Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH:10]1([N:13]2[CH:17]=[C:16]([C:18]3[CH:27]=[C:26]4[C:21]([NH:22][C@@H:23]([CH3:36])[CH2:24][N:25]4[C:28]([O:30][CH:31]4[CH2:35][CH2:34][CH2:33][CH2:32]4)=[O:29])=[CH:20][CH:19]=3)[CH:15]=[N:14]2)[CH2:12][CH2:11]1.[CH:37]1([C:40](Cl)=[O:41])[CH2:39][CH2:38]1>ClCCCl>[CH:37]1([C:40]([N:22]2[C:21]3[C:26](=[CH:27][C:18]([C:16]4[CH:15]=[N:14][N:13]([CH:10]5[CH2:12][CH2:11]5)[CH:17]=4)=[CH:19][CH:20]=3)[N:25]([C:28]([O:30][CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35]3)=[O:29])[CH2:24][C@@H:23]2[CH3:36])=[O:41])[CH2:39][CH2:38]1
Reactant: O=C(Cl)C1CC1
Reactant: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CN(C(=O)OC2CCCC2)c2cc(-c3cnn(C4CC4)c3)ccc2N1C(=O)C1CC1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 76.3 %

Procedure:
N,N-Diisopropylethylamine (0.148 mL 0.846 mmol) was added to a solution of (S)-cyclopentyl 7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.062 g, 0.169 mmol) and cyclopropanecarbonyl chloride (0.077 mL, 0.846 mmol) in 1,2-dichloroethane (2.0 mL), and the mixture stirred at 50° C. for 2.5 h. The reaction mixture was concentrated to afford a brown oil. This material was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 0-50% ethyl acetate-hexane) to afford (S)-cyclopentyl 4-(cyclopropanecarbonyl)-7-(1-cyclopropyl-1H-pyrazol-4-yl)-3-methyl-3,4-dihydroquinoxaline-1(2H)-carboxylate (0.056 g, 76%) as a an off-white solid. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.71-0.91 (m, 3 H), 0.93-1.12 (m, 8 H), 1.48-1.99 (m, 9 H), 3.42-3.55 (m, 1 H), 3.75 (tt, J=7.33, 3.81 Hz, 1 H), 3.93 (br dd, J=12.75, 6.30 Hz, 1 H), 4.86-4.98 (m, 1 H), 5.14 (td, J=5.50, 2.79 Hz, 1 H), 7.29-7.44 (m, 2 H), 7.76 (s, 1 H), 7.91 (s, 1 H), 8.17 (s, 1 H). MS (ESI, pos. ion) m/z 435 [M+1]+.
Reaction SMILES: C(O)C.[F:4][C:5]([F:41])([F:40])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24](CC4C=CC=CC=4)[CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1.[H][H]>[Pd].C(O)(=O)C>[F:40][C:5]([F:4])([F:41])[C:6]1[CH:39]=[CH:38][C:9]([C:10]([NH:12][C:13]2[N:17]([CH2:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[C:16]3[CH:34]=[CH:35][CH:36]=[CH:37][C:15]=3[N:14]=2)=[O:11])=[CH:8][CH:7]=1
Reactant: O=C(Nc1nc2ccccc2n1CCCN1CCN(Cc2ccccc2)CC1)c1ccc(C(F)(F)F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(Nc1nc2ccccc2n1CCCN1CCNCC1)c1ccc(C(F)(F)F)cc1
Yield: 63.9 %

Procedure:
To a solution composed of 75 ml. ethanol and 1 ml. glacial acetic acid was added 2-(4-trifluoromethylbenzamido)-1-[3-(4-benzyl-1-piperazinyl)propyl]benzimidazole (500 mg., 0.96 millimole) and 100 mg. of 10% Pd/C catalyst. The mixture was shaken on a Paar apparatus at about 2 atm. pressure of hydrogen and 40° C. for 2.5 hrs. at which time the reaction was complete. The catalyst was removed by filtration and the filtrate was evaporated in vacuo to yield a white solid, which on trituration under acetone yielded 300 mg. (63.9% yield) of 2-(4-trifluoromethylbenzamido)-1-[3-(1-piperazinyl)propyl]benzimidazole, as a white crystalline solid, m.p. 184°-185° C.
Reaction SMILES: [N:1]1([CH:6]([C:10]2[CH:11]=[C:12]([NH2:17])[C:13]([NH2:16])=[CH:14][CH:15]=2)[CH:7]([CH3:9])[CH3:8])[CH:5]=[CH:4][N:3]=[CH:2]1.C(O)(=O)C.O=[C:23]([CH2:27][CH2:28][CH3:29])[C:24](O)=[O:25].[OH-].[Na+]>O>[N:1]1([CH:6]([C:10]2[CH:11]=[C:12]3[C:13](=[CH:14][CH:15]=2)[NH:16][C:24](=[O:25])[C:23]([CH2:27][CH2:28][CH3:29])=[N:17]3)[CH:7]([CH3:8])[CH3:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CC(C)C(c1ccc(N)c(N)c1)n1ccnc1
Reactant: CCCC(=O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1nc2cc(C(C(C)C)n3ccnc3)ccc2[nH]c1=O
Temperature: 0 °C

Procedure:
To a stirred and cooled (0° C.) mixture of 9 parts of 4-[1-(1H-imidazol-1-yl)-2-methylpropyl]-1,2-benzenediamine in 80 parts of acetic acid and 20 parts of water were added 5 parts of 2-oxopentanoic acid. The reaction mixture was stirred for 12 hours at room temperature. The whole was poured into ice water and neutralized with a sodium hydroxide solution 3N. The product was extracted three times with 130 parts of dichloromethane. The combined extracts were dried, filtered and evaporated. For obtaining 6-[1-(1H-imidazol-1yl)-2-methylpropyl]-3-propyl-2(1H)-quinoxalinone, the residue was purified by column chromatography (HPLC) over silica gel using a mixture of dichloromethane and methanol (98:2 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-butanone and 1,1'-oxybisethane. The precipitated product was filtered off and stirred in cold 4-methyl-2-pentanone. After filtration, the product was recrystallized from a mixture of methanol and 2-propanone, yielding 1.6 parts (13.2%) of the above product; mp. 259.7° C. (comp. 100).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH:22]4[CH2:24][CH2:23]4)=[CH:20][C:19]([CH:25]4[CH2:27][CH2:26]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:3]=1.[CH3:32][O:33][CH2:34][C@@H:35]1[CH2:39][O:38][C:37](=[O:40])[NH:36]1>>[CH:22]1([C:21]2[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[C@H:35]([CH2:34][O:33][CH3:32])[CH2:39][O:38][C:37]5=[O:40])=[CH:3][C:4]=4[S:28]([CH3:31])(=[O:30])=[O:29])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=[C:19]([CH:25]3[CH2:27][CH2:26]3)[CH:20]=2)[CH2:24][CH2:23]1
Reactant: CS(=O)(=O)c1cc(Br)ccc1C(=O)N1CCN(c2ncc(C3CC3)cc2C2CC2)CC1
Reactant: COC[C@@H]1COC(=O)N1
Product: COC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCN(c3ncc(C4CC4)cc3C3CC3)CC2)c(S(C)(=O)=O)c1
Yield: 31.5 %

Procedure:
By reaction and treatment in the same manner as in Example 111 and using (4-bromo-2-methanesulfonylphenyl)[4-(3,5-dicyclopropylpyridin-2-yl)piperazin-1-yl]methanone (400 mg) described in Preparation Example 89 and (R)-4-methoxymethyloxazolidin-2-one (104 mg) described in Preparation Example 38, the title compound (138.6 mg) was obtained.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:33]2[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:40])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([NH:6][C:4]([C:3]3[CH:20]=[CH:21][C:22]([CH3:24])=[CH:23][C:2]=3[C:33]3[CH:34]=[CH:35][C:36]([C:39]([NH:41][CH2:42][CH2:43][C:44]([O:46][CH2:47][CH3:48])=[O:45])=[O:40])=[N:37][CH:38]=3)=[O:5])=[CH:8][CH:9]=2)=[CH:14][CH:15]=1
Reactant: CCOC(=O)CCNC(=O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1ccc(C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: CCOC(=O)CCNC(=O)c1ccc(-c2cc(C)ccc2C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)cn1
Temperature: 85 °C

Procedure:
2-bromo-N-(4′-chloro-[1,1′-biphenyl]-4-yl)-4-methylbenzamide (50 mg, 0.13 mmol), ethyl 3-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)picolinamido)propanoate (68 g, 0.16 mmol), Pd(dppf)Cl2 (9 mg, 0.01 mmol), and 2M aqueous K2CO3 (0.13 mL g, 0.25 mmol) were dissolved in 1,4-dioxane (2 mL) and the resulting mixture was heated to 85° C. After 16 h the resulting mixture was cooled to room temperature and purified directly via column chromatography to yield the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([N+:18]([O-])=O)[CH:15]=[CH:16][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=1)[NH2:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCOc1cccc([N+](=O)[O-])c1
Agent: [Pt]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCOc1cccc(N)c1

Procedure:
Prepared from 3-[2-(tert.butyloxycarbonylamino)ethoxy]-nitrobenzene by hydrogenation in methanol at ambient temperature in the presence of platinum/charcoal, Rf value: 0.42 (silica gel; petroleum ether/ethyl acetate=1:1)
Reaction SMILES: C1C2C(COC(=O)[NH:17][CH:18]([C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])=[O:32])[CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])C3C(=CC=CC=3)C=2C=CC=1.N1CCCCC1>CC#N>[NH2:17][C@@H:18]([CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:30])[C:31]([O:33][CH2:34][CH2:35][CH2:36][CH2:37][O:38][N+:39]([O-:41])=[O:40])=[O:32]
Reactant: CC(C)(C)OC(=O)NCCCCC(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)OCCCCO[N+](=O)[O-]
Solvent: CC#N
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)NCCCC[C@H](N)C(=O)OCCCCO[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of S)-4-(nitrooxy)butyl 1-(9H-fluoren-9-yl)-13,13-dimethyl-3,11-dioxo-2,12-dioxa-4,10-diazatetradecane-5-carboxylate (2.52 g, 4.30 mmol) in CH3CN (30 ml), piperidine (2.12 ml, 21.5 mmol) was added in the dark, the reaction was stirred at rt for 25 min. Then the mixture was concentrated to a small volume and diluted with EtOAc (150 ml) and washed with 5% aqueous NaHPO4 (2×70 ml). The organic layer was dried over sodium sulphate and concentrated under reduced pressure.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:21][C:22]1([C:28]([NH:30][C@H:31]([CH2:36][OH:37])[CH2:32][CH2:33][S:34][CH3:35])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]>CS(C)=O.C(Cl)Cl>[S:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH:12]=[C:11]1[C:19]([NH:21][C:22]1([C:28]([NH:30][C@H:31]([CH:36]=[O:37])[CH2:32][CH2:33][S:34][CH3:35])=[O:29])[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1)=[O:20]
Reactant: CSCC[C@@H](CO)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: ClCCl
Product: CSCC[C@@H](C=O)NC(=O)C1(NC(=O)c2cc3ccccc3s2)CCCCC1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
Under an argon gas atmosphere, 245 mg (1.9 mmol) of N,N-diisopropylethylamine was added dropwise to a solution of 297 mg (1.9 mmol) of sulfur trioxide-pyridine complex in 10 ml of dimethyl sulfoxide and 5 ml of anhydrous methylene chloride under ice-cooling, and the mixture was stirred for 15 minutes. Further, under ice-cooling, 100 mg (0.23 mmol) of N-[[1-[(2-benzothienylcarbonyl)amino]cyclohexyl]carbonyl]-L-methioninol was added to the reaction solution, and the mixture was stirred at the same temperature for 2 hours. The reaction solution was poured to ice-water and the mixture was extracted with ethyl acetate twice. The organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and after it was dried with anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. 20 ml of diisopropyl ether was added to the residue, and the mixture was stirred at room temperature for 18 hours. The obtained crystal was collected by filtration to quantitatively obtain the title compound.
Reaction SMILES: C([O:3][C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([C:11]([F:14])([F:13])[F:12])=[CH:7][C:6]=1[O:15][CH2:16][CH3:17])C.[Li+].[OH-]>C1COCC1.CO>[CH2:16]([O:15][C:6]1[CH:7]=[C:8]([C:11]([F:12])([F:13])[F:14])[CH:9]=[CH:10][C:5]=1[C:4]([OH:18])=[O:3])[CH3:17]
Reactant: CCOC(=O)c1ccc(C(F)(F)F)cc1OCC
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCOc1cc(C(F)(F)F)ccc1C(=O)O
Yield: 88 %

Procedure:
2-Hydroxy-4-trifluoromethyl-benzoic acid (1.20 g, 5.82 mmol) was reacted with ethyliodide (2.2 eq) and K2CO3 (1.69 g) in DMF solution. The reaction mixture was quenched by adding H2O. The mixture was extracted with ethyl acetate (40 ml×3). A combined organic layer was washed sat NaHCO3 solution (30 ml), H2O (40 ml×5), and brine, and then dried over MgSO4. The filterate was concentrated in vacuo to yield 2-ethoxy-4-trifluoromethyl benzoic acid ethyl ester. The ester obtained above was reacted with 1 N LiOH (15 ml) in THF and CH3OH cosolvent for 2 hrs as described above to yield title compound (1.20 g, 88%)
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.O.O.O.[F-].[Si]([O:29][CH:30]([CH2:41][CH2:42][CH2:43][CH3:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32])(C(C)(C)C)(C)C.O.CCOC(C)=O>C1COCC1>[OH:29][CH:30]([CH2:41][CH2:42][CH2:43][CH3:44])[C:31]([NH:33][C:34]1[CH:39]=[CH:38][C:37]([CH3:40])=[CH:36][N:35]=1)=[O:32]
Reactant: CCCCC(O[Si](C)(C)C(C)(C)C)C(=O)Nc1ccc(C)cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CCCCC(O)C(=O)Nc1ccc(C)cn1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
Tetrabutylammoniumfluoride trihydrate (302 mg, 0.96 mmol) was added to a stirred solution of 2-{[tert-butyl(dimethyl)silyl]oxy}-N-(5-methylpyridin-2-yl)hexanamide (Step 2) (215 mg, 0.64 mmol) in THF (5 mL). The reaction mixture was kept at ambient temperature for 1 h. Water and EtOAc were added and the two phases were separated. The organic phase was washed with water, dried over MgSO4 and concentrated in vacuo. The residue was purified with column chromatography (silica gel, eluting with DCM/EtOAc:2/1) to give the title compound as a colourless solid (135 mg), 1H NMR (300 MHz, CDCl3) δ 9.46 (br s, 1H), 8.20 (d, 1H), 8.04 (d, 1H), 7.55 (dd, 1H), 5.47 (br s, 1H), 4.29 (m, 1H), 2.31 (s, 3H), 1.98 (m, 1H), 1.76 (m, 1H), 1.52 (m, 2H), 1.38 (m, 2H), 0.92 (t, 3H).
Reaction SMILES: Cl[C:2]([S:4]Cl)=[O:3].[C:6]([NH2:11])(=[O:10])[CH:7]([CH3:9])[CH3:8].Cl>>[CH:7]([C:6]1[O:10][C:2](=[O:3])[S:4][N:11]=1)([CH3:9])[CH3:8]
Reactant: CC(C)C(N)=O
Reactant: O=C(Cl)SCl
Agent: Cl
Product: CC(C)c1nsc(=O)o1
Yield: 87.9 %

Procedure:
Chlorocarbonyl sulphenyl chloride (41.9 g, 0.32 mol) is added dropwise to a stirred solution of isobutyramide (25.2 g, 0.29 mol) under dry nitrogen at room temperature. When the addition is complete, the mixture is refluxed for 8 hours, during which time hydrogen chloride gas is evolved. The solvent is removed in vacuo and the residue is distilled to give 5-isopropyl-[1,3,4]oxathiazolin-2-one (37 g, 88%) as a yellow oil, b.p. 58°-59° C./8 mmHg.
Reaction SMILES: ClCC([NH:5][C:6]([N:8]([C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:21][C:20]([C:26]3[CH:31]=[C:30]([Cl:32])[CH:29]=[C:28]([Cl:33])[CH:27]=3)([C:22]([F:25])([F:24])[F:23])[O:19][N:18]=2)=[CH:13][C:12]=1[CH3:34])[CH3:9])=[O:7])=O.C(N(CC)CC)C>CO>[C:6]([N:8]([CH3:9])[C:10](=[O:35])[C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH2:21][C:20]([C:26]3[CH:27]=[C:28]([Cl:33])[CH:29]=[C:30]([Cl:32])[CH:31]=3)([C:22]([F:25])([F:23])[F:24])[O:19][N:18]=2)=[CH:13][C:12]=1[CH3:34])(=[O:7])[NH2:5]
Reactant: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C(=O)NC(=O)CCl
Solvent: CCN(CC)CC
Solvent: CO
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)N(C)C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 0.40 g of N-chloroacetyl-N′-[4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazole-3-yl]-2-methylbenzoyl]-N′-methyl urea synthesized in Synthetic Example 27 and 0.04 g of triethylamine in 4 mL of methanol was stirred at room temperature for 2 hours. After the completion of the reaction, the solvent was distilled off under reduced pressure. The residue was purified with silica gel column chromatography that was eluated with ethyl acetate-hexane (gradient of 1:4 to 4:1) to obtain 0.31 g of the aimed product as white crystal.
Reaction SMILES: CC(O)=O.C[O:6][CH:7](OC)[CH2:8][CH:9]1[C:13](=[O:14])[CH2:12][CH2:11][CH:10]1[CH2:15][C:16]([O:18][CH3:19])=[O:17]>O>[O:14]=[C:13]1[CH2:12][CH2:11][CH:10]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:9]1[CH2:8][CH:7]=[O:6]
Reactant: COC(=O)CC1CCC(=O)C1CC(OC)OC
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)CC1CCC(=O)C1CC=O
Temperature: 45 °C
Yield: 89 %

Procedure:
In a 4 liter jacketed reactor, a mixture of 1,236 liter of AcOH and 1,236 liter of water was heated to 45° C. Then to this mixture were added 494 g of methyl [2-(2,2-dimethoxyethyl)-3-oxocyclopentyl]acetate. The resulting reaction medium was stirred at 46-49° C. until completion of the conversion of the acetal to aldehyde. Distillation under vacuum allowed for the direct isolation of the purified title compound with a yield of 89% (overall yield from Example 1: 66%).
Reaction SMILES: [NH2:1][C@H:2]([C:7]1[CH:12]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[CH:10]=[C:9]([Br:17])[CH:8]=1)[CH2:3][C:4]([OH:6])=[O:5].[CH2:18](O)[CH3:19]>>[CH2:18]([O:5][C:4](=[O:6])[CH2:3][C@H:2]([NH2:1])[C:7]1[CH:12]=[C:11]([C:13]([CH3:14])([CH3:16])[CH3:15])[CH:10]=[C:9]([Br:17])[CH:8]=1)[CH3:19]
Reactant: CCO
Reactant: CC(C)(C)c1cc(Br)cc([C@@H](N)CC(=O)O)c1
Product: CCOC(=O)C[C@H](N)c1cc(Br)cc(C(C)(C)C)c1

Procedure:
Absolute ethanol (500 mL, saturated with anhydrous HCl gas) was added to (S)-3-amino-3-(3-bromo-5-tert-butylphenyl)-propionic acid (37 g, 0.12 mol) and the reaction mixture was heated at reflux for 2 h to give a colorless solution. The solvent was removed in vacuo to give a cream-yellow foamy solid. The solid was washed with diethyl ether/hexane and the dried to give a yellow foamy solid (41 g).
Reaction SMILES: C([N:4]1[C:8]2=[N:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][CH:12]=[C:7]2/[C:6](=[C:17](\OCC)/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)/[C:5]1=[O:27])(=O)C.[NH2:28][C:29]1[CH:34]=[CH:33][C:32]([N:35]([CH3:46])[C:36](=[O:45])[CH2:37][N:38]2[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]2)=[CH:31][CH:30]=1.N1CCCCC1>CN(C=O)C>[CH3:46][N:35]([C:32]1[CH:33]=[CH:34][C:29]([NH:28]/[C:17](/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[C:6]2\[C:5](=[O:27])[NH:4][C:8]3[C:7]\2=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[N:9]=3)=[CH:30][CH:31]=1)[C:36](=[O:45])[CH2:37][N:38]1[CH2:43][CH2:42][N:41]([CH3:44])[CH2:40][CH2:39]1
Reactant: CN1CCN(CC(=O)N(C)c2ccc(N)cc2)CC1
Reactant: CCO/C(=C1/C(=O)N(C(C)=O)c2nc(C(=O)OC)ccc21)c1ccccc1
Solvent: C1CCNCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(n1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(C)CC2)cc1)c1ccccc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
Step-2: To a solution of (E)-methyl 1-acetyl-3-(ethoxy(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (2.6 g, 7.10 mmol) in DMF (5 mL) was added N-(4-aminophenyl)-N-methyl-2-(4-methylpiperazin-1-yl)acetamide (1.94 g, 7.43 mmol) at RT and the reaction mixture was heated to 110° C. and stirred for 1 h. The reaction mixture was allowed to cool to RT, treated with piperidine (3 mL) and stirred for 30 min. The reaction mixture was evaporated and the resultant residue was purified by silica gel column chromatography using 5% CH3OH in dichloromethane as eluent to afford (Z)-methyl 3-(((4-(N-methyl-2-(4-methylpiperazin-1-yl)acetamido)phenyl)amino)(phenyl)methylene)-2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-6-carboxylate as yellow solid. MS (ES+): m/z 541.1 (MH+).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1.C(=O)(O)[O-].[Na+].[CH3:32][S:33](Cl)(=[O:35])=[O:34]>ClCCl>[CH3:32][S:33]([NH:2][C@H:3]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N:14]3[CH2:18][C@H:17]([CH2:19][N:20]4[CH:24]=[CH:23][N:22]=[N:21]4)[O:16][C:15]3=[O:25])=[CH:10][C:9]=2[F:26])[CH2:4]1)(=[O:35])=[O:34]
Reactant: N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)(=O)N[C@H]1CCN(c2ccc(N3C[C@H](Cn4ccnn4)OC3=O)cc2F)C1
Reaction time: 18 h
Yield: 10.1 %

Procedure:
(5R)-3-(4-((3S)-3-Aminopyrrolidin-1-yl)-3-fluorophenyl)-5-(1,2,3-triazol-1-ylmethyl)-oxazolidin-2-one hydrochloride (250 mg, 0.65 mM), in dichloromethane (20 ml) was cooled to 0° and treated with 5% sodium bicarbonate solution (10 ml). The resulting suspension was stirred vigorously, methanesulfonyl chloride (290 mg, 2.5 mM) added, and stirring continued for 18 hours at ambient temperature. Dichloromethane (10 ml) was added, the organic layer separated, and diluted with isohexane (30 ml). The precipitate was filtered, triturated with 2% sodium dihydrogen phosphate, and purified by chromatography on a 2 g silica Mega Bond Elut® column, eluting with a gradient increasing in polarity from 0 to 8% methanol in dichloromethane. Relevant fractions were combined and evaporated to give the desired product (28 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][C:34]([C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)=[O:35].C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:12]3[CH2:16][CH2:15][CH2:14][N:13]3[C:17]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[N:9][C:10]=2[C:39]2[CH:38]=[CH:37][C:36]([C:34](=[O:35])[NH:33][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=3)=[CH:41][CH:40]=2)[CH:5]=[CH:6][N:7]=1
Reactant: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(Br)c12
Reactant: O=C(Nc1ccccn1)c1ccc(B(O)O)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Nc1nccn2c([C@@H]3CCCN3C(=O)OCc3ccccc3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Temperature: 140 °C
Yield: 76.8 %

Procedure:
(S)-benzyl 2-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (0.237 mmol, 98.5 mg) and 4-(pyridin-2-yl-aminocarbonyl)benzeneboronic acid (0.260 mmol, 63.0 mg) were suspended in a mixture of 2N aqueous potassium carbonate solution (2.37 mmol, 1.18 mL) and dioxane (2.96 mL). Nitrogen was bubbled through the mixture, followed by the addition of 1,1′-bis(diphenylphosphino)ferrocene palladium (ii) chloride (0.059 mmol, 47.8 mg). The reaction mixture was heated for 20 minutes at 140° C. in the microwave. Water was added to the reaction mixture, followed by an extraction with ethyl acetate (2×). The combined organic layer was washed with brine, dried over magnesium sulfate and evaporated. The product was purified using silica gel and dichloromethane/methanol=9/1 v/v % as eluent to afford 97.1 mg of (S)-benzyl 2-(8-amino-1-(4-(pyridin-2-ylcarbamoyl)phenyl)imidazo[1,5-a]pyrazin-3-yl)pyrrolidine-1-carboxylate (77%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C(C1C=CC(S([O-])(=O)=O)=CC=1)(=O)C.[Na+].[OH:28][CH2:29][CH2:30][NH2:31].Cl>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH:31][CH2:30][CH2:29][OH:28])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: NCCO
Agent: CC(=O)c1ccc(S(=O)(=O)[O-])cc1
Agent: Cl
Agent: [Na+]
Product: CC(=O)c1ccc(S(=O)(=O)NCCO)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The damp 4-acetylbenzenesulfonyl chloride from 100 g. of sodium 4-acetylbenzenesulfonate is added to a stirred solution of 500 ml. of 50% aqueous 2-hydroxyethylamine. The mixture is stirred at room temperature for 16 hours, then acidified with hydrochloric acid and cooled to 0°-5° C. The precipitate of 4-acetyl-N-(2-hydroxyethyl)benzenesulfonamide is collected by filtration, washed with water and dried; m.p. 119°-121° C. after crystallization from water.