Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:35]([S:37]([NH2:40])(=[O:39])=[O:38])[CH3:36]>>[CH3:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:40][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 27.4 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.061 g, 0.14 mmol) obtained in step 2 and ethanesulfonamide (0.073 g, 0.70 mmol), the title compound (0.021 g, 27%) was obtained.
Reaction SMILES: [CH:1]1([N:4]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][C:21](OC)=[O:22])[CH2:16][CH2:15]2)[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH:1]1([N:4]([C@H:14]2[CH2:19][CH2:18][C@H:17]([CH2:20][CH2:21][OH:22])[CH2:16][CH2:15]2)[C:5](=[O:13])[C:6]2[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)C[C@H]1CC[C@H](N(C(=O)c2ccc(F)cc2)C2CC2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)N(C1CC1)[C@H]1CC[C@H](CCO)CC1

Procedure:
To a solution of methyl 2-(trans-4-(N-cyclopropyl-4-fluorobenzamido)cyclohexyl)acetate (0.100 g, 0.30 mmol) in THF (3 mL) was added lithium aluminum hydride (1.0 M solution in THF) (0.15 ml, 0.15 mmol) at 0° C. The reaction was quenched with saturated NH4Cl (10 mL) after 15 minutes. The mixture was extracted with EtOAc twice. The organic phase was dried over Na2SO4 and concentrated in vacuo. The crude product was purified by prep TLC eluting with 5% MeOH—CH2Cl2. The desired alcohol product was obtained as a white solid (52 mg). MS: 306 (M+1), C18H24FNO2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].C(=O)([O-])[O-].[Na+].[Na+].[N+:31]([O-])([N+]([O-])=O)=[O:32].CO>O1CCCC1.C(Cl)Cl.O>[Cl:1][CH2:2][CH2:3][N:4]([N:31]=[O:32])[C:5]([N:7]([CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=C(NCCCl)N(C1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Reactant: O=[N+]([O-])[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: O
Product: O=NN(CCCl)C(=O)N(C1CCCCC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 70.1 %

Procedure:
3.7 g of 1-(2-chloroethyl)-3-cyclohexyl-3-(D-galactopyranosyl) urea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is further stirred at the same temperature for 10 minutes. After the reaction, 10 ml of methanol and 3 ml of water are added to the mixture, and the aqueous mixture is stirred vigorously for 10 minutes. Said aqueous mixture is dried and filtered. The filtrate is evaporated to remove solvent. Then, the residue obtained is purified by silica gel chromatography (Solvent: ethyl acetate-chloroform-methanol (5:2:1)). 2.8 g of 1-(2-chloroethyl)-1-nitroso-3-cyclohexyl-3-(D-galactopyranosyl)urea are thereby obtained as yellow caramel.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([C:9]([O:11]C)=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2].C(O)C.[OH-].[Na+].Cl>CO.ClCCl.O>[C:1]([C:3]1[CH:8]=[C:7]([C:9]([OH:11])=[O:10])[CH:6]=[CH:5][C:4]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2ccccc2)c(C#N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Solvent: CO
Product: N#Cc1cc(C(=O)O)ccc1-c1ccccc1
Reaction time: 2 h
Yield: 96.4 %

Procedure:
To methyl 2-cyano-4-biphenylcarboxylate (D26) (935 mg, 3.94 mmol) was added ethanol (18 ml) but dissolution did not occur so dichloromethane (10 ml) was added. Sodium hydroxide (2 ml, 4.00 mmol) was then added and the reaction stirred for 2 h. To the mixture was added dichloromethane (20 mL) and 2M aqueous HCl (10 mL). The layers were separated and the aqueous extracted with further dichloromethane (20 mL). The combined organic phase was dried (phase separator) and the solvent removed in vacuo to give a white solid, which was dissolved in methanol (30 mL) and aqueous sodium hydroxide was added (2M, 3 mL). The reaction was stirred at room temperature for 1 h before addition of water (20 mL). The reaction was stirred for a further 1 h. Dichloromethane (60 mL) was added and the mixture shaken and the layers separated. The aqueous phase was extracted with further dichloromethane (50 mL) before the combined organic phase was dried (phase separator) and the solvent removed in vacuo to give the title compound as a white solid, (849 mg, 3.80 mmol). δH (d6-DMSO, 400 MHz): 13.60 (1H, br s), 8.38 (1H, d), 8.28 (1H, dd), 7.78 (1H, d), 7.63 (2H, m), 7.60-7.50 (3H, m). MS (ES): C14H9NO2 requires 223; found 222 (M−H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]23[CH2:19][CH2:18][C:15]([C:20]4[N:24]5[C:25]6[CH:31]=[CH:30][N:29](S(C7C=CC(C)=CC=7)(=O)=O)[C:26]=6[N:27]=[CH:28][C:23]5=[N:22][N:21]=4)([CH2:16][CH2:17]2)[CH2:14][CH2:13]3)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.C(OC(NC12CCC(C(O)=O)(CC1)CC2)=O)(C)(C)C.ClC1C=C(S(Cl)(=O)=O)C=CC=1.[OH-].[Na+]>O1CCOCC1>[C:20]1([C:15]23[CH2:16][CH2:17][C:12]([NH:11][S:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)(=[O:9])=[O:10])([CH2:19][CH2:18]2)[CH2:13][CH2:14]3)[N:24]2[C:25]3[CH:31]=[CH:30][NH:29][C:26]=3[N:27]=[CH:28][C:23]2=[N:22][N:21]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2nnc(C45CCC(NS(=O)(=O)c6cccc(Cl)c6)(CC4)CC5)n23)cc1
Agent: CC(C)(C)OC(=O)NC12CCC(C(=O)O)(CC1)CC2
Agent: O=S(=O)(Cl)c1cccc(Cl)c1
Agent: [Na+]
Solvent: C1COCCO1
Product: O=S(=O)(NC12CCC(c3nnc4cnc5[nH]ccc5n34)(CC1)CC2)c1cccc(Cl)c1
Temperature: 60 °C
Yield: 86 %

Procedure:
A 100 mL round-bottomed flask was charged with 3-chloro-N-(4-(6-tosyl-6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)benzenesulfonamide (0.14 g, 0.22 mmol, prepared using A from Preparation #9 and 4-(tert-butoxycarbonylamino)bicyclo-[2.2.2]octane-1-carboxylic acid [Prime Organics], C with TEA, I, and N from 3-chlorobenzenesulfonyl chloride) and 1,4-dioxane (5 mL) to give a tan suspension and then aqueous NaOH (1N, 0.45 mL, 0.45 mmol, J. T. Baker) was added. The suspension was heated at about 60° C. for about 3 h. The reaction mixture was cooled to ambient temperature and the solvents were removed under reduced pressure. Upon addition of NH4OAc (50 mM aqueous buffer solution), a solid precipitated that was collected by vacuum filtration, washed with water, and dried to give N-(4-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)bicyclo[2.2.2]octan-1-yl)-3-chlorobenzenesulfonamide as a white solid (0.088 g, 86%): LC/MS (Table 2, Method a) Rt=1.88 min; MS m/z: 457 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][C:21]3[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=3)=[CH:16][CH:15]=2)[CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[Cl:27][C:24]1[CH:25]=[CH:26][C:21]([O:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C@@H:10]3[CH2:11][CH2:12][NH:8][CH2:9]3)=[CH:15][CH:16]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(Oc3ccc(Cl)cc3)cc2)C1
Agent: Cl
Solvent: C1COCCO1
Product: Clc1ccc(Oc2ccc(O[C@@H]3CCNC3)cc2)cc1
Reaction time: 24 h
Yield: 46.4 %

Procedure:
(R)-3-[4-(4-Chloro-phenoxy)-phenoxy]-pyrrolidine-1-carboxylic acid tert-butyl ester (1 g, 2.56 mmol) was taken into 4N HCl in dioxane (10 mL), and the reaction was run at room temperature for 24 h. The mixture was concentrated to dryness, and the resulting oil was triturated with diethyl ether to obtain the title product (344 mg, 41%); LCMS, m/z 290 (M+1, free amine) 81% pure; 1H NMR (400 MHz, DMSO); δ 2.13-2.16 (m, 2H), 3.24-3.33 (m, 4H), 5.11 (s, 1H), 6.95 (d, J=8.8, 2H), 7.04 (s, 4H), 7.40 (d, J=8.8, 2H), 9.66 (s, 2H).
Reaction SMILES: C1(O[C:8](=[O:24])[NH:9][CH2:10][CH2:11][CH2:12][C:13]2[C:14]([O:22][CH3:23])=[N:15][C:16]([CH3:21])=[C:17]([CH2:19][CH3:20])[CH:18]=2)C=CC=CC=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH2:19]([C:17]1[CH:18]=[C:13]([CH2:12][CH2:11][CH2:10][NH:9][C:8]([N:36]2[CH2:35][CH2:34][N:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[O:26][CH3:25])[CH2:38][CH2:37]2)=[O:24])[C:14]([O:22][CH3:23])=[N:15][C:16]=1[CH3:21])[CH3:20]
Reactant: CCc1cc(CCCNC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCc1cc(CCCNC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 67 %

Procedure:
Phenyl-N-[3-(5-ethyl-2-methoxy-6-methylpyridin-3-yl)propyl]carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.[CH:25]([C:28]1[CH:29]=[C:30]([CH:42]=[CH:43][C:44]=1[O:45][CH3:46])[O:31][C:32]1[C:39]([Cl:40])=[CH:38][C:35](CO)=[CH:34][C:33]=1[Cl:41])([CH3:27])[CH3:26]>C(OCC)C>[Cl:40][C:39]1[CH:38]=[C:35]([CH:34]=[C:33]([Cl:41])[C:32]=1[O:31][C:30]1[CH:42]=[CH:43][C:44]([O:45][CH3:46])=[C:28]([CH:25]([CH3:26])[CH3:27])[CH:29]=1)[CH2:20][Br:24]
Reactant: COc1ccc(Oc2c(Cl)cc(CO)cc2Cl)cc1C(C)C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: COc1ccc(Oc2c(Cl)cc(CBr)cc2Cl)cc1C(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.2 %

Procedure:
To a stirred solution of triphenylphosphine (0.42 g, 1.61 mmol) and CBr4 (0.534 g, 1.61 mmol) in diethyl ether (15.0 mL) at room temperature was added 4-(3′-iso-propyl-4′-methoxyphenoxy)-3,5-dichlorobenzyl alcohol (0.50 g, 1.46 mmol). The reaction mixture was stirred at room temperature for 16 h, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel, eluting with acetone-hexanes (1:9) to afford 3,5-dichloro-4-(3′-iso-propyl-4′-methoxyphenoxy)benzyl bromide (0.320 g, 54%): 1H NMR (300 MHz, DMSO-d6): δ 7.77 (s, 2 H), 6.82 (m, 2 H), 6.38 (m, 1 H), 4.75 (s, 2 H), 3.75 (s, 3 H), 3.22 (m, 1 H), 1.13 (d, J=6.0 Hz, 6 H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=hexanes-acetone (1:4); Rf=0.46.
Reaction SMILES: C([O:4][CH2:5][C:6]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1)=[N:15][C:14]([Cl:29])=[CH:13][CH:12]=2)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:29][C:14]1[N:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]=[CH:9][C:8]([C:6](=[O:7])[CH2:5][OH:4])=[C:17]2[NH:18][C@H:19]1[CH2:24][CH2:23][C@H:22]([CH2:25][N:26]([CH3:28])[CH3:27])[CH2:21][CH2:20]1
Reactant: CC(=O)OCC(=O)c1cnc2ccc(Cl)nc2c1N[C@H]1CC[C@H](CN(C)C)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: CN(C)C[C@H]1CC[C@H](Nc2c(C(=O)CO)cnc3ccc(Cl)nc23)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(6-chloro-4-{trans-4-[(dimethylamino)methyl]cyclohexylamino}-1,5-naphthyridin-3-yl)-2-oxoethyl acetate (90 mg, 0.22 mmol) in methanol was added freshly ground potassium carbonate (90 mg, 0.65 mmol) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with satd. aq. sodium bicarbonate and extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the desired product (18 mg, 22%) as a yellow solid. ESI MS m/z 377 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:13][CH2:12][C:9]([C:14]3[NH:22][C:21]4[C:20](=[S:23])[NH:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:8][CH2:7]2.[OH-].[Na+].[CH3:31]CO>O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][CH2:5][C:6]12[CH2:7][CH2:8][C:9]([C:14]3[NH:22][C:21]4[C:20]([S:23][CH3:31])=[N:19][C:18](=[O:24])[N:17]([CH2:25][CH2:26][CH3:27])[C:16]=4[N:15]=3)([CH2:10][CH2:11]1)[CH2:12][CH2:13]2
Reactant: CCCn1c(=O)[nH]c(=S)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Reactant: CCO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCn1c(=O)nc(SC)c2[nH]c(C34CCC(CCC(=O)OC)(CC3)CC4)nc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-[4-(2-Oxo-3-propyl-6-thioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)-bicyclo[2.2.2]oct-1-yl]-propionic acid methyl ester (100 mg) was dissolved in 2 mL of EtOH and 1 mL of H2O. NaOH (20 mg) was added as a solution in 1 mL of H2O, followed by Mel (23 uL, 1.5 eq). The resulting reaction mixture was stirred at rt for 30 min. It was then extracted with EtOAc. The organic layer was dried (Na2SO4) and concentrated under reduced pressure to afford 105 mg of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[CH3:12].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:13]([O:8][C:5]1[C:4]([N+:9]([O-:11])=[O:10])=[C:3]([CH3:12])[C:2]([Cl:1])=[CH:7][CH:6]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(Cl)ccc(O)c1[N+](=O)[O-]
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Cc1c(Cl)ccc(OCc2ccccc2)c1[N+](=O)[O-]
Yield: 99.9 %

Procedure:
A mixture of 1.50 g (8.00 mmols) of 4-chloro-3-methyl-2-nitrophenol, 1.50 g (8.80 mmols) of benzyl bromide, 2.43 g (17.6 mmols) of potassium carbonate and 70 ml of acetone was refluxed for 2 hours. Thereafter insoluble matters were filtered off and the filtrate was concentrated under reduced pressure. The residue was isolated and purified by silica gel column chromato- graphy to give 2.22 g (>99%) of 3-benzyloxy-6-chloro-2-nitrotoluene.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][C:6]=1[N+:14]([O-])=O>[Pd].CCO>[NH2:11][C:8]1[CH:7]=[C:6]2[C:5]([CH2:4][C:3](=[O:2])[NH:14]2)=[CH:10][CH:9]=1
Reactant: COC(=O)Cc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2c(c1)NC(=O)C2

Procedure:
An EtOH solution of (2,4-dinitro-phenyl)-acetic acid methyl ester was treated with H2 balloon and catalyzed with Pd/c (10%, 500 mg) at RT. The resulting mixture was filtered through a layer of Celite® and concentrated in vacuum to afford the desired compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C@@H:10]3[CH2:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH2:15][C@H:9]3[C:8]([CH3:20])([CH3:19])[O:7][C:6]=2[CH:5]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1.COC(C1C[C@@H]2C3C(O)=CC(CCCCC)=CC=3OC(C)(C)[C@H]2CC=1)=O>>[OH:1][C:2]1[C:11]2[C@H:10]3[CH2:12][C:13]([C:16]([OH:18])=[O:17])=[CH:14][CH2:15][C@@H:9]3[C:8]([CH3:19])([CH3:20])[O:7][C:6]=2[CH:5]=[C:4]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:3]=1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C(=O)O)C[C@@H]21
Agent: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(C(=O)OC)C[C@H]21
Product: CCCCCc1cc(O)c2c(c1)OC(C)(C)[C@H]1CC=C(C(=O)O)C[C@H]21

Procedure:
By the same procedure described before for preparing (XI) in Example 7, hydrolysis of the (6aS,10aS)-ester (XVII) (22 mg, 0.061 mmol) with argon sparged 2N NaOH (3 mL) in argon sparged methanol (4 mL) at room temperature for 18 h gave, after work-up, 22 mg of a gum. This was subjected to preparative TLC on silica, eluting with hexanes-CHCl3 -MeOH (7:2:1) to give, from the main band, 16 mg, 76%, of the (6aS,10aS)-acid (XVIII) as a glass, [α]D +310° (CHCl3), M+ 344.1983 (Calc 344.1988).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]1[C:11]2([CH2:14][NH:13][CH2:12]2)[CH2:10][N:9]1[C:15]1[N:20]=[C:19]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]3)[CH:18]=[N:17][CH:16]=1.[CH3:33][O:34][C:35]1[CH:39]=[C:38]([C:40](O)=[O:41])[O:37][N:36]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.CCOC(C)=O>[CH3:33][O:34][C:35]1[CH:39]=[C:38]([C:40]([N:13]2[CH2:12][C:11]3([CH2:10][N:9]([C:15]4[N:20]=[C:19]([C:21]5[CH:22]=[C:23]6[C:28](=[CH:29][CH:30]=5)[N:27]([CH3:31])[C:26](=[O:32])[CH2:25][CH2:24]6)[CH:18]=[N:17][CH:16]=4)[CH2:8]3)[CH2:14]2)=[O:41])[O:37][N:36]=1
Reactant: COc1cc(C(=O)O)on1
Reactant: CN1C(=O)CCc2cc(-c3cncc(N4CC5(CNC5)C4)n3)ccc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(C(=O)N2CC3(C2)CN(c2cncc(-c4ccc5c(c4)CCC(=O)N5C)n2)C3)on1
Temperature: 25 °C
Yield: 22.7 %

Procedure:
To a solution of 6-(6-(2,6-diazaspiro[3.3]heptan-2-yl)pyrazin-2-yl)-1-methyl-3,4-dihydroquinolin-2(1H)-one 2,2,2-trifluoroacetate (intermediate A-36, 0.030 g, 0.067 mmol) in DCM (1 mL) were added 3-methoxyisoxazole-5-carboxylic acid (0.014 g, 0.1 mmol) and TBTU (0.024 g, 0.073 mmol) followed by Hünig's base (0.022 g, 0.167 mmol) and the reaction mixture was stirred at room temperature over night. The reaction mixture was diluted with EtOAc, poured into sat. NaHCO3 solution (5 mL) and extracted with EtOAc (2×10 mL). Combined organics were dried over Na2SO4, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography eluting with a 0 to 5% MeOH-DCM gradient to give the title compound (0.007 g, 20%) as a yellow solid. MS: 461.3 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([C:13](=[O:18])[C:14]([F:17])([F:16])[F:15])=[C:5]2[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1.[NH:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1>>[F:15][C:14]([F:17])([F:16])[C:13]([C:6]1[C:7]([CH3:12])=[N:8][C:9]2[C:4]([C:5]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:3][C:2]([N:26]1[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27]1)=[CH:11][CH:10]=2)=[O:18]
Reactant: Cc1nc2ccc(Br)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reactant: OC1CCNC1
Product: Cc1nc2ccc(N3CCC(O)C3)cc2c(-c2ccc(F)cc2)c1C(=O)C(F)(F)F
Reaction time: 16 h
Yield: 39 %

Procedure:
The title compound was prepared from 1-[6-Bromo-4-(4-fluoro-phenyl)-2-methyl-quinolin-3-yl]-2,2,2-trifluoro-ethanone [example 24] and 3-pyrrolidinol according to the procedure of example 25, except that the reaction time was of 16 h. Yield: 39%; MS: m/z=419 (M+H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][CH2:12][C@H:13]1[CH2:18][NH:17][CH2:16][CH2:15][NH:14]1.[CH3:19][C:20]1[S:29][C:28]2[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=[C:23](N)[C:22]=2[CH:21]=1.CN1CCCC1=O>C(OCC)(=O)C.O>[CH3:19][C:20]1[S:29][C:28]2[NH:27][C:26]3[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=3[N:24]=[C:23]([N:17]3[CH2:16][CH2:15][NH:14][C@@H:13]([CH2:12][CH2:11][C:2]4[CH:3]=[CH:4][C:5]5[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=5)[CH:1]=4)[CH2:18]3)[C:22]=2[CH:21]=1
Reactant: c1ccc2cc(CC[C@H]3CNCCN3)ccc2c1
Reactant: Cc1cc2c(s1)Nc1ccccc1N=C2N
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1cc2c(s1)Nc1ccccc1N=C2N1CCN[C@@H](CCc2ccc3ccccc3c2)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 34.2 %

Procedure:
Combine (S)-2-(2-naphthalen-2-yl-ethyl)-piperazine (854 mg, 3.72 mmol), 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (895 mg, 3.72 mmol) and 1-methyl-2-pyrrolidinone (8 mL). Heat at reflux. After 5 h, cool to ambient temperature and dilute with ethyl acetate and water. Extract with ethyl acetate. Wash the extracts with water and brine, dry over sodium sulfate, filter and concentrate the filtrate. Purify by silica gel chromatography using 2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give 576 mg (34%) of the title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1). HR-MS calculated for C28H29N4S: 453.2113. Found 453.2116. HPLC: Symmetry C18 column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile. Retention time 5.7 min; 100% pure.
Reaction SMILES: [OH:1][CH:2]([CH2:16][CH2:17][OH:18])[CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:19][O:20][C:21]1[CH:42]=[CH:41][C:24]([C:25](Cl)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)=[CH:23][CH:22]=1>N1C=CC=CC=1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([C:25]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[CH:42][CH:41]=2)([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:18][CH2:17][CH2:16][CH:2]([OH:1])[CH2:3][CH2:4][NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: O=C(NCCC(O)CCO)OCc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(OCCC(O)CCNC(=O)OCc2ccccc2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Benzyl 3,5-dihydroxypentylcarbamate (7.3 g, 28.8 mmoles) is co-evaporated twice with anhydrous pyridine (100 mL each) and then is dissolved in anhydrous pyridine (300 mL). The solution is chilled in an ice bath, and 4,4′-dimethoxytritylchloride (9.8 g, 28.9 mmoles) is added. The reaction is allowed to warm to ambient temperature and is stirred for 16 hours. The yellow solution is then evaporated to near dryness, and the residue is dissolved in dry toluene (250 mL). The toluene mixture is chilled for 1 hour at 4° C., then filtered. The collected solid is washed with toluene (50 mL) and the combined toluene filtrates are evaporated to a dark yellow syrup. The syrup is dried in vacuo for at least 24 hours at ambient temperature. The crude product is purified on silica gel (500 mL bed volume) eluting with hexanes:ethyl acetate:triethylamine (90:5:5 [v/v/v], 300 mL, then 85:10:5 [v/v/v], 1000 mL, then 80:15:5 [v/v/v], 1000 mL, then 75:20:5 [v/v/v], 1000 mL, then 70:25:5 [v/v/v], 2000 mL, then 50:45:5 [v/v/v], 2000 mL). Fractions containing pure product by thin layer chromatography are pooled and evaporated to a pale yellow syrup. The syrup is dried well in vacuo. The yield is 15.4 g (96%).
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14](=S)[CH2:15][C:16](=O)[CH3:17])=[O:4].[C:20]1([CH2:26][CH2:27][NH:28][NH2:29])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH2:7][N:6]1[C:14]1[N:28]([CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:29]=[C:16]([CH3:17])[CH:15]=1)=[O:4]
Reactant: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1C(=S)CC(C)=O
Reactant: NNCCc1ccccc1
Product: COC(=O)[C@@H]1C[C@@H](S(C)(=O)=O)CN1c1cc(C)nn1CCc1ccccc1

Procedure:
In analogy to the procedure described in example 192 h, (2S,4R)-4-methanesulfonyl-1-(3-oxo-thiobutyryl)-pyrrolidine-2-carboxylic acid methyl ester was reacted with 1-(2-phenylethyl)hydrazine (CAS Reg. No. 51-71-8) to give the title compound as brown solid. MS (ESI): m/z=392.6 [M+H]+.