Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]([C@H:11]1[C@@H:15]2[C@@H:16]3[C@@:29]([CH3:32])([CH2:30][CH2:31][C@@:14]2([CH2:38][OH:39])[CH2:13][CH2:12]1)[C@@:28]1([CH3:33])[C@@H:19]([C@:20]2([CH3:37])[C@@H:25]([CH2:26][CH2:27]1)[C:24]([CH3:35])([CH3:34])[C@@H:23]([OH:36])[CH2:22][CH2:21]2)[CH2:18][CH2:17]3)=[CH2:10]>ClCCl>[CH3:32][C@:29]12[C@:28]3([CH3:33])[CH2:27][CH2:26][C@H:25]4[C:24]([CH3:34])([CH3:35])[C@@H:23]([OH:36])[CH2:22][CH2:21][C@:20]4([CH3:37])[C@H:19]3[CH2:18][CH2:17][C@@H:16]1[C@@H:15]1[C@@:14]3([CH2:38][O:39][C@H:11]1[C:9]([CH3:8])([CH3:10])[CH2:12][CH2:13]3)[CH2:31][CH2:30]2
Reactant: C=C(C)[C@@H]1CC[C@]2(CO)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC[C@H](O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)CC[C@]23CC[C@]4(C)[C@H](CC[C@@H]5[C@@]6(C)CC[C@H](O)C(C)(C)[C@@H]6CC[C@]54C)[C@H]2[C@H]1OC3
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Trifluoroacetic acid (5 ml, 99%) was added to betulin (2 g) in 50 ml of dichloromethane at 0° C. The resulting solution was stirred for 30 minutes, poured into 100 ml of cracked ice, extracted with CH2Cl2 (3×10 ml), washed with concentrated NaHCO3 (2×20 ml) and water (2×20 ml), and dried over anhydrous Na2SO4. Evaporation of the solvent gave allobetulin, which was recrystallized from hexane-dichloromethane to yield white needles (yield 1.98 g, mp 268-269° C. [lit. 265-268° C.]); IR (KBr) 3448.5, 2941.5, 2866.6, 1780.7, 1456.6, 1384.4, 1168.9, 1035.0, cm−1; 1H NMR (CDCl3) δ 3.75 (D, J=10.3 Hz, 1H, 28-H), 3.51 (S, 1H, 19-H), 3.41 (D, J=10.3 Hz, 1H, 28-H), 3.18 (DD, 1H, 3-H), 0.74, 0.76, 0.81, 0.88, 0.89, 0.94, 0.94 (all S, 7×3H, 27-, 23-, 24-, 25-, 26-, 29-, 30-Me), 1.01-1.74 (complex CH—, CH2, 25H); 13C NMR (CDCl3) δ 88.41, 79.38, 71.49, 55.77, 51.35, 47.07, 40.99, 40.88, 40.87, 39.16, 37.52, 36.95, 36.51, 34.40, 34.18, 32.96, 29.08, 28.27, 27.57, 26.72, 26.72, 26.50, 24.82, 21.26, 18.54, 16.79, 15.96, 15.72, 13.82; MS (EI) 442, 424, 411, 371, 355, 303, 273, 257, 245, 231, 220, 207, 203, 189, 177, 162, 149, 135.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:8][O:7][C:6]2=[C:9](C(O)=O)[S:10][C:11](C(O)=O)=[C:5]2[O:4][CH2:3]1.COC(C)(C)C>N1C2C(=CC=CC=2)C=CC=1.[Cr]([O-])([O-])=O.[Cu+2]>[F:18][C:2]1([F:1])[CH2:8][O:7][C:6]2=[CH:9][S:10][CH:11]=[C:5]2[O:4][CH2:3]1
Reactant: O=C(O)c1sc(C(=O)O)c2c1OCC(F)(F)CO2
Agent: O=[Cr]([O-])[O-]
Agent: [Cu+2]
Solvent: COC(C)(C)C
Solvent: c1ccc2ncccc2c1
Product: FC1(F)COc2cscc2OC1
Yield: 39.9 %

Procedure:
300 mg (1.07 mmol) of 3,3-difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine-6,8-dicarboxylic acid was heated at 175° C. with 77 mg of copper chromite in 3.0 mL of quinoline for 1.5 hours. After cooling and mixing with 35 mL of tert-butyl methyl ether, the resulting mixture was washed three times with 2N hydrochloric acid, then three times with deionized water, dried with anhydrous magnesium sulphate and finally evaporated to dryness yielding 138 mg of raw product. The raw product was purified by column chromatography using Kieselgel 60 and cyclohexane as eluant. 82 mg of 3,3-difluoro-3,4-dihydro-2H-thieno[3,4-b][1,4]-dioxepine (M3) was obtained corresponding to a yield of 40% with a melting point of 66–67° C., as characterized by:
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Br[C:27]1C=CC(N)=C(C)C=1.P(Cl)(Cl)(Cl)=O.N>O>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([Cl:23])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][C:15]=4[CH3:27])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Reactant: Cc1cc(Br)ccc1N
Agent: N
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Br)cc2c(Cl)c(Cc3ccc(-n4cccn4)cc3)c(Cl)nc12
Temperature: 105 °C
Reaction time: 5 h

Procedure:
A mixture of 2-(4-(1H-pyrazol-1-yl)benzyl)malonic acid (20.0 g, 71.5 mmol, Intermediate 6, step b) and 4-bromo-2-methylaniline (13.3 g, 71.5 mmol) in phosphorus oxychloride (66.8 mL, 712 mmol) was heated at 105° C. After 5 hours, the mixture was cooled to room temperature and added to water (600 mL) with cooling so that the internal temperature did not exceed 35° C. The pH of the mixture was adjusted to 8-9 by the slow addition of saturated aqueous ammonia solution such that the internal temperature did not exceed 35° C. After 30 minutes of stirring at room temperature, the mixture was filtered and the solid material was suspended in acetonitrile (200 mL), sonicated and filtered. The solid material was collected and suspended in DCM (80 mL), sonicated and filtered and washed with ether (40 mL). The filtrate was concentrated, suspended in DCM (40 mL), sonicated and filtered to provide more of the desired product. To 5 g of the isolated solid, DCM (300 mL) and aqueous saturated NaHCO3 (100 mL) were added and the mixture was transferred to a separatory funnel, and the layers were separated. The DCM layer was further washed with brine (100 mL), dried (MgSO4), filtered and the solvents were removed under reduced pressure. The crude material was purified using flash-column chromatography on silica gel eluting with DCM to provide 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloro-8-methylquinoline as an off-white solid.
Reaction SMILES: [H-].[Na+].C[O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])=[C:9](Cl)[N:8]=1)=[O:6].[CH:21]1([CH2:24][OH:25])[CH2:23][CH2:22]1>>[CH:21]1([CH2:24][O:25][C:9]2[N:8]=[C:7]([C:5]([OH:4])=[O:6])[CH:12]=[CH:11][C:10]=2[N:13]2[CH2:17][CH2:16][CH2:15][S:14]2(=[O:19])=[O:18])[CH2:23][CH2:22]1
Reactant: COC(=O)c1ccc(N2CCCS2(=O)=O)c(Cl)n1
Reactant: OCC1CC1
Agent: [H-]
Agent: [Na+]
Product: O=C(O)c1ccc(N2CCCS2(=O)=O)c(OCC2CC2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46 %

Procedure:
Sodium hydride (0.029 g, 0.86 mmol) was added in portions to a solution of cyclopropanemethanol (CAN 2516-33-8, 20 mL) and the reaction mixture was stirred for 30 min at room temperature. 6-Chloro-5-(1,1-dioxido-isothiazolidin-2-yl)-pyridine-2-carboxylic acid methyl ester (0.050 g, 0.17 mmol) was added and the mixture was heated to 100° C. overnight, quenched with water and concentrated under reduced pressure. The residue was dissolved in water, extracted with ethyl acetate (50 mL). The pH of the aqueous layer was adjusted to 2 by addition of 1 N hydrochloric acid and subsequently extracted with ethyl acetate (3×20 mL). The combined extracts were washed with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (silica gel, 4 g, 33% ethyl acetate in petroleum ether) to yield the title compound (25 mg, 0.08 mmol, 46%) as yellow solid; MS (EI): m/e=313.1 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][CH:10]=[O:11])=[C:4]([CH3:12])[C:3]=1[CH3:13].Br[CH2:15][C:16]([CH3:24])=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(OCC)(=O)C.CCCCCC>[CH3:12][C:4]1[C:3]([CH3:13])=[C:2]([O:1][CH2:15][C:16]([CH3:24])=[CH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][CH:10]=[O:11]
Reactant: CC(=Cc1ccccc1)CBr
Reactant: Cc1cc(O)c(C)c(C)c1NC=O
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC(=Cc1ccccc1)COc1cc(C)c(NC=O)c(C)c1C
Yield: 41 %

Procedure:
By using N-(4-hydroxy-2,3,6-trimethylphenyl)formamide and 1-(3-bromo-2-methyl-1-propenyl)benzene, the title compound was synthesized according to Reference Example 17a. Yield: 41%. Melting point: 152-154° C. (Ethyl acetate-hexane).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:9]=[C:10]([C:32]([O:34]CC)=[O:33])[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:12]=2[N:13]=1.[OH-].[Na+]>C1COCC1.O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][NH:7][C:8]1[CH:9]=[C:10]([C:32]([OH:34])=[O:33])[C:11]2[C:16]([CH3:17])=[N:15][N:14]([CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:12]=2[N:13]=1
Reactant: CCOC(=O)c1cc(NCc2ccco2)nc2c1c(C)nn2Cc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nn(Cc2ccc(Oc3ccccc3)cc2)c2nc(NCc3ccco3)cc(C(=O)O)c12
Yield: 60.5 %

Procedure:
(see, e.g., Neres, J., et al., J Med Chem 2013, 56, 2385-405). A solution of ester 51 (40 mg, 0.08 mmol) and 1N NaOH (3.5 mL, 3.5 mmol) in THF (1.5 mL) was refluxed for 3 h. Reaction mixture was diluted with water (10 mL) and washed with EtOAc (10 mL×2). Aqueous layer was acidified with 1N HCl and extracted with EtOAc (10 mL×2). Combined organic extracts were washed with brine, dried (Na2SO4) and filtered. The solvent was removed under reduced pressure to give the title compound (22 mg, 61%) as an orange solid. 99% pure by HPLC. 1H NMR (500 MHz, DMSO-d6) δ 7.79 (t, J=5.1 Hz, 1H), 7.54 (s, 1H), 7.34 (t, J=7.6 Hz, 2H), 7.27 (d, J=8.1 Hz, 2H), 7.10 (t, J=6.8 Hz, 1H), 6.95 (d, J=7.9 Hz, 2H), 6.90 (d, J=8.3 Hz, 2H), 6.86 (s, 1H), 6.33 (s, 1H), 6.25 (s, 1H), 5.35 (s, 2H), 4.57 (d, J=5.2 Hz, 2H), 2.41 (s, 3H). 13C NMR (125 MHz, DMSO-d6) δ 167.35, 157.85, 157.05, 156.29, 153.26, 152.02, 142.37, 140.38, 135.41, 133.48, 130.46, 130.44, 130.08, 123.85, 118.98, 118.97, 110.81, 107.38, 103.37, 49.09, 37.87, 15.96. ESI MS: m/z 455.0 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2[CH2:26][NH:27][CH2:28][CH3:29])[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=1)[CH3:5].[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:1][O:2][C:3](=[O:30])[C@H:4]([C:6]1[CH:7]=[C:8]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:23])([F:24])[F:25])=[CH:18][C:17]=2[CH2:26][N:27]([CH2:28][CH3:29])[C:39]([NH:38][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:40])[CH:9]=[C:10]([C:12]([F:14])([F:15])[F:13])[CH:11]=1)[CH3:5]
Reactant: O=C=NCc1ccccc1
Reactant: CCNCc1cc(C(F)(F)F)ccc1-c1cc([C@H](C)C(=O)OC)cc(C(F)(F)F)c1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@H](C)C(=O)OC)cc(C(F)(F)F)c1)C(=O)NCc1ccccc1

Procedure:
(S)-2-(2′-ethylaminomethyl-5,4′-bis-trifluoromethyl-biphenyl-3-yl)-propionic acid methyl ester and benzyl isocyanate.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].Cl[C:5]1[N:10]=[C:9]([C:11]2[C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1.[H-].[Na+]>CN(C=O)C.C(Cl)Cl>[CH2:1]([S:3][C:5]1[N:10]=[C:9]([C:11]2[C:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[N:23]=[CH:22][CH:21]=3)=[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]3[N:12]=2)[CH:8]=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCS
Reactant: Clc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCSc1cccc(-c2nn3ccccc3c2-c2ccnc3ccccc23)n1
Yield: 91.5 %

Procedure:
Add ethanethiol (0.71 mL, 0.96 mmol) to a solution of 4-[2-(6-chloro-pyridin-2-yl)-pyrazolo[1,5-a]pyridin-3-yl]-quinoline (37 mg, 0.1 mmol) in DMF (2.5 mL) at 0° C. Add sodium hydride (38 mg, 0.96 mmol), stir the mixture at room temperature for 72 hours. Dilute the reaction mixture with methylene chloride (50 mL) and wash with water (2×50 mL), brine (1×50 mL). Dry the combined organic layers with sodium sulfate and concentrate. Purify the residue by flash column chromatography (SiO2, 50% ethyl acetate/hexanes) to give the title compound 35 mg (91%) as an off-white solid.
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[Br:12][C:13]1[S:17][C:16]([C:18]([C@H:20]2[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]2)=[CH2:19])=[N:15][CH:14]=1>C(Cl)Cl>[Br:12][C:13]1[S:17][C:16]([C:18]2([C@H:20]3[CH2:25][CH2:24][C@H:23]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:22][CH2:21]3)[CH2:19][O:9]2)=[N:15][CH:14]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=C(c1ncc(Br)s1)[C@H]1CC[C@H](C(=O)OCC)CC1
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](C2(c3ncc(Br)s3)CO2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
mCPBA (130 mg, 0.582 mmol) was added was added to a solution of ethyl trans-4-[1-(5-bromo-1,3-thiazol-2-yl)ethenyl]cyclohexanecarboxylate (182 mg, 0.529 mmol) in DCM (3 ml) at 0° C. The mixture was then allowed to stir at room temperature for 17 h, diluted with dichlormethane and washed with sodium hydroxide (2M in H2O). The aqueous layer was extracted with DCM and the combined organic layers were washed with brine, dried, concentrated in vacuo. The residue was purified on silica gel (0-15% EtOAc in hexane) to afford ethyl trans-4-[2-(5-bromo-1,3-thiazol-2-yl)oxiran-2-yl]cyclohexanecarboxylate. MS ESI calc'd. for C14H18BrNO3S [M+H]+ 360. found 360.
Reaction SMILES: C([N:8]1[C:12]2([CH2:16][CH2:15][N:14]([C:17]3[CH:18]=[N:19][CH:20]=[C:21]([O:23][CH2:24][CH3:25])[CH:22]=3)[CH2:13]2)[CH2:11][CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.[H][H]>C(O)C.[OH-].[OH-].[Pd+2]>[CH2:24]([O:23][C:21]1[CH:22]=[C:17]([N:14]2[CH2:15][CH2:16][C:12]3([NH:8][CH2:9][CH2:10][CH2:11]3)[CH2:13]2)[CH:18]=[N:19][CH:20]=1)[CH3:25]
Reactant: CCOc1cncc(N2CCC3(CCCN3Cc3ccccc3)C2)c1
Reactant: [H][H]
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Product: CCOc1cncc(N2CCC3(CCCN3)C2)c1
Yield: 91.1 %

Procedure:
To a solution of 1-benzyl-7-(5-ethoxy-3-pyridyl)-1,7-diazaspiro[4.4]nonane (540 mg, 1.6 mmol) in ethanol (25 mL) in a pressure bottle was added concentrated HCl (1 mL) and Pearlman's catalyst (Pd(OH)2, 20% on carbon, 50 mg). The solution was shaken under 50 psi of hydrogen gas for 8 h. The catalyst was removed by filtration through Celite, and the filter cake was washed with ethanol (20 mL). The solvent was removed by rotary evaporation, and the residue was basified with saturated aqueous sodium bicarbonate to pH 8-9. Solid sodium chloride (2 g) was added, and the mixture was extracted with chloroform (4×20 mL). The combined chloroform extracts were dried (Na2SO4), filtered and concentrated by rotary evaporation to afford 360.7 mg of the desired compound as a light brown viscous liquid (91.1%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([O:17]C(C)(C)C)=[O:16])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12](=[O:22])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:11]=1
Reactant: CC(C)(C)OC(=O)CCC(=O)c1ccc(OCc2ccccc2F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCC(=O)c1ccc(OCc2ccccc2F)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of tert-Butyl 4-(4-(2-fluorobenzyloxy)phenyl)-4-oxobutyrate (Step B, 1.27 g, 4.2 mmol) in dichloromethane (25 ml) was treated with trifluoroacetic acid (5 ml). The reaction mixture was stirred at ambient temperature for 3 hours and concentrated in vacuo. The purification was done by flash chromatography on silica gel column (chloroform:methanol, 95:5 spiked with acetic acid) to afford the title compound as a white powder.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:11][CH2:12][C@H:13]([NH:18][CH2:19][C@@H:20]([OH:42])[C@@H:21]([NH:31]C(=O)OCC1C=CC=CC=1)[CH2:22][C:23]1[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=1)[CH2:14][CH:15]([CH3:17])[CH3:16])[CH:9]=[CH2:10].O.[OH-].[Ba+2].[OH-]>COCCOC.O>[CH2:8]([O:11][CH2:12][C@H:13]([NH:18][CH2:19][C@@H:20]([OH:42])[C@@H:21]([NH2:31])[CH2:22][C:23]1[CH:24]=[C:25]([F:30])[CH:26]=[C:27]([F:29])[CH:28]=1)[CH2:14][CH:15]([CH3:16])[CH3:17])[CH:9]=[CH2:10]
Reactant: C=CCOC[C@@H](CC(C)C)NC[C@@H](O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OCc1ccccc1
Agent: [Ba+2]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: COCCOC
Solvent: O
Product: C=CCOC[C@@H](CC(C)C)NC[C@@H](O)[C@@H](N)Cc1cc(F)cc(F)c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 57.3 %

Procedure:
Step AO (2): To a solution of benzyl (2S,3R)-4-((R)-1-(allyloxy)-4-methylpentan-2-ylamino)-1-(3,5-difluorophenyl)-3-hydroxybutan-2-ylcarbamate trifluoroacetate salt (560 mg, 1.19 mmol) in DME (9.0 mL) and water (6.0 mL) was added barium hydroxide monohydrate (1.35 g, 7.11 mmol). The reaction mixture was stirred at 110° C. in a high pressure vial for 18 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuum. The residue was purified by reverse phase chromatography to give (2R,3S)-1-((R)-1-(allyloxy)-4-methylpentan-2-ylamino)-3-amino-4-(3,5-difluorophenyl)butan-2-ol double trifluoroacetate salt (243 mg, 57%) as a colorless oil. LC-MS (M+H)+=357.09.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[N:19][C:18]([NH2:21])=[CH:17][CH:16]=1.[CH3:22][O:23][C:24](=[O:29])[CH2:25][C:26](Cl)=[O:27]>>[CH3:22][O:23][C:24](=[O:29])[CH2:25][C:26]([NH:21][C:18]1[N:19]=[N:20][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)=[N:5][O:6][C:2]=2[CH3:1])=[CH:16][CH:17]=1)=[O:27]
Reactant: COC(=O)CC(=O)Cl
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(N)nn1
Product: COC(=O)CC(=O)Nc1ccc(OCc2c(-c3ccccc3)noc2C)nn1
Yield: 32 %

Procedure:
As described for example 18, 6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridazin-3-ylamine (200 mg, 0.7 mmol) was converted, using chlorocarbonyl-acetic acid methyl ester instead of methoxyacetyl chloride, to the title compound (88 mg, 32%) which was obtained as a white solid. MS: m/e=383.3 [M+H]+.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:29])[NH2:28])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42]>>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:33][CH2:34][C:35]([O:37][CH2:38][CH3:39])=[O:36])[C:9]([C:11]1[CH:32]=[CH:31][C:14]2[N:15]([CH3:30])[C:16]([CH2:18][N:19]([C:21]3[CH:26]=[CH:25][C:24]([C:27](=[NH:28])[NH:29][C:41]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH3:51])=[O:42])=[CH:23][CH:22]=3)[CH3:20])=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCCCCCCCOC(=O)Cl
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CN(C)c1ccc(C(=N)N)cc1)n2C)c1ccccn1
Agent: Cl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(N(C)Cc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 36 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)-N-methylaminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 36% of theory, C37H47N7O5 (669.8); EKA mass spectrum: (M+H)+=670; (M+H+Na)++=346.8; (M+2H)++=335.6.
Reaction SMILES: Cl.[CH3:2][O:3][C:4]([C@H:6]1[CH2:10][C@@H:9]([NH2:11])[CH:8]=[CH:7]1)=[O:5].[C:12]1([C:18](Cl)([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(CC)CC)C>C(Cl)Cl>[C:18]([NH:11][C@@H:9]1[CH2:10][C@H:6]([C:4]([O:3][CH3:2])=[O:5])[CH:7]=[CH:8]1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COC(=O)[C@@H]1C=C[C@H](N)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C=C[C@H](NC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 17 h
Yield: 105.3 %

Procedure:
Methyl-(1S,4R)-4-aminocyclopent-2-ene-1-carboxylate hydrochloride (5.50 g) was suspended in methylene chloride (60 mL), to which triphenylmethyl chloride (9.06 g, 0.0325 mol) was added. The mixture was then cooled to 0° C. Triethylamine (10.8 mL, 0.0774 mol) was then added dropwise keeping the temperature less than 10° C. Upon completion of addition, the mixture was allowed to warm to 20-25° C. The mixture was left to stir at 20-25° C. for 17 hours. The mixture was then washed with water (3×50 mL). The aqueous washes were combined and extracted with DCM (50 mL). The organics were combined and washed with brine (20 mL) and the solvent was removed under reduced pressure to afford the title compound as a brown oil (12.5 g) which was used without further purification. 1H NMR (300 MHz, CDCl3, δ): 7.58 (m, 6H), 7.27 (m, 6H), 7.18 (m, 3H), 5.57 (m, 1H), 4.93 (m, 1H), 3.76 (m, 1H), 3.65 (s, 3H), 3.18 (m, 1H), 2.11 (m, 1H), 1.90 (m, 1H) and 1.53 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([NH2:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(O)C>[CH2:1]([N:8]([CH3:12])[CH2:9][CH2:10][NH:20][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: CN(CCCl)Cc1ccccc1
Solvent: CCO
Product: CN(CCNCc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 59 %

Procedure:
128 g (0.7 mol) of the compound obtained in Step b dissolved in 600 ml of ethanol are added dropwise to 150 g (1.4 mol) of benzylamine diluted in 200 ml of warm ethanol. The mixture is stirred at room temperature for 24 hours and the solvent is evaporated off in vacuo. Benzylamine hydrochloride crystallises from a mixture of methylene chloride and acetone, and is removed by filtration. The filtrates are saturated with gaseous hydrogen chloride and the hydrochloride of the desired compound crystallises from a methylene chloride/ether mixture. 105 g of white crystals are obtained.
Reaction SMILES: N([O-])=O.[Na+].[F:5][B-](F)(F)F.[Na+].Cl[C:12]1[C:19]([Cl:20])=[C:18](Cl)[C:17]([F:22])=[CH:16][C:13]=1[C:14]#[N:15].[F-:23].[K+]>CS(C)=O>[Cl:20][C:19]1[C:12]([F:5])=[C:13]([CH:16]=[C:17]([F:22])[C:18]=1[F:23])[C:14]#[N:15]
Reactant: N#Cc1cc(F)c(Cl)c(Cl)c1Cl
Reactant: [F-]
Reactant: F[B-](F)(F)F
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#Cc1cc(F)c(F)c(Cl)c1F

Procedure:
The reduction of 2,3,4-trichloro-5-fluoronitrobenzene (i) with Fe--HCI in hot water gives 2,3,4-trichloro-5-fluoroaniline (ii), which, by diazotization with NaNO2 --HCI and reaction with sodium tetra-fluoroborate and cuprous cyanide, is converted to 2,3,4-trichloro-5-fluorobenzonitrile (iii). The reaction of (iii) with KF in DMSO at 140° affords 3-chloro-2,4,5-trifluorobenzonitrile (iv), which, by hydrolysis with 30% HBr in refluxing acetic acid, gives 3-chloro-2,4,5-trifluorobenzamide (v). The hydrolysis of (v) with 18N H2SO4 at 135° yields the corrsponding benzoic acid (vi), which is treated with refluxing SOCl2 to afford the acyl chloride (vii). The condensation of (vii) with diethyl malonate (viii) by means of Mg-ethanol in hot toluene gives diethyl 3-chloro-2,4,5-trifluorobenzoylmalonate (ix), which is partially decarboxylated with p-toluenesulfonic acid in refluxing water to give ethyl 3-chloro-2,4,5-trifluorobenzoylacetate (x). The condensation of (x) with triethyl orthoformate (xi) in refluxing acetic anhydride yields ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-ethoxyacrylate (xii), which is treated with cyclopropylamine (xiii) in ethanol to afford ethyl 2-(3-chloro-2,4,5-trifluorobenzoyl)-3-(cyclopropylamino)acrylate (xiv). The cyclization of (xiv) by means of NaF in DMF at 150° gives ethyl 8-chloro-1-cyclopropyl-6,7-difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylate (xv), which is hydrolyzed with H2SO4 in refluxing water-acetic acid to the corresponding carboxylic acid (xvi).