Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][CH:13]([C:17]4[C:18]([C:23](O)=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1.[CH2:30]([NH2:32])[CH3:31].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:1][C:2]1[C:6]([C:7]2[C:16]3[O:15][CH2:14][C@H:13]([C:17]4[C:18]([C:23]([NH:32][CH2:30][CH3:31])=[O:24])=[N:19][CH:20]=[CH:21][CH:22]=4)[N:12]4[C:26](=[O:28])[NH:27][C:10]([C:11]=34)=[CH:9][CH:8]=2)=[C:5]([CH3:29])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1ccc2[nH]c(=O)n3c2c1OCC3c1cccnc1C(=O)O
Reactant: CCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1ncccc1[C@H]1COc2c(-c3c(C)noc3C)ccc3[nH]c(=O)n1c23
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.8 %

Procedure:
A solution of 3-[7-(3,5-Dimethylisoxazol-4-yl)-2-oxo-1,2,4,5-tetrahydroimidazo[1,5,4-de][1,4]benzoxazin-4-yl]pyridine-2-carboxylic acid (30.0 mg, 0.0764 mmol) (from step 2) in N,N-dimethylformamide (1.0 mL) was treated with ethylamine (10.8 μL, 0.191 mmol) followed by N,N-diisopropylethylamine (66.6 μL, 0.382 mmol) and stirred at room temperature for 5 min. The reaction mixture was subsequently treated with benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate [Aldrich #: 226084](50.7 mg, 0.115 mmol) and stirred at room temperature for 1 h. Purification by preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 60 mL/min) gave the desired product (23 mg, 71%) as a single enantiomer. 1H NMR (400 MHz, DMSO-d6) δ 9.03 (t, J=5.9 Hz, 1H), 8.58 (dd, J=4.6, 1.4 Hz, 1H), 7.49 (dd, J=8.0, 4.6 Hz, 1H), 7.11 (dd, J=8.0, 1.2 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.54-6.41 (m, 1H), 4.64-4.45 (m, 2H), 3.43-3.24 (m, 2H), 2.24 (s, 3H), 2.07 (s, 3H), 1.15 (t, J=7.2 Hz, 3H); LCMS calculated for C22H22N5O4 (M+H)+: m/z=420.2. found: 420.2.
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]=[C:15]([N:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)[C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:31]([O:33][CH:34]([Cl:36])[CH3:35])=[O:32]>ClCCl>[CH3:1][C:2]1[S:6][C:5]2=[N:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[N:14]([C:31]([O:33][CH:34]([Cl:36])[CH3:35])=[O:32])[C:15]([N:16]3[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]3)=[C:4]2[CH:3]=1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN(C)CC1
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc2c(s1)=Nc1ccccc1N(C(=O)OC(C)Cl)C=2N1CCN(C)CC1
Reaction time: 3 h
Yield: 58.4 %

Procedure:
To a solution of olanzapine (1.70 g, 5.44 mmol) in dichloromethane (50 mL) at 0° C. was added triethylamine (1.14 mL, 8.16 mmol) followed by 1-chloroethyl chloroformate (0.70 mL, 6.53 mmol) dropwise. TLC after 3 hours indicated starting material still remaining therefore more 1-chloroethyl chloroformate (0.2 mL) was added and stirred for a further 2 hours. The reaction was diluted with dichloromethane (20 mL) and washed with aq satd NaHCO3 (50 mL), dried (MgSO4) and concentrated. The crude product was purified by column chromatography on silica eluting with 2-5% MeOH/dichloromethane to give 1-chloroethyl 2-methyl-4-(4-methylpiperazin-1-yl)-5H-benzo[b]thieno[2,3-e][1,4]diazepine-5-carboxylate (1.33 g, 58% yield) as an orange foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].C(O)CCCCCO.C(OC=C)(=O)C.[CH:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][O:30]C=C)=[CH2:22]>C1(C)C=CC=CC=1>[CH:21]([O:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][OH:30])=[CH2:22]
Reactant: C=COCCCCCCOC=C
Agent: O=C([O-])[O-]
Agent: OCCCCCCO
Agent: [Na+]
Solvent: C=COC(C)=O
Solvent: Cc1ccccc1
Product: C=COCCCCCCO
Temperature: 100 °C
Reaction time: 6 h

Procedure:
To a mixture of di-μ-chlorobis(1,5-cyclooctadiene)diiridium(I) [Ir(cod)Cl]2 (6.7 mg, 0.01 mmol) and sodium carbonate (64 mg, 0.6 mmol) in toluene (1.0 ml), 1,6-hexanediol (118 mg, 1 mmol) and vinyl acetate (344 mg, 4 mmol) were added, followed by stirring at 100° C. in an atmosphere of argon gas for 6 hours. The reaction mixture was analyzed by gas chromatography to find that 1,6-bis(vinyloxy)hexane and 6-vinyloxy-1-hexanol were produced in yields of 87% and 2%, respectively, with a conversion from 1,6-hexanediol of 97%.
Reaction SMILES: C[O:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1.B(Br)(Br)Br.C(OCC)(=O)C>ClCCl>[OH:2][C:3]1[C:8]([C:9]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:10]=2[C:11]([O:13][CH3:14])=[O:12])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1OC
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COC(=O)c1cc([N+](=O)[O-])ccc1-c1cccnc1O
Temperature: 0 °C
Reaction time: 3 h
Yield: 54 %

Procedure:
Methyl 2-(2-methoxypyridin-3-yl)-5-nitrobenzoate (Reference Compound No. 1-3-(1), 200 mg, 0.694 mmol) was dissolved in anhydrous dichloromethane (2 mL), then boron tribromide (118 μL, 1.25 mmol) was added thereto at −78° C. The reaction mixture was stirred at 0° C. for 3 hours, and then poured into ice-water (30 mL). Ethyl acetate (50 mL) was added, and then separated. The organic layer was washed with saturated brine (50 mL), dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled reference compound (102 mg) as a yellow solid. (Yield 54%)
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:32][CH2:31]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1.[CH3:33][O:34][CH2:35][C:36](Cl)=[O:37]>>[CH3:33][O:34][CH2:35][C:36]([N:1]1[CH2:6][CH2:5][CH2:4][C@H:3]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH:30]4[CH2:31][CH2:32]4)[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:2]1)=[O:37]
Reactant: COCC(=O)Cl
Reactant: O=C(N[C@H]1CCCNC1)c1c[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc12
Product: COCC(=O)N1CCC[C@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)C1

Procedure:
Starting from 4-(5-Cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (S)-piperidin-3-ylamide (example A148) and methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7]([CH2:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([OH:14])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4].[CH2:30](OCC)C.Cl>CO>[CH2:1]([C:5]1[N:6]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[Cl:29])[C:7]([CH2:10][CH:11]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]([O:14][CH3:30])=[O:13])=[CH:8][N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ncc(CC(Cc2ccccc2)C(=O)O)n1Cc1ccccc1Cl
Reactant: CCOCC
Agent: Cl
Solvent: CO
Product: CCCCc1ncc(CC(Cc2ccccc2)C(=O)OC)n1Cc1ccccc1Cl
Reaction time: 48 h
Yield: 90 %

Procedure:
A solution of 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-2-benzylpropanoic acid [Example 8] (0.5 g) was dissolved in methanol (100 mL) and treated with excess diethyl ether saturated with dry hydrochloric acid. The mixture was kept at 25° C. for 48 hours. The solvents were evaporated, the residue dissolved in a small amount of methanol. Crystallization was induced with diethyl ether. The solid was collected, washed with diethyl ether, and dried to afford 0.47 g (90%) of the title compound; mp 118.5°-120.5° C.
Reaction SMILES: O[C@@:2]12[C@@H:19]3[C@H:10]([C@H:11]4[C@@:15]([CH2:17][CH2:18]3)([CH3:16])[C:14](=[O:20])[CH2:13][CH2:12]4)[C@H:9](C)[CH2:8][C:7]1=[CH:6][C:5](=[O:22])[CH2:4][CH2:3]2.S(=O)(=O)(O)O.P(=O)(O)(O)O.O>ClCCl.C(Cl)(Cl)Cl>[CH3:16][C@:15]12[CH2:17][CH2:18][C:19]3[C@@H:10]([CH2:9][CH2:8][C:7]4[C:2]=3[CH2:3][CH2:4][C:5](=[O:22])[CH:6]=4)[C@@H:11]1[CH2:12][CH2:13][C:14]2=[O:20]
Reactant: C[C@@H]1CC2=CC(=O)CC[C@]2(O)[C@H]2CC[C@]3(C)C(=O)CC[C@H]3[C@H]12
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: C[C@]12CCC3=C4CCC(=O)C=C4CC[C@H]3[C@@H]1CCC2=O
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
A mixture of the products (III) and (IV) from example 18 (210.3 Mmoles) was slurried in 130 ml of dichloromethane and added over 30 minutes to a mixture of 103 ml of 96% sulfuric acid and 1.7 ml of 85% phosphoric acid which had been precooled to 2° C. The reaction was complete 90 minutes after the addition was finished. The mixture was added to 200 grams of ice and 100 ml of water; this was extracted with several portions of dichloromethane. The organic phase was concentrated to about 100 ml and 400 ml of isopropyl alcohol was added. This solution was concentrated to about 300 ml volume and cooled slowly to −20° C. The crystalline mass was filtered, washed with 2×30 ml of cold isopropanol and dried to give the product. The m.p. was 138.6-139.0° C., and the optical rotation [α]D=−132.5° (Cl, chloroform). NMR (CDCl3); 1.02 ppm (3H, s), 1.3-3.0 ppm, several multiplets, 5.70 ppm (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>C(O)CCC.O>[CH3:1][C:2]1[CH:3]=[C:4]([C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][CH:15]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: COc1ccc(B(O)O)cc1C
Reactant: O=C(O)c1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CCCCO
Solvent: O
Product: COc1ccc(-c2ccc(C(=O)O)cc2)cc1C
Temperature: 80 °C
Yield: 30.3 %

Procedure:
3-Methyl-4-methoxyphenylboronic acid (542 mg) was combined with 4-iodobenzoic acid (810 mg), cesium carbonate (5.32 g), toluene (16 mL), water (8 mL) and n-butanol (4 mL). The mixture was degassed under vacuum with argon purging after which, tetrakis-triphenylphosphine palladium (38 mg) was added. The reaction was heated to 80° C. for 20 hours after which, it was cooled to room temperature and diluted with ethyl acetate (16 mL). The layers were separated and the organics were concentrated to dryness. The residue was purified on silica gel (50% to 100% ethyl acetate/hexane over 40 minutes) giving 3′-methyl-4′-methoxy-4-biphenylcarboxylic acid (240 mg). Yield=30%
Reaction SMILES: [C:1]1(B(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.I[C:11]1[C:15]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:25])=[O:24])=[C:14]([CH3:31])[N:13]([CH2:32][C:33]([O:35][CH2:36]C)=[O:34])[C:12]=1[CH3:38].C(=O)([O-])[O-].[Na+].[Na+]>CO.C1(C)C=CC=CC=1>[CH3:38][C:12]1[N:13]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[C:14]([CH3:31])=[C:15]([S:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[S:23]([N:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)(=[O:25])=[O:24])[C:11]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccccc1
Reactant: CCOC(=O)Cn1c(C)c(I)c(Sc2ccccc2S(=O)(=O)N2CCCC2)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)Cn1c(C)c(Sc2ccccc2S(=O)(=O)N2CCCC2)c(-c2ccccc2)c1C
Temperature: 100 °C
Yield: 23.1 %

Procedure:
To a solution of phenylboronic acid (26.9 mg, 0.221 mmol) in methanol (1.0 mL) and toluene (1.0 mL) was added ethyl 2-(3-iodo-2,5-dimethyl-4-(2-(pyrrolidin-1-ylsulfonyl)phenylthio)-1H-pyrrol-1-yl)acetate (121 mg, 0.221 mmol), palladium tetrakistriphenylphosphine (12.8 mg, 0.0110 mmol) and sodium carbonate (0.090 mL, 0.18 mmol). The reaction mixture was heated at 100° C. for 2.5 hours, then heated at 60° C. for 16 hours, after which an additional 0.10 equiv. of both phenylboronic acid and palladium tetrakistriphenylphosphine were added. The reaction was then heated at 100° C. for one more hour, after which it was allowed to cool down to room temperature, poured over ice water (10 mL), extracted with ether (2×20 mL), and washed with water (1×30 mL). The combined organic layers were dried (sodium sulfate), filtered, and concentrated. Purification by column chromatography on silica gel afforded methyl 2-(2,5-dimethyl-3-phenyl-4-(2-(pyrrolidin-1-ylsulfonyl)phenylthio)-1H-pyrrol-1-yl)acetate (0.0246 g, 0.0510 mmol, 23% yield) as a light brown residue. LCMS: ES+ [M+H]+=485.3
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]5[CH2:29][CH2:28]5)[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:16]=2)[N:11](COCC[Si](C)(C)C)[CH:10]=1)=[O:8])[CH3:5].C(O)(C(F)(F)F)=O.C(N)CN>ClCCl>[CH3:1][O:2][CH2:3][C@@H:4]([NH:6][C:7]([C:9]1[C:17]2[C:12](=[N:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([CH:27]5[CH2:29][CH2:28]5)[CH:25]=4)[N:20]([CH3:30])[N:19]=3)[N:16]=2)[NH:11][CH:10]=1)=[O:8])[CH3:5]
Reactant: COC[C@H](C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4ccc(C5CC5)cc34)nc12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: NCCN
Product: COC[C@H](C)NC(=O)c1c[nH]c2ncc(-c3nn(C)c4ccc(C5CC5)cc34)nc12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 38 %

Procedure:
In a 10 mL round-bottom flask, 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide (34 mg, 0.065 mmol) and TFA (0.5 ml, 6.5 mmol) were combined with dichloromethane (1.5 ml) to give an orange solution. The reaction mixture was stirred at room temperature for 2.5 h then concentrated under reduced pressure. The resultant crude solid was dissolved in dichloromethane (1.5 mL) and ethylenediamine (0.11 ml, 1.6 mmol) was added. The reaction mixture was stirred at room temperature for 18 h then concentrated and the residue was precipitated with water. The suspension was stirred for 1 h and the crude solid collected by filtration. The crude solid was purified by trituration (dichloromethane/heptane) to afford 10 mg (38%) of 2-(5-cyclopropyl-1-methyl-1H-indazol-3-yl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((S)-2-methoxy-1-methyl-ethyl)-amide as an off-white solid. MS: [M+H]+=405; 1H NMR (300 MHz, DMSO-d6) δ: 12.79 (br. s., 1H), 9.09 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H), 8.26 (d, J=8.3 Hz, 1H), 7.66 (d, J=8.7 Hz, 1H), 7.10 (dd, J=8.7, 1.5 Hz, 1H), 4.28-4.43 (m, 1H), 4.15 (s, 3H), 3.53 (dd, J=9.1, 4.5 Hz, 1H), 3.45 (dd, J=9.1, 4.9 Hz, 1H), 3.20 (s, 3H), 2.18-2.25 (m, 1H), 1.35 (d, J=6.8 Hz, 3H), 0.94-1.02 (m, 2H), 0.76 (td, J=5.3, 4.2 Hz, 2H).
Reaction SMILES: [Li].[C:2]([O:6][C:7](=[O:23])[NH:8][C@H:9]1[CH2:13][C@@H:12]([CH3:14])[N:11](CC2C=CC=CC=2)[C:10]1=[O:22])([CH3:5])([CH3:4])[CH3:3]>N.C1COCC1>[C:2]([O:6][C:7](=[O:23])[NH:8][C@H:9]1[CH2:13][C@@H:12]([CH3:14])[NH:11][C:10]1=[O:22])([CH3:4])([CH3:3])[CH3:5]
Reactant: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N1Cc1ccccc1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](NC(=O)OC(C)(C)C)C(=O)N1
Temperature: 35 °C
Reaction time: 0.25 h

Procedure:
To a blue solution of lithium metal (0.237 g, 34.2 mmol) in NH3 (1) (200 mL) at −78° C. was added a solution of 13-6 (2.60 g, 8.54 mmol) in THF (15 mL). The mixture was stirred for 15 minutes, then quenched by the addition of ammonium chloride until the blue color dispersed. An additional 30 mL of THF was added, and the mixture warmed to 35° C. to evaporate the ammonia. MgSO4 was added,the mixture was filtered through a celite pad. Following evaporative removal of the solvent, the residue was chromatographed (silica gel, 70:20:10 chloroform/ethyl acetate/MeOH) to give 13-7 as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[NH:7][S:8][C:4]=2[CH:3]=1.[CH2:12]([N:16]=[C:17]=[O:18])[CH2:13][CH2:14][CH3:15]>>[CH2:12]([NH:16][C:17]([N:7]1[C:6](=[O:9])[C:5]2[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][C:4]=2[S:8]1)=[O:18])[CH2:13][CH2:14][CH3:15]
Reactant: CCCCN=C=O
Reactant: O=c1[nH]sc2cc(Cl)ccc12
Product: CCCCNC(=O)n1sc2cc(Cl)ccc2c1=O

Procedure:
Following the synthetic procedure of 6a as described in Example 1, compound 6w (90% yield) was synthesized from 6-chloro-benzo[d]isothiazol-3-one and n-butyl isocyanate as a white solid. IR(CHCl3) 3294, 1713, 1540 cm−1; 1H-NMR (DMSO-d6) δ0.89 (t, J=7.3 Hz, 3H), 1.26-1.37 (m, 2H), 1.47-1.55 (m, 2H), 3.28-3.34 (m, 2H), 7.50 (d, J=8.3 Hz, 1H), 7.91 (d, J=8.3 Hz, 1H), 8.14 (s, 1H), 8.76 (t, J=5.6 Hz, 1H); ESIMS m/e 284 and 286 (M++1, 35Cl and 37Cl).
Reaction SMILES: [ClH:1].[Si:2]([O:19][C@H:20]([C:34]1[S:35][CH:36]=[CH:37][N:38]=1)[C@H:21]1[CH2:26][CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>ClCCl>[ClH:1].[Si:2]([O:19][C@H:20]([C:34]1[S:35][CH:36]=[CH:37][N:38]=1)[C@H:21]1[CH2:26][CH2:25][CH2:24][NH2+:23][CH2:22]1)([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]([C@H](O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c2nccs2)C1
Agent: Cl
Solvent: ClCCl
Product: CC(C)(C)[Si](O[C@H](c1nccs1)[C@H]1CCC[NH2+]C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
30 ml of hydrogen chloride (4 M in 1,4-dioxane) were added dropwise at +5° C. to a solution of 1.08 g (2.0 mmol) of tert-butyl (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-ylmethyl]-piperidine-1-carboxylate in 30 ml of dichloromethane. The reaction mixture was stirred at room temperature for 2 hours. Evaporation gave 1.03 g of (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-yl-methyl]piperidinium hydrochloride; HPLC/MS (M+H)+=437; rotation value in methanol [α]20D=−18.1°. The hydrochloride was dissolved in 10 ml of water, cooled in an ice bath, and 1 ml of sodium hydroxide solution (2 M) was added dropwise. The precipitate was taken up with ethyl acetate, washed with saturated sodium chloride solution, dried over sodium sufate, filtered and evaporated, giving 0.8 g of (S)-3-[(S)-(tert-butyldiphenylsilanyloxy)thiazol-2-ylmethyl]piperidine as amorphous resin; HPLC/MS (M+H)+=437; rotation value in methanol [α]20D=−22.1°. 1H NMR (400 MHz, DMSO) δ 7.69-7.56 (m, 4H), 7.52-7.38 (m, 6H), 7.38-7.26 (m, 2H), 4.84 (d, J=6.6, 1H), 4.03 (q, J=7.1, 1H), 2.94 (d, J=11.2, 1H), 2.73 (d, J=11.8, 1H), 2.25-2.10 (m, 2H), 1.78 (dtd, J=10.5, 6.9, 3.3, 1H), 1.49-1.30 (m, 2H), 1.19-1.10 (m, 2H), 1.04-0.93 (m, 9H).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH2:39]([C:41]1[CH:42]=[C:43]([C:54](=[N:56]O)[NH2:55])[S:44][C:45]=1[CH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1)[CH3:40].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[CH2:39]([C:41]1[CH:42]=[C:43]([C:54]2[N:56]=[C:12]([C:11]3[CH:10]=[CH:9][C:8]([O:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)=[CH:16][CH:15]=3)[O:14][N:55]=2)[S:44][C:45]=1[CH2:46][O:47][CH:48]1[CH2:53][CH2:52][CH2:51][CH2:50][O:49]1)[CH3:40]
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCc1cc(C(N)=NO)sc1COC1CCCCO1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3ccc(Oc4ccccc4)cc3)n2)sc1COC1CCCCO1

Procedure:
The crude product of the title compound was synthesized by conducting the similar reaction to that mentioned in Example 5 (5a) using 4-phenoxybenzoic acid (0.16 g, 0.73 mmol), 1-hydroxybenzotriazole (0.12 g, 0.76 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.15 g, 0.76 mmol), 4-ethyl-N′-hydroxy-5-[(tetrahydro-2H-pyran-2-yloxy)methyl]thiophene-2-carboximidamide (0.17 g, 0.69 mmol) that was obtained in Example 22 (22d) and tetrabutylammonium fluoride (a 1.0 M solution in tetrahydrofuran, 14 ml, 1.4 mmol). Subsequently, the crude product of the title compound thus obtained was purified by chromatography on a silica gel column using a mixed solvent of ethyl acetate and hexane (0:10 to 2:8) as the eluent to afford the title compound (0.25 g) in a yield of 78% as a colourless oily product.
Reaction SMILES: [C:1]1([CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[O:16][C:15](=[O:18])[CH2:14][CH2:13]2.[OH-:20].[K+]>CO>[OH:16][C:17]1[C:8]([O:7][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[CH3:19])=[CH:9][CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][C:15]([OH:20])=[O:18]
Reactant: Cc1ccccc1Oc1cccc2c1OC(=O)CC2
Reactant: [OH-]
Agent: [K+]
Solvent: CO
Product: Cc1ccccc1Oc1cccc(CCC(=O)O)c1O
Yield: 17.3 %

Procedure:
A mixture of 8-(o-tolyloxy)chroman-2-one (5.4 g) and potassium hydroxide (2 g) in methanol (50 ml) was refluxed under heating for 30 minutes. After cooling, the reaction mixture was evaporated, and the oily residue was dissolved in water, washed with diethyl ether, acidified with conc. hydrochloric acid and then extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated. The residue was recrystallized twice from a mixture of ethyl acetate and n-hexane to give 3-[2-hydroxy-3-(o-tolyloxy)phenyl]propionic acid (1.0 g). mp 106°-107° C.
Reaction SMILES: [CH2:1]([NH:5][C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)[CH:2]([CH3:4])[CH3:3].[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](Cl)=[O:23]>ClCCl>[Cl:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]([N:5]([C@H:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([O:17][CH3:18])=[O:16])[CH:13]=2)[CH2:8][CH2:7]1)[CH2:1][CH:2]([CH3:4])[CH3:3])=[O:23]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NCC(C)C)CC2
Reactant: O=C(Cl)c1ccccc1Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2c(c1)[C@H](N(CC(C)C)C(=O)c1ccccc1Cl)CC2
Reaction time: 0.25 h
Yield: 51 %

Procedure:
TEA (1.4 ml, 10.1 mmol, 2.5 eq) was added dropwise at 0° C. to a solution of (R)-methyl 3-(isobutylamino)-2,3-dihydro-1H-indene-5-carboxylate (A-08) (1.0 g, 4.04 mmol, 1 eq) in dichloromethane (25 ml), and stirring was carried out for 15 min. Then 2-chlorobenzoic acid chloride (0.61 ml, 4.858 mmol, 1.2 eq) was added at that temperature, and stirring was carried out for 1 h at RT. After monitoring by thin-layer chromatography, the reaction mixture was diluted with dichloromethane (75 ml), washed with water and sat. NaCl solution (in each case 50 ml), dried over sodium sulfate and purified by column chromatography (silica gel, 2% MeOH in dichloromethane). Yield: 51% (800 mg, 2.078 mmol).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21]C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CC)[C@@H](C1C=CC=CC=1)O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C@@H:19]([NH2:23])[CH2:20][CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: CC[C@H](N)[C@H](O)c1ccccc1
Agent: Cl
Product: CC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1

Procedure:
was synthesised in the same way as (91a) from (1R,2S)-2-amino-1-phenylbutan-1-ol hydrochloride (95b, 53 mg, 0.26 mmol).