Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1N2CN3CN(C2)CN1C3.C1CCN2C(=NCCC2)CC1.[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH2:41][C@@H:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]>C(Cl)Cl>[C:22]([O:26][C:27](=[O:49])[CH2:28][C@H:29]([C:39]1[O:40][CH:41]=[C:42]([C:44]([O:46][CH2:47][CH3:48])=[O:45])[N:43]=1)[CH2:30][CH2:31][CH2:32][CH:33]1[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1)([CH3:25])([CH3:24])[CH3:23]
Reactant: CCOC(=O)[C@@H]1COC([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)=N1
Agent: C1N2CN3CN1CN(C2)C3
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reaction time: 0.08 h

Procedure:
A suspension of CuBr2 (20.88 g, 93.5 mmol) and HMTA (13.1 g, 93.5 mmol) in degassed DCM (250 ml) was treated with DBU (14.0 ml, 93.5 mmol) and the dark solution formed was stirred in a water bath for 5 minutes. A solution of ethyl (4S)-2-[(1R)-1-(2-tert-butoxy-2-oxoethyl)-4-cyclohexylbutyl]-4,5-dihydro-1,3-oxazole-4-carboxylate (preparation 152) (9.24 g, 23.4 mmol) in degassed DCM (30 ml) was added dropwise to the reaction mixture and stirred at room temperature for a further 3 hours. The solvent was removed under reduced pressure. The resdue was dissolved in EtOAc and washed with a 1:1 solution of NH3(aq):NH4Cl. The aqueous extract was washed with EtOAc (2×380 ml). The combined organic extracts were washed with 2M HCl (500 ml), sat. NaHCO3 (500 mL) and brine (500 ml). The organic extracts were dried over anhydrous MgSO4 and filtered. The solvent was removed under reduced pressure. The crude material was purified on a silica column eluting with a solvent gradient of EtOAc:pentane (0:100) gradually changing to (25:75) to afford the title compound as colourless oil which formed needles on standing (7.39 g, 80%).
Reaction SMILES: [NH2:1][C@@H:2]1[C@@H:6]([C:7]([OH:9])=[O:8])[O:5][C@@H:4]([N:10]2[CH:18]=[N:17][C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C:20](=[O:27])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C@@H:3]1[OH:28].[C:29](Cl)(=[O:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[C:20]([NH:19][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[C:16]=1[N:17]=[CH:18][N:10]2[C@@H:4]1[O:5][C@H:6]([C:7]([OH:9])=[O:8])[C@@H:2]([NH:1][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:3]1[OH:28])(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: N[C@H]1[C@@H](O)[C@H](n2cnc3c(NC(=O)c4ccccc4)ncnc32)O[C@@H]1C(=O)O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@H](C(=O)O)[C@@H](NC(=O)c2ccccc2)[C@H]1O)c1ccccc1
Yield: 39.3 %

Procedure:
1-(6-Benzoylamino-9H-purin-9-yl)-3-benzoylamino-1,3-dideoxy-β-D-ribofuranuronic acid (125 mg) was prepared by reacting 1-(6-benzoylamino-9H-purin-9-yl)-1,3-dideoxy-3-amino-β-D-ribofuranuronic acid (250 mg) prepared in Example 1 with benzoyl chloride (110 mg) according to a similar manner to that of Example 17, mp. 112°-118° C. (dec.).
Reaction SMILES: [CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][C:4]([OH:6])=O.[CH2:23]([CH2:25][NH2:26])[OH:24]>>[CH3:1][C:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:22])[CH2:11][CH2:12][CH2:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[CH:3][C:4]([NH:26][CH2:25][CH2:23][OH:24])=[O:6]
Reactant: CC(=CC(=O)O)CCCC(C)CCCC(C)CCCC(C)C
Reactant: NCCO
Product: CC(=CC(=O)NCCO)CCCC(C)CCCC(C)CCCC(C)C
Yield: 95 %

Procedure:
The procedure of Example 1 was repeated except that 6.2 g of 3,7,11,15-tetramethyl-2-hexadecenoic acid and 1.8 ml of ethanolamine were used as starting materials. 6.7 g (yield 95%) of the title compound was obtained as a colorless oil.
Reaction SMILES: COCCN(S(F)(F)[F:11])CCOC.[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24]O)=[N:19][C:18]=1[NH2:26]>ClCCl>[CH3:14][O:15][C:16](=[O:27])[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][F:11])=[N:19][C:18]=1[NH2:26]
Reactant: COC(=O)c1ccc(CCO)nc1N
Reactant: COCCN(CCOC)S(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(CCF)nc1N
Yield: 7.8 %

Procedure:
A solution of (bis(2-methoxyethyl)amino)sulfur trifluoride (2.39 g, 10.8 mmol) in dichloromethane (30 mL) was cooled with a dry ice-methanol bath, and 2-amino-6-(2-hydroxyethyl)-nicotinic acid methyl ester (50 mg, 0.255 mmol) was added thereto dropwise. After dropwise addition the cold bath was immediately removed, and the solution was gradually allowed to room temperature. Water and ethyl acetate were added to the reaction solution, which was then partitioned. The organic layer was separated, the solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography, and the title compound (4 mg, 0.020 mmol, 7.9%) was obtained as a white solid.
Reaction SMILES: F[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N+:12]([O-])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]([C:19]1[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][N:20]=1)=[O:18].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl.[Pd]>[CH3:15][O:16][C:17]([C:19]1[CH:24]=[C:23]([O:25][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]([NH2:12])=[CH:4][CH:3]=2)[CH:22]=[CH:21][N:20]=1)=[O:18]
Reactant: O=[N+]([O-])c1ccc(F)c2ccccc12
Reactant: COC(=O)c1cc(O)ccn1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Oc2ccc(N)c3ccccc23)ccn1
Temperature: 100 °C
Reaction time: 5 h
Yield: 51.9 %

Procedure:
To a solution of 1-fluoro-4-nitro-naphthalene (1.0 g, 5.24 mmol) in dry DMF (22 mL) was added 4-hydroxy-pyridine-2-carboxylic acid methyl ester (0.993 g, 5.24 mmol) and K2CO3 (7.24 g, 52.4 mmol). The resulting yellow suspension was stirred at 100° C. under argon for five h. After cooling to room temperature, the solution was diluted with CH2Cl2 (62 mL) and 10% Pd/C (1 g) was added. The suspension was stirred under a H2 balloon for 72 h. The reaction was then filtered through a plug of diatomaceous earth and rinsed with EtOAc (150 mL) and extracted with H2O (3×100 mL), brine (1×100 mL) and dried over MgSO4. The solvent was removed via rotary evaporation and the resulting oil was applied to a flash silica column eluting with MeOH:CH2Cl2 (2:98) to provide the title compound (800 mg, 52%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:13][CH3:14])=[N:4][C:5]2[C:10]([N:11]=1)=[CH:9][C:8]([F:12])=[CH:7][CH:6]=2.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].N1C=CC=CC=1>ClCCl>[F:12][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]=[C:3]([O:13][CH3:14])[C:2]([NH:1][C:16](=[O:17])[O:18][CH2:19][CH3:20])=[N:11]2
Reactant: CCOC(=O)Cl
Reactant: COc1nc2ccc(F)cc2nc1N
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1nc2cc(F)ccc2nc1OC
Temperature: 25 °C
Reaction time: 10 h
Yield: 93 %

Procedure:
3-Amino-6-fluoro-2-methoxyquinoxaline (580 mg, 3.00 mmol) and ethyl chloroformate (391 mg, 3.60 mmol) were dissolved in dichloromethane (50 ml) at room temperature and thereto pyridine (285 mg, 3.60 mmol) was added. The mixture was stirred at room temperature for 10 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (3:1) mixture and concentration gave 740 mg of the titled compound (yield, 93%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][NH2:15]>>[S:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[CH2:14][NH:15][CH:5]1[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]1
Reactant: NCc1cccs1
Reactant: CN1CCC(=O)CC1
Product: CN1CCC(NCc2cccs2)CC1

Procedure:
1-Methyl-4-piperidone (0.5 g, 4.4 mmol, 1.0 eq.), 2-thienylmethylamine (0.52 g, 1.0 eq.).
Reaction SMILES: [NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3].C1C2C(COC([NH:23][CH2:24][P:25]([OH:50])([O:27][CH:28]([C:31]3[CH:47]=[C:46]4[N:34]([CH2:35][C:36]5[C:37]4=[N:38][C:39]4[C:44]([CH:45]=5)=[CH:43][CH:42]=[CH:41][CH:40]=4)[C:33](=[O:48])[C:32]=3[CH3:49])[CH2:29][CH3:30])=[O:26])=O)C3C(=CC=CC=3)C=2C=CC=1>O>[NH2:23][CH2:24][P:25]([OH:50])([O:27][CH:28]([C:31]1[CH:47]=[C:46]2[N:34]([CH2:35][C:36]3[C:37]2=[N:38][C:39]2[C:44]([CH:45]=3)=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:33](=[O:48])[C:32]=1[CH3:49])[CH2:29][CH3:30])=[O:26].[NH:1]([CH2:4][CH3:5])[CH2:2][CH3:3]
Reactant: CCC(OP(=O)(O)CNC(=O)OCC1c2ccccc2-c2ccccc21)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Solvent: CCNCC
Solvent: O
Product: CCC(OP(=O)(O)CN)c1cc2n(c(=O)c1C)Cc1cc3ccccc3nc1-2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of Et2NH (10 mL) and (±)-7-[1-[[[[[(9-fluorenylmethoxy)carbonyl]amino]methyl]hydroxyphosphinyl]oxy]propyl]-8-methylindolizino[1,2-b]quinolin-9(11H)-one (328 mg, 0.51 mmol) was stirred at room temperature in a capped vial for 3 h. The reaction mixture was stripped to dryness, and H2O was added. The this partial solution was extracted with EtOAc, filtered and lyophilized to give a viscous oil which was triturated with CH3CN to produce a golden solid. The solid was dissolved in H2O and lyophilized to give the title compound as a partial Et2NH salt. 1H NMR (CDCl3 /MeOH-d4) d 8.49 (s, 1H), 8.12 (d, J=8.7 Hz, 1H), 8.00 (d, J=8.3 Hz, 1H), 7.84 (m, 1H), 7.69 (overlapping s and m, 2H), 5.59 (dd, J=14.9, 6.5 Hz, 1H), 5.27 (s, 2H), 2.98 (q, J=7.2 Hz, ~1.1H), 2.85 (dd, J=12.7, 2.6 Hz, 2H), 2.31 (s, 3H), 2.02-1.83 (m, 2H), 1.31 (t, I=7.3 Hz, ~1.8H), 1.05 (t, J=7.4 Hz, 3H). Anal. Calcd for C20H22N3O4P.1/4 C4H11N.5 H2O: C, 49.68; H, 6.90; N, 8.97. Found: C, 50.08; H, 6.49; N, 8.46.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:25]=[CH:24][C:15]([C:16]([N:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)=[O:17])=[CH:14][CH:13]=2)=[N:2]1.[CH:26]([O:29][C:30]1[C:31](=O)[C:32](=[O:38])[C:33]=1[O:34]C(C)C)([CH3:28])[CH3:27].C(N(CC)CC)C>CO>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:13]=[CH:14][C:15]([C:16]([N:18]3[CH2:23][CH2:22][N:21]([C:31]4[C:32](=[O:38])[C:33](=[O:34])[C:30]=4[O:29][CH:26]([CH3:28])[CH3:27])[CH2:20][CH2:19]3)=[O:17])=[CH:24][CH:25]=2)=[N:2]1
Reactant: O=C(c1ccc(/C=C/c2n[nH]c3ccccc23)cc1)N1CCNCC1
Reactant: CC(C)Oc1c(OC(C)C)c(=O)c1=O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)Oc1c(N2CCN(C(=O)c3ccc(/C=C/c4n[nH]c5ccccc45)cc3)CC2)c(=O)c1=O
Temperature: 25 °C
Reaction time: 13 h
Yield: 79.9 %

Procedure:
(E)-1-{4-[2-(1H-indazol-3-yl)vinyl]benzoyl}piperazine (1.0 g, 2.5 mmol) obtained in Example 18 was dissolved in methanol (9.9 mL), and the solution was added with 3,4-diisopropoxy-3-cyclobutene-1,2-dione (0.69 g, 3.5 mmol) and triethylamine (0.69 mL, 4.9 mmol), followed by stirring at room temperature for 13 hours. The reaction mixture was concentrated under reduced pressure, and the crude product was added with ethanol, followed by stirring. The deposited crystal was collected by filtration to obtain (E)-3-{4-[4-(2-(1H-indazol-3-yl)vinyl)benzoyl]piperazin-1-yl}-4-isopropoxy-3-cyclobutene-1,2-dione (0.94 g, 81%).
Reaction SMILES: C([O:8][C@H:9]1[CH2:15][C@@H:14]([O:16][CH3:17])[C:13]2([CH2:19][CH3:20])[O:18][C@@H:10]1[CH2:11][O:12]2)C1C=CC=CC=1.C(O)(=O)C.[H][H]>C(O)C.[Pd]>[CH2:19]([C:13]12[O:18][C@H:10]([CH2:11][O:12]1)[C@@H:9]([OH:8])[CH2:15][C@H:14]2[O:16][CH3:17])[CH3:20]
Reactant: [H][H]
Reactant: CCC12OC[C@@H](O1)[C@@H](OCc1ccccc1)C[C@H]2OC
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: CCC12OC[C@@H](O1)[C@@H](O)C[C@H]2OC

Procedure:
A solution of (1R,2S,4R)-2-benzyloxy-5-ethyl-4-methoxy-6,8-dioxabicyclo[3.2.1]octane (see Example 15.2) (3.4 g) in absolute ethanol (150 ml) containing acetic acid (2 ml) and 5% palladium on barium sulphate (1 g) was shaken in a hydrogen atmosphere at 40 p.s.i for 24 h, and then the solution was filtered and the solvent was removed. Chromatography of the residue on silica gel gave the title alcohol; m.p. 52°-53° C.; [α]D -97.1°; 13C nmr data: 108.2 (C-5), 78.7 and 78.0 (C-1 and C-4), 66.9 (C-2), 66.3 (C-7), 57.6 (OCH3), 27.0 and 26.0 (C-3 and CH2CH3), and 6.4 (CH2CH3).
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH2:18])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17].[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C(Cl)Cl>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH:7]([CH3:9])[CH3:8])[C:3]=1[C:10]1[CH:11]=[C:12]([NH:18][C:27]([NH:26][C:23]2[CH:24]=[CH:25][C:20]([F:19])=[CH:21][CH:22]=2)=[O:28])[CH:13]=[CH:14][C:15]=1[O:16][CH3:17]
Reactant: O=C=Nc1ccc(F)cc1
Reactant: COc1ccc(N)cc1-c1c(Br)cnn1C(C)C
Solvent: ClCCl
Product: COc1ccc(NC(=O)Nc2ccc(F)cc2)cc1-c1c(Br)cnn1C(C)C
Reaction time: 8 h
Yield: 32.1 %

Procedure:
To a solution of 3-(4-bromo-2-isopropyl-2H-pyrazol-3-yl)-4-methoxy-phenylamine (0.08 g, 0.258 mmol) in CH2Cl2, was added 4-fluoro phenyl isocyanate (0.036 g, 0.263 mmol) and stirred overnight. The resulting precipitate was filtered and washed with methylene chloride/hexane (1:1), and dried in vacuo to yield Compound 50 as a colorless solid (0.037 g, 32%). LCMS m/z (%)=449 M+H+ (81Br, 58), 447 M+H+ (79 Br, 63), 1H NMR (400 MHz, CDCl3) δ: 7.5 (s, 1H), 7.346 (d, 1.95 Hz, 2H), 7.326 9bs, 1H), 7.151 (d, J=4.77 Hz, 1H), 7.124 (t, 1H), 6.995 (d, J=1.87 Hz, 2H), 6.869 (d, J=5.42 Hz, 1H), 6.847 (d, J=4.71 Hz, 1H), 4.045 (m, 1H), 3.651 (s, 3H), 1.333 (d, J=6.61 Hz, 3H), 1.160 (d, J=6.61 Hz, 3H).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH3:24])=[N:8][C:9]2[C:14]([C:15]=1[NH2:16])=[C:13]([O:17][CH2:18][CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:12]=[CH:11][CH:10]=2)=[O:5])C.[OH-].[Na+]>CCO>[NH2:16][C:15]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][C:13]=2[O:17][CH2:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[N:8]=[C:7]([CH3:24])[C:6]=1[C:4]([OH:5])=[O:3]
Reactant: CCOC(=O)c1c(C)nc2cccc(OCC3CCCC3)c2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc2cccc(OCC3CCCC3)c2c(N)c1C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
To a solution of ethyl-4-amino-5-(cyclopentylmethoxy)-2-methylquinoline-3-carboxylate (Example 18a, 16.8 g, 51.2 mmol) in EtOH (100 mL) was added NaOH (2 N, 64 mL) at room temperature. The reaction mixture was refluxed for 4 h. After it was cooled down to room temperature, the reaction solution was filtered to remove any possible solid residue. The filtrate was carefully neutralized with 2N HCl to pH 7 at 0° C. The resultant precipitate was collected by filtration, washed with water, re-dissolved in EtOH (500 mL) and water (30 mL), and treated with activated charcoal (650 mg) at 70° C. for 0.5 h. The charcoal was removed by filtration, and the filtrate was concentrated and stored at 4° C. overnight. The resulting precipitate was collected by filtration, washed with cold 25% EtOH in H2O, and dried under vacuum at 60° C. overnight to give the title compound as an off-white solid (7.5 g, 49%). 1H NMR (400 MHz, DMSO-d6) δ 1.31-1.37 (m, 2H), 1.53-1.64 (m, 4H), 1.79-1.85 (m, 2H), 2.47-2.50 (m, 1H), 2.75 (s, 3H), 4.11 (d, J=8.8 Hz, 2H), 7.03 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.4 Hz, 1H), 7.66 (t, J=8.0 Hz, 1H), 8.77 (brs, 1H), 12.26 (brs, 1H), 12.75 (brs, 1H). 1H NMR (400 MHz, CD3OD) δ 1.39-1.49 (m, 2H), 1.63-1.77 (m, 4H), 1.91-1.98 (m, 2H), 2.51-2.61 (m, 1H), 2.78 (s, 3H), 4.16 (d, J=8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.72 (t, J=8.0 Hz, 1H). MS 301 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:7][C:8](Cl)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2].[SH:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[S:7][C:8]([S:15][C:16]2[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=2)=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)=[O:5])[CH3:2]
Reactant: Oc1ccc(S)cc1
Reactant: CCOC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(O)cc2)s1
Temperature: 25 °C

Procedure:
The product from Example 351A (1 equiv) and 4-mercaptophenol (1 equiv) were dissolved in dimethylformamide and cesium carbonate (5 equiv) added. The resultant mixture was stirred at 80° C. for 2.5 hours, cooled to room temperature and water added. The solution was extracted with ethyl acetate, the organic extracts dried and concentrated under vacuum to provide the title product.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[N:13]=[C:12]3[N:14]([CH3:18])[N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][C:9]=2[CH:19]=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[CH2:28][NH2:29].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[F:23][C:24]([F:37])([F:38])[C:25]1[CH:26]=[C:27]([CH:30]=[C:31]([C:33]([F:36])([F:34])[F:35])[CH:32]=1)[CH2:28][NH:29][CH2:19][C:9]1[CH:10]=[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH3:18])[C:12]2=[N:13][C:8]=1[N:7]([CH2:6][CH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:21][CH3:22]
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: CCN(CC1CCCC1)c1nc2c(cc1C=O)c(C)nn2C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCN(CC1CCCC1)c1nc2c(cc1CNCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c(C)nn2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
A mixture of 6-(cyclopentylmethyl-ethyl-amino)-1,3-dimethyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (5.3 g, 17.0 mmol) and 3,5-bis-trifluoromethylbenzylamine (4.7 g, 0.019 mol) in MeOH and acetic acid (2 drops) was stirred at RT for 30 min. After cooling to 0° C., sodium cyanoborohydride (2.2 g, 35.0 mmol) was added slowly over a period of about 10 min. After stirring at RT for 30 min, the reaction mixture was concentrated in vacuo. Water (50 mL) was added to the residue and stirred for 30 min. The solid was filtered off, washed with water followed by petroleum ether, and dried in vacuo to yield colorless solid (72%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:21]=[CH:20][C:17](C=O)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:30])C=1.C(=O)([O-])O.[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:21]=[CH:20][C:17]([OH:30])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C=O)cc2)C1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)cc2)C1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 73 %

Procedure:
To a solution of 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)benzaldehyde (500 mg) in methylene chloride (10 ml) was added 70% 3-chloroperbenzoic acid (712 mg) with ice-cooling, and the mixture was stirred at room temperature for 4.5 hours. After completion of the reaction, aqueous sodium hydrogencarbonate solution and aqueous sodium thiosulfate solution were added, and the mixture was extracted with methylene chloride and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was dissolved in methanol (3.4 ml) and thereto was added 1N aqueous sodium hydroxide solution (1.7 ml), and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, 10% aqueous citric acid solution was added, and the mixture was extracted with chloroform and washed successively with water and saturated brine. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained solid was washed with diethyl ether and dried under reduced pressure to give the title compound (350 mg).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][NH:22][C:23](=O)[O:24]C3C=CC=CC=3)=[CH:16][CH:15]=2)[N:3]=1.[CH3:32][C:33]1[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=1>>[CH3:1][C:2]1[C:6]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[C:5]([CH3:13])[N:4]([C:14]2[CH:15]=[CH:16][C:17]([CH2:20][CH2:21][NH:22][C:23]([NH:42][S:39]([C:35]3[CH:36]=[CH:37][CH:38]=[C:33]([CH3:32])[CH:34]=3)(=[O:41])=[O:40])=[O:24])=[CH:18][CH:19]=2)[N:3]=1
Reactant: Cc1nn(-c2ccc(CCNC(=O)Oc3ccccc3)cc2)c(C)c1-c1ccccc1
Reactant: Cc1cccc(S(N)(=O)=O)c1
Product: Cc1cccc(S(=O)(=O)NC(=O)NCCc2ccc(-n3nc(C)c(-c4ccccc4)c3C)cc2)c1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 22 from phenyl 2-[4-(3,5-dimethyl-4-phenyl-1H-pyrazol-1-yl)phenyl]ethylcarbamate (step 1 of Example 22) and 3-methylbenzenesulfonamide: 1H-NMR (CDCl3) δ 7.72-7.66 (2H, m), 7.46-7.22 (11H, m), 6.45 (1H, br.s), 3.48-3.45 (2H, m), 2.86-2.81 (2H, m), 2.39 (3H, s), 2.32 (3H, s), 2.25 (3H, s).
Reaction SMILES: [NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([OH:9])=O.[NH:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13].C(N(CC)CC)C>C(Cl)Cl>[NH:1]1[C:5](=[O:6])[CH2:4][CH2:3][C@H:2]1[C:7]([N:10]1[CH2:16][CH2:15][CH2:14][C@H:11]1[CH2:12][OH:13])=[O:9]
Reactant: OC[C@@H]1CCCN1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CC[C@@H](C(=O)N2CCC[C@H]2CO)N1
Temperature: 25 °C
Reaction time: 3 h
Yield: 23.3 %

Procedure:
L-pyroglutamic acid (100 g, 0.775 mol), L-prolinol (78.3 g, 0.775 mol) and triethylamine (322 ml) are dissolved in methylene chloride (2.5 l), and a solution of DMC (196.5 g, 1.163 mol) in methylene chloride (600 ml) is added dropwise over a period of forty minutes under water-cooling. The mixture is stirred for a further 3 hours at room temperature, and the reaction liquid is filtered to remove insolubles. The filtrate is concentrated to dryness under reduced pressure, and the residue is crystallized from dioxane-ether to give L-pyroglutamyl-L-prolinol (38.4 g, 23.3%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][N:2]=1.[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14]Cl.[S:20]([O-:24])([OH:23])(=[O:22])=[O:21].C(O)(C)C>C(#N)C>[S:20]([O-:24])([OH:23])(=[O:22])=[O:21].[Cl:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[CH2:14][N+:2]1[CH2:3][CH2:4][C:5]2[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:1]=1
Reactant: ClCc1ccccc1Cl
Reactant: C1=NCCc2ccccc21
Agent: O=S(=O)([O-])O
Solvent: CC(C)O
Solvent: CC#N
Product: Clc1ccccc1C[N+]1=Cc2ccccc2CC1

Procedure:
The title compound is prepared analogously to Example A from 3,4-dihydroisoquinoline and 2-chlorobenzyl chloride in acetonitrile. The melting point of the hydrogensulphate is 190°-192° C. (from isopropanol).
Reaction SMILES: [N:1]1([CH:7]=[CH:8][CH:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH3:10])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6].[H][H]>[Pd].C(O)(=O)C>[N:1]1([CH2:7][CH2:8][CH:9]([N:11]2[CH2:15][CH2:14][CH2:13][C:12]2=[O:16])[CH3:10])[CH2:5][CH2:4][CH2:3][C:2]1=[O:6]
Reactant: CC(C=CN1CCCC1=O)N1CCCC1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(CCN1CCCC1=O)N1CCCC1=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
60 g of 1,3-bis-(1-pyrrolidonyl)butene, 1000 ml of glacial acetic acid and 10 g of 10% palladium on carbon were mixed under inert gas. Subsequently, hydrogen was passed in while stirring at room temperature. The hydrogen uptake was complete after about 30 min. Reaction was allowed to continue at room temperature for a further 90 min. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The oily crude product was subsequently distilled under reduced pressure.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH2:4]1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:17][S:18]([O:1][CH2:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH:5]([NH:9][C:10]([O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[O:16])[CH2:4]1)(=[O:20])=[O:19]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NC1CCCC(CO)C1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1CCCC(COS(C)(=O)=O)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl 3-(hydroxymethyl)cyclohexylcarbamate (7.9 mmol), methanesulfonyl chloride (23.7 mmol) and triethylamine (119 mmol) in DCM (100 ml) was stirred at rt overnight. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (3×100 mL). The extracts were combined, dried using anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was progressed to the next step without purification.