Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=O)=[CH:27][CH:26]=2)=[CH:4][CH:3]=1.Cl.[NH2:37][CH2:38][C:39]([O:41]C(C)(C)C)=[O:40].CN1CCOCC1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:25]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([NH:37][CH2:38][C:39]([OH:41])=[O:40])=[O:33])=[CH:27][CH:26]=2)=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)CN
Reactant: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)O)cc2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(C(=O)CS[C@H]2C(=O)N(c3ccc(F)cc3)[C@@H]2c2ccc(OCC(=O)NCC(=O)O)cc2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of [4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-methoxyphenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetic acid (0.150 g, 0.30 mmol), tert-butyl glycinate hydrochloride (0.0635 g, 0.38 mmol) and N-methylmorpholine (0.10 ml, 0.91 mmol) in DCM (2 ml) was stirred at room temperature. TBTU (0.128 g, 0.40 mmol) was added and the mixture was stirred overnight. Trifluoroacetic acid (4.0 ml) was added and after 2 h the solvent was removed under reduced pressure. The residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0.1M ammonium acetate buffer as eluent. The solvent was removed under reduced pressure and 0.159 g (95%) of the title product was obtained. M/z 553.02.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15](=[O:29])[NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH3:18])[CH2:3]1.CCN(S(F)(F)[F:36])CC>C(Cl)Cl>[F:36][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[C@@H:4]([C:15](=[O:29])[NH:16][C@H:17]([C:19]2[CH:24]=[CH:23][C:22]([C:25]([O:27][CH3:28])=[O:26])=[CH:21][CH:20]=2)[CH3:18])[CH2:3]1
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(O)CCN2C(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CC(F)CCN2C(=O)OC(C)(C)C)cc1
Temperature: -20 °C
Reaction time: 1 h
Yield: 34 %

Procedure:
A solution of (2R)-tert-butyl 4-hydroxy-2-(((S)-1-(4-(methoxycarbonyl)phenyl)ethyl)carbamoyl)piperidine-1-carboxylate (D61) (261 mg, 0.64 mmol) in DCM (10 ml) cooled at −20° C. was treated with DAST (0.17 ml, 1.28 mmol) and the reaction mixture stirred 1 h at −20° C. then at RT for 18 hrs. DAST (0.17 ml, 1.28 mmol) was added and the mixture further stirred 24 hrs. The reaction was quenched with NaHCO3 sat. sol. and extracted with DCM (3×10 ml), dried over MgSO4 and evaporated in vacuo. The residue was loaded onto a SPE-Si cartridge (20 g) eluting with a mixture DCM/EtOAc 90/10. Collected fractions after solvent evaporation afforded the title compound (D62) (89 mg)
Reaction SMILES: [Cl-].[Ca+2].[Cl-].[BH4-].[Na+].[OH:6][C@@:7]([C:29]1[CH:38]=[CH:37][C:36]2[C:31](=[CH:32][CH:33]=[C:34]([C:39]([NH:41][CH3:42])=[O:40])[CH:35]=2)[CH:30]=1)([C:14]1[N:15]=[CH:16][N:17](S(C2C=CC(C)=CC=2)(=O)=O)[CH:18]=1)[CH2:8][C:9](OCC)=[O:10].Cl.[OH-].[Na+]>C(O)C.O1CCCC1.O.C(OCC)(=O)C>[OH:6][C@@:7]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[CH:35]=[C:34]([C:39]([NH:41][CH3:42])=[O:40])[CH:33]=[CH:32]2)([C:14]1[N:15]=[CH:16][NH:17][CH:18]=1)[CH2:8][CH2:9][OH:10]
Reactant: CCOC(=O)C[C@](O)(c1ccc2cc(C(=O)NC)ccc2c1)c1cn(S(=O)(=O)c2ccc(C)cc2)cn1
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNC(=O)c1ccc2cc([C@@](O)(CCO)c3c[nH]cn3)ccc2c1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 125 %

Procedure:
To a solution of anhydrous calcium chloride (1.86 g, 16.3 mmol) in ethanol (32 mL) were added sodium borohydride (1.27 g, 33.6 mmol) and ethanol (5 mL) at −10° C., and the mixture was stirred at −10° C. for 30 min. To the reaction mixture was added dropwise a solution of ethyl (3S)-3-hydroxy-3-{6-[(methylamino)carbonyl]-2-naphthyl}-3-(1-tosyl-1H-imidazol-4-yl)propanoate (2.5 g, 5.6 mmol) in tetrahydrofuran (73 mL)/ethanol (10 mL), and tetrahydrofuran (5 mL) at −10° C. The obtained reaction mixture was stirred at 7° C. for 21 hr, and to the obtained reaction mixture were added dropwise water (100 mL), 1 mol/L hydrochloric acid (40 mL) and ethyl acetate (200 mL) at 10° C. or below, and the mixture was stirred. To the separated organic layer was added 0.2 mol/L hydrochloric acid (14 mL) at 5° C., and the mixture was stirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To the separated organic layer was added again 0.2 mol/L hydrochloric acid (14 mL) at 5° C., and the mixture was stirred. The reaction mixture was adjusted to pH 7.5 with 0.5 mol/L aqueous sodium hydroxide solution at 5° C. To the separated organic layer was added water (10 mL), and the mixture was adjusted to pH 9.5 with 0.5 mol/L aqueous sodium hydroxide solution. To the separated organic layer was added water (120 mL), and the mixture was heated to 60° C., and stirred for 3 hr. The separated organic layer was concentrated at 60° C. under reduced pressure to give 6-[(1S)-1,3-dihydroxy-1-(1H-imidazol-4-yl)propyl]-N-methyl-2-naphthamide (2.3 g, 7.0 mmol).
Reaction SMILES: [Mg].[O:2]([CH2:10][CH2:11][C:12]1[CH:13]=[C:14](Br)[CH:15]=[CH:16][CH:17]=1)[Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[NH2:19][C:20]1[N:24]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[N:23]=[CH:22][C:21]=1[C:32]([O:34]C1C=CC=CN=1)=S>O1CCCC1>[NH2:19][C:20]1[N:24]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[N:23]=[CH:22][C:21]=1[C:32](=[O:34])[C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][CH2:10][O:2][Si:3]([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4])[CH:13]=1
Reactant: CC(C)(C)[Si](C)(C)OCCc1cccc(Br)c1
Reactant: Nc1c(C(=S)Oc2ccccn2)cnn1-c1ccc(F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OCCc1cccc(C(=O)c2cnn(-c3ccc(F)cc3)c2N)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 35.9 %

Procedure:
Into an oven dried flask containing magnesium turnings (0.386 g, 15.9 mmol) and tetrahydrofuran (10 ml) was added 3-(2-tert-butyldimethylsiloxyethyl)bromobenzene (5.0 g, 15.9 mmol) and the reaction mixture was heated at reflux. After 3 h, the reaction mixture was cooled to room temperature and 5-amino-1-(4-fluorophenyl)-4-(2-pyridylthiocarboxy)pyrazole (2.37 g, 7.6 mmol) was added and the stirring was continued for 16 h. The reaction mixture was concentrated in vacuo. The residue was dissolved in ethyl acetate and washed with aqueous ammonium chloride and brine and dried over sodium sulfate. The organics were removed in vacuo and the residue was purified by flash chromatography (elution gradient: 10-30% ethyl acetate/hexane) to give 5-amino-1-(4-fluorophenyl)-4-[3-(2-tert-butyldimethylsiloxyethyl)benzoyl]pyrazole (1.20 g).
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].C([N-]C(C)C)(C)C.[Li+].[CH3:26][O:27][CH2:28]Cl.Cl>O1CCCC1.O>[C:14]([O:13][C:11](=[O:12])[CH:10]([CH2:26][O:27][CH3:28])[CH2:9][C:4]1([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: COCCl
Reactant: CC(C)(C)OC(=O)CCC1(C(=O)O)CCCC1
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COCC(CC1(C(=O)O)CCCC1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
A solution of t-butyl 3-(1-carboxycyclopentyl)propanoate (1.0 g, 4.13 mmole) in dry tetrahydrofuran was added to a stirred solution of lithium diisopropylamide (9.29 mmole) in dry tetrahydrofuran (50 ml) at -78° C. under nitrogen. After 0.5 hours, chloromethyl methyl ether (0.53 g, 6.58 mmole) was added and the mixture was allowed to warm to room temperature over 16 hours. The solution was poured into water, acidified to pH 3 with 2N hydrochloric acid and extracted with ethyl acetate (3×50 ml). The organic layer was separated, dried over magnesium sulphate and evaporated to give a colourless oil that was chromatographed on silica gel eluting with a mixture of diethyl ether and dichloromethane (1:9-1:4 by volume). Evaporation of the appropriate fractions gave the title compound as a colourless oil (0.78 g, 66%). Found: C,62.75; H,8.94. C15H26O5 requires: C,62.91; H,9.15%.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C:7]1[CH:8]=[C:9]([CH:27]=[CH:28][CH:29]=1)[CH2:10][N:11]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]2[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=2)[C:21](O)=[O:22])=[N:12]1)=[O:5])[CH3:2].Cl>C1COCC1>[CH2:1]([O:3][C:4](=[O:5])[NH:6][C:7]1[CH:29]=[CH:28][CH:27]=[C:9]([CH2:10][N:11]2[C:16](=[O:17])[CH:15]=[CH:14][C:13]([C:18]3[CH:26]=[CH:25][CH:24]=[C:20]([CH2:21][OH:22])[CH:19]=3)=[N:12]2)[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(C(=O)O)c3)ccc2=O)c1
Agent: Cl
Solvent: C1CCOC1
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3cccc(CO)c3)ccc2=O)c1
Temperature: 0 °C
Reaction time: 15 h

Procedure:
2 g (5.1 mmol) of 3-[1-(3-ethoxycarbonylaminobenzyl)-6-oxo-1,6-dihydropyridazin-3-yl]benzoic acid are suspended in 60 ml of THF, and 12.7 ml (12.7 mmol) of borane/THF complex (1M) are added dropwise under a nitrogen atmosphere with ice-cooling. The mixture is stirred at 0° C. for 15 h. 6 ml of 2N HCl are added to the reaction mixture, which is then stirred at room temperature for 12 h. The reaction mixture is evaporated, the residue is dissolved in ethyl acetate, dried over sodium sulfate and evaporated. The product is purified by means of preparative HPLC.
Reaction SMILES: [NH:1]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([O:10]CC1C=CC=CC=1)=[O:9])=[O:5])[CH3:3]>C(O)C.[Pd]>[NH:1]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[C@H:2]([C:4]([NH:6][CH2:7][C:8]([OH:10])=[O:9])=[O:5])[CH3:3]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCC(=O)O
Reaction time: 24 h

Procedure:
1 g (3 mmol) of Boc-Ala-Gly-OBzl (11) is dissolved in 50 ml of absolute ethanol (Aldrich) followed by addition of 100 mg of 10% Pd-C (Aldrich) in a 100 ml round bottom flask equipped with a stirring bar. The reaction mixture is stirred under hydrogen gas atmosphere using a balloon on the top of the round bottom flask. After 24 h, the reaction mixture is filtered to remove the Pd-C; the filtrate is evaporated to give Boc-Ala-Gly-OH (12). 1H-NMR (CDCl3): 1.33 (3H, d, J=7 Hz), 1.41 (9H, s), 3.97 (2H, d, J=5.6 Hz), 4.2 (1H, m), 6.18 (1H, br), 7.50 (1H, br). FABMS: 247 (M+1).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](O)=[O:21])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[I:23][C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][C:30]=1[CH3:31])[NH2:27].CCN=C=NCCCN(C)C>C(Cl)Cl>[C:4]([O:3][C:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:21])[NH:27][C:26]3[CH:28]=[CH:29][C:30]([CH3:31])=[C:24]([I:23])[CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: Cc1ccc(N)cc1I
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)cc1I
Temperature: 25 °C
Reaction time: 48 h

Procedure:
N-Boc-4-(4-carboxyphenyl)piperidine (200 mg, 0.66 mmol) and 3-iodo-4-methyl aniline (153 mg, 0.72 mmol) in DCM (10 mL) was treated with EDCI (380 mg, 1.98 mmol) at rt. After stirring for 48 hr at rt the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was collected, concentrated and the residue was chromatographed on a silica gel column with a 0-30% EtOAc in hexanes to afford the corresponding intermediate 4-[4-(3-Iodo-4-methyl-phenylcarbamoyl)-phenyl]-piperidine-1-carboxylic acid tert-butyl ester. This intermediate was then dissolved in a 30% TFA in CH2Cl2 mixture (10 mL). Upon consumption of the starting material, as judged by TLC, the solution was partitioned between EtOAc and water. The water layer was basified to pH 12 with solid NaOH. The organic layer was then collected, dried over Na2SO4, filtered and concentrated to a residue that without further delay was dissolved in DMSO (5 mL). The mixture was then treated with 4-fluoro ethyl benzoate (550 mg, 3.28 mmol), diisopropyl ethyl amine (3 mL) and a catalytic amount of DMAP and heated at 120° C. in a sealed tube for 4 days. The reaction mixture was then cooled, partitioned between EtOAc and water. The EtOAc layer was collected dried over Na2SO4 filtered and concentrated to a solid that after suspension in CH2Cl2 and filtration afforded the product (100 mg, Yield: 53%). HRMS m/z calcd for C28H29N2O3I [M+H]+: 569.1296. Found: 569.1294.
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][CH:10]([C:14](OC)=[O:15])[CH:9]1[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.[BH4-].[Na+]>O>[CH2:1]([N:8]1[CH:9]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([O:24][CH3:25])[CH:19]=2)[CH:10]([CH2:14][OH:15])[CH2:11][C:12]1=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C1CC(=O)N(Cc2ccccc2)C1c1cccc(OC)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1cccc(C2C(CO)CC(=O)N2Cc2ccccc2)c1
Temperature: 50 °C

Procedure:
To 42.1 gm. of methyl 1-benzyl-2-(3-methoxyphenyl)-5-oxopyrrolidin-3-carboxylate in 436 ml. of absolute methanol was slowly added at -10° to -5°, 37.9 gm. of sodium borohydride. The reaction mixture was left in the ice bath until it came to ambient temperature. Concentration in vacuo provided a white gum which was suspended in water and heated to 50° C. The gum was extracted with chloroform, dried (Na2SO4), filtered, and concentrated in vacuo to yield 22.8 gm. of yellow oil.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[N:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[CH:27]1([C:30]2[N:34]([CH2:35][CH3:36])[N:33]=[C:32]([NH:37][C:38](=O)[O:39]C3C=CC=CC=3)[CH:31]=2)[CH2:29][CH2:28]1.[H-].[Na+]>C1COCC1>[CH:27]1([C:30]2[N:34]([CH2:35][CH3:36])[N:33]=[C:32]([NH:37][C:38]([N:1]3[C:9]4[C:4](=[CH:5][C:6]([O:10][C:11]5[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[N:12]=5)=[CH:7][CH:8]=4)[CH:3]=[CH:2]3)=[O:39])[CH:31]=2)[CH2:28][CH2:29]1
Reactant: CCn1nc(NC(=O)Oc2ccccc2)cc1C1CC1
Reactant: CN(Cc1nccc(Oc2ccc3[nH]ccc3c2)n1)C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1nc(NC(=O)n2ccc3cc(Oc4ccnc(CN(C)C(=O)OC(C)(C)C)n4)ccc32)cc1C1CC1
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl (4-(1H-indol-5-yloxy)pyrimidin-2-yl)methyl(methyl)carbamate (35 mg, 0.099 mmol) in THF (2 ml) is added phenyl 5-cyclopropyl-1-ethyl-1H-pyrazol-3-ylcarbamate (29.5 mg, 0.109 mmol), which is prepared as described in Example 5-S. The mixture is put at 0° C. and NaH (60% dispersion in oil; 11.85 mg, 0.296 mmol) is then added and the reaction is then stirred for 30 minutes. The reaction is then quenched with 10% AcOH/MeOH (0.3 mL) and further diluted with DCM and saturated aqueous NaHCO3. The resulting layers are then separated and the aqueous layer is extracted two additional times with DCM. The organic layers are combined, dried over anhydrous Na2SO4, filtered, and concentrated. The resulting residue is purified via FCC (10-100% EtOAc (2.5% EtOH)/DCM) to give the title compound. MS (ESI) m/z 532.3 (M+1).
Reaction SMILES: [O:1]1[CH:3]([CH2:4][CH2:5][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][CH3:19])[CH2:2]1.[CH3:20][NH:21][CH2:22][CH2:23][OH:24]>C(O)C>[OH:24][CH2:23][CH2:22][N:21]([CH2:2][CH:3]([OH:1])[CH2:4][CH2:5][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][CH3:19])[CH3:20]
Reactant: CNCCO
Reactant: CCCCCCCCCCCCCCCCC1CO1
Solvent: CCO
Product: CCCCCCCCCCCCCCCCC(O)CN(C)CCO
Temperature: 80 °C
Reaction time: 18 h
Yield: 66.9 %

Procedure:
A 300-ml flask equipped with a stirrer was charged with 26.85 g (0.1 mol) of 1,2-epoxyoctadecane, 7.51 g (0.1 mol) of N-methylethanolamine and 50 ml of ethanol, and the contents were stirred at 80° C. for 18 hours. After the solvent was distilled off under reduced pressure, the resultant residue was purified by column chromatography on silica gel, thereby obtaining 23.0 g (yield: 67%) of the title compound (IIc-2).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:17](OC(=O)C)(=[O:19])[CH3:18].O>C(Cl)(Cl)Cl.CN(C)C1C=CN=CC=1>[C:17]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1)(=[O:19])[CH3:18]
Reactant: CC(=O)OC(C)=O
Reactant: c1ccc2c(c1)CCN2
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 11.9 g of indoline in 100 ml of chloroform is cooled to 0° C. 13.9 ml of triethylamine are added and a solution of 10.4 ml of acetic anhydride in 10 ml of chloroform is then added dropwise, followed by 0.1 g of 4-dimethylaminopyridine. After stirring for two hours at RT, water is added to the reaction mixture, extraction is carried out with chloroform, the organic phase is dried over sodium sulfate and the solvent is evaporated off under vacuum to give 15.44 g of the expected product, which is used as such.
Reaction SMILES: [OH:1][C@H:2]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:3][N:4]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH2:32][CH2:33][O:34][CH3:35])(=[O:31])=[O:30])=[O:27])=[C:22]([S:36][CH:37]([CH3:39])[CH3:38])[CH:21]=2)=[CH:16][CH:15]=1)C(=O)OC(C)(C)C.C(OC(=O)C)C.[ClH:52]>C(OCC)(=O)C>[ClH:52].[OH:1][C@H:2]([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:3][NH:4][CH2:12][CH2:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([NH:28][S:29]([CH2:32][CH2:33][O:34][CH3:35])(=[O:30])=[O:31])=[O:27])=[C:22]([S:36][CH:37]([CH3:39])[CH3:38])[CH:21]=2)=[CH:18][CH:19]=1
Reactant: COCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCN(C[C@H](O)c3ccccc3)C(=O)OC(C)(C)C)cc2)cc1SC(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: COCCS(=O)(=O)NC(=O)c1ccc(-c2ccc(CCNC[C@H](O)c3ccccc3)cc2)cc1SC(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl [(2R)-2-hydroxy-2-phenylethyl][2-[3′-(isopropylthio)-4′-[[[(2-methoxyethyl)sulfonyl]amino]carbonyl]-4-biphenylyl]ethyl]carbamate (3.92 g) in ethyl acetate (20 ml) was added hydrogen chloride ethyl acetate solution (4M, 20 ml) and stirred at room temperature overnight. The resulting solid was collected by filtration and dried to give 4′-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]-3-(isopropylthio)-N-[(2-methoxyethyl)sulfonyl]-4-biphenylcarboxamide hydrochloride (3.15 g).
Reaction SMILES: [Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([O:11]CC)=[O:10])[C:4]=2[CH:3]=1.[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[S:6][CH:7]=[C:8]([C:9]([OH:11])=[O:10])[C:4]=2[CH:3]=1
Reactant: CCOC(=O)c1csc2cc(OC)c(Br)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc2scc(C(=O)O)c2cc1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.4 %

Procedure:
Ethyl 5-bromo-6-methoxybenzo[b]thiophene-3-carboxylate (D4) (0.42 g, 0.0013 mole) in ethanol (20 ml) and water (5 ml) was treated with sodium hydroxide powder (0.14 g, 0.0035 mole). The reaction mixture was heated under reflux for 2 hours and stirred at ambient temperature for 16 hours. The solvent was removed in vacuo and the residue diluted with water (25 ml), acidified with 5N hydrochloric acid, extracted into ethyl acetate, dried (Na2SO4) and evaporated in vacuo to afford the title compound (0.36 g, 93%) as a beige solid.
Reaction SMILES: [OH-].[Na+].FC(F)(F)C(O)=O.[CH3:10][N:11]1[C:15]([CH2:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:14][N:13]=[CH:12]1.[ClH:22]>C1COCC1>[ClH:22].[CH3:10][N:11]1[C:15]([CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:14][NH:13][CH2:12]1
Reactant: COC(=O)CCc1cncn1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CN1CNC=C1CCC(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
2 ml of an aqueous solution of sodium hydroxide at 30% are added to a solution of 320 mg (1.13 mmol) of methyl 3-(3-methyl-3H-imidazol-4-yl)propionate tri-fluoroacetate in 10 ml of THF. The reaction medium is stirred at ambient temperature for 16 hours and then cooled to 0° C., and concentrated hydrochloric acid is added dropwise until pH 1 is obtained. After filtration, the filtrate is evaporated. 87 mg of 3-(3-methyl-1H-imidazol-4-yl)propionic acid hydrochloride are obtained with a yield of 39%.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][OH:5].[H-].[Na+].Cl[C:25]1[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=1.O>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH2:6][CH2:7][CH2:8][CH:9]([CH3:21])[CH2:10][CH2:11][CH2:12][CH:13]([CH3:20])[CH2:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[CH2:3][CH2:4][O:5][C:25]1[O:29][C:28]([C:30]([OH:32])=[O:31])=[CH:27][CH:26]=1
Reactant: O=C(O)c1ccc(Cl)o1
Reactant: CC(C)CCCC(C)CCCC(C)CCCC(C)CCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)CCCC(C)CCCC(C)CCCC(C)CCOc1ccc(C(=O)O)o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 59.8 g (0.2 mole) of 3,7,11,15-tetramethyl-1-hexadecanol and 19.2 g (0.4 mole) of sodium hydride (50% in oil) in 1 liter of toluene is refluxed with stirring for 2 hours then cooled to room temperature. To the mixture 29.3 g (0.2 mole) of 5-chloro-2-furoic acid is added and the mixture is refluxed with stirring for 24 hours. Upon cooling to room temperature the mixture is acidified with glacialacetic acid and water is added. The toluene layer is evaporated and allowed to crystallize to give 5-(3,7,11,15-tetramethylhexadecyloxy)-2-furoic acid.
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][N:5]([CH3:21])[C:6]1[CH:11]=[CH:10][C:9]([B:12]2[O:16][C:15]([CH3:18])([CH3:17])[C:14]([CH3:20])([CH3:19])[O:13]2)=[CH:8][CH:7]=1.I[C:24]1C=CC(N2CC[C@H](N(C)C)C2)=CC=1>>[CH3:1][N:2]([CH3:22])[C@H:3]1[CH2:24][CH2:21][N:5]([C:6]2[CH:7]=[CH:8][C:9]([B:12]3[O:16][C:15]([CH3:17])([CH3:18])[C:14]([CH3:20])([CH3:19])[O:13]3)=[CH:10][CH:11]=2)[CH2:4]1
Reactant: CN(C)CCN(C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: CN(C)[C@H]1CCN(c2ccc(I)cc2)C1
Product: CN(C)[C@H]1CCN(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)C1

Procedure:
The title compound was synthesized according to the synthesis of N,N,N′-trimethyl-N′-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ethane-1,2-diamine, except substituting (S)-1-(4-iodophenyl)-N,N-dimethylpyrrolidin-3-amine (500 mg, 1.58 mmol). The title compound was purified by silica gel chromatography (MeOH/CH2Cl2, 5:95 to 15:85) followed by passing a solution of the desired product (20 mL MeOH) through a PoraPak Rxn CX ionic exchange column as a yellow solid (125 mg, 25%). 1H NMR and LCMS were identical to the enantiomer, (R)—N,N-dimethyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrrolidin-3-amine.