Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][CH:20]([CH2:23][N:24]([CH3:31])[CH:25]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]3)[CH2:19][CH2:18]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][S:8][C:6]=2[N:7]=1.[NH:32]1[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33]1>C(#N)C>[CH3:31][N:24]([CH2:23][CH:20]1[CH2:21][CH2:22][N:17]([C:4]2[C:5]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[CH:9][S:8][C:6]=3[N:7]=[C:2]([N:32]3[CH2:36][CH2:35][CH:34]([C:37]([NH2:39])=[O:38])[CH2:33]3)[N:3]=2)[CH2:18][CH2:19]1)[CH:25]1[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26]1
Reactant: NC(=O)C1CCNC1
Reactant: CN1CCC(N(C)CC2CCN(c3nc(Cl)nc4scc(-c5ccccc5)c34)CC2)C1
Solvent: CC#N
Product: CN1CCC(N(C)CC2CCN(c3nc(N4CCC(C(N)=O)C4)nc4scc(-c5ccccc5)c34)CC2)C1
Temperature: 140 °C

Procedure:
N—[[1-(2-chloro-5-phenyl-thieno[2,3-d]pyrimidin-4-yl)-4-piperidyl]methyl]-N,1-dimethyl-pyrrolidin-3-amine (100 mg, 0.219 mmol) and pyrrolidine-3-carboxamide (300 mg, 2.63 mmol) were stirred in dry acetonitrile (1.5 ml) and heated in a microwave at 140° C. for 0.5 h. The solvent was evaporated and the crude residue purified by flash column chromatography (0 to 5% 7.0M NH3/MeOH in dichloromethane) to give 1-[4-[4-[[methyl-(1-methylpyrrolidin-3-yl)amino]methyl]-1-piperidyl]-5-phenyl-thieno[2,3-d]pyrimidin-2-yl]pyrrolidine-3-carboxamide as an off white solid (25 mg, 21%). m/z (M+H)+534.3, RT=2.69 min.
Reaction SMILES: [C:1]12(O)[CH2:9][CH:5]([C:6]1([CH3:8])[CH3:7])[CH2:4][CH2:3][C:2]2([OH:11])[CH3:10].[CH3:13][CH:14]([CH3:19])[CH2:15][B:16](O)[OH:17]>C(OCC)C>[CH3:13][CH:14]([CH3:19])[CH2:15][B:16]1[O:17][C@@H:3]2[CH2:4][C@@H:5]3[CH2:9][C@H:1]([C@:2]2([CH3:10])[O:11]1)[C:6]3([CH3:8])[CH3:7]
Reactant: CC1(O)CCC2CC1(O)C2(C)C
Reactant: CC(C)CB(O)O
Solvent: CCOCC
Product: CC(C)CB1O[C@@H]2C[C@@H]3C[C@@H](C3(C)C)[C@]2(C)O1
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.6 %

Procedure:
A mixture of (+)-pinanediol (23.9 g, 0.140 mol) and 2-methylpropylboronic acid (15 g, 0.147 mol) in diethyl ether (300 ml) was stirred at room temperature for 24 h. The mixture was dried over anhydrous sodium sulfate and purified by column chromatography (Silica gel 230-400 mesh), eluting with hexane:ethyl acetate 90:10 mixture. The product was obtained as a clear oil (32.6 g, 94% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20](O)=[O:21])[C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])=[O:7])=[CH:4][CH:3]=1.[NH2:25][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27]>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([NH:25][C@H:26]([C:28]([O:30][CH3:31])=[O:29])[CH3:27])=[O:21])[C:9]2[C:10]([CH3:16])=[CH:11][CH:12]=[CH:13][C:14]=2[CH3:15])=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1cccc(C)c1N(CCCC(=O)O)C(=O)c1ccc(Cl)cc1
Reactant: COC(=O)[C@H](C)N
Product: COC(=O)[C@H](C)NC(=O)CCCN(C(=O)c1ccc(Cl)cc1)c1c(C)cccc1C

Procedure:
Analogously to Example 1, by using equivalent quantities, reacting N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyric acid and methyl L-alaninate and suitable processing produces methyl N-[N-(p-chlorobenzoyl)-4-(2,6dimethylanilino)butyryl]-L-alaninate (M.P. 91° to 92°), saponification of which and processing of the reaction product yields N-[N-(p-chlorobenzoyl)-4-(2,6-dimethylanilino)butyryl]-L-alanine (M.P. 159° to 161°).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][N:20]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([NH2:30])=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C(O)(=O)C>[C:10]([O:14][C:15]([N:17]1[CH2:18][CH2:19][N:20]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([NH:30][C:2]3[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=3)=[CH:28][CH:29]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1N
Solvent: CC(=O)O
Product: Cc1cnc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)nc1N
Temperature: 70 °C

Procedure:
A mixture of 2-chloro-5-methyl-pyrimidin-4-ylamine (0.35 g, 2.4 mmol) and 4-(4-amino-benzyl)-piperazine-1-carboxylic acid tert-butyl ester (0.80 g, 2.8 mmol) in acetic acid (20 mL) was heated at 70° C. for 1 d. After cooling to room temperature, the mixture was concentrated. The residue was taken in water (30 mL) and neutralized with 10% NaOH solution until pH ˜10. The resulting aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the title compound used in the next step without purification. MS (ES+): m/z 399 (M+H)+.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:34][C:35]1[CH:40]=[C:39]([CH:41]([CH:43]2[CH2:45][CH2:44]2)[OH:42])[C:38]([S:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:37][N:36]=1)(=[O:33])=[O:32]>ClCCl.C(OCC)(=O)C>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[S:31]([NH:34][C:35]1[CH:40]=[C:39]([C:41]([CH:43]2[CH2:44][CH2:45]2)=[O:42])[C:38]([S:46][C:47]2[CH:52]=[CH:51][C:50]([S:53]([N:56]3[CH2:61][CH2:60][CH2:59][CH2:58][CH2:57]3)(=[O:55])=[O:54])=[CH:49][CH:48]=2)=[CH:37][N:36]=1)(=[O:33])=[O:32]
Reactant: O=S(=O)(Nc1cc(C(O)C2CC2)c(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)cn1)c1ccc(Cl)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1cc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50.5 %

Procedure:
Dess Martin periodinane (60 mg, 0.14 mmol) was added to a stirred solution of 2,4-dichloro-N-{4-(cyclopropyl-hydroxy-methyl)-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin-2-yl}-benzenesulfonamide (74 mg, 0.12 mmol) in dichloromethane (5 ml) and the mixture stirred at room temperature overnight under nitrogen. The reaction was diluted with ethyl acetate (30 ml), washed with NaHCO3 solution (20 ml), dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash column chromatography using ethyl acetate 2/3 hexane as eluent to give 2,4-dichloro-N-{4-cyclopropanecarbonyl-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyridin -2-yl}-benzenesulfonamide as a yellow solid (38 mg, 51%). 1H NMR (CDCl3): 8.32 (1 H, s, py); 8.08 (1 H, d, Ar); 7.57 (2 H, d, Ar); 7.46 (1 H, s, py); 7.36 (1 H, d, Ar); 7.27 (2 H, d, Ar); 2.89 (4 H, m, 2×CH2 pip); 2.17 (1 H, m, COCH); 1.54 (4 H, m, 2×CH2 pip); 1.33 (2 H, m, CH2 pip); 0.82 (4 H, m, 2×CH2 cprop). HPLC (Luna 2, Gradient 5): rt=6.47 minutes. LCMS rt=7.24 minutes, 627 (M+H)+. By a similar method using the appropriate starting materials the following can be prepared:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:24])([C@H:16]([N:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(#N)C.C(OCC)(=O)C>[NH:31]([C:32]([N:21]1[CH2:20][CH2:19][N:18]([C@H:16]([CH3:17])[C@:9]([C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])([OH:24])[CH2:10][N:11]2[CH:15]=[N:14][CH:13]=[N:12]2)[CH2:23][CH2:22]1)=[O:33])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H](N1CCNCC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCOC(C)=O
Solvent: CC#N
Product: C[C@@H](N1CCN(C(=O)Nc2ccccc2)CC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a ice cooled solution of (2R,3R)-2-(2,4-diflurophenyl)-3-(piperazin-1-yl)-1-(1H-1,2,4-triazole-1-yl)butan-2-ol 2 (150 mg, 0.44 mmol) in acetonitrile (10 ml) was added phenylisocyanate (60 mg, 0.5 mmol) in acetonitrile (4 ml). The reaction mixture was stirred at 0° C. for 2 h, diluted with 20 ml of ethyl acetate and successively washed with water, brine and dried over sodium sulphate. This organic extract was concentrated and the residue was purified by passing through a column of silica gel (hexane/EtOAc) to give the title compound as a colorless solid (170 mg, 84%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([O:23]CC3C=CC([N+]([O-])=O)=CC=3)=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:4][CH2:3]1.O1CCCC1.[ClH:47]>O>[ClH:47].[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([C:8]([C@@H:10]2[CH2:14][C@H:13]([S:15][C:16]3[C@H:17]([CH3:40])[C@@H:18]4[C@@H:35]([C@H:36]([OH:38])[CH3:37])[C:34](=[O:39])[N:19]4[C:20]=3[C:21]([OH:23])=[O:22])[CH2:12][N:11]2[CH3:41])=[O:9])[CH2:6][CH2:7]1
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)O)=C(S[C@H]3C[C@@H](C(=O)N4CCN(C)CC4)N(C)C3)[C@H](C)[C@H]12

Procedure:
A solution of 720 mg of 4-nitrobenzyl (1R, 5S,6S)-2-[(2S,4S)-2-(4-methyl-1-piperazinylcarbonyl)-1-methylpyrrolidin-4-ylthio]-6-[(1R)-1-hydroxyethyl]-1-methyl-1-carbapen-2-em-3-carboxylate [prepared as described in step (a) above] in 60 ml of a 1:1 by volume mixture of tetrahydrofuran and water was mixed with 1.2 ml of 1N aqueous hydrochloric acid, and the mixture was hydrogenated by bubbling hydrogen through it at room temperature for 2 hours in the presence of 800 mg of 10% w/w palladium-on-charcoal. The catalyst was then removed by filtration and the filtrate was washed with diethyl ether. The aqueous solution was concentrated by evaporation under reduced pressure, the residue was subjected to column chromatography using a Lobar column (Merck, LiChroprep RP-8, size B) and the column was eluted with 3% by volume aqueous methanol. Those fractions containing the title compound were combined and concentrated by evaporation under reduced pressure, to give 326 mg of the title compound as a colorless powder.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:5]([C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[C:6]([CH:8]([OH:10])[CH3:9])[CH:7]=1.C(N(CC)C(C)C)(C)C.[CH3:34][S:35](Cl)(=[O:37])=[O:36]>C(Cl)Cl>[CH3:34][S:35]([O:10][CH:8]([C:6]1[CH:7]=[C:2]([Cl:1])[C:3]([CH3:24])=[C:4]([C:19]([NH:21][CH2:22][CH3:23])=[O:20])[C:5]=1[C:11]1[CH:12]=[C:13]([F:18])[CH:14]=[C:15]([F:17])[CH:16]=1)[CH3:9])(=[O:37])=[O:36]
Reactant: CS(=O)(=O)Cl
Reactant: CCNC(=O)c1c(C)c(Cl)cc(C(C)O)c1-c1cc(F)cc(F)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCNC(=O)c1c(C)c(Cl)cc(C(C)OS(C)(=O)=O)c1-c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a mixture of 4-chloro-N-ethyl-3′,5′-difluoro-6-(1-hydroxyethyl)-3-methylbiphenyl-2-carboxamide (185 mg, 0.523 mmol) in methylene chloride (3 mL) was added N,N-diisopropylethylamine (0.18 mL, 1.0 mmol), followed by methanesulfonyl chloride (0.061 mL, 0.78 mmol). The reaction was stirred at rt for 10 min, quenched by pouring onto iced water, and extracted with dichloromethane. The combined organic layers were washed with aq. sodium bicarbonate, dried over magnesium sulfate, and evaporated to dry. The residue was used directly in next step (0.226 g, 100%). LCMS calculated for C19H21ClF2NO4S (M+H)+: m/z=432.1; Found: 432.1.
Reaction SMILES: [N:1]([C@H:4]1[C@@H:9]([CH3:10])[CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:27]=3[F:33])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[N+]=[N-]>CO.CCOC(C)=O.[Pd]>[NH2:1][C@H:4]1[C@@H:9]([CH3:10])[CH2:8][C@@H:7]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][C:12]=2[NH:17][C:18](=[O:34])[C:19]2[CH:24]=[CH:23][C:22]([F:25])=[C:21]([C:26]3[C:27]([F:33])=[CH:28][CH:29]=[CH:30][C:31]=3[F:32])[N:20]=2)[CH2:6][C@H:5]1[NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39]
Reactant: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N=[N+]=[N-]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: C[C@H]1C[C@@H](c2ccncc2NC(=O)c2ccc(F)c(-c3c(F)cccc3F)n2)C[C@@H](NC(=O)OC(C)(C)C)[C@H]1N
Reaction time: 16 h
Yield: 100 %

Procedure:
Degass a solution of tert-butyl (1R,2S,3S,5R)-2-azido-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate (1.0 equiv.) in MeOH/EtOAc (3/1, 0.04 M). To this solution was added Pd/C (0.2 equiv.) and purge with Ar and H2. The mixture was stirred under H2 for 16 hrs. Filter the mixture over cetlite and wash the cake with MeOH. Concentrate the filtrate to yield tert-butyl (1R,2S,3S,5R)-2-amino-5-(3-(6-(2,6-difluorophenyl)-5-fluoropicolinamido)pyridin-4-yl)-3-methylcyclohexylcarbamate in 100% yield). LC/MS (m/z)=556.3 (MH+), Rt=0.73 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[N:7][N:8]([CH2:16][C:17]2[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[C:19]([C:27]([F:30])([F:29])[F:28])[CH:18]=2)[C:9]=1[C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=O.[BH4-].[Na+].O>CO>[F:26][C:23]([F:24])([F:25])[C:21]1[CH:22]=[C:17]([CH:18]=[C:19]([C:27]([F:28])([F:30])[F:29])[CH:20]=1)[CH2:16][N:8]1[C:9]([C:10]2[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=2)=[C:5]([CH2:3][OH:2])[N:6]=[N:7]1
Reactant: COC(=O)c1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: OCc1nnn(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1-c1cccnc1
Temperature: 70 °C
Yield: 75 %

Procedure:
Dissolve 1-(3,5-bis-trifluoromethyl-benzyl)-5-pyridin-3-yl-1H-[1,2,3]triazole-4-carboxylic acid methyl ester in MeOH. Add NaBH4 (2.64 g, 3 eq) and warm to reflux overnight (70° C.). Cool to RT and slowly pour into a separatory funnel containing an equal volume of water. Extract with CH2Cl2. Concentrate and recrystallize from EtOAc/Hexanes to give the 7.0 g (75%) of the title compound. MS (IS) 403.2 (M+1); 1H NMR: (400 MHz, CD3OD) δ: 8.65 (dd, J=5.2, 1.6 Hz, 1H) 8.53-8.52 (m, 1H), 7.89 (s, 1H), 7.86-7.83 (m, 1H), 7.60 (s, 2H), 7.56-7.53 (m, 1H), 5.83 (s, 2H), 4.59 (s, 2H).
Reaction SMILES: Cl[CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1.[C:23]([O-:26])(=[O:25])[CH3:24].[K+]>CN(C=O)C.O>[C:23]([O:26][CH2:2][C:3]1[N:7]=[C:6]([CH:8]([CH3:22])[C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([F:21])[CH:10]=2)[O:5][N:4]=1)(=[O:25])[CH3:24]
Reactant: CC(c1ccc(-c2ccccc2)c(F)c1)c1nc(CCl)no1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)OCc1noc(C(C)c2ccc(-c3ccccc3)c(F)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.7 %

Procedure:
To a solution of 1.32 g of 3-chloromethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole in 30 ml of dry DMF was added 1.58 g of potassium acetate. After stirring at room temperature overnight, the reaction mixture was diluted with water and extracted with benzene. The organic phase was washed with water, dried over sodium sulfate and evaporated. The residue was chromatographed over silica gel using benzene to yield 0.96 g of 3-acetoxymethyl-5-(3-fluoro-4-phenyl-α-methylbenzyl)-1,2,4-oxadiazole, nD23 1.5635.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([OH:10])[CH:9]=1)=[O:3].[CH2:11]1[O:21][C:20]2[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][C:13]=2[O:12]1.[OH-].[Na+]>CO>[OH:10][C:8]1[CH:9]=[C:4]([CH:5]=[CH:6][CH:7]=1)[C:2](=[O:3])[CH:1]=[CH:16][C:15]1[CH:18]=[CH:19][C:20]2[O:21][CH2:11][O:12][C:13]=2[CH:14]=1
Reactant: CC(=O)c1cccc(O)c1
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc2c(c1)OCO2)c1cccc(O)c1

Procedure:
3-Hydroxy acetophenone, 2 (2.7 g, 20 mmol), 3,4-methylenedioxy benzaldehyde, 6 (3 g, 20 mmol) and 50% aqueous sodium hydroxide (5 mL) in methanol (40 mL) were reacted under reflux as in 7 to yield 12. Yield 4.1 g (76%); mp 188-189° C.; MS (FAB) 269 (M++1); IR (KBr) 3389, 1659; 1H NMR (300 MHz, DMSO-d6) δ 9.84 (s, 1H), 7.73 (d, J=15.6 Hz, 1H), 7.64 (d, J=15.9 Hz, 1H), 7.63 (s, 1H), 7.62 (d, J=5.4 Hz, 1H), 7.45 (s, 1H), 7.36 (t, J=7.9 Hz, 1H), 7.30 (d, J=7.8 Hz, 1H), 7.05 (dd, J=7.9 Hz, 2.4 Hz, 1H), 6.98 (d, J=7.8 Hz, 1H), 6.09 (s, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:13][CH2:12][S:11][CH2:10][CH2:9]1.I([O-])(=O)(=O)=[O:25].[Na+]>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C:14]2[CH2:18][CH:17]([CH2:19][NH:20][C:21](=[O:23])[CH3:22])[O:16][N:15]=2)[CH:5]=[CH:6][C:7]=1[N:8]1[CH2:9][CH2:10][S:11](=[O:25])[CH2:12][CH2:13]1
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: CC(=O)NCC1CC(c2ccc(N3CCSCC3)c(F)c2)=NO1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(=O)NCC1CC(c2ccc(N3CCS(=O)CC3)c(F)c2)=NO1
Temperature: 25 °C
Reaction time: 48 h
Yield: 85.9 %

Procedure:
1.0 g (2.97 mmol) of N-({3-[3-fluoro-4-(4-thiomorpholinyl)phenyl]-4,5-dihydro-5-isoxazolyl}methyl)acetamide is suspended in 20 ml methanol/5 ml acetone in a 100 ml one neck round bottom flask. The suspension is treated with sodium meta periodate (666 mg, 3.12 mmole) in 20 ml water and the reaction mixture is stirred 48 hours at room temperature. The organics are removed in vacuo and the aqueous residue is filtered to remove a fine white solid. The solid is washed with water followed by diethyl ether to give 902 mg the title compound) as a solid. mp=204-205° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([NH:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24])=[O:15])(=[O:10])=[O:11])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: NCCS(=O)(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)NCCS(=O)(=O)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.252 g (10 mmol) of 2aminoethanesulfonic acid, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is dissolved in distilled water, extracted with ethyl acetate, and converted into the free acid by treatment with acidic cation exchanger. The title compound is obtained by freeze-drying the aqueous solution.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:21]([Cl:22])=[N:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:13]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.Cl.[CH3:24][N:25]([CH2:27][C:28](Cl)=[O:29])[CH3:26].C(N(C(C)C)C(C)C)C>C(Cl)Cl>[Cl:22][C:21]1[C:12]([NH:11][S:8]([C:5]2[CH:4]=[CH:3][C:2]([NH:1][C:28](=[O:29])[CH2:27][N:25]([CH3:26])[CH3:24])=[CH:7][CH:6]=2)(=[O:10])=[O:9])=[N:13][C:14]2[C:19]([N:20]=1)=[CH:18][CH:17]=[CH:16][CH:15]=2
Reactant: Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Reactant: CN(C)CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)CC(=O)Nc1ccc(S(=O)(=O)Nc2nc3ccccc3nc2Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
To a suspension of 4-amino-N-(3-chloroquinoxalin-2-yl)benzenesulfonamide (2 g; 4.5 mmol; 1 eq) in DCM (100 mL) is added dimethylaminoacetyl chloride hydrochloride (710 mg; 4.5 mmol; 1 eq) and N-ethyldiisopropylamine (2.3 mL; 13.5 mmol; 3 eq) and the reaction mixture is stirred at room temperature overnight. To complete the reaction, dimethylaminoacetyl chloride hydrochloride (1.06 g; 6.74 mmol; 1.5 eq) is added and the reaction mixture is allowed to stir another 2 days. The precipitate formed is filtered off and the filtrate is treated with a solution of citric acid. The precipitate in the organic phase is filtered and the aqueous phase is basified with Na2CO3. The product is extracted with DCM and the organic phase is concentrated to near dryness to afford 1.5 g (80%) of the title compound as a yellow powder. HPLC (max plot) 85%; Rt 2.37 min. UPLC/MS (ES+) 420.2, (ES−) 418.3.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=1[C:8]([F:11])([F:10])[F:9].C(NC(C)C)(C)C.[Li].[Cl:22][C:23]1[N:31]=[CH:30][CH:29]=[CH:28][C:24]=1[C:25](Cl)=[O:26]>C1COCC1>[Cl:22][C:23]1[C:24]([C:25]([NH:1][C:2]2[C:3]([Cl:13])=[N:4][C:5]([CH3:12])=[CH:6][C:7]=2[C:8]([F:9])([F:11])[F:10])=[O:26])=[CH:28][CH:29]=[CH:30][N:31]=1
Reactant: Cc1cc(C(F)(F)F)c(N)c(Cl)n1
Reactant: O=C(Cl)c1cccnc1Cl
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: Cc1cc(C(F)(F)F)c(NC(=O)c2cccnc2Cl)c(Cl)n1
Reaction time: 0.08 h
Yield: 72.6 %

Procedure:
To a cooled (-78° C.) solution of 2.1 g of the 3-amino-2-chloro-6-methyl-4-(trifluoromethyl)pyridine in 10 ml of THF was added dropwise over 3 min. 7 ml of lithium diisopropylamine (LDA, 1.5 M in cyclohexane). The mixture was stirred 5 min., and 0.9 g of 2-chloronicotinoyl chloride in 3 ml of THF was added over 1 min. After 5 min. an additional 3 ml of LDA solution was added followed by an additional 0.5 g of the acid chloride in 1 ml of THF. The resulting mixture was stirred 10 min. and then quenched with 100 ml of water. After partitioning with 30 ml of ethyl acetate, the organic phase was extracted with water and the combined aqueous phases extracted with methylene chloride, dried (magnesium sulfate), filtered and evaporated to give the crude product. This was washed with a small amount of ethyl acetate and dried to give 1.3 g of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15](O)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1.O>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([N:11]4[CH:10]=[CH:14][N:13]=[CH:12]4)=[O:16])=[C:10]3[C@@H:9]3[CH2:18][CH2:19][CH2:20][N:8]3[C:7](=[O:21])[C:6]=2[CH:22]=1
Reactant: O=C(O)c1ncn2c1[C@@H]1CCCN1C(=O)c1cc(F)ccc1-2
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2cc(F)ccc2-n2cnc(C(=O)n3ccnc3)c2[C@@H]2CCCN12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
14.53 g (89.6 mmol) of N,N'-carbonyldiimidazole are introduced portion wise into a suspension of 20 g (66.4 mmol) of (S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepine-1-carboxylic acid in 70 ml of N,N-dimethylformamide. The solution obtained is stirred at room temperature and at 50°, in each case for 1 hour, and is then poured into about 300 ml of water. After stirring for 20 minutes the suspension obtained is suction filtered and the residue is washed with water. After drying at 90° for 16 hours in a water-jet vacuum there is obtained 1-[[(S)-7-fluoro-11,12,13,13a-tetrahydro-9-oxo-9H-imidazo[1,5-a]pyrrolo[2,1-c][1,4]benzodiazepin-1-yl]carbonyl]imidazole of melting point 206°-207°.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[ClH:14].O=[C:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH:17]1[C:22](OC)=[O:23]>>[ClH:14].[CH3:12][O:11][C:7]1[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[C:4]2[C:16]3[CH2:21][CH2:20][NH:19][CH2:18][C:17]=3[C:22](=[O:23])[O:13][C:5]=2[CH:6]=1
Reactant: COc1cc(O)cc(OC)c1OC
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Product: COc1cc2oc(=O)c3c(c2c(OC)c1OC)CCNC3
Yield: 55 %

Procedure:
Prepared by the method described in Example 1 from 3,4,5-trimethoxyphenol (25 g, 0.14 moles) and methyl 4-oxo-3-piperidinecarboxylate hydrochloride (18.8 g, 0.097 moles). Recrystallization from dilute aqueous hydrochloric acid yielded the product (17.5 g) as the hydrochloride, mp 232°-234° C.