol, 1.4 equiv) in THF (20 mL) was stirred for 1.5 h at 5° C., under an argon atmosphere. 2-(Trimethylsilyl)ethoxymethyl chloride (1.5 mL, 8.6 mmol, 1.1 equiv) was then added. The reaction mixture was stirred for 2.5 h at 5° C., quenched by addition of a saturated aqueous solution of NH4Cl, and extracted with EtOAc. The combined organic phase was washed with H2O and brine, dried (sodium sulfate), filtered and concentrated. The residue was purified by silica gel column chromatography (Hex/EtOAc, 3:1) to afford 1.76 g of the title compound as a yellow oil: ES-MS: 244.1 [M+H]+; tR=4.63 min (System 1); TLC: Rf=0.19 (Hex/EtOAc, 3:1).