Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][O:7][C:8]1[CH:13]=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[C:11]([NH2:21])=[CH:10][C:9]=1[NH:22][C:23]1[N:28]=[C:27]([C:29]2[CH:30]=[N:31][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=23)[CH:26]=[CH:25][N:24]=1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:6][O:7][C:8]1[C:9]([NH:22][C:23]2[N:28]=[C:27]([C:29]3[CH:30]=[N:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][C:33]=34)[CH:26]=[CH:25][N:24]=2)=[CH:10][C:11]([NH:21][C:1](=[O:4])[CH:2]=[CH2:3])=[C:12]([C:14]2[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH:19]=2)[CH:13]=1
Reactant: COc1cc(C2=CCN(C)CC2)c(N)cc1Nc1nccc(-c2cnn3c2CCCC3)n1
Reactant: C=CC(=O)Cl
Solvent: CO
Solvent: ClCCl
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4c3CCCC4)n2)c(OC)cc1C1=CCN(C)CC1
Reaction time: 0.5 h
Yield: 59.5 %

Procedure:
A solution of acryloyl chloride (30 μL, 0.37 mmol) in CH2Cl2 (2 mL) was added dropwise over 5 minutes to 4-methoxy-6-(1-methyl-3,6-dihydro-2H-pyridin-4-yl)-N′-[4-(4,5,6,7-tetrahydropyrazolo[1,5-a]pyridin-3-yl)pyrimidin-2-yl]benzene-1,3-diamine (Intermediate 136, 154 mg, 0.36 mmol) in CH2Cl2 (5 mL), which was cooled in an ice/CH3OH bath. The mixture was then stirred for 0.5 h. The mixture was then diluted with 10% CH3OH/CH2Cl2 and the resulting solution was washed with sat. NaHCO3, dried (MgSO4) and then concentrated in vacuo. Purification by FCC, eluting with 0-10% methanolic ammonia in CH2Cl2 gave the title compound (104 mg, 60%) as an pale yellow solid after trituration with diethyl ether/heptane; 1H NMR: 1.76-1.84 (2H, m), 1.91-1.98 (2H, m), 2.27 (3H, s), 2.32-2.39 (2H, m), 2.48-2.56 (2H, m), 2.96-2.99 (2H, m), 3.08 (2H, t), 3.90 (3H, s), 4.11 (2H, t), 5.65-5.76 (2H, m), 6.21 (1H, d), 6.49 (1H, dd), 6.84 (1H, s), 7.07 (1H, d), 7.84 (1H, s), 8.10 (1H, s), 8.32-8.37 (2H, m), 9.33 (1H, s); m/z: ES+ MH+ 486.73.
Reaction SMILES: [OH-].[Na+].[Br:3][C:4]1[C:12]2[NH:11][C@H:10]3[CH2:13][CH2:14][NH:15][CH2:16][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C1COCC1>[Br:3][C:4]1[C:12]2[NH:11][C@H:10]3[CH2:13][CH2:14][N:15]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:16][C@H:9]3[C:8]=2[CH:7]=[CH:6][CH:5]=1
Reactant: CCOC(=O)Cl
Reactant: Brc1cccc2c1N[C@H]1CCNC[C@@H]21
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)N1CC[C@@H]2Nc3c(Br)cccc3[C@@H]2C1
Temperature: 25 °C

Procedure:
(4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate may be prepared by first obtaining [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) as a free base by using 50% aqueous sodium hydroxide solution and extracting the product into MTBE. The conversion to (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate may then be done by cooling a suspension of compounds of [4aS,9bR]-6-bromo-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indole (36.0 g, 0.142 mol)) in THF (300 ml) and triethylamine (24 ml) in an ice-water bath. Ethyl chloroformate is added dropwise (13.5 ml, 0.142 mol) via a syringe pump over 1 hour. The ice-water bath is removed and the reaction mixture is stirred at room temperature for another hour. The reaction mixture is passed through a pad of celite and the solvent is evaporated to give (4aS,9bR)-ethyl 6-bromo-3,4,4a,5-tetrahydro-1H-pyrido[4,3-b]indole-2(9bH)-carboxylate). 1H NMR (CDCl3, 300 MHz): 1.20-1.35 (m, 3H), 1.73-1.85 (m, 1H), 1.85-1.99 (m, 1H), 3.22-3.52 (m, 3H), 3.52-3.66 (m, 1H), 3.66-3.95 (Br, 1H), 3.95-4.21 (m, 4H), 6.60 (t, J=7.7 Hz, 1H), 7.04 (d, J=7.2 Hz, 1H), 7.20 (d, J=8.1 Hz, 1H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:6]=[C:7]([O:22][C:23](=[O:37])[N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:9]=[CH:10][N:11]([C:20]=2[N:21]=1)[C@@H:12]1[O:19][C@H:16]([CH2:17][OH:18])[C@@H:14]([OH:15])[CH2:13]1)(=[O:3])[NH2:2].[CH3:38][O:39][C:40]1[CH:61]=[CH:60][C:43]([C:44](Cl)([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)=[CH:42][CH:41]=1.O.C(=O)(O)[O-].[Na+]>N1C=CC=CC=1>[C:1]([NH:4][C:5]1[N:6]=[C:7]([O:22][C:23](=[O:37])[N:24]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:8]2[N:9]=[CH:10][N:11]([C:20]=2[N:21]=1)[C@@H:12]1[O:19][C@H:16]([CH2:17][O:18][C:44]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)([C:45]2[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=2)[C:43]2[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:61][CH:60]=2)[C@@H:14]([OH:15])[CH2:13]1)(=[O:3])[NH2:2]
Reactant: NC(=O)Nc1nc(OC(=O)N(c2ccccc2)c2ccccc2)c2ncn([C@H]3C[C@H](O)[C@@H](CO)O3)c2n1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc(C(OC[C@H]2O[C@@H](n3cnc4c(OC(=O)N(c5ccccc5)c5ccccc5)nc(NC(N)=O)nc43)C[C@@H]2O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
The above-obtained 2-N-carbamoyl-6-O-diphenylcarbamoyldeoxyguanosine (1.19 g, 2.35 mmol) was azeotroped with anhydrous pyridine three times and dissolved in anhydrous pyridine (23 mL), and 4,4′-dimethoxytrityl chloride (917 mg, 2.70 mmol) was added thereto. The mixture was stirred at room temperature for 2 hours, and sodium bicarbonate water (8 mL) was added thereto to terminate the reaction. Then, the reaction solution was extracted with ethyl acetate (150 mL)/sodium bicarbonate water (120 mL) once and then with ethyl acetate (150 mL)/brine (100 mL) twice. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (N60: spherical neutral silica gel) with methanol/2% to 3% chloroform containing 1% triethylamine to give 2-N-carbamoyl-5′-O-(4,4′-dimethoxytrityl)-6-O-diphenylcarbamoyldeoxyguanosine (1.45 g, 76%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.C[N:23]([CH3:26])C=O>C1(CCN)CCCCC=1.C(O)C>[C:5]1([CH2:6][CH2:26][NH:23][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]2[CH:11]=[CH:10][C:9]([C:6]3[C:5]4[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=4[O:8][N:7]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:21][CH2:2][CH2:3][CH:4]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: CN(C)C=O
Agent: NCCC1=CCCCC1
Solvent: CCO
Product: O[C@H](CNCCC1=CCCCC1)COc1ccc(-c2noc3cc(F)ccc23)cc1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 2-(1-cyclohexenyl)ethylamine in ethanol, essentially as described above in Example 70. Purity by LC/MS=100%, [M+H]+=411.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.[NH2:8][C:9]1[N:10]=[C:11]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][C@H:22]([O:27][CH2:28][CH3:29])[C:23]([O:25][CH3:26])=[O:24])=[CH:17][CH:16]=2)[N:12]([CH3:14])[N:13]=1.[CH2:30](OCC)C>C(N(CC)CC)C.O1CCCC1>[CH2:28]([O:27][C@@H:22]([CH2:21][C:18]1[CH:17]=[CH:16][C:15]([C:11]2[N:12]([CH3:14])[N:13]=[C:9]([NH:8][CH3:5])[N:10]=2)=[CH:20][CH:19]=1)[C:23]([O:25][CH3:26])=[O:24])[CH3:29].[CH2:28]([O:27][C@@H:22]([CH2:21][C:18]1[CH:19]=[CH:20][C:15]([C:11]2[N:12]([CH3:14])[N:13]=[C:9]([NH:8][CH3:30])[N:10]=2)=[CH:16][CH:17]=1)[C:23]([OH:25])=[O:24])[CH3:29]
Reactant: CCOCC
Reactant: COS(=O)(=O)OC
Reactant: CCO[C@@H](Cc1ccc(-c2nc(N)nn2C)cc1)C(=O)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCO[C@@H](Cc1ccc(-c2nc(NC)nn2C)cc1)C(=O)O
Product: CCO[C@@H](Cc1ccc(-c2nc(NC)nn2C)cc1)C(=O)OC
Temperature: 35 °C
Yield: 60 %
Yield: 16 %

Procedure:
0.2 ml (2.2 mmol) of dimethyl sulfate is added to a mixture of 0.6 g (2 mmol) of methyl 3-[4-(5-amino-2-methyl-2H-[1,2,4]triazol-3-yl)phenyl]-2(S)-ethoxypropanoate, 0.3 ml (2.2 mmol) of triethylamine and 40 ml of ethyl ether. The reaction medium is heated at 35° C. for 4 hours. The reaction changed very little, 20 ml of tetrahydrofuran, 0.3 ml of triethylamine and 0.2 ml (2.2 mmol) of dimethyl sulfate are added and the reaction medium is heated at 40° C. for a further 24 hours. The reaction medium is evaporated to dryness. The residue obtained is purified by thin-layer chromatography on silica eluted with a 97/3 and then 95/5 dichloromethane/methanol mixture. 0.1 g (16%) of methyl 2(S)-ethoxy-3-[4-(2-methyl-5-methylamino-2H-[1,2,4]triazol-3-yl)phenyl]propanoate and 0.4 g (60%) of 2(S)-ethoxy-3-[4-(2-methyl-5-methylamino-2H-[1,2,4]triazol-3-yl)phenyl]propionic acid are obtained.
Reaction SMILES: C[O:2][C:3](=[O:23])[C:4]1[CH:9]=[C:8]([NH:10][CH:11]([CH2:13][CH3:14])[CH3:12])[N:7]=[C:6]([O:15]CC2C=CC=CC=2)[CH:5]=1.[H][H]>CO.C(OCC)(=O)C.[Pd]>[CH:11]([NH:10][C:8]1[CH:9]=[C:4]([CH:5]=[C:6]([OH:15])[N:7]=1)[C:3]([OH:23])=[O:2])([CH2:13][CH3:14])[CH3:12]
Reactant: [H][H]
Reactant: CCC(C)Nc1cc(C(=O)OC)cc(OCc2ccccc2)n1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCC(C)Nc1cc(C(=O)O)cc(O)n1

Procedure:
Treat a solution of 2-benzyloxy-6-sec-butylamino-isonicotinic acid methyl ester (340 mg, 1.036 mmol) in methanol (15 mL) and ethyl acetate (5 mL) with 10% Pd/C (150 mg). Stir the mixture under a balloon containing hydrogen gas for 2.5 h. Filter through a filtering agent, wash with ethyl acetate and concentrate to give the title compound which is used directly in the next step without further purification.
Reaction SMILES: [Mn]([O-])(=O)(=O)=[O:2].[K+].[Na].[CH3:8][C:9]1([CH3:20])[S:13][C@@H:12]2[CH2:14][C:15](=[O:16])[N:11]2[C@H:10]1[C:17]([OH:19])=[O:18].[OH2:21]>C(O)(=O)C>[CH3:8][C:9]1([CH3:20])[S:13](=[O:2])(=[O:21])[C@@H:12]2[CH2:14][C:15](=[O:16])[N:11]2[C@H:10]1[C:17]([OH:19])=[O:18]
Reactant: CC1(C)S[C@@H]2CC(=O)N2[C@H]1C(=O)O
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: O
Agent: [K+]
Agent: [Na]
Solvent: CC(=O)O
Product: CC1(C)[C@H](C(=O)O)N2C(=O)C[C@H]2S1(=O)=O
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 78 %

Procedure:
To a solution of 6.51 g. (41 mmole) of potassium permanganate in 130 ml. of water and 4.95 ml. of glacial acetic acid, cooled to ca. 5° C., was added a cold (ca. 5° C.) solution of 4.58 g. (21 mmole) of the sodium salt of penicillanic acid in 50 ml. of water. The mixture was stirred at ca. 5° C. for 20 minutes and then the cooling bath was removed. Solid sodium bisulfite was added until the color of the potassium permanganate had been discharged, and then the mixture was filtered. To the aqueous filtrate was added half its volume of saturated sodium chloride solution, and then the pH was adjusted to 1.7. The acidic solution was extracted with ethyl acetate. The extracts were dried, and the evaporated in vacuo, to give 3.47 g. of the title product. The aqueous mother liquor was saturated with sodium chloride, and further extracted with ethyl acetate. The ethyl acetate solution was dried and evaporated in vacuo, to give a further 0.28 g. of product. The total yield was therefore 3.75 g. (78% yield). The NMR spectrum (DMSO-d6) of the product showed absorptions at 1.40 (s, 3H), 1.50 (s, 3H), 3.13 (d of d's, 1H, J1 =16 Hz, J2 =2 Hz), 3.63 (d of d's, 1H, J1 =16 Hz, J2 =4 Hz), 4.22 (s, 1H) and 5.03 (d of d's, 1H, J1 =4 Hz, J2 =2 Hz) ppm.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([NH:18]S(C(C)(C)C)=O)([CH3:17])[CH3:16])=[CH:11][CH:10]=2)[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=1.Cl.CCCCCC>C(Cl)Cl.O1CCOCC1>[ClH:1].[NH2:18][C:15]([C:12]1[CH:11]=[CH:10][C:9]([NH:8][C:6]2[C:5]([N+:25]([O-:27])=[O:26])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[CH:14][CH:13]=1)([CH3:17])[CH3:16]
Reactant: CC(C)(NS(=O)C(C)(C)C)c1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)(N)c1ccc(Nc2nc(Cl)ccc2[N+](=O)[O-])cc1
Reaction time: 0.5 h

Procedure:
Deprotection/protection: To a solution of N-(1-{4-[(6-chloro-3-nitropyridin-2-yl)amino]phenyl}-1-methylethyl)-2-methylpropane-2-sulfinamide (107 mg) in DCM (5 ml) was added dropwise a solution of hydrogen chloride in dioxane (4 M, 130 ul) at room temperature. The reaction mixture was stirred for 30 min. Hexane was added to the suspension and the solid was filtered to give N-[4-(1-amino-1-methylethyl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride. To a suspension of N-[4-(1-amino-1-methylethyl)phenyl]-6-chloro-3-nitropyridin-2-amine hydrochloride in THF (3 ml) chilled to 0° C. was added saturated sodium bicarbonate solution (6 ml) and followed by a solution of di-tert-butyl dicarbonate (167 mg) in THF (3 ml) dropwise. After being stirred at room temperature over night, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution and brine. The organics were dried over anhydrous sodium sulfate and concentrated under reduced pressure. Purification by column chromatography (3-30% ethyl acetate in hexanes) gave the product (99 mg, 2 steps 93%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[C@:9]12([CH3:19])[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH2:12][C:10]2=O>>[CH3:19][C@:9]12[C:16]([CH3:18])([CH3:17])[CH:13]([CH2:14][CH2:15]1)[CH:12]=[C:10]2[C:2]#[C:1][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)C2
Reactant: C#Cc1ccccn1
Product: CC1(C)C2C=C(C#Cc3ccccn3)[C@]1(C)CC2

Procedure:
Reactants: 2-ethynylpyridine (6.0 mmol, 618 mg), (1R)-(+)-camphor (6.0 mmol, 912 mg); yields 2-{[(1R)-1,7,7-trimethylbicyclo[2.2.1]hept-2-e-n-2-yl]ethynyl }pyridine as a transparent yellow oil (125 mg, 9% overall yield). 1H NMR (CDCl3, 300 MHz) Δ8.57 (m, 1H), 7.64 (m, 1H), 7.43 (m, 1H), 7.17 (m, 1H), 6.49 (d, J=3 Hz, 1H), 2.41 (t, J=3 Hz, 1H), 1.92 (br m, 1H), 1.65 (m, 1H), 1.18 (m, 1H), 1.17 (s, 3H), 1.09 (br m, 1H), 0.84 (s, 3H), 0.82 (s, 3H). MS (EI ionization) 237 (M+).
Reaction SMILES: [OH-:1].[K+].Cl[C:4]1[S:5][C:6]2[C:11]([NH:12][C@H:13]([CH2:16][C:17]([F:20])([CH3:19])[CH3:18])[CH2:14][OH:15])=[N:10][C:9]([S:21][C@H:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[CH3:23])=[N:8][C:7]=2[N:31]=1.[CH3:32]O>[Na+].[Cl-]>[F:20][C:17]([CH3:19])([CH3:18])[CH2:16][C@@H:13]([NH:12][C:11]1[C:6]2[S:5][C:4]([O:1][CH3:32])=[N:31][C:7]=2[N:8]=[C:9]([S:21][C@H:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[F:30])[CH3:23])[N:10]=1)[CH2:14][OH:15]
Reactant: C[C@H](Sc1nc(N[C@@H](CO)CC(C)(C)F)c2sc(Cl)nc2n1)c1ccccc1F
Reactant: [OH-]
Reactant: CO
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Product: COc1nc2nc(S[C@@H](C)c3ccccc3F)nc(N[C@@H](CO)CC(C)(C)F)c2s1
Temperature: 50 °C

Procedure:
KOH (0.050 g, 0.89 mmol) was added to (2R)-2-[(2-chloro-5-{[(1S)-1-(2-fluorophenyl)ethyl]thio}[1,3]thiazolo[4,5-d]pyrimidin-7-yl)amino]-4-fluoro-4-methylpentan-1-ol in MeOH (5 mL) and the mixture was heated to 50° C. After 3 h the mixture was diluted with NaCl (aq) and extracted with CHCl3, the organic phase was dried (MgSO4) and evaporated to give the title compound.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[O:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:8][C:7]=1[CH2:17][O:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]O>C1(C)C=CC=CC=1>[Cl:3][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[CH:26][C:19]=1[O:18][CH2:17][C:7]1[N:8]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:10][C:6]=1[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccccc1CO
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccccc2)nc1COc1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Thionyl chloride (1.69 g) was added dropwise to a stirred suspension of 2-(5-methyl-2-phenyl4-oxazolylmethoxy)benzyl alcohol (4.00 g) in toluene (60 ml) at 0° C. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The residual crystals were dissolved in ethyl acetate and washed with aqueous sodium bicarbonate and water. The ethyl acetate layer was separated, dried (MgSO4), and concentrated to give 4-(2-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole as crystals. Recrystallization from ethyl acetate-hexane gave colorless needles (3.50 g, yield 82%). m.p. 103-104° C.
Reaction SMILES: [CH3:1][C:2]1[N:11]=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(C1C=C[N:18]=[C:17](CN)C=1)(C)C>>[C:17]([C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([CH3:1])[N:11]=1)#[N:18]
Reactant: COC(=O)c1cccnc1C
Reactant: CC(C)c1ccnc(CN)c1
Product: COC(=O)c1ccc(C#N)nc1C

Procedure:
methyl 6-cyano-2-methylnicotinate was synthesized from methyl 2-methylnicotinate following the general procedure as described for 4-isopropyl-2-pyridylmethylamine.
Reaction SMILES: C([Mg]Cl)CCC.C(NC(C)C)(C)C.[C:14]1([S:20]([N:23]2[C:31]3[C:26](=[C:27]([N:32]4[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]4)[CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24]2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[I:45]I>C1COCC1>[I:45][C:24]1[N:23]([S:20]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:22])=[O:21])[C:31]2[C:26]([CH:25]=1)=[C:27]([N:32]1[CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34][CH2:33]1)[CH:28]=[CH:29][CH:30]=2
Reactant: CC(C)(C)OC(=O)N1CCN(c2cccc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Reactant: II
Agent: CCCC[Mg]Cl
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cccc3c2cc(I)n3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of butylmagnesium chloride (1 mL, 1 mmol, 2.0 M in ether) and di-isopropyl amine (0.279 mL, 2 mmol) in dry THF (5 mL) was stirred for 4 h under inert atmosphere at room temperature. A solution of tert-butyl 4-[1-(phenylsulfonyl)-1H-indol-4-yl]-1-piperazinecarboxylate (220 mg, 0.5 mmol) in THF (2 mL) was added slowly and the resulting mixture stirred for 2 h at room temperature. A solution of iodine (380 mg, 2.2 mmol) in THF (2 mL) was added dropwise and the mixture was stirred overnight. After evaporation of the solvent in vacuo, the residue was treated with an aqueous solution of NH4Cl (10 mL). The mixture was extracted with CH2Cl2 (3×10 mL) and the combined organic layers were dried (MgSO4) and concentrated in vacuo. The residue was purified by column chromatography (SiO2) using CH2Cl2 as eluent to give, 100 mg (35%). 1H NMR (500 MHz, CDCl3) δ 8.05-7.80 (m, 3H), 7.60-7.35 (m, 3H), 7.19 (t, J=8 Hz, 1H), 6.98 (s, 1H), 6.72 (d, J=8 Hz, 1H), 3.62 (m, 4H), 3.05 (m, 4H), 1.47 (m, 9H); MS (ESI+) for m/z 568 (M+H)+.
Reaction SMILES: [CH:1]1([C:4]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)(O)[CH3:5])[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.[CH3:21][S:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:32]=1[NH:31][CH:30]=[CH:29]2>ClCCl>[CH:1]1([C:4]([C:29]2[C:28]3[C:32](=[C:24]([CH2:23][S:22][CH3:21])[CH:25]=[CH:26][CH:27]=3)[NH:31][CH:30]=2)([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[CH3:5])[CH2:3][CH2:2]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: CC(O)(c1ccc(F)cc1)C1CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(F)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
559 mg (3.10 mmol) of the compound from Example 77A and 0.26 ml (3.39 mmol) of trifluoroacetic acid were added to 500 mg (2.82 mmol) of the compound from Example 8A in 12 ml of dichloromethane. The reaction mixture was stirred at RT for 30 min and then diluted with dichloromethane, washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by preparative HPLC (mobile phase: acetonitrile/water gradient) resulted in 361 mg (38% of theory) of the title compound.
Reaction SMILES: [CH3:1][C@@:2]1([CH2:8][CH2:9][C:10]2[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=2)[CH2:6][O:5][C:4](=[O:7])[NH:3]1.[OH-].[K+].O.[C:19](O)(=O)[C@H:20]([C@@H](C(O)=O)O)[OH:21].O1CCC[CH2:30]1>CO.C(Cl)Cl>[C:4]([O:5][CH2:6][C@@:2]([NH:3][C:20](=[O:21])[CH3:19])([CH3:1])[CH2:8][CH2:9][C:10]1[N:11]([CH3:15])[CH:12]=[CH:13][CH:14]=1)(=[O:7])[CH3:30]
Reactant: C1CCOC1
Reactant: Cn1cccc1CC[C@]1(C)COC(=O)N1
Reactant: O=C(O)[C@@H](O)[C@H](O)C(=O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(=O)N[C@](C)(CCc1cccn1C)COC(C)=O
Reaction time: 2 h
Yield: 53 %

Procedure:
(4R)-4-Methyl-4-[2-(1-methylpyrrol-2-yl)ethyl]-1,3-oxazolidin-2-one (17.9 g, 86.0 mmol) obtained in Reference example 1 (1f) was dissolved in a mixture of tetrahydrofuran (250 mL) and methanol (125 mL) and a 5N aqueous potassium hydroxide solution (125 mL) was added thereto, followed by heating under reflux of the mixture for 4 days. After cooling, water and methylene chloride were added to the reaction mixture to separate it. The thus obtained organic phase was separated and dried over anhydrous sodium sulfate. After filtration, the solvent was evaporated under reduced-pressure and the residue was dissolved in ethanol (260 mL). D-(−)-tartaric acid (6.45 g, 43.0 mmol) was added thereto and the mixture was stirred for 2 hours. The precipitated crystal was collected by filtration to obtain a crude crystal (20.7 g). The crude crystal (18.7 g) was recrystallized from a mixture of ethanol (370 mL) and water (37 mL) and the thus obtained crystal was recrystallized again from a mixture of ethanol (300 mL) and water (30 mL). Further, the obtained crystal was recrystallized again from a mixture of ethanol (240 mL) and water (24 mL) to obtain the title compound (10.5 g, yield: 53%) as a colourless scaly crystal.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][CH:6]1Br)(=[O:3])[CH3:2].[OH:20][C:21]1[C:26]2[N:27]=[CH:28][O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[CH2:8][S:7][C@H:6]1[O:20][C:21]1[C:26]2[N:27]=[CH:28][O:29][C:25]=2[CH:24]=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: Oc1cccc2ocnc12
Reactant: CC(=O)O[C@H]1[C@H](OC(C)=O)CSC(Br)[C@@H]1OC(C)=O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1cccc2ocnc12
Yield: 41 %

Procedure:
By carrying out the process in a manner similar to example 7, starting from 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide and 4-hydroxybenzoxazole, the desired product is obtained in the form of a white solid with a yield of 41%.
Reaction SMILES: ClC1C=CC(C(C2C=C(C=CC=2)/C=C/[C:19]([OH:21])=[O:20])N2CCN(C)CC2)=CC=1.Br[C:28]1[CH:29]=[C:30]([CH:46]=[CH:47][CH:48]=1)[CH:31]([N:39]1[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]1)[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1>O1CCCC1>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([CH:31]([C:30]2[CH:29]=[C:28]([CH:48]=[CH:47][CH:46]=2)[C:19]([OH:21])=[O:20])[N:39]2[CH2:44][CH2:43][N:42]([CH3:45])[CH2:41][CH2:40]2)=[CH:33][CH:34]=1
Reactant: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(/C=C/C(=O)O)c2)CC1
Reactant: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(Br)c2)CC1
Solvent: C1CCOC1
Product: CN1CCN(C(c2ccc(Cl)cc2)c2cccc(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 33 %

Procedure:
The intermediate from Example 1, 1-(3-bromo-4'-chlorobenzhydryl)-4-methylpiperazine (1.10 g, 2.90 mmol), was dissolved in 10 mL of dry tetrahydrofuran and dried further over 4A molecular sieves for 24 hours. The solution was transferred to a dry flask under nitrogen and cooled to -78°. n-Butyllithium in hexane (1.1M, 2.6 ml) was added dropwise and the solution was stirred for 10 minutes at -78°. Carbon dioxide gas was bubbled into the reaction until the red solution turned yellow. The reaction was warmed to room temperature and the solvent was evaporated. The residue was dissolved in 20 mL of water and made basic with several drops of 1M sodium hydroxide. The aqueous solution was extracted with two 50 mL portion of ether and the pH was adjusted to 7-8 with 1M hydrochloric acid. After chilling in an ice bath, the precipitate was collected by filtration to give 341 mg (33%) of 3-(4-chloro-α-(4-methyl-1-piperazinyl)benzyl)benzoic acid as a white powder, m.p. 225°-230° (dec.). Calc. for C19H21ClN2O2. 0.75 H2O: C, 63.68; H, 6.33; N, 7.82; Cl, 9.89. Found: C, 63.68; H, 6.34; N, 7.82; Cl, 9.89.