Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([C:7](=O)[CH2:8][C:9]([O:11]CC)=O)=[CH:3][CH:2]=1.Cl.[CH3:16][C:17]1([CH3:24])[CH2:22][NH:21][C:20]([NH2:23])=[N:19][CH2:18]1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.ClCCl>[CH3:16][C:17]1([CH3:24])[CH2:22][N:21]2[C:9](=[O:11])[CH:8]=[C:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[N:23]=[C:20]2[NH:19][CH2:18]1
Reactant: CCOC(=O)CC(=O)c1ccncc1
Reactant: CC1(C)CN=C(N)NC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: ClCCl
Product: CC1(C)CNc2nc(-c3ccncc3)cc(=O)n2C1
Yield: 80.5 %

Procedure:
A mixture of 5.9 g (30.55 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate, 5.0 g (30.55 mmol) of 5,5-dimethyl-1,4,5,6-tetrahydro-2-pyrimidinamine monohydrochloride (prepared by analogy to the method described in U.S. Pat. No. 4,262,122) and 6.33 g (45.82 mmol) of potassium carbonate in 60 ml of ethanol was heated at reflux temperature during 12 h. The cooled suspension was filtered and the solvent removed by evaporation. The residue obtained was dissolved in dichloromethane and washed with water. The organic phase was dried and evaporated to give 6.30 g (80%) of product as a beige solid. Mp.: 152-154° C.
Reaction SMILES: [CH2:1]([OH:27])[CH2:2][CH2:3][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][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].C(N(CC)CC)C.[Cl:35][C:36]1[CH:41]=[CH:40][C:39]([S:42](Cl)(=[O:44])=[O:43])=[CH:38][CH:37]=1>C(Cl)Cl>[CH2:1]([O:27][S:42]([C:39]1[CH:40]=[CH:41][C:36]([Cl:35])=[CH:37][CH:38]=1)(=[O:44])=[O:43])[CH2:2][CH2:3][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][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCCCCCCCCCOS(=O)(=O)c1ccc(Cl)cc1
Yield: 21.9 %

Procedure:
A solution of hexacosanol (250 mgs, 0.654 mmol), triethylamine (125 1, 0.900 mmol) and 4-chlorobenzenesulphonyl chloride (150 mgs, 0.711 mmol) in methylene chloride (30 ml) is stirred at room temperature for 120 h. The reaction mixture is then diluted with methylene chloride (20 ml) and washed with water (2×50 ml). The organic phase is dried over magnesium sulphate, filtered and concentrated to give a crude product. Flash column chromatography on silica gel (10:1 hexane:ethyl acetate) followed by recrystallization from methanol gives n-hexacosanyl-4-chlorobenzenesulphonate (80 mgs, 22%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([O:28][CH3:29])[C:5]([N:8](COCC[Si](C)(C)C)[S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[C:13]=2[Cl:19])(=[O:11])=[O:10])=[N:6][CH:7]=1.[F:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][SH:38])=[CH:33][CH:32]=1>>[Cl:19][C:13]1[C:14]([Cl:18])=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([NH:8][C:5]1[C:4]([O:28][CH3:29])=[N:3][C:2]([S:38][CH2:37][C:34]2[CH:35]=[CH:36][C:31]([F:30])=[CH:32][CH:33]=2)=[CH:7][N:6]=1)(=[O:10])=[O:11]
Reactant: COc1nc(Br)cnc1N(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(Cl)c1Cl
Reactant: Fc1ccc(CS)cc1
Product: COc1nc(SCc2ccc(F)cc2)cnc1NS(=O)(=O)c1cccc(Cl)c1Cl

Procedure:
Prepared as for Example 101b using N-(5-bromo-3-methoxy-2-pyrazinyl)-2,3-dichloro-N-{[2-(trimethylsilanyl)ethoxy]methyl}benzenesulphonamide (Example 55a) (0.4 g) and (4-fluorophenyl)methanethiol (0.13 g). The intermediate product containing the SEM group was purified by silica gel chromatography eluting with ethyl acetate/iso-hexane mixtures. Deprotection as for Example 101b gave the title compound. Yield 0.2 g
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[N:1]1([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:19][CH2:18][CH:17]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1CCNCC1
Reactant: O=C1CCN(c2ccc(CN3CCOCC3)cc2)CC1
Product: c1cc(N2CCC(N3CCCCC3)CC2)ccc1CN1CCOCC1

Procedure:
Prepared from the product of Example 19 and piperidine.
Reaction SMILES: [C:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([CH3:3])=[CH2:2].[H][H]>O1CCOCC1.[Pd]>[CH:1]([C:4]1[S:18][C:7]2[O:8][C:9]3[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=3[NH:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1cc2c(s1)Oc1ccccc1NC2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: C1COCCO1
Product: CC(C)c1cc2c(s1)Oc1ccccc1NC2=O
Temperature: 40 °C
Reaction time: 7.5 h
Yield: 76.3 %

Procedure:
2-Isopropenylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (780 mg) was suspended in dioxane (40 ml) and 10% palladium-activated charcoal (100 mg) was added. Hydrogen was sealed in and the mixture was stirred at 40° C., 50 atm for 7.5 hours. The catalyst was filtered off and the solvent was evaporated under reduced pressure to give 2-isopropylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one (600 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:18])=[CH:9][C:8]([CH3:19])=[CH:7][C:6]=2[CH3:20].C([O:24][C:25]1[CH:35]=[CH:34][C:28]([CH:29]=[CH:30][C:31](Cl)=[O:32])=[CH:27][CH:26]=1)(=O)C.O1CCCC1.C(=O)([O-])O.[Na+]>O>[Cl:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[C:10]2[C:5](=[C:6]([CH3:20])[CH:7]=[C:8]([CH3:19])[CH:9]=2)[N:4]=[CH:3][C:2]=1[NH:1][C:31](=[O:32])[CH:30]=[CH:29][C:28]1[CH:34]=[CH:35][C:25]([OH:24])=[CH:26][CH:27]=1
Reactant: Cc1cc(C)c2ncc(N)c(-c3ccccc3Cl)c2c1
Reactant: CC(=O)Oc1ccc(C=CC(=O)Cl)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C)c2ncc(NC(=O)C=Cc3ccc(O)cc3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 78.3 %

Procedure:
A mixture of 3-amino-4-(2-chlorophenyl)-6,8-dimethylquinoline (282 mg), 4-acetoxycinnamoyl chloride (250 mg) and tetrahydrofuran (5 ml) was stirred at room temperature for 6 hours. After being diluted with water and made neutral with a sodium hydrogen carbonate saturated solution, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed, and the residue was dissolved in tetrahydrofuran-methanol solution (1:1, 6 ml). Then, 2N-hydrochloric acid was added to the solution which was thereafter stirred at room temperature for 1.5 hours. The resultant solution was diluted with water, adjusted to pH 4 by addition of 2N-hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The resultant was removed to give crystals of 4-(2-chlorophenyl)-3-(4-hydroxycinnamoylamino)-6,8-dimethylquinoline (335 mg, 78.3%). The obtained crystals were recrystallized from ethanol to afford colorless needles.
Reaction SMILES: [C:1]([O:13]C)(=[O:12])[C:2]1[CH:11]=[CH:10][CH:9]=[C:4]([C:5]([O:7][CH3:8])=[O:6])[CH:3]=1.[OH-].[Na+]>CC(C)=O.CO>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([C:1]([OH:13])=[O:12])[CH:3]=1
Reactant: COC(=O)c1cccc(C(=O)OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: CO
Product: COC(=O)c1cccc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73 %

Procedure:
A solution of dimethyl isophthalate (25 g, 128.75 mmol) was dissolved in acetone (250 mL) and a solution of NaOH (5.4 g, 135 mmol) in methanol (50 mL) was added dropwise. A white precipitated was observed and the slurry was stirred for 18 h at room temperature. Then powdered NaOH (0.5 g) was added. The acetone was evaporated until dryness and the white residue was dissolved in water (250 mL), extracted with diethylether (2×100 mL). The aqueous solution was acidified with concentrated HCl to pH 4˜5 and the white precipitate was filtered, dried under vacuum and the desired monoacid obtained (17 g, 94.36 mmol, 73% yield) as a white solid.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][NH2:14].[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22](Cl)=[CH:21][N:20]=1)=[O:18]>CS(C)=O>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[N:23][C:22]([NH:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:21][N:20]=1)=[O:18]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: Cc1onc(-c2ccccc2)c1CN
Solvent: CS(C)=O
Product: COC(=O)c1cnc(NCc2c(-c3ccccc3)noc2C)cn1
Temperature: 25 °C
Yield: 85 %

Procedure:
A solution of (5-methyl-3-phenyl-4-isoxazolyl)methylamine (2.4 g, 12.7 mmol) and 5-chloro-pyrazine-2-carboxylic acid methyl ester (2.2 g, 12.7 mmol) in DMSO (15 mL) was heated with microwave irradiation to 160° C. for 30 min. After cooling to room temperature the reaction mixture was extracted with ethyl acetate, and the combined extracts were washed with water. The organic phase was dried over sodium sulfate, concentrated and chromatographed (SiO2, heptane:ethyl acetate=100:0 to 20:80). The oily product obtained was triturated with diisopropylether and ethyl acetate to afford the title compound (3.5 g, 84%) as an off-white solid. MS: m/e=325.4[M+H]+.
Reaction SMILES: Cl.Cl.Cl.[N:4]1([CH2:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)=[O:12])[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28]Br)([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25](=[O:30])[NH:26][CH2:27][CH2:28][N:7]1[CH2:8][CH2:9][N:4]([CH2:10][C:11](=[O:12])[NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:5][CH2:6]1)([CH3:23])([CH3:22])[CH3:21]
Reactant: O=C(CN1CCNCC1)Nc1ccccn1
Reactant: CC(C)(C)OC(=O)NCCBr
Agent: Cl
Product: CC(C)(C)OC(=O)NCCN1CCN(CC(=O)Nc2ccccn2)CC1

Procedure:
The title compound is synthesized by coupling of 2-piperazin-1-yl-N-pyridin-2-yl-acetamide trihydrochloride dehydrate (commercially available from ABCR GmbH) and (2-Bromo-ethyl)-carbamic acid tert-butyl ester analogously to the preparation of Intermediate 269.2 as a colorless oil; ES-MS: M+H=364.3: CtRet=4.07.
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@H:6]1[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:4].[CH3:23][C:24]1[CH:25]=[C:26]([N:30]=[C:31]=[O:32])[CH:27]=[CH:28][CH:29]=1.C(Cl)(Cl)Cl>C1CCCCC1>[CH3:23][C:24]1[CH:25]=[C:26]([NH:30][C:31](=[O:32])[NH:1][CH2:2][C:3]([N:5]2[C@@H:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][S:7][C@H:6]2[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: Cc1cccc(N=C=O)c1
Reactant: CC(C)(C)OC(=O)[C@H]1CS[C@@H](c2ccccc2)N1C(=O)CN
Solvent: ClC(Cl)Cl
Solvent: C1CCCCC1
Product: Cc1cccc(NC(=O)NCC(=O)N2[C@@H](C(=O)OC(C)(C)C)CS[C@H]2c2ccccc2)c1

Procedure:
The operation is carried out in a fashion similar to that described in Example 34, but starting from 0.3 g of tert-butyl (2S,4S)-3-(2 aminoacetyl)-2-phenyl-4-thiazolidinecarboxylate and 0.12 cm3 of 3-methylphenyl isocyanate. After vigorous stirring in cyclohexane, 0.16 g of tert-butyl (2S,4S)-3-{2-[3-(3-methylphenyl)ureido]acetyl}-2-phenyl-4-thiazolidinecarboxylate is thus obtained in the form of an amorphous pale yellow powder ([α]D20 =-62.0°±1.1° (C=1.02%; CHCl3)). [Proton NMR (250 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C., general description valid for the other products of the thiazolidine family (at 120° C.): 1.50 (bs, 9H, (CH3)3); 2.3 (s, 3H, CH3); 3.25 and 3.5 (ABX, 2H, CH2S); 3.7 and 4.05 (ABX, 2H, CH2N); 5.0 (bd, 1H, CHN); 6.2 (bds, 1H, NH); 6.4 (bs, 1H, SCHN); 6.7 (bd, 1H, N--C6H4 --C in position 4 or 6); 7.05 to 7.2 (m, 3H, N--C6H4 --C in position 2, 4 and 5); 7.35 (m, 3H, C6H5); (bd, 2H, C6H5); 8.35 (bs, 1H, NH). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 2990, 2940, 2860, 1745, 1650, 1615, 1600, 1560, 1495, 1460, 1375, 1155, 785, 735, 700].
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([O:10][C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][N:15]=[CH:14]3)=[N:8][CH:9]=1)([O-:3])=[O:2].[F:20][C:21]1[CH:26]=[CH:25][C:24](B(O)O)=[CH:23][CH:22]=1.C(N(CC)CC)C>CS(C)=O.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][C:7]4[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][N:8]=4)=[CH:19][CH:18]=3)[CH:14]=[N:15]2)=[CH:23][CH:22]=1
Reactant: O=[N+]([O-])c1ccc(Oc2ccc3[nH]ncc3c2)nc1
Reactant: OB(O)c1ccc(F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)nc1
Reaction time: 72 h
Yield: 20.5 %

Procedure:
To a solution of 5-(5-Nitro-pyridin-2-yloxy)-1H-indazole (1.0 g, 3.9 mmol) in 15 mL of DMSO was added copper (II) acetate (0.71 g, 3.9 mmol), powdered 4A molecular sieves (0.2 g), 4-fluorophenylboronic acid (0.60 g, 4.3 mmol) and triethylamine (2.7 mL, 20 mmol). The resulting mixture was stirred under an oxygen atmosphere for 3 days. After filtering through a plug of Celite and silica gel, the mixture was concentrated in vacuo, adsorbed to silica gel, and purified by column chromatography eluting with 0-20% ethyl acetate-hexanes, affording 0.28 g of 1-(4-Fluoro-phenyl)-5-(5-nitro-pyridin-2-yloxy)-1H-indazole as a colorless syrup. 1H NMR (CD3OD, 400 MHz): δ 8.17 (s, 1H), 7.7-7.8 (m, 3H), 7.61 (d, 1H, J=2.8 Hz), 7.39 (d, 1H, J=2.0 Hz), 7.30 (m, 2H), 7.22 (m, 2H), 6.77 (1H, d, J=8.8 Hz) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:13][CH2:12][CH2:11][C:10]([F:15])([F:14])[C@@H:9]1[NH:16][C:17]([C:19]1[S:20][C:21]([CH3:37])=[C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[C:31]([O:33][CH:34]([F:36])[F:35])[CH:30]=[N:29][C:28]=23)[CH:23]=1)=[O:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl.[OH-].[Na+]>[NH2:7][C@H:8]1[C@@H:9]([NH:16][C:17]([C:19]2[S:20][C:21]([CH3:37])=[C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[C:31]([O:33][CH:34]([F:35])[F:36])[CH:30]=[N:29][C:28]=34)[CH:23]=2)=[O:18])[C:10]([F:14])([F:15])[CH2:11][CH2:12][CH2:13]1
Reactant: Cc1sc(C(=O)N[C@@H]2[C@H](NC(=O)OC(C)(C)C)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1sc(C(=O)N[C@@H]2[C@H](N)CCCC2(F)F)cc1-c1cnn2cc(OC(F)F)cnc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.4 %

Procedure:
tert-Butyl{(1R,2R)-2-[({4-[6-(difluoromethoxy)pyrazolo[1,5-a]pyrimidin-3-yl]-5-methylthiophen-2-yl}carbonyl)amino]-3,3-difluorocyclohexyl}carbamate (0.900 g, 1.61 mmol) was dissolved in dichloromethane (8 mL) and trifluoroacetic acid (1.50 mL, 19.5 mmol) added. The reaction was stirred at room temperature for 16 h. After deprotection was complete, the mixture was diluted with 1N NaOH. The aqueous layer was extracted 3× with dichloromethane. The organic layers were combined, dried with sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography (0-16% MeOH/DCM) to give the title compound (0.371 g, 0.811 mmol). LRMS (APCI) calc'd for (C19H19F4N5O2S) [M+H]+, 458.1; found 458.0. 1H NMR (CDCl3, 500 MHz) δ 8.66 (d, J=2.5, 1H), 8.48 (d, J=2.5, 1H), 8.26 (s, 1H), 7.92 (s, 1H), 7.06 (d, J=8.8, 1H), 6.61 (t, J=71.5, 1H), 4.45 (m, 1H), 3.32 (m, 1H), 2.57 (s, 3H), 2.17 (m, J=8.6, 1H), 1.47-1.92 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:20])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([O:12]C)=[O:11])[CH:7]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>CCOCC>[Cl:1][C:2]1[C:3]([O:20][CH2:25][CH2:24][CH2:23][O:22][CH3:21])=[CH:4][C:5]([O:18][CH3:19])=[C:6]([CH:8]([CH2:14][CH2:15][CH2:16][CH3:17])[CH2:9][C:10]([OH:12])=[O:11])[CH:7]=1
Reactant: COCCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCCCC(CC(=O)OC)c1cc(Cl)c(O)cc1OC
Solvent: CCOCC
Product: CCCCC(CC(=O)O)c1cc(Cl)c(OCCCOC)cc1OC

Procedure:
Following a similar procedure to that described in Preparation 45A(i), but using methyl 3-(5-chloro-4-hydroxy-2-methoxyphenyl)heptanoate (prepared as described in Preparation 56B) and 3-methoxy-1-tosyloxypropane, the corresponding ether derivative was obtained. Hydrolysis of this derivative and subsequent treatment of the reaction mixture were conducted in a similar manner to that described in Preparation 7 to give the title compound as a viscous substance.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[C:15]([CH:16]=[CH2:17])=[N:14][N:13]([CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:8]=2[N:9]=[C:10](Cl)[CH:11]=1)=[O:5])C.[OH:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[OH:24][C:25]1[CH:30]=[CH:29][C:28]([C:10]2[CH:11]=[C:6]([C:4]([OH:3])=[O:5])[C:7]3[C:15]([CH:16]=[CH2:17])=[N:14][N:13]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:8]=3[N:9]=2)=[CH:27][CH:26]=1
Reactant: C=Cc1nn(C2CCCCO2)c2nc(Cl)cc(C(=O)OCC)c12
Reactant: OB(O)c1ccc(O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Yield: 143.7 %

Procedure:
To a solution of 6-chloro-1-(tetrahydro-pyran-2-yl)-3-vinyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid ethyl ester (2.00 g, 5.96 mmol), described in example 16.1, in dioxane (54 mL) were added 4-hydroxyphenylboronic acid (0.90 g, 6.55 mmol) and an aqueous solution of cesium carbonate (0.4 M, 27 mL, 10.8 mmol). The resulting solution was degassed using argon, tetrakis(triphenylphosphine)palladium (0.62 g, 0.54 mmol) was then added and the reaction mixture was refluxed overnight. Dioxane was removed under vacuum, water was added and then the mixture was acidified to pH=2. The aqueous phase was extracted with a mixture of tetrahydrofuran and EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered, concentrated under vacuum to give the title compound (3.13 g) as a brown foam which was used without further purification.
Reaction SMILES: F[C:2]1(C)[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH2:3]1.[N:12]1([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[N+:8]([C:4]1[CH:3]=[C:2]([N:15]2[CH2:14][CH2:13][N:12]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][CH2:16]2)[CH:7]=[CH:6][CH:5]=1)([O-:10])=[O:9]
Reactant: CC1(F)C=CC=C([N+](=O)[O-])C1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc([N+](=O)[O-])c2)CC1
Reaction time: 72 h
Yield: 413.6 %

Procedure:
5.0 g (3.54 mmol) of 1-fluoro-3-nitrotoluene, 9.89 g (5.31 mmol) of tert-butyl 1-piperazinecarboxylate and 27.0 g (19.5 mmol) of potassium carbonate are solubilized under an argon atmosphere in DMSO (60 ml), then the reaction medium is taken to 100° C. for 72 hours. The reaction medium is then cooled down using an ice bath then poured into ice-cold water. The product is extracted using 3 times 50 ml of dichloromethane. The organic solution is dried over magnesium sulphate, followed by filtration and concentration under vacuum. Purification on a silica column is then carried out (eluent=heptane 70%/ethyl acetate 30%) in order to produce a yellow solid. The yellow solid is further purified by recrystallization from diisopropyl ether in order to produce 4.5 g of the expected product (yield 42.0%). Melting point: 82.0-92.0° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([OH:13])[C@H:10]([OH:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CS(O[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])(=O)=O.O>CS(C)=O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([O:13][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35])[C@H:10]([O:14][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH3:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)C[C@H]1O
Reactant: CCCCCCCCCCCCCCOS(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCCCCCCCCCCCCCO[C@@H]1CN(Cc2ccccc2)C[C@H]1OCCCCCCCCCCCCCC
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
(3R,4R)-1-Benzylpyrrolidine-3,4-diol (Diverchim S. A.; 150 mg, 0.776 mmol) was dissolved in dimethylsulfoxide (4 mL). After adding potassium hydroxide (348 mg, 6.21 mmol), the solution was stirred at 100° C. for 15 minutes. The reaction solution was further stirred at 100° C. for 4 hours after adding a dimethylsulfoxide (4 mL) solution of tetradecyl methanesulfonate (Nu-Chek Prep., Inc.; 568 mg, 1.94 mmol). The mixture was cooled to room temperature, and, after adding water, the aqueous layer was extracted with ethyl acetate. The organic layer was washed with water and a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure after filtration. The resulting residue was purified by silica gel column chromatography (chloroform 100%) to give compound VI-5 (449 mg, 98.6%).
Reaction SMILES: Cl.[NH2:2]O.[CH:4]1([C:7](=[O:18])[C:8](=[CH:14]OCC)[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5]1>C(O)C>[CH:4]1([C:7]2[O:18][N:2]=[CH:14][C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:6][CH2:5]1
Reactant: CCOC=C(C(=O)OCC)C(=O)C1CC1
Reactant: NO
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cnoc1C1CC1
Yield: 57.7 %

Procedure:
A mixture of hydroxylamine hydrochloride (105.0 g. 1.51 mole), ethyl β-cyclopropyl-α-ethoxymethylene-β-ketopropionate (320.0 g., 1.51 mole) [prepared in Step A], and 1200 ml of ethanol was refluxed for 2 h. The solvent was removed in vacuo and the residue was partitioned between water and ether. The organic phase was separated, washed again with water, dried and evaporated to leave a dark, greasy solid. Trituration of the crude product under Skellysolve B gave 158 g of the title compound.
Reaction SMILES: [C-:1]#[N:2].[Na+].[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH2:8]Cl>O.C(O)C>[CH3:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[CH3:13])[CH2:8][C:1]#[N:2]
Reactant: [C-]#N
Reactant: Cc1ccc(CCl)cc1C
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1ccc(CC#N)cc1C
Temperature: 25 °C
Yield: 79 %

Procedure:
To a solution of 6.8 g of 90% sodium cyanide dissolved in 6.5 ml of distilled water while being subjected to heating was added a solution of 15.5 g of 3,4-dimethylbenzyl chloride in 20 ml of dry ethanol; and the resultant mixture was heated at the boiling temperature for 10 hours and then cooled to room temperature. This solution was added to 50 ml of distilled water and extracted twice with 150 ml of ethyl ether. The organic solvent was removed to obtain 11.5 g(yield 79%) of 3,4-dimethylbenzyl cyanide, which was dissolved in 50 ml of dry tetrahydrofuran. The organic solution was slowly added to a dispersion of 6.0 g of LiALH4 suspended in 150 ml of dry tetrahydrofuran; and the mixture was heated at the boiling point for 14 hours. This reaction mixture was cooled to room temperature; and 16 ml of 1N NaOH and 8 ml of distilled water were slowly added thereto. Thereafter, this reaction mixture was filtered through a Celite layer to obtain solids, which were dissolved in a mixture of 250 ml of ethyl ether and 250 ml of ethyl alcohol and filtered. After the filtrate was basified with 5N NaOH aqueous solution and extracted with dichloromethane(200 ml×2), the solvent was evaporated and distilled under reduced pressure to provide 5.6 g(yield 48%) of the title compound.