Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:22])=[CH:3]1.[BH4-].[Na+]>CO.O>[CH2:1]=[C:2]1[CH2:19][CH2:18][C@@:17]2([CH2:20][OH:21])[C:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[OH:22])=[CH:3]1
Reactant: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)C(=O)CC[C@@H]34)[C@@]2(CO)CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: C=C1C=C2CC[C@@H]3[C@H](CC[C@]4(C)[C@@H](O)CC[C@@H]34)[C@@]2(CO)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-methylene-androst-4-ene-19-ol-17-one in methanol was added a 2 molar excess of sodium borohydride. The mixture was stirred overnight at room temperature, diluted with water, extracted with ethyl acetate, washed with water, the organic layer separated, and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by thick layer chromatography over silica gel using n-hexane-ethyl acetate as a solvent.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([CH3:15])=[CH:13][N:14]=1)=[O:8].[H-].[Na+].Cl[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH3:18])=[C:6]([CH:16]=1)[C:7](/[N:9]=[C:10]1\[S:11][C:12]([CH3:15])=[CH:13][N:14]\1[CH2:22][C:23]1[N:24]=[CH:25][S:26][CH:27]=1)=[O:8]
Reactant: ClCc1cscn1
Reactant: COc1ccc(Cl)cc1C(=O)Nc1ncc(C)s1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(Cl)cc1C(=O)/N=c1\sc(C)cn1Cc1cscn1
Reaction time: 0.5 h
Yield: 71.7 %

Procedure:
To a solution of Example 79A (2.65 g, 9.4 mmol) in DMF (20 mL) at 0° C. was added sodium hydride (60% dispersion in mineral oil, 0.247 g, 10.3 mmol). The reaction mixture was stirred for 30 min. and then treated with commercially available 4-(chloromethyl)thiazole (1.25 g, 9.4 mmol). The resulting mixture was stirred at room temperature for 18 hr, poured into water (100 mL) and extracted with EtOAc (2×100 mL). The organics were washed with water, brine (2×100 mL), dried over MgSO4 and concentrated. The residue was purified by using an Analogix® Intelliflash280™ (SiO2, 0-50% ethyl acetate in hexanes) to afford the title compound (2.56 g, 72% yield). 1H NMR (300 MHz, DMSO-D6) δ ppm 2.28 (s, 3H), 3.77 (s, 3H), 5.50 (s, 2H), 7.10 (d, J=8.7 Hz, 1H), 7.31 (d, J=1.6 Hz, 1H), 7.38-7.52 (m, 2H), 7.63 (dd, J=14.5, 2.6 Hz, 1H), 9.09 (d, J=2.0 Hz, 1H). MS (DCI) m/z 398 (M+H)+; MS (DCI) m/z 380 (M+H)+. Anal. Calculated for C16H14ClN3O2S2: C, 50.59; H, 3.71; N, 11.06. Found: C, 50.57; H, 3.02; N, 11.03.
Reaction SMILES: [C:1]1([C:7]2[C:16]3[C:11](=[C:12]([C:17](OC)=O)[CH:13]=[CH:14][CH:15]=3)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5]C=CC=1.C1([C:27]2C3C(=C(CO)C=CC=3)C=C[N:28]=2)C=CC=CC=1>>[CH2:1]([C:7]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:17][C:27]#[N:28])[C:11]=2[CH:10]=[CH:9][N:8]=1)[CH2:6][CH3:5]
Reactant: OCc1cccc2c(-c3ccccc3)nccc12
Reactant: COC(=O)c1cccc2c(-c3ccccc3)nccc12
Product: CCCc1nccc2c(CC#N)cccc12

Procedure:
1-Amino-2-(2-hydroxymethylphenyl)ethane and butyryl chloride were successively reacted in the same way as in steps (b) and (c) of Example 12 to afford 1-butyrylamino-2-(2-hydroxymethylphenyl)ethane as an oil. The product was successively reacted in the same way as in steps (d), (e), (f) and (g) of Example 12 to afford 1-n-propylisoquinoline-5-acetonitrile.
Reaction SMILES: [CH3:1][Si:2]([CH3:14])([CH3:13])[C:3]#[C:4][CH2:5][O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1.[CH:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH3:14][Si:2]([CH3:13])([CH3:1])[C:3]#[C:4][CH:5]([O:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][O:8]1)[CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:7][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: c1ccccc1
Reactant: C[Si](C)(C)C#CCOC1CCCCO1
Product: C[Si](C)(C)C#CC(C/C=C\CCc1ccccc1)OC1CCCCO1

Procedure:
Reaction of trimethyl(3-(tetrahydro-2H-pyran-2-yloxy)prop-1-ynyl)silane (4.6 g, 21.6 mmol 4.6 g, 21.6 mmol) and (z)-5-bromo-pent-3-enyl)-benzene, (4.1 g, 18 mmol)) according to General Procedure 11.A provided the title compound. The material was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([OH:23])=O)[C:9]=2[S:24][CH3:25])=[CH:4][CH:3]=1.C1C=NC2N(O)N=NC=2C=1.Cl.CN(C)CCCN=C=NCC.[NH2:48][N:49]1[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]1>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=3[Cl:20])[N:11]=[C:10]([C:21]([NH:48][N:49]3[CH2:54][CH2:53][CH2:52][CH2:51][CH2:50]3)=[O:23])[C:9]=2[S:24][CH3:25])=[CH:6][CH:7]=1
Reactant: CSc1c(C(=O)O)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reactant: NN1CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Product: CSc1c(C(=O)NN2CCCCC2)nn(-c2ccc(Cl)cc2Cl)c1-c1ccc(Cl)cc1
Reaction time: 16 h

Procedure:
To a magnetically stirred solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-1H-pyrazole-3-carboxylic acid (4.69 g, 11.3 mmol) in dichloromethane (100 ml) was successively added 7-aza-1-hydroxybenzotriazole (HOAt) (2.2 g, 16.0 mmol), (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCl) (3.1 g, 16.1 mmol) and 1-aminopiperidine (1.6 gram, 16.0 mmol). After stirring for 16 h, the resulting mixture was successively washed with water (3×), dried over Na2SO4, filtered and concentrated to give a crude solid. This crude solid was further purified by flash chromatography (silica gel, EtOAc/heptane=22178 (v/v)) and trituration with n-heptane/methanol to give 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylsulfanyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide: compound 1 (0.55 gram, 10% yield). Melting point: 172.4-174.5° C. 1H-NMR (CDCl3, 400 MHz) δ 1.41-1.49 (m, 2H), 1.72-1.81 (m, 4H), 2.40 (s, 3H), 2.83-2.95 (m, 4H), 7.15 (br d, J=8 Hz, 2H), 7.28-7.35 (m, 4H), 7.42 (br d, J=2 Hz, 1H), 7.94 (br s, 1H). 13C-NMR (CDCl3, 100 MHz) δ 20.03, 23.32, 25.29, 57.02, 113.66, 126.20, 127.99, 128.74, 130.36, 130.48, 131.24, 132.85, 135.59, 135.64, 136.41, 147.08, 147.30, 158.62.
Reaction SMILES: O.NN.[O:4]=[C:5]1[C@@H:11]([N:12]2C(=O)C3=CC=CC=C3C2=O)[CH2:10][S:9][CH:8]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]1[CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30]>CO>[NH2:12][C@H:11]1[CH2:10][S:9][CH:8]([C:23]2[S:24][CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]([CH2:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[C:5]1=[O:4]
Reactant: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N2C(=O)c3ccccc3C2=O)C1=O
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CN1CC(c2cccs2)SC[C@H](N)C1=O
Reaction time: 48 h
Yield: 90.2 %

Procedure:
7 ml of hydrazine hydrate were added to a suspension of 34.1 g of t-butyl α-[5-oxo-6(R)-phthalimido-2-(2-thienyl)perhydro-1,4-thiazepin-4-yl]acetate [prepared as described in step (f) above] in 340 ml of methanol, to form a homogeneous solution. This was left standing for 2 days at room temperature, and then the resulting precipitate was filtered off. The filtrate was condensed by evaporation under reduced pressure, and then 200 ml of methylene chloride were added to the residue. The mixture was stirred and insoluble matter was filtered off. The filtrate was washed with water and dried over anhydrous magnesium sulfate, after which the solvent was evaporated off. The residue was crystallized by adding diisopropyl ether containing a small amount of hexane, to yield 22.3 g of the title compound, melting at 81°-82° C.
Reaction SMILES: [ClH:1].Cl.Cl.N1C=C(CN2C3C=CC([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)=CC=3CN(C(=O)C(F)(F)F)C(CC3C=CC=CC=3)C2)N=C1.Cl.[NH:41]1[CH:45]=[C:44]([CH2:46][N:47]2[C:53]3[CH:54]=[CH:55][C:56](C#N)=[CH:57][C:52]=3[CH2:51][N:50]([S:60]([CH3:63])(=[O:62])=[O:61])[C@H:49]([CH2:64]C3C=CC=CC=3)[CH2:48]2)[N:43]=[CH:42]1>>[ClH:1].[ClH:1].[NH:41]1[CH:45]=[C:44]([CH2:46][N:47]2[C:53]3[CH:54]=[CH:55][C:56]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)=[CH:57][C:52]=3[CH2:51][N:50]([S:60]([CH3:63])(=[O:62])=[O:61])[C@H:49]([CH2:64][C:26]3[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=3)[CH2:48]2)[N:43]=[CH:42]1
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Reactant: CS(=O)(=O)N1Cc2cc(C#N)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccccc1
Agent: Cl
Product: CS(=O)(=O)N1Cc2cc(-c3ccccc3)ccc2N(Cc2c[nH]cn2)C[C@H]1Cc1ccncc1
Yield: 99 %

Procedure:
Example 365 was prepared as a light yellow solid in 99% yield from Compound B of Example 226 and D-(4-pyridyl)alanine by the following sequence: Compound C of Example 226; Compound D of Example 226; Compound B of Example 264; Compound D of Example 264.
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:15].[H-].[Na+].Br[CH2:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1[C:31]([F:34])([F:33])[F:32].[I-].[Na+]>CN(C=O)C>[Cl:14][C:10]1[N:9]=[C:8]2[N:7]([CH2:20][C:21]3[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=3[C:31]([F:33])([F:32])[F:34])[C:6]([CH3:15])=[C:5]([CH2:4][C:3]([OH:2])=[O:16])[C:13]2=[CH:12][CH:11]=1
Reactant: COC(=O)Cc1c(C)[nH]c2nc(Cl)ccc12
Reactant: CS(=O)(=O)c1ccc(CBr)c(C(F)(F)F)c1
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(CC(=O)O)c2ccc(Cl)nc2n1Cc1ccc(S(C)(=O)=O)cc1C(F)(F)F
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a stirred, ice-cooled solution of (6-chloro-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester (Example 99e) (0.03 g, 0.13 mmol) in DMF (1.0 ml) under an inert atmosphere of Argon is added sodium hydride (0.006 g of a 60% dispersion in mineral oil, 0.14 mmol). The reaction mixture is stirred at 0° C. for 45 minutes and then treated with 1-bromomethyl-4-methanesulfonyl-2-trifluoromethyl-benzene (Example 95a) (0.067 g, 0.21 mmol) followed by sodium iodide (0.031 g, 0.21 mmol). Stirring is continued at 0° C. for 2 hours and then the reaction mixture is poured onto water (15 ml) and extracted with DCM (5 ml). The organic portion is separated and concentrated in vacuo. The resulting crude is purified by chromatography on silica eluting with ethyl acetate/iso-hexane (1:8 increasing to 1:4) to yield the product which was further purified by trituration with ethyl acetate/iso-hexane to afford the titled product. (MH+ 475).
Reaction SMILES: Cl[C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[CH2:11]([SH:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([S:18][C:2]1[C:9]([OH:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: SCc1ccccc1
Reactant: O=Cc1cccc(O)c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(O)c1SCc1ccccc1
Temperature: 100 °C
Reaction time: 48 h

Procedure:
174 g of 2-chloro-3-hydroxybenzaldehyde are dissolved in 1 l of dimethylformamide, 126 ml of benzylmercaptan and 174 g of potassium carbonate are added, and the mixture is stirred for 2 days at 100° C. The reaction mixture is poured into ice-water and extracted using diethyl ether, and the organic phase is washed with saline, dried over sodium sulfate, filtered and concentrated. Silica gel chromatography with ethyl acetate/hexane (1:4) as the mobile phase gives 51.6 g of 2-benzylthio-3-hydroxybenzaldehyde. 31.6 g of this are emulsified in 66 ml of water, and 16.1 g of hydroxylamine-O-sulfonic acid and 1.84 g of sodium sulfate are added. After one hour, 32 ml of each water and methylene chloride are added, and the mixture is treated with 40.4 g of sodium hydrogen carbonate in portions. The reaction mixture is stirred for 2 hours at room temperature and then taken up in methylene chloride, and the organic phase is extracted using 1N potassium hydroxide solution. The aqueous-basic phase is brought to a pH of 1 using concentrated hydrochloric acid and extracted using methylene chloride. The organic phase is dried over sodium sulfate, filtered and concentrated. Recrystallisation from toluene gives 5.93 g of 7-hydroxy-1,2-benzisothiazole of m.p. 185°-187° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1.[CH3:15][Si]([N-][Si](C)(C)C)(C)C.[Na+].C([O-])(O)=O.[Na+].O>C1COCC1>[CH3:1][O:2][C:3](=[O:14])[CH:4]([CH3:15])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]#[N:13])[CH:7]=1
Reactant: COC(=O)CCc1cccc(C#N)c1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)C(C)Cc1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.3 %

Procedure:
To a solution of 3-(3-cyano-phenyl)-propionic acid methyl ester of Step A (220 mg, 1.16 mmol) in THF (5 mL) at −78° C. was added sodium bis(trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol). The reaction was stirred for 0.5 h and Mel (0.08 mL, 1.28 mmol) was added. After 1 h, a solution of saturated NaHCO3:water (1:1) was added and the reaction was warmed to room temperature. The aqueous solution was washed with CH2Cl2 (3×) and the combined organic solutions were dried (MgSO4), filtered, and concentrated. Medium pressure chromatography (6:1 hexanes:EtOAc) provided the title compound of Step B as a colorless oil (62 mg). 1H NMR (400 MHz, CDCl3) δ 7.50-7.34 (m, 4H), 3.62 (s, 3H), 3.01 (m, 1H), 2.71 (m, 2H), 1.16 (d, 3H).
Reaction SMILES: Cl.[CH2:2]([C:4]1([CH2:36][CH3:37])[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][C:13]([NH:16][CH2:17][C@@H:18]([C:20]2[CH:21]=[CH:22][C:23]([OH:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:29])=[O:28])[CH:25]=2)[OH:19])([CH3:15])[CH3:14])[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]1=2)[CH3:3].CC(C)=O>CO>[CH2:36]([C:4]1([CH2:2][CH3:3])[O:9][C:8](=[O:10])[N:7]([CH2:11][CH2:12][C:13]([NH:16][CH2:17][CH:18]([C:20]2[CH:21]=[CH:22][C:23]([OH:31])=[C:24]([NH:26][S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=2)[OH:19])([CH3:14])[CH3:15])[C:6]2[CH:32]=[CH:33][CH:34]=[CH:35][C:5]1=2)[CH3:37]
Reactant: CCC1(CC)OC(=O)N(CCC(C)(C)NC[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)c2ccccc21
Agent: Cl
Solvent: CO
Solvent: CC(C)=O
Product: CCC1(CC)OC(=O)N(CCC(C)(C)NCC(O)c2ccc(O)c(NS(C)(=O)=O)c2)c2ccccc21

Procedure:
The (R)- and (S)-enantiomers of this embodiment may be obtained by common methods known in the art. Particular importance attaches to the (R)-enantiomer of this embodiment according to the invention. The angle of rotation of (R)- N-(5-{2-[3-(4,4-diethyl-2-oxo-4H-benzo[d][1,3]oxazin-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-2-hydroxy-phenyl)-methanesulphonamide hydrochloride (cocrystallised with a molecule of acetone) is −28.8° (c=1%, in methanol at 20° C.).
Reaction SMILES: C([O:5][C:6](=[O:34])[C:7]([CH3:33])([CH3:32])[CH2:8][NH:9][C:10]([C:12]1[N:13]=[C:14]([C:30]#[N:31])[C:15]2[C:20]([C:21]=1[OH:22])=[CH:19][CH:18]=[C:17]([O:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:16]=2)=[O:11])(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:30]([C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[C:17]([O:23][CH:24]3[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]3)[CH:16]=2)[C:21]([OH:22])=[C:12]([C:10]([NH:9][CH2:8][C:7]([CH3:33])([CH3:32])[C:6]([OH:34])=[O:5])=[O:11])[N:13]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(OC3CCCCC3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 16.9 %

Procedure:
A mixture of 3-[(1-cyano-7-cyclohexyloxy-4-hydroxy-isoquinoline-3-carbonyl)-amino]-2,2-dimethyl-propionic acid tert-butyl ester (55 mg, 0.118 mmol) in (½) TFA/CH2Cl2 (3 mL) was stirred at room temperature for 3 h and concentrated. Residue was taken up with 30 mL of water and the resultant suspension was basified by 1 N NaOH to pH=9-10. The clear solution was then acidified by 1 N HCl to pH=3-4. Precipitate was collected and dried. Crude product was triturated with MeOH (3 mL). Solid was collected and dried in vacuo to provide the title compound 8.6 mg (0.02 mmol) in 18% yield. LC-MS ESI−: 410.00 (M−1)−.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]=[C:9]=[O:10].[NH2:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]>C1COCC1>[I:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:10])[NH:11][C:12]1[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: O=C=Nc1ccccc1I
Reactant: CCOC(=O)c1ccccc1N
Solvent: C1CCOC1
Product: CCOC(=O)c1ccccc1NC(=O)Nc1ccccc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 78.3 %

Procedure:
To a solution of 2-iodophenyl isocyanate (3.36 g, 13.7 mmol) in THF (250 mL) was added ethyl 2-aminobenzoate (5.1 mL, 34.5 mmol). The resulting mixture was stirred at room temperature for 8 hours, evaporated and chromatographed (silica gel, 10% EtOAc in hexanes) to give 4.4 g (78%) of ethyl 2-(2-iodophenylureido)benzoate as a white solid, mp 162°-164° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]1([C:11]([O:13]C)=[O:12])[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1.Cl>CO>[CH3:3][C:4]1([C:11]([OH:13])=[O:12])[CH2:5][CH2:6][C:7](=[O:10])[CH2:8][CH2:9]1
Reactant: COC(=O)C1(C)CCC(=O)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC1(C(=O)O)CCC(=O)CC1
Yield: 89.4 %

Procedure:
50 ml of a 3N aqueous sodium hydroxide solution was added to a solution of 5 g of methyl 1-methyl-4-oxo-1-cyclohexanecarboxylate, which is disclosed in a literature [T. Sohda, K. Meguro, and Y. Kawamatsu, Chem. Pharm. Bull., 32, 2267-2278 (1984)], in 150 ml of methanol. The resultant solution was reacted for 2 hours, while it was refluxed. After reaction, 2N hydrochloric acid was added to the solution, acidifying the solution. The solution was extracted five times with 50 ml of ethyl acetate. The organic layer obtained was washed three times with an aqueous sodium chloride solution and was then dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The oily substance obtained was subjected to column chromatography using 50 g of silica gel. From the fraction eluted with hexane and ethyl acetate=2:1, the solvent was removed in vacuo, yielding 4.1 g of 1-methyl-4-oxo-1-cyclohexanecarboxyic acid as a colorless oil, which had the following physiochemical properties:
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[N:7]([C@@H:10]([C@@H:26]([CH2:32][CH3:33])[CH2:27][C:28]([F:31])([F:30])[F:29])[C:11](N1[C@H](CC2C=CC=CC=2)COC1=O)=[O:12])=[N+]=[N-]>C1COCC1>[NH2:7][C@@H:10]([C@@H:26]([CH2:32][CH3:33])[CH2:27][C:28]([F:29])([F:30])[F:31])[CH2:11][OH:12]
Reactant: CC[C@@H](CC(F)(F)F)[C@H](N=[N+]=[N-])C(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC[C@@H](CC(F)(F)F)[C@H](N)CO
Temperature: 25 °C
Yield: 100.4 %

Procedure:
To a gray slurry of LAH (100 mg, 2.65 mmol) in THF (3 mL) at −10° C. was added (4R)-3-[(2S,3S)-2-azido-3-ethyl-5,5,5-trifluoropentanoyl]-4-benzyl-1,3-oxazolidin-2-one (300 mg, 0.78 mmol) as a solution in THF (2 mL) dropwise over 5 min. The resulting slurry was allowed to warm to 25° C. for 19 h. The reaction was quenched by sequential addition of H2O (0.3 mL), 1N NaOH (0.9 mL) and H2O (0.3 mL) at 0° C. The precipitate that formed after 5 h was filtered off. The mother liquor was dried over MgSO4, filtered and concentrated to obtain (2S,3S)-2-amino-3-ethyl-5,5,5-trifluoropentan-1-ol as a light yellow oil (145 mg, 98%). Mass Spectrum (−ESI): 184 (M−H)−.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH2:7]([O:10][C:11]1[C:12]([Cl:21])=[CH:13][C:14]([F:20])=C([CH:19]=1)C(O)=O)[CH:8]=[CH2:9]>CN(C)C=O.C1(C)C=CC=CC=1>[CH2:7]([O:10][C:11]1[C:12]([Cl:21])=[CH:13][C:14]([F:20])=[C:1]([CH:19]=1)[C:2]([Cl:4])=[O:3])[CH:8]=[CH2:9]
Reactant: O=C(Cl)C(=O)Cl
Reactant: C=CCOc1cc(C(=O)O)c(F)cc1Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: C=CCOc1cc(C(=O)Cl)c(F)cc1Cl

Procedure:
With ice-cooling, 1 drop of dimethylformamide and 49.2 g (0.38 mol) of oxalyl chloride were added in succession to a solution of 59.7 g (0.26 mol) of 5-allyloxy-4-chloro-2-fluorobenzoic acid in 0.5 1 of toluene. After the evolution of gas had ceased, the mixture was concentrated to about half its volume. In this form, the product solution was used for the next step.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[C:8]([C:10](=O)[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3].C([BH3-])#[N:23].[Na+].C([O-])(=O)C>>[CH2:1]([C:4]1[CH:9]=[C:8]([CH:10]([NH2:23])[CH3:11])[CH:7]=[CH:6][C:5]=1[C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[O:20][CH3:21])[CH:2]=[CH2:3]
Reactant: [BH3-]C#N
Reactant: C=CCc1cc(C(C)=O)ccc1-c1cc(F)ccc1OC
Agent: CC(=O)[O-]
Agent: [Na+]
Product: C=CCc1cc(C(C)N)ccc1-c1cc(F)ccc1OC

Procedure:
A mixture of 3′-allyl-4′-hydroxyacetophenone (0.352 g, 2.0 mmol), N-phenyl-bis(trifluoromethane) sulfonimide) (0.710 g, 2.0 mmol) and potassium carbonate (0.830 g, 6.0 mmol) in tetrahydrofuran (3.0 ml) was heated in a microwave oven at 120° C. for 10 min. The resultant mixture was treated with 5-fluoro-2-methoxyphenyl boronic acid (0.680 g, 0.4 mmol), tetrakis(triphenylphosphine)palladium (0) (0.060 g, 0.05 mmol) and dimethylformamide (1.0 ml) and heated in a microwave oven at 120° C. for 10 min. The mixture was partitioned between ethyl acetate and dilute aqueous sodium carbonate solution. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 9:1 heptane/ethyl acetate. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone. A solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethanone (0.319 g, 1.1 mmol), sodium cyanoborohydride (0.140 g, 2.2 mmol) and ammomium acetate (1.7 g, 22 mmol) was stirred under nitrogen at ambient temperature for 72 h, evaporated to dryness under reduced pressure and partitioned between dichloromethane and brine. The organic phase was dried over anhydrous sodium sulfate, the solvent evaporated and the residue purified by flash chromatography over silica gel eluting with 98:2 ethyl acetate/2M ammonia in methanol. Evaporation of solvent under reduced pressure gave 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine. To a solution of 1-(2-allyl-5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethylamine (19.0 mg, 0.07 mmol) in dichloromethane (1 ml) was added triethylamine (6.7 mg, 0.07 mmol) and 3,4-di-fluorophenyl sulfonyl chloride (14.2 mg, 0.06 mmol). The solution was stirred overnight and the solvent evaporated. The residue was purified by flash chromatography over silica gel eluting with dichloromethane. Evaporation of solvent under reduced pressure gave the title compound. 1H NMR (400 MHz, CDCl3): δ 7.52-7.42 (m, 2H), 7.13 (q, 1H), 7.04-6.90 (m, 4H), 6.88-6.83 (m, 1H), 6.77 (q, 1H), 5.67 (dt, 1H), 4.99-4.82 (m, 3H), 4.57 (dq, 1H), 3.71 (s, 3H), 3.09 (br s, 2H), 1.51 (d, 3H) ppm; MS (ESI) m/z: value [M+H]+.