Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C@:3]12[CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][C@H:4]1[N:5]([C:8]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])[CH2:6][CH2:7]2.C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH3:1][O:2][C@:3]12[CH2:19][NH:18][CH2:17][C@H:4]1[N:5]([C:8]([O:10][C@@H:11]([CH3:16])[C:12]([F:15])([F:14])[F:13])=[O:9])[CH2:6][CH2:7]2
Reactant: CO[C@@]12CCN(C(=O)O[C@@H](C)C(F)(F)F)[C@@H]1CN(C(=O)OC(C)(C)C)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CO[C@@]12CCN(C(=O)O[C@@H](C)C(F)(F)F)[C@@H]1CNC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of 5-tert-butyl 1-[(2S)-1,1,1-trifluoropropan-2-yl] (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-1,5-dicarboxylate (15 mg) in CHCl3 (0.5 mL) was added TFA (0.5 mL). After stirring for 1 hour at room temperature, the mixture was poured into saturated aqueous solution of NaHCO3 and extracted with CHCl3. The extract was dried over Na2SO4 and concentrated to give (2S)-1,1,1-trifluoropropan-2-yl (3aR,6aR)-3a-methoxyhexahydropyrrolo[3,4-b]pyrrole-1(2H)-carboxylate as a pale yellow foam.
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][C:5]2[NH:6][C:7](=[O:12])[CH:8]([CH2:10][CH3:11])[S:9][C:4]=2[CH:3]=1.[N+:15]([C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1)([O-:17])=[O:16].C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.C(O)C.O.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>[CH2:10]([CH:8]1[C:7](=[O:12])[NH:6][C:5]2[CH:13]=[CH:14][C:2]([C:22]3[CH:21]=[CH:20][CH:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:23]=3)=[CH:3][C:4]=2[S:9]1)[CH3:11]
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Reactant: CCC1Sc2cc(Br)ccc2NC1=O
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: [K+]
Solvent: O
Solvent: COCCOC
Solvent: CCO
Product: CCC1Sc2cc(-c3cccc([N+](=O)[O-])c3)ccc2NC1=O
Temperature: 25 °C
Yield: 7.4 %

Procedure:
A solution of 7-bromo-2-ethyl-4H-benzo[1,4]thiazin-3-one (2 g, 7.3 mmol), 3-nitrophenyl boronic acid (1.22 g, 7.3 mmol), potassium carbonate (3 g, 22 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.84 g, 0.72 mmol) in dimethoxyethane (100 ml), ethanol (25 ml), and water (25 ml) was heated to reflux for 6 hours. After cooling to room temperature, the mixture was diluted with water and extracted with EtOAc (3×40 mL). The combined organic extracts were washed with water, then brine, dried (MgSO4) and evaporated. The residue was recrystallized from ethanol to afford the title compound as tan crystals (0.17 g, 7.3%): mp 180° C.; MS (EI) m/z 314 (M+).
Reaction SMILES: [Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](OCC)=[O:29])[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:33]([O:50][CH2:51][C@@H:52]([NH2:54])[CH3:53])([C:46]([CH3:49])([CH3:48])[CH3:47])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C[Al](C)C.C(O)(=O)C.C(OCC)(=O)C>C1C=CC=CC=1>[Si:1]([O:18][CH:19]1[CH2:22][N:21]([C:23]2[S:24][CH:25]=[C:26]([C:28](=[O:29])[NH:54][C@@H:52]([CH3:53])[CH2:51][O:50][Si:33]([C:46]([CH3:48])([CH3:49])[CH3:47])([C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)[N:27]=2)[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CCOC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Reactant: C[C@H](N)CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Agent: C[Al](C)C
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Solvent: CC(=O)O
Product: C[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)NC(=O)c1csc(N2CC(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)C2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
Subsequently, to a solution of 3-t-butyldiphenylsilyloxy-1-(4-ethoxycarbonyl-1,3-thiazol-2-yl)azetidine (2.0 g, 4.29 mmol) (obtained as described in Reference Example 2(1)) in benzene (100 ml) was added a solution of 0.67M (1S)-2-(t-butyldiphenylsilyloxy)-1-methylethylamine-trimethylaluminium in benzene (12.9 ml) at room temperature under an atmosphere of nitrogen. The mixture was heated under reflux overnight. After checking the completion of the reaction, 10% aqueous acetic acid solution (100 ml) and ethyl acetate (200 ml) were added to the reaction mixture in an ice bath, and the resulting mixture was stirred at room temperature for 1 hour. After adding ethyl acetate thereto, the reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using n-hexane:ethyl acetate (6:1→2:1) as the eluant to afford 3-t-butyldiphenylsilyloxy-1-{4-[(1S)-2-(t-butyldiphenylsilyloxy)-1-methylethylcarbamoyl]-1,3-thiazol-2-yl}azetidine (2.77 g, yield 88%) as a pale brown solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH:10]([CH3:12])[CH3:11])[C:5]([NH2:8])=[CH:6][CH:7]=1.[C:13]([O:17][C:18]([NH:20][C@@H:21]([CH3:25])[C:22](O)=O)=[O:19])([CH3:16])([CH3:15])[CH3:14].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.CN(C)CCCN=C=NCC>C(Cl)Cl.C(O)(=O)C>[C:13]([O:17][C:18](=[O:19])[NH:20][C@H:21]([C:22]1[N:9]([CH:10]([CH3:12])[CH3:11])[C:4]2[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=2[N:8]=1)[CH3:25])([CH3:16])([CH3:15])[CH3:14]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CC(C)Nc1cc(F)ccc1N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: CC(=O)O
Product: CC(C)n1c([C@H](C)NC(=O)OC(C)(C)C)nc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
4-Fluoro-N2-isopropylbenzene-1,2-diamine (0.7 g, 5.07 mmol) was dissolved in DCM (10 mL) and (S)-2-tert-butoxycarbonylaminopropionic acid (1.06 g, 5.58 mmol) added. To the resultant dark red solution was added HOAt (0.76 g, 5.58 mmol), followed by N-methyl morpholine (1.23 mL, 11.15 mmol) and N-(3-dimethylaminopropyl)-N′ ethylcarbodiimide (1.07 g, 5.58 mmol). The resultant blue/black solution was stirred at RT overnight, under an atmosphere of nitrogen. The mixture was diluted with DCM (40 mL) and washed with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The organic fraction was dried (MgSO4), filtered and concentrated in vacuo to afford a dark red oil. This was purified by column chromatography (silica gel, gradient 0-20% EtOAc in DCM) to afford a red oil which solidified on standing. This was dissolved in acetic acid (20 mL) and heated at 70° C. overnight. The resultant mixture was allowed to cool to RT and was concentrated in vacuo to afford the title compound as a dark red gum (1.0 g, 88%). This material was used in the next step without any purification. LCMS (Method B): RT 2.78 min [M+H]+ 322.2
Reaction SMILES: CS(O[CH:6]1[CH2:11][CH2:10][O:9][CH2:8][CH2:7]1)(=O)=O.[Br:12][C:13]1[CH:14]=[N:15][NH:16][CH:17]=1.C([O-])([O-])=O.[K+].[K+].CN(C=O)C>>[Br:12][C:13]1[CH:14]=[N:15][N:16]([CH:6]2[CH2:11][CH2:10][O:9][CH2:8][CH2:7]2)[CH:17]=1
Reactant: Brc1cn[nH]c1
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Brc1cnn(C2CCOCC2)c1
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.3 %

Procedure:
The mixture of tetrahydro-2H-pyran-4-yl methanesulfonate (U-2) (1.8 g, 10 mmol), 4-bromo-1H-pyrazole (1.46 g, 10 mmol) and K2CO3(1.4 g, 10 mmol) in DMF (10 mmol) was stirred at 80° C. overnight, then purified by chromatography to afford the title compound (861 mg). MS (m/z): 231 (M+1)+.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[C:20]([N:22]2[CH2:36][C:25]3=[C:26]4[N:31]([N:32]=[C:24]3[CH2:23]2)[C:30]([CH3:33])=[C:29]([Cl:34])[C:28]([CH3:35])=[N:27]4)=[O:21])[CH2:9]1
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CN(C(=O)OC(C)(C)C)C1)C3
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccc(F)cc1OC1CNC1)C3
Yield: 18.5 %

Procedure:
A solution of 3-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-5-fluoro-phenoxy]-azetidine-1-carboxylic acid tert-butyl ester (472 mg; 0.91 mmol; 1 eq.) and TFA (4 mL) in DCM (4 mL) was stirred at room temperature for 1 hour then concentrated in vacuo. The residue was taken up in water, the pH was made basic with 5M NaOH and extracted with DCM (2×). The combined organic phase was dried over magnesium sulfate and concentrated in vacuo. The resulting solid was triturated in water and filtered off to afford the title compound (70 mg, 18%) as a white solid. 1H NMR (CDCl3) δ 7.38-7.31 (m, 1H), 6.80-6.72 (m, 1H), 6.38 (dt, J=10.5, 2.0 Hz, 1H), 5.04-4.96 (m, 3H), 4.65 (s, 2H), 3.93-3.87 (m, 2H), 3.79-3.72 (m, 2H), 2.91 (s, 2H), 2.86 (s, 1H), 2.69 (s, 1H), 2.63 (s, 2H). HPLC (max plot) 94.9%, Rt 2.56 min. UPLC/MS: (MS+) 416.2 ([M+H]+).
Reaction SMILES: S1C=CC(CC=O)=C1.[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][OH:22])[CH:17]=[CH:18][CH:19]=2)=[CH:10]1>C(Cl)Cl.CCOCC>[S:9]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[C:16]([CH2:20][CH:21]=[O:22])[CH:17]=[CH:18][CH:19]=2)=[CH:10]1
Reactant: OCCc1cccc(-c2ccsc2)c1
Agent: O=CCc1ccsc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=CCc1cccc(-c2ccsc2)c1

Procedure:
The title compound is prepared as described in Example 12 (Procedure B) for 3-thiophenylacetaldehyde but using 2-(3-thiophen-3-yl-phenyl)-ethanol. The title compound: ES-MS: 200.9 [M−H]−; single peak at tR=4.53 min (System 2); Rf=0.63 (CH2Cl2/Et2O, 95/5).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][NH:15][C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][CH2:27]Br)=[CH:24][CH:23]=1>>[CH3:1][C:2]1[C:6]([CH2:7][N:8]2[CH:12]=[C:11]([N:13]3[C:17](=[O:18])[CH2:16][N:15]([CH2:27][CH2:26][C:25]4[CH:29]=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[C:14]3=[O:19])[CH:10]=[N:9]2)=[C:5]([CH3:20])[O:4][N:3]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: Cc1noc(C)c1Cn1cc(N2C(=O)CNC2=O)cn1
Product: Cc1noc(C)c1Cn1cc(N2C(=O)CN(CCc3ccc(F)cc3)C2=O)cn1
Yield: 34 %

Procedure:
Prepared as in example 10-52 from 3-(1-((3,5-dimethylisoxazol-4-yl)methyl)-1H-pyrazol-4-yl)imidazolidine-2,4-dione (example 10-1) and 4-fluorophenethyl bromide. Yield: 34%. MS M+H calculated 398.16. found 398.1. The title compound was shown to inhibit hT2R08 bitter receptor and had an IC50 of 0.01 μM.
Reaction SMILES: [N:1]1([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:12]3[C:13](=[O:16])[O:14][CH2:15][C:11]=3[CH:10]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:19][C:20]1[C:21]([CH2:30][CH:31]=O)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26].[C:33]([BH3-])#N.[Na+]>CO>[F:19][C:20]1[C:21]([CH2:30][CH2:31][N:4]2[CH2:5][CH2:6][N:1]([CH2:7][CH2:8][C:9]3[CH:18]=[CH:17][C:12]4[C:13](=[O:16])[O:14][CH2:15][C:11]=4[C:10]=3[CH3:33])[CH2:2][CH2:3]2)=[CH:22][C:23]([O:28][CH3:29])=[C:24]([CH:27]=1)[C:25]#[N:26]
Reactant: [BH3-]C#N
Reactant: O=C1OCc2cc(CCN3CCNCC3)ccc21
Reactant: COc1cc(CC=O)c(F)cc1C#N
Agent: [Na+]
Solvent: CO
Product: COc1cc(CCN2CCN(CCc3ccc4c(c3C)COC4=O)CC2)c(F)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-[2-(piperazin-1-yl)ethyl]-2-benzofuran-1(3H)-one (95 mg, 0.27 mmol) and 5-fluoro-2-methoxy-4-(2-oxoethyl)benzonitrile (40 mg, 0.23 mmol) in methanol (1.0 mL) at 0° C. was added sodium cyanoborohydride (20 mg, 0.32 mmol) and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated and purified by mass-directed HPLC to provide 5-fluoro-2-methoxy-4-(2-{4-[2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)benzonitrile. LC-MS (IE, m/z): 438.4 [M+1]+. (0.034 μM)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([C:18](OC(C)(C)C)=O)[CH2:14][CH2:13]1)[NH:8][CH2:7][CH2:6]2.CC(C)([O-])C.[K+].[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36](Cl)=[O:37])=[CH:34][C:33]=1[CH3:41]>C1COCC1>[Br:31][C:32]1[CH:40]=[CH:39][C:35]([C:36]([N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:11]([N:12]4[CH2:13][CH2:14][N:15]([CH3:18])[CH2:16][CH2:17]4)[CH:10]=3)[CH:6]=[CH:7]2)=[O:37])=[CH:34][C:33]=1[CH3:41]
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: COc1cc2c(cc1N1CCN(C(=O)OC(C)(C)C)CC1)NCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1cc2ccn(C(=O)c3ccc(Br)c(C)c3)c2cc1N1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 15.8 %

Procedure:
To a mixture of intermediate 2 (0.25 g, 1.0 mmol) and potassium t-butoxide (0.114 g, 1 mmol) in dry THF (15 ml) was added 4-bromo-3-methyl benzoyl chloride (0.238 g, 1.0 mmol) in dry THF (10 ml). The resulting mixture was stirred at room temperature for 72 h, then poured onto water and extracted with dichloromethane (3×). The organic layers were combined, dried (Na2SO4), filtered and concentrated in vacuo to give the crude product Purification by Fcc eluting with 3% methanol/dichloromethane gave the title compound as a pale yellow oil (70 mg, 15%).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:8]=[CH:9][C:10]2[CH:14]=[C:13]([C:15]3[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([NH:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[N:16]=3)[S:12][C:11]=2[CH:33]=1)=[O:6].C1COCC1.[ClH:39]>CO.O>[ClH:21].[ClH:39].[ClH:21].[Cl:21][C:20]1[C:15]([C:13]2[S:12][C:11]3[CH:33]=[C:7]([C:5]([OH:6])=[O:4])[CH:8]=[CH:9][C:10]=3[CH:14]=2)=[N:16][C:17]([NH:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]2)=[N:18][CH:19]=1
Reactant: COC(=O)c1ccc2cc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)sc2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4ccc(C(=O)O)cc4s3)n2)CC1
Temperature: 25 °C
Yield: 67 %

Procedure:
Aqueous LiOH solution (2.0 M, 2.8 mL) is added to a stirred suspension of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-6-carboxylic acid methyl ester (0.840 g, 1.80 mmol) in MeOH (20 mL)/THF (20 mL)/H2O (6 mL), the resultant mixture is heated at 70° C. for 4.5 hours. While heating the solution, 5.0 N HCl (3.4 mL) is added in one portion then the solution is allowed to cool to ambient temperature to from a suspension. After filtration, the solid is dried in a vacuum oven at 60° C. for 4 hours to give the title compound (0.64 g, 67% yield). ES+(m/z) 446 (35Cl) and 448 (37Cl) [M+H].
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1.C([Li])CCC.[CH3:23][C:24]([CH3:26])=[O:25]>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:24]([OH:25])([CH3:26])[CH3:23])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:3]=1
Reactant: Cn1cnc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 0 °C

Procedure:
4-(2-Chloro-9-methyl-9H-purin-6-yl)morpholine (233 mg) was cooled in 5 mL of anhydrous THF to −78° C. before adding 2 eq of a 2.5 M solution of n-butyl lithium. The reaction was stirred for 1 hour at −78° C. upon which 3 eq of acetone were added. The reaction was subsequently warmed to 0° C. after 30 minutes. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was concentrated to give crude 2-(2-chloro-9-methyl-6-morpholino-9H-purin-8-yl)propan-2-ol (95 mg).
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:17])=[C:11](F)[C:12]=3[O:14][CH3:15])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:34]([CH3:35])[CH2:33][NH:32][CH2:31]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1CCN2C(=NCCC2)CC1>C(#N)C>[C:22]([O:26][C:27]([NH:29][C@H:30]1[C@H:34]([CH3:35])[CH2:33][N:32]([C:11]2[C:12]([O:14][CH3:15])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=2[F:17])[CH2:31]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1c(N2C[C@@H](C)[C@H](NC(=O)OC(C)(C)C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A mixture of 1-cyclopropyl-6,7-difluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid (0.40 g), trans-3-t-butoxycarbonylamino-4-methylpyrrolidine (0.41 g), DBU (0.21 g) and anhydrous acetonitrile (5 ml) was refluxed for 2.5 hours and then the reaction mixture was concentrated under reduced pressure. The residue was dissolved in chloroform (40 ml) and washed with 10% aqueous citric acid solution (20 ml) and with saturated saline (20 ml) successively. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was crystallized from ethanol to give 7-(trans-3-t-butoxycarbonylamino-4-methyl-1-pyrrolidinyl)-1-cyclopropyl-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolinecarboxylic acid. To a suspension of these crystals in methanol (5 ml) was added concentrated hydrochloric acid (5 ml) dropwise. After stirring for 1.5 hours at room temperature, the reaction mixture was neutralized with concentrated aqueous ammonia, the resulting crystals were collected by filtration and washed with water sufficiently to give the title compound (0.29 g) as colorless powder, mp 214°-215° C.
Reaction SMILES: Cl.[CH2:2]([N:9]([CH2:31][C@@H:32]([C:34]1[CH:45]=[CH:44][C:37]2[O:38]C(C)(C)[O:40][CH2:41][C:36]=2[CH:35]=1)[OH:33])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C(O)C>[CH2:2]([N:9]([CH2:31][C@H:32]([OH:33])[C:34]1[CH:45]=[CH:44][C:37]([OH:38])=[C:36]([CH2:41][OH:40])[CH:35]=1)[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[C:23]([S:27]([NH2:30])(=[O:29])=[O:28])[CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: CC1(C)OCc2cc([C@@H](O)CN(CCCCCCOCCCCc3cccc(S(N)(=O)=O)c3)Cc3ccccc3)ccc2O1
Agent: Cl
Solvent: CCO
Product: NS(=O)(=O)c1cccc(CCCCOCCCCCCN(Cc2ccccc2)C[C@H](O)c2ccc(O)c(CO)c2)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 85.5 %

Procedure:
Hydrochloric acid (80 ml, 1M) was added dropwise to a stirred solution of 3-{4-[(6-{benzyl[(2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl]amino}hexyl)oxy]butyl}benzenesulfonamide (20 g) in ethanol (100 ml) at 0° C. Upon complete addition the mixture was stirred at 5° C. for 1 h before being allowed to warm to room temperature. A portion (50 ml) of the ethanol was removed under reduced pressure and the remaining mixture was diluted with ethyl acetate (250 ml). The mixture was then washed with water (100 ml), saturated sodium bicarbonate solution (100 ml) and brine (100 ml) before being dried over anhydrous Na2SO4. The suspension was filtered and concentrated under reduced pressure to give the title compound (16 g) as an oil. LC R=4.02 min, δ (DMSO-d6) 9.15 (1H, s), 7.65 (1H, s), 7.64 (1H, d, J 8.8 Hz), 7.45 (2H, m), 7.27 (8H, m), 6.94 (1H, dd, J 8.2 Hz), 6.67 (1H, d, J 8.2 Hz), 4.92 (1H, t, J 5.7 Hz), 4.67 (1H, s), 4.56 (1H, m), 4.45 (2H, d, J 5.7 Hz), 3.61 (2H, m), 3.34 (2H, t, J 6.3 Hz), 3.28 (2H, t, J 6.2 Hz), 2.66 (2H, m), 2.50 (2H, m), 2.39 (2H, m), 1.61 (2H, m), 1.50 (2H, m), 1.39 (4H, m), 1.16 (4H, m).
Reaction SMILES: [CH3:1][N:2]([CH3:39])[CH2:3][CH2:4][N:5]([C:16]1[CH:38]=[CH:37][C:19]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:18][CH:17]=1)C(OCC1C=CC=CC=1)=O>CO.[Pd]>[ClH:36].[ClH:36].[CH3:39][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:16]1[CH:38]=[CH:37][C:19]([C:20]([N:22]2[CH2:23][CH2:24][N:25]([CH2:28][CH2:29][C:30]3[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=3)[CH2:26][CH2:27]2)=[O:21])=[CH:18][CH:17]=1
Reactant: CN(C)CCN(C(=O)OCc1ccccc1)c1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Agent: [Pd]
Solvent: CO
Product: CN(C)CCNc1ccc(C(=O)N2CCN(CCc3ccc(Cl)cc3)CC2)cc1
Product: Cl

Procedure:
1.9 g of 1-{4-[N-(2-dimethylaminoethyl)-N-benzyloxycarbonylamino]-benzoyl}-4-[2-(4-chlorophenyl)ethyl]piperazine are hydrogenated in 30 ml of methanol in the presence of 0.4 g of palladium-on-carbon. The mixture is filtered off with suction, concentrated by evaporation, rendered alkaline with 2N NaOH and extracted with ether. The mixture is concentrated by evaporation and recrystallised from ether. The 1-[4-(2-dimethylaminoethylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine melts at 74°-78°. With alcoholic hydrochloric acid, 1-[4-(2-dimethylaminoethylamino)benzoyl]-4-[2-(4-chlorophenyl)ethyl]piperazine hydrochloride having a melting point >275° is obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1.[OH-].[NH4+:44]>>[NH2:44][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]3([CH3:26])[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)=[N:10][C:9]=2[C:27]2[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][S:34]([C:37]3[CH:41]=[CH:40][O:39][CH:38]=3)(=[O:36])=[O:35])[C:28]=2[F:42])[CH:5]=[CH:4][N:3]=1
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(Cl)n3)s2)CC1
Agent: [OH-]
Product: CC(C)(C)OC(=O)N1CCC(C)(c2nc(-c3cccc(NS(=O)(=O)c4ccoc4)c3F)c(-c3ccnc(N)n3)s2)CC1
Temperature: 90 °C

Procedure:
A suspension of 1,1-dimethylethyl 4-(5-(2-chloro-4-pyrimidinyl)-4-{2-fluoro-3-[(3-furanylsulfonyl)amino]phenyl}-1,3-thiazol-2-yl)-4-methyl-1-piperidinecarboxylate (65 mg, 0.103 mmol) in ammonium hydroxide solution (28%, 2 mL, 51.4 mmol) sealed in a 5-mL microwave tube was heated at 90° C. for 3 h under the microwave conditions. The mixture was concentrated and dried under high vacuum to the title compound (64 mg). MS (ESI): 558.6 [M+1−56]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[CH2:7][CH:8]([OH:22])[CH2:9][C@H:10]([OH:21])[CH2:11][O:12][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:3])[CH3:2].CO[C:26](OC)([CH3:28])[CH3:27].C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[CH2:7][C@H:8]1[CH2:9][C@@H:10]([CH2:11][O:12][C:13](=[O:20])[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[O:21][C:26]([CH3:28])([CH3:27])[O:22]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(C)(C)OC
Reactant: CC(C)(C)OC(=O)CC(O)C[C@H](O)COC(=O)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](COC(=O)c2ccccc2)OC(C)(C)O1
Temperature: 20 °C
Reaction time: 4 h
Yield: 72 %

Procedure:
To a solution composed of 8.94 g (27.6 mmol) of (5S)-6-benzoyloxy-3,5-dihydroxyhexanoic tert-butyl ester produced in Example 15, 35.8 mL of 2,2-dimethoxypropane, and 2.5 mL of methylene chloride was added 269 mg (1.4 mmol) of p-toluenesulfonic acid-1H2O, and the mixture was stirred at 20° C. for 4 hours, after which 500 mL of saturated sodium hydrogen carbonate solution was added. The aqueous layer was separated and further extracted with 2 portions of methylene chloride, 20 mL each, and the organic layers were combined. The combined solution was dehydrated over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure to give a colorless oil. This residue was purified by silica gel column chromatography (Kieselgel 60, product of Merck; hexane:acetone=10:1) to give 7.24 g of 2-[(4R,6S)-2,2-dimethyl-6-benzoyloxymethyl-1,3-dioxan-4-yl]acetic tert-butyl ester (white solid). Yield: 72%.