Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([CH:18]2[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]2)[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)[Cl:33].Cl>CO>[ClH:33].[O:31]=[C:13]1[C@@H:12]([NH:11][C:9](=[O:10])[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:17][CH2:16][CH2:15][N:14]1[CH:18]1[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)N1CCC(N2CCC[C@H](NC(=O)OCc3ccccc3)C2=O)CC1
Agent: Cl
Solvent: CO
Product: O=C(N[C@H]1CCCN(C2CCNCC2)C1=O)OCc1ccccc1
Reaction time: 8 h
Yield: 100 %

Procedure:
A flask was charged with (S)-tert-butyl 3-(benzyloxycarbonylamino)-2-oxo-1,4′-bipiperidine-1′-carboxylate (Example 39, Steps A-B; 10.0 g, 23.2 mmol), DCM (60 mL), methanol (6 mL), HCl (57.9 mL, 232 mmol) and the reaction was stirred overnight. The organic solvents were removed under reduced pressure to provide (S)-benzyl 2-oxo-[1,4′-bipiperidin]-3-ylcarbamate hydrochloride (8.52 g, 100% yield). Mass spectrum (apci) m/z=332.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[CH3:10].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17]>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([O:9][Si:20]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:23])[CH3:22])=[CH:4][C:3]=1[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Cc1cc(O)cc(C)c1Br
Agent: c1c[nH]cn1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(O[Si](C)(C)C(C)(C)C)cc(C)c1Br
Temperature: 0 °C
Yield: 97.3 %

Procedure:
To a solution of 4-bromo-3,5-dimethylphenol (25.4 g, 126.2 mmol) and imidazole (9.5 g, 138.9 mmol) in N,N-dimethylformamide (300 mL) was added tert-butyldimethylchlorosilane (20.9 g, 138.9 mmol) under stirring at 0° C., and the mixture was stirred at room temperature for 5 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-hexane/ethyl acetate=10/1) to give the title compound (38.7 g, yield 97%) as a colorless oil.
Reaction SMILES: [C:1]([N:8]1[CH2:15][C@H:14]([OH:16])[CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[F:17][C:18]1[C:23](O)=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28].C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C>[F:17][C:18]1[C:23]([O:11][C:10](=[O:12])[C@@H:9]2[CH2:13][C@@H:14]([OH:16])[CH2:15][N:8]2[C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[C:22]([F:25])[C:21]([F:26])=[C:20]([F:27])[C:19]=1[F:28]
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Boc-trans-4-hydroxy-L-proline (3.5 kg) (prepared as described in Step 1) and pentafluorophenol (3.06 kg) were dissolved in ethyl acetate (52 L). The solution was treated with a solution of dicyclohexylcarbodiimide (3.43 kg) in ethyl acetate (8 L) and the mixture was stirred at room temperature for 2 hours. The resulting slurry was cooled to 0° C., filtered and the solids washed with ethyl acetate (15 L). The filtrate was evaporated at atmospheric pressure to a volume of 10 L and diluted with hexane (100 L). The resulting mixture was stirred at room temperature overnight and then cooled to 0° C. for 1 hour. The solid was collected by filtration, washed with cold (° C.) 10:1 hexane/ethyl acetate (15 L) and dried at 45° C. in vacuo to afford the title compound as a white crystalline solid.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=1)[CH2:9][C:8]2([CH3:29])[CH3:28])=[O:4].[OH-].[Na+].Cl>CO.O1CCCC1.O>[CH3:28][C:8]1([CH3:29])[C:7]2[C:12](=[CH:13][CH:14]=[C:5]([C:3]([OH:4])=[O:2])[CH:6]=2)[NH:11][CH:10]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[CH:16]=2)[CH2:9]1
Reactant: COC(=O)c1ccc2c(c1)C(C)(C)CC(c1cccc(N3CCN(C)CC3)c1)N2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(c2cccc(C3CC(C)(C)c4cc(C(=O)O)ccc4N3)c2)CC1
Temperature: 60 °C
Reaction time: 16 h
Yield: 99.7 %

Procedure:
To a stirred mixture solution of 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (610 mg, 1.49 mmol) in methanol (7.5 mL) and tetrahydrofuran (15 mL) was added 30% sodium hydroxide in water (7.5 mL). The reaction mixture was stirred at 60° C. for 16 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo to afford 4,4-dimethyl-2-[3-(4-methyl-piperazin-1-yl)-phenyl]-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (564 mg, 99%) as a light white solid which was used for next step without further purification: MS (ESI) M+1=380.2.
Reaction SMILES: Br[C:2]1[CH:9]=[N:8][CH:7]=[C:6]([N:10]2[CH2:22][CH2:21][N:13]3[C:14]4[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=4[CH:20]=[C:12]3[C:11]2=[O:23])[C:3]=1[CH:4]=[O:5].[CH3:24][N:25]1[CH:30]=[C:29](B2OC(C)(C)C(C)(C)O2)[CH:28]=[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)[C:26]1=[O:51].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CC#N.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]>[CH3:24][N:25]1[C:26](=[O:51])[C:27]([NH:40][C:41]2[CH:50]=[C:44]3[CH2:45][N:46]([CH3:49])[CH2:47][CH2:48][N:43]3[N:42]=2)=[CH:28][C:29]([C:2]2[CH:9]=[N:8][CH:7]=[C:6]([N:10]3[CH2:22][CH2:21][N:13]4[C:14]5[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=5[CH:20]=[C:12]4[C:11]3=[O:23])[C:3]=2[CH:4]=[O:5])=[CH:30]1
Reactant: O=Cc1c(Br)cncc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: CN1CCn2nc(Nc3cc(B4OC(C)(C)C(C)(C)O4)cn(C)c3=O)cc2C1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: CC#N
Product: CN1CCn2nc(Nc3cc(-c4cncc(N5CCn6c(cc7c6CCCC7)C5=O)c4C=O)cn(C)c3=O)cc2C1
Temperature: 100 °C
Yield: 56.9 %

Procedure:
A 100-mL single-neck round-bottomed flask was charged with 3-bromo-5-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)isonicotinaldehyde 101f (298 mg, 0.7 mmol), 1-methyl-3-(5-methyl-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-ylamino)-5-(4,4,5,5-tetra-methyl-1,3,2-dioxaborolan-2-yl)pyridin-2(1H)-one 135a (325 mg, 0.84 mmol), PdCl2(dppf) (30 mg, 0.035 mmol), K3PO4 (300 mg, 1.4 mmol), and NaOAc.3H2O (200 mg, 1.4 mmol) in CH3CN (70 mL). The system was evacuated and refilled with Argon. The reaction mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by flash column chromatography eluting with 25:1 DCM/MeOH to afford 138a (220 mg, 55%) as a pale yellow solid. MS: [M+H]+ 553.3.
Reaction SMILES: [O:1]1[CH2:5][C:4](=[O:6])[CH2:3][C:2]1=[O:7].[F:8][C:9]([F:15])([F:14])[CH2:10][C:11](O)=[O:12].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C.CC#N>[OH:6][C:4]1[CH2:5][O:1][C:2](=[O:7])[C:3]=1[C:11](=[O:12])[CH2:10][C:9]([F:15])([F:14])[F:8]
Reactant: O=C(O)CC(F)(F)F
Reactant: O=C1COC(=O)C1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CC#N
Solvent: ClCCl
Product: O=C(CC(F)(F)F)C1=C(O)COC1=O
Temperature: 0 °C

Procedure:
To a cool (0° C.), stirred suspension of furan-2,4(3H,5H)-dione (16.46 g, 164 mmol) in DCM (650 mL) was added TEA (23.0 mL, 165 mmol), DMAP (6.04 g, 49.4 mmol), 3,3,3-trifluoropropanoic acid (16.0 mL, 181 mmol) and DCC (40.70 g, 197 mmol) resulting in a yellow homogenous solution. The solution was stirred at 0° C., and then was allowed to warm to room temperature as the bath warmed while stirring overnight. The suspension was filtered and the solid was washed with DCM. The deep red filtrate was concentrated under reduced pressure. The residue was partitioned between EtOAc and 1M HCl (400 mL). The organic phase was washed with brine, dried (Na2SO4), filtered and concentrated under reduced pressure to afford an amber solid. This was dissolved in a minimum amount of CH3CN, to which DCM was added to form a precipitate. The suspension was allowed to stand in the freezer overnight. It was sonicated then cooled and filtered, the solid was washed with cold DCM and then dried to provide Preparation 1A (31.62 g, 91%) as a cream solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 13.07 (1H, br. s.), 4.29 (2H, s), 3.80 (2H, q, J=11.67 Hz).
Reaction SMILES: OC1C=CC=CN=1.[C:8]([O:12][C:13](=[O:41])[NH:14][C@H:15]([C@@H:33]1[CH2:37][C@@H:36]([CH2:38][CH3:39])[C:35](=[O:40])[O:34]1)[CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])([CH3:11])([CH3:10])[CH3:9].[CH3:42][C:43]([CH3:47])([CH3:46])[CH2:44][NH2:45]>O>[C:8]([O:12][C:13](=[O:41])[NH:14][C@@H:15]([CH2:16][N:17]1[CH2:22][C:21](=[O:23])[N:20]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[Cl:30])[CH2:19][C:18]1([CH3:32])[CH3:31])[C@@H:33]([OH:34])[CH2:37][C@H:36]([C:35](=[O:40])[NH:45][CH2:44][C:43]([CH3:47])([CH3:46])[CH3:42])[CH2:38][CH3:39])([CH3:9])([CH3:11])[CH3:10]
Reactant: CC(C)(C)CN
Reactant: CC[C@@H]1C[C@@H]([C@H](CN2CC(=O)N(c3ccccc3Cl)CC2(C)C)NC(=O)OC(C)(C)C)OC1=O
Agent: Oc1ccccn1
Solvent: O
Product: CC[C@H](C[C@H](O)[C@H](CN1CC(=O)N(c2ccccc2Cl)CC1(C)C)NC(=O)OC(C)(C)C)C(=O)NCC(C)(C)C
Temperature: 80 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
24 mg of 2-hydroxypyridine (0.26 mmol) was added to a solution of 250 mg of {(S)-2-[4-(2-chlorophenyl)-2,2-dimethyl-5-oxopiperazin-1-yl]-1-[(2S,4R)-4-ethyl-5-oxotetrahydrofuran-2-yl]ethyl}carbamic acid t-butyl ester obtained in Example (106i) (0.51 mmol) in (2,2-dimethylpropyl)amine (1.20 ml) (10.2 mmol), and the mixture was stirred at 80° C. for two hours. The reaction mixture was cooled and then water was added, followed by extraction with methylene chloride. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/acetone=3/1-2/1) to obtain 246 mg of the title compound (yield: 83%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[N+:21]([O-])=O.[Sn](Cl)Cl>CCO.O1CCOCC1>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]3[N:13]=[CH:14][C:15]([C:17]([F:20])([F:19])[F:18])=[N:16][C:11]3=[N:10][CH:9]=2)=[CH:4][C:3]=1[NH2:21]
Reactant: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: C1COCCO1
Solvent: CCO
Product: Cc1ccc(-c2cnc3nc(C(F)(F)F)cnn23)cc1N
Temperature: 50 °C
Yield: 98.6 %

Procedure:
7-(4-Methyl-3-nitrophenyl)-3-trifluoromethylimidazo[1,2-b][1,2,4]triazine (0.27 g, 0.83 mmol) was dissolved in EtOH/1,4-dioxane (20 ml, 1:1) at ambient temperature under an atmosphere of nitrogen and tin(II) chloride (0.80 g, 4.13 mmol) added. This stirred mixture was warmed at 50° C. for 6 h. The solvents were removed in vacuo, ice-water/NaHCO3 was added and extracted with dichloromethane. These extracts were washed with water and saturated brine then dried (MgSO4), filtered and concentrated in vacuo. Purification by chromatography (silica gel, dichloromethane) gave 0.24 g of the title compound as a red solid: 1H NMR (400 MHz, CDCl3) δ 2.26 (3H, s), 3.75–3.85 (2H, br), 7.22 (1H, d, J 7.8), 7.40 (1H, dd, J 1.7, 7.8), 7.43 (1H, d, J 1.7), 8.55 (1H, s), 8.76 (1H, s); MS (ES+) m/z 294 [M+H]+.
Reaction SMILES: [C:1]([C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8](=[O:30])[C:9]4[CH:21]=[CH:20][C:19](OS(C(F)(F)F)(=O)=O)=[CH:18][C:10]=4[C:11]([CH3:17])([CH3:16])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1)#[N:2].[CH2:31](O)[CH2:32]C.C([B-](F)(F)F)=C.[K+].C(N(CC)CC)C>O>[CH3:16][C:11]1([CH3:17])[C:12]2[NH:13][C:14]3[C:6](=[CH:5][CH:4]=[C:3]([C:1]#[N:2])[CH:15]=3)[C:7]=2[C:8](=[O:30])[C:9]2[CH:21]=[CH:20][C:19]([CH:31]=[CH2:32])=[CH:18][C:10]1=2
Reactant: CCCO
Reactant: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: O
Product: C=Cc1ccc2c(c1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 60 °C
Reaction time: 4 h
Yield: 80 %

Procedure:
Under nitrogen atmosphere, trifluoro-methanesulfonic acid 3-cyano-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazol-8-yl ester (Compound B1, 1.00 g, 2.302 mmol) was added with n-propanol (20 mL), potassium vinyltrifluoroborate (854 mg, 3.0 eq.), dichloro-((bis-diphenylphosphino)ferrocenyl)palladium (217 mg, 0.1 eq.) and triethylamine (1.11 ml, 3.0 eq.) in order and the resultant was stirred at 60° C. for 4 hr. Upon the completion of the reaction, water was added to the reaction solution. The resulting precipitates were filtered and washed with distilled water, and the residues were dried to obtain the title compound (666 mg, 80%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[C:5](=O)[CH2:6][C:7]1[N:12]=[C:11]([C:13]2[C:18]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:16]=[CH:15][N:14]=2)[CH:10]=[CH:9][C:8]=1[C:23]#[N:24])[CH3:2].[F:27][C:28]([F:37])([F:36])[C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1.O>CC(O)=O>[CH2:1]([O:3][C:4]([C:5]1[CH:6]=[C:7]2[C:8]([CH:9]=[CH:10][C:11]([C:13]3[C:18]([C:19]([F:20])([F:22])[F:21])=[CH:17][CH:16]=[CH:15][N:14]=3)=[N:12]2)=[C:23]([NH:33][C:32]2[CH:34]=[CH:35][C:29]([C:28]([F:36])([F:37])[F:27])=[CH:30][CH:31]=2)[N:24]=1)=[O:26])[CH3:2]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)C(=O)Cc1nc(-c2ncccc2C(F)(F)F)ccc1C#N
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cc2nc(-c3ncccc3C(F)(F)F)ccc2c(Nc2ccc(C(F)(F)F)cc2)n1
Temperature: 100 °C

Procedure:
Dissolve 3-(5-cyano-3′-trifluoromethyl-[2,2′]bipyridinyl-6-yl)-2-oxo-propionic acid ethyl ester (70 mg, 0.193 mmol) and 4-trifluoromethyl aniline (31 mg, 0.193 mmol) in AcOH (1 mL). Heat the mixture at 100° C. for 1.5 hours. Cool the mixture in ice and add H2O (5 mL). Extract three times with EtOAC (3×10 mL). Combine the organic extracts and wash with 1 N NaOH (30 mL) and brine (30 mL). Dry the organic extract over Na2SO4 and remove the solvent under reduced pressure. Purify the crude product using silica gel chromatography eluting with hexane/acetone (3:1) to yield the title compound. MS 507.15 (M+1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH2:13][NH:14][C:15]3[CH:16]=[C:17]([C:20]([OH:22])=O)[NH:18][N:19]=3)=[C:11]([CH3:23])[O:10][N:9]=2)=[CH:4][CH:3]=1.[OH:24][CH2:25][CH:26]([NH2:28])[CH3:27]>>[OH:24][CH2:25][CH:26]([NH:28][C:20]([C:17]1[NH:18][N:19]=[C:15]([NH:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:9][O:10][C:11]=2[CH3:23])[CH:16]=1)=[O:22])[CH3:27]
Reactant: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)O)[nH]n1
Reactant: CC(N)CO
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1cc(C(=O)NC(C)CO)[nH]n1
Yield: 32 %

Procedure:
As described for example 152, 5-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-2H-pyrazole-3-carboxylic acid was converted, using 2-hydroxy-1-methylethylamine instead of 2-hydroxy-2-methylpropylamine, to the title compound (13 mg, 32%) which was obtained as an off white solid. MS: m/e=374.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.C(=O)(O)[O-].[Na+].Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17]>C(OCC)C>[CH2:19]([O:18][C:16]([NH:1][C:2]1([C:7]([OH:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1)=[O:17])[CH3:20]
Reactant: NC1(C(=O)O)CCCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Product: CCOC(=O)NC1(C(=O)O)CCCC1
Reaction time: 6 h

Procedure:
To an aqueous solution (35 ml) of 1-amino-1-carboxycyclopentane (1.29 g; 10 mmol) and sodium bicarbonate (1.85 g; 22 mmol), a solution of ethyl chloroformate (1.30 g; 12 mmol) in diethyl ether (10 ml) was added at room temperature and followed by stirring for 6 hours. The organic layer was separated from the aqueous layer and extracted with a saturated aqueous solution of sodium bicarbonate. The combined aqueous layers were acidified with conc. hydrochloric acid and extracted with chloroform. The extract was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give 1-ethoxycarbonylamino-1-carboxycyclopentane as a colorless solid.
Reaction SMILES: [N+:1]([CH2:4][CH:5]1[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2)([O-])=O.N.[ClH:16]>C(O)C.O.[Ni]>[ClH:16].[NH2:1][CH2:4][CH:5]1[O:9][B:8]([OH:10])[C:7]2[CH:11]=[CH:12][CH:13]=[CH:14][C:6]1=2
Reactant: O=[N+]([O-])CC1OB(O)c2ccccc21
Agent: [Ni]
Agent: Cl
Agent: N
Solvent: O
Solvent: CCO
Product: NCC1OB(O)c2ccccc21
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of 3-(nitromethyl)benzo[c][1,2]oxaborol-1(3H)-ol (965 mg, 5 mmol) in ethanol (30 mL) were added ammonia (2M solution in ethanol, 18 mL, 36 mmol) and Raney 2800 Nickel (⅓ teaspoon of a slurry in water). The reaction mixture was subjected to hydrogenation at 45 atmospheres for 2 h at rt. The resulting mixture was filtered through Celite and the filtrate was concentrated in vacuo yielding the crude amine. The amine was dissolved in dioxanes (10 mL) and HCl (4M in dioxanes, 5 mL, 20 mmol) was added. After 1 h, the suspension was concentrated and the resulting solid was washed with hexanes followed by ether yielding 3-(aminomethyl)benzo[c][1,2]oxaborol-1(3H)-ol hydrochloride (917 mg, 4.6 mmol, 92% yield) as a white solid.
Reaction SMILES: [CH:1]([CH:4]1[CH:9]2[CH2:10][CH:6]([CH:7]=[CH:8]2)[CH:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:3])[CH3:2]>[Pd].C(O)C>[CH:1]([CH:4]1[CH:9]2[CH2:10][CH:6]([CH2:7][CH2:8]2)[CH:5]1[C:11]([O:13][CH2:14][CH3:15])=[O:12])([CH3:3])[CH3:2]
Reactant: CCOC(=O)C1C2C=CC(C2)C1C(C)C
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C1C2CCC(C2)C1C(C)C
Reaction time: 1 h

Procedure:
0.35 g of 5% palladium on charcoal as catalyst was added to 6.5 g of ethyl 3-isopropyl-5-bicycloheptene-2-carboxylate (mixture of isomers obtained according to Example 5) dissolved in 30 ml of ethanol, after which the mixture was hydrogenated at 20° C. for 1 hour under a hydrogen pressure of 100 kPa. The catalyst was then filtered off, the filtrate evaporated down and the evaporation residue distilled. 5.7 g were obtained of the desired compound as a mixture of endo- and exo-isomer. b.p.: 89° C./0.7 kPa; NMR (of the mixture): 0.7-1.0 (6H); 1.2 (3H, t); 1.0-2.5 (11H); 3.9-4.2 (2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:26][CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22](=[NH:25])[NH:23][OH:24])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[C:32](N1CCCCC1)#[N:33]>>[NH2:33][C:32]1[O:24][N:23]=[C:22]([C:19]2[N:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C@@H:12]([C:4]3[CH:5]=[CH:6][C:7]([S:8]([CH3:11])(=[O:9])=[O:10])=[C:2]([Cl:1])[CH:3]=3)[CH2:26][CH:27]3[CH2:28][CH2:29][CH2:30][CH2:31]3)=[N:17][CH:18]=2)[N:25]=1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C(=N)NO)cn2)cc1Cl
Reactant: N#CN1CCCCC1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3noc(N)n3)cn2)cc1Cl
Temperature: 130 °C
Yield: 37 %

Procedure:
A mixture of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(N-hydroxycarbamimidoyl)-pyrazin-2-yl]-propionamide (prepared as in Example 1, 7.00 g, 15.02 mmol) in N-cyanopiperidine (25 mL) was heated at 130° C. in a sealed tube for 1.5 h. The mixture was allowed to cool to 25° C. and then concentrated under a stream of anhydrous nitrogen overnight. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/2 ethyl acetate/hexanes) afforded the N-[5-(5-amino-[1,2,4]oxadiazol-3-yl)-pyrazin-2-yl]-2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionamide (2.74 g, 37%) as an off-white solid: mp 262–264° C.; (ES)+-HRMS m/e calcd for C21H23ClN6O4S2 (M+Na)+ 513.1082, found 513.1088.
Reaction SMILES: [C:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][C:4]=1[C:10]([F:13])([F:12])[F:11])#[N:2].[C:14](Cl)(=[O:18])[C:15]([CH3:17])=[CH2:16]>>[C:14]([NH:7][C:6]1[CH:8]=[CH:9][C:3]([C:1]#[N:2])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:5]=1)(=[O:18])[C:15]([CH3:17])=[CH2:16]
Reactant: C=C(C)C(=O)Cl
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Using 4-cyano-3-trifluoromethylaniline and methacryloyl chloride as starting materials, the title compound is prepared according to the method described in J. Med. Chem., 1988, 954–959.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:37][CH2:38][O:39][CH3:40])=[C:14]([NH:16][C:17]2[C:18]([NH:27][S:28]([CH:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)(=[O:30])=[O:29])=[N:19][C:20]3[C:25]([N:26]=2)=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:15]=1.CCN(CC)CC>C(Cl)Cl>[C:1]([N:34]1[CH2:35][CH2:36][CH:31]([S:28]([NH:27][C:18]2[C:17]([NH:16][C:14]3[CH:15]=[C:10]([O:9][CH3:8])[CH:11]=[CH:12][C:13]=3[CH2:37][CH2:38][O:39][CH3:40])=[N:26][C:25]3[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=3)[N:19]=2)(=[O:30])=[O:29])[CH2:32][CH2:33]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: COCCc1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCc1ccc(OC)cc1Nc1nc2ccccc2nc1NS(=O)(=O)C1CCN(C(C)=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.6 %

Procedure:
Acetic anhydride (21 mg; 0.2 mmol; 1.2 eq) is added to a suspension of N-(3-{[5-methoxy-2-(2-methoxyethyl)phenyl]amino}quinoxalin-2-yl)piperidine-4-sulfonamide (100 mg; 0.17 mmol; 1 eq) in DCM (10 mL), followed by Et3N (0.06 mL; 0.43 mmol; 2.5 eq) and the reaction mixture is stirred at room temperature for 2 h. The solution is diluted to 30 mL with DCM, washed successively with 0.1 M HCl and brine, dried over MgSO4 and concentrated in vacuo to give a yellow solid. The residue is recrystallised from a mixture of DCM/n-pentane to afford 59 mg (67%) of the title compound as a pale yellow solid. 1H NMR (DMSO-d6) δ 12.25 (s, 1H), 9.15 (s, 1H), 7.95-7.81 (m, 2H), 7.50-7.44 (m, 1H), 7.37-7.26 (m, 2H), 7.22 (d, J=8.4 Hz, 1H), 6.71 (dd, J=8.4, 2.6 Hz, 1H), 4.53 (br d, J=12.8 Hz, 1H), 3.97 (br d, J=13.3 Hz, 1H), 3.78 (s, 3H), 3.60-3.36 (m, 3H), 3.25 (s, 3H), 3.10 (br t, J=12.0 Hz, 1H), 2.78 (t, J=6.0 Hz, 2H), 2.58 (br t, J=12.7 Hz, 1H), 2.19 (br d, J=12.7 Hz, 2H), 2.02 (s, 3H), 1.80-1.50 (m, 2H). HPLC (max plot) 99%; Rt 3.85 min. UPLC/MS (ES+) 512.2, (ES−) 512.3.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].N(CCO)CCO>C1COCC1>[C:4]1([C@@H:1]([OH:3])[CH3:2])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Solvent: C1CCOC1
Solvent: OCCNCCO
Product: C[C@H](O)c1ccccc1
Reaction time: 7 h
Yield: 72.4 %

Procedure:
Under a nitrogen atmosphere, with stirring, acetophenone (3.05 mL, 26 mmol) was added to a solution of diisopinocampheylchloroborane (9.0 g, 28 mmol) in THF (20 mL) at -25° C. A yellow color developed immediately. The reaction was complete after 7 h at -25° C. (followed by 11B NMR after methanolysis of an aliquot). The volatiles were pumped off at aspirator pressure and the α-pinene was removed under reduced pressure (0.1 mm Hg, 8 h). The residue was dissolved in ethyl ether (100 mL) and diethanolamine (2.2 equiv) was added. The separated solid was filtered off after 2 h and washed twice with pentane (~30 mL). The combined ether and pentane filtrates were concentrated. The residue, upon distillation (bp 118° C., 22 mm Hg) provided [S]-1-phenylethanol (2.3 g, 72% yield) [α]20D-42.6° (neat) after purification by preparative gas liquid chromatography on Carbowax 20M; 98% ee based on -43.5° for maximum reported rotation. Gas chromatography analysis of its α-methoxy-α-(trifluoromethyl)phenylacetate (made from (+)-MTPA chloride, Aldrich) on Supelcowax glass capillary column (15 m) showed a composition of 98.7% S+1.3% R (i.e., 97.4% ee), in good agreement with the optical rotation measurement.