Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1.[F:16][C:17]1([F:23])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C[O-].[Na+].O>C(#N)C.CO.CN(C=O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:20]2[CH2:21][CH2:22][C:17]([F:23])([F:16])[CH2:18][CH2:19]2)[CH:5]=[C:4]([CH2:9][O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[N:3]=1
Reactant: FC(F)(F)COCc1cc(Cl)nc(Cl)n1
Reactant: FC1(F)CCNCC1
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: FC(F)(F)COCc1cc(N2CCC(F)(F)CC2)nc(Cl)n1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To an ice-cold solution of 2,4-dichloro-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (0.120 g, 0.46 mmol) in acetonitrile (2 mL) was a solution of 4,4-difluoropiperidine (0.217 g, 1.38 mmol) and sodium methoxide (30 wt % in methanol, 0.188 mL, 1.01 mmol) in MeOH (2 mL) added. The reaction was stirred at 0° C. for 2 hours. Water and DMF was added and the residue was purified by preparative HPLC to give the title compound as a dry film (0.110 g, 69%).
Reaction SMILES: C([NH:11][CH2:12][C:13]1[CH:44]=[CH:43][C:16]([C:17]([NH:19][C@@H:20]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[C:21]([OH:23])=[O:22])=[O:18])=[CH:15][CH:14]=1)(OCC1C=CC=CC=1)=O>CO.[Pd]>[NH2:11][CH2:12][C:13]1[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@@H:20]([CH2:24][CH2:25][CH2:26][CH2:27][N:28]([CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)[C:29]([O:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[O:30])[C:21]([OH:23])=[O:22])=[O:18])=[CH:43][CH:44]=1
Reactant: CC(C)(C)OC(=O)N(CCCC[C@H](NC(=O)c1ccc(CNC(=O)OCc2ccccc2)cc1)C(=O)O)Cc1ccccn1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCCC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)O)Cc1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.3 %

Procedure:
The compound obtained in Example 41-4 (0.02 g) was dissolved in methanol (0.5 ml). After the addition of 10% Pd—C (0.02 g), the mixture was stirred for 2 hours under hydrogen atmosphere at room temperature. After the reaction, the catalyst was removed by filtration and solvent was removed by distillation. The residue was dried under vacuum to obtain the title compound (0.01 g) as colorless oil.
Reaction SMILES: C([O:5][C:6]([C:8]1[NH:9][C:10]([CH3:19])=[C:11]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[C:12]=1[CH3:13])=O)(C)(C)C.C(OCC)(OCC)OCC>FC(F)(F)C(O)=O>[CH3:19][C:10]1[NH:9][C:8]([CH:6]=[O:5])=[C:12]([CH3:13])[C:11]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: CCOC(=O)c1c(C)[nH]c(C(=O)OC(C)(C)C)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(OCC)OCC
Product: CCOC(=O)c1c(C)[nH]c(C=O)c1C
Temperature: 15 °C
Reaction time: 1 h
Yield: 64 %

Procedure:
A mixture of 2-tert-butyloxycarbonyl-3,5-dimethyl-4-ethoxycarbonylpyrrole and triethyl orthoformate (1.5 equiv.) in trifluoroacetic acid was stirred at 15° C. for 1 hour. The reaction was concentrated and the residue was purified to give (64%) 2,4-dimethyl-3-ethoxycarbonyl-5-formylpyrrole as yellow needles.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([OH:13])[CH2:11]Cl)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCl.[OH-].[Na+]>O>[CH2:1]([O:8][CH2:9][CH:10]1[O:13][CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC(CCl)COCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Product: c1ccc(COCC2CO2)cc1
Temperature: 5 °C
Yield: 91 %

Procedure:
A 2,000 mL, 3-necked flask equipped with a mechanical stirrer and thermometer was charged with 3-benzyloxy-2-hydroxypropyl chloride (353 g, 1.76 mol) and dichloromethane (1,000 mL). This mixture was stirred and cooled in an ice bath to ca. 5° C. Aqueous 50% NaOH (176 g) was added in portions while the temperature was kept under 30° C. After addition was complete, the reaction mixture was stirred 4 hours at 25° C. Water (1,000 mL) was added to dissolve the salts. The organic phase was separated from the aqueous phase, washed with ice water (3×500 mL), dried and reduced in vacuo to yield 263 g (92%) of pure 3-benzyloxy-1,2-epoxypropane.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH2:10])=[O:9])=[CH:4][CH:3]=1.[NH2:11][C:12]1[S:13][C:14]([CH2:22][CH2:23][CH2:24][CH3:25])=[CH:15][C:16]=1[C:17](OCC)=[O:18]>>[CH2:22]([C:14]1[S:13][C:12]2[N:11]=[C:2]3[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[O:9])=[CH:6][N:7]3[C:17](=[O:18])[C:16]=2[CH:15]=1)[CH2:23][CH2:24][CH3:25]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: CCCCc1cc(C(=O)OCC)c(N)s1
Product: CCCCc1cc2c(=O)n3cc(C(N)=O)ccc3nc2s1
Yield: 15.8 %

Procedure:
From 6.2 g (0.040 mol) of 6-chloro-3-pyridinecarboxamide (Aldrich Chemical Company) and 9.0 g (0.040 mol) of 2-amino-5-butyl-3-thiophenecarboxylic acid, ethyl ester and heating in a wax bath at 180-195° C. for one hundred forty-five minutes and then at 185-200° C. for ninety minutes, following the procedure of Example 22 there is obtained 1.9 g of 2-butyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carboxamide; mp 266-267° C. after recrystallization from glacial acetic acid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:15](=[O:17])[CH3:16].[O:18]1[CH2:23][CH2:22][CH2:21][C:20](=O)[CH2:19]1.N1CCCC1>C1(C)C=CC=CC=1>[O:8]([C:5]1[CH:4]=[C:3]2[C:2](=[CH:7][CH:6]=1)[O:1][C:20]1([CH2:21][CH2:22][CH2:23][O:18][CH2:19]1)[CH2:16][C:15]2=[O:17])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CCCOC1
Reactant: CC(=O)c1cc(Oc2ccccc2)ccc1O
Solvent: C1CCNC1
Solvent: Cc1ccccc1
Product: O=C1CC2(CCCOC2)Oc2ccc(Oc3ccccc3)cc21
Yield: 51.4 %

Procedure:
To a solution of 1-(2-hydroxy-5-phenoxyphenyl)ethanone (2.0 g, 8.77 mmol) in toluene (30 mL) was added dihydro-2H-pyran-3(4H)-one (1.14 g, 11.40 mmol) and pyrrolidine (0.81 g, 11.40 mmol), and the reaction mixture was refluxed overnight. After cooling, the mixture was concentrated. The residue was washed with 1 N HCl, brine, dried and concentrated to give the crude product, which was purified by chromatography to afford 6-phenoxy-2′,4′,5′,6′-tetrahydrospiro[chroman-2,3′-pyran]-4-one (1.40 g, 52%). 1H-NMR (CDCl3): 0.79 (m, 1H), 1.52 (m, 2H), 1.67 (m, 1H), 1.92 (m, 1H), 2.08 (m, 1H), 2.57-2.61 (q, 2H), 3.51 (m, 2H), 3.88 (m, 2H), 6.89 (d, 2H), 7.03 (m, 2H), 7.18 (m, 1H), 7.26 (t, 2H), 7.39 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([O:9][C:10]2[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=2)[CH:6]=[CH:7][CH:8]=1.CC([N:21]([C@@H:25]([C:28](NC1C=NC(OC2C=CC(C#N)=C(C(C)C)C=2)=CC=1)=[O:29])[CH2:26][CH3:27])[C:22](=O)[O-:23])(C)C.Cl>ClCCl.CN(C1C=CN=CC=1)C.CCOCC>[CH2:26]([C@H:25]1[NH:21][C:22](=[O:23])[N:14]([C:13]2[CH:15]=[CH:16][C:10]([O:9][C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)=[CH:11][CH:12]=2)[C:28]1=[O:29])[CH3:27]
Reactant: CC[C@H](C(=O)Nc1ccc(Oc2ccc(C#N)c(C(C)C)c2)nc1)N(C(=O)[O-])C(C)(C)C
Reactant: COc1cccc(Oc2ccc(N)cc2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CC[C@H]1NC(=O)N(c2ccc(Oc3cccc(OC)c3)cc2)C1=O
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To Boc-anhydride (138 mg, 0.631 mmol) in dichloromethane (1 mL) was added DMAP (55.1 mg, 0.451 mmol) followed by a solution of 4-{[3-(methyloxy)phenyl]oxy}aniline (97 mg, 0.451 mmol) in dichloromethane (1 mL). The mixture was stirred for 10 min. The brown solution thus obtained was added to Solution 1 via syringe with shaking at 35° C. and shaking was continued at this temperature for 2 hours. The solution was then kept at room temperature for ca. 64 hours. Conc. aq. HCl (ca. 0.8 mL) was added and the heterogenous mixture was heated at 100° C. for 2 hours with shaking, allowing the DCM to distill off through a glass capillary. After cooling to room temperature, the residue was diluted with water (ca. 3 mL) and extracted with dichloromethane (2 times ca. 2 mL). The dichloromethane extracts were concentrated under vacuum. The residue was purified by silica gel chromatography (Biotage system, 10 g column) eluting with a gradient cHex/EtOAc from 95/5 to 0/100 to give a brown viscous oil that was dissolved in Et2O (ca. 0.7 mL) and cHex (ca. 0.1 mL) and kept over night. The overstanding faint brown solution was decanted from a small quantity of a brown oil that had separated out. As the solvent was allowed to evaporate from this solution crystallisation initiated. The material thus obtained was allowed to dry and then triturated with Et2O (2 times ca. 0.5 mL) to afford, after drying, the title compound as a solid (28 mg).
Reaction SMILES: [C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:13][CH:12]([NH:28]C(OC(C)(C)C)=O)[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1>Cl.O1CCOCC1>[C:1]1([CH3:37])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22](=[O:27])[C:23]([CH3:24])([CH3:25])[CH3:26])[CH2:13][CH:12]([NH2:28])[C:11]2=[O:36])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)OC(C)(C)C)CN2C(=O)C(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(N)CN2C(=O)C(C)(C)C
Temperature: 50 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
1-(2-Toluoylmethyl) -2-oxo-3-tert-butoxycarbonylamino-5-pivaloyl-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine (1.00 g) was suspended in 4N HCl-dioxane (10 ml), the suspension was stirred at 50° C. for one hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, the solution was washed with diethyl ether, alkaline with saturated aqueous sodium bicarbonate, and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (ethyl acetate), to thereby obtain 538 mg of the titled compound.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29]C)=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C(#N)C.O>[CH3:26][O:25][C:24]1[C:3](=[O:2])[C:4]([CH3:31])=[C:5]([CH2:6][C:7]2[CH:8]=[CH:9][C:10]([C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)=[C:11]([CH:15]=2)[C:12]([OH:14])=[O:13])[C:22](=[O:29])[C:23]=1[O:27][CH3:28]
Reactant: COc1c(C)c(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: COC1=C(OC)C(=O)C(Cc2ccc(-c3ccccc3)c(C(=O)O)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.3 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-phenylbenzoic acid (340 mg, 0.7819 mmol) was dissolved in a mixed solvent of acetonitrile (30 ml) and water (10 ml), then CAN (1.10 g, 2.0072 mmol) was added thereto at room temperature and the mixture was stirred for 3 hour. The reaction solution was poured into water and extracted with ether. The extract was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by silica gel column chromatography (5% methanol-methylene chloride) to give the title compound (234 mg, 0.5969 mmol, 76%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[C:20]2[O:21][C:22]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[N:24]=2)[CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>ClCCl>[OH:6][C:7]1[CH:8]=[C:9]([CH2:13][CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]2[C:20]2[O:21][C:22]([C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[C:23]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[N:24]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: COc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Oc1cccc(CC2CCCCC2c2nc(-c3ccccc3)c(-c3ccccc3)o2)c1
Temperature: 25 °C
Reaction time: 22 h
Yield: 84.7 %

Procedure:
1.0 M Solution of boron tribromide in dichloromethane (1.25 ml) was added dropwise to a stirred solution of 2-[2-[(3-methoxyphenyl)methyl]cyclohexyl]-4,5-diphenyloxazole (370 mg) in dichloromethane (2.0 ml) under ice cooling. The resulting mixture was stirred at the same temperature for 2 hours and at room temperature for 22 hours, and then a mixture of ethyl acetate and sodium bicarbonate aqueous solution was added thereto. The organic layer was washed with sodium bicarbonate aqueous solution and brine, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was chromatographed over silica gel using n-hexane--ethyl acetate as an eluent to afford 2-[2-[(3-hydroxyphenyl)methyl]-cyclohexyl]-4,5-diphenyloxazole (303 mg) as a syrup.
Reaction SMILES: Br[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1.[CH2:12]([NH2:19])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CS(C)=O.O>[CH2:12]([NH:19][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([Br:11])[CH:3]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Brc1cc(Br)c2nonc2c1
Reactant: NCc1ccccc1
Solvent: O
Solvent: CS(C)=O
Product: Brc1cc(NCc2ccccc2)c2nonc2c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 42.7 %

Procedure:
4,6-dibromobenzo[c][1,2,5]oxadiazole 4 (0.9678 g, 3.48 mmol) and benzylamine (1.9 mL, 17.4 mmol) were dissolved in DMSO (10.5 mL) under argon and stirred in a sealed tube for 3 days, after which time, the tube was heated to 60° C. for 12 hours. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl (aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The dark solid was recrystallized from EtOH and the dark crystals were collected by filtration and dried to afford 0.4516 g (43% yield) of N-benzyl-6-bromobenzo[c][1,2,5]oxadiazol-4-amine. This material (0.1980 g, 0.651 mmol), benzoylpiperazine hydrochloride (0.1771 g, 0.781 mmol) and Cs2CO3 (0.6353 g, 1.95 mmol) were added to a tube. The tube was evacuated and purged with argon (3×). Toluene (2 mL) and NMP (1.2 mL) were then added to the tube and its contents were degassed for 15 minutes, at which point Pd2(dba)3 (0.0119 g, 0.0130 mmol) and BINAP (0.0162 g, 0.026 mmol) were quickly added, the tube was sealed and heated at 100° C. overnight. Upon cooling to room temperature, the reaction was diluted with water and extracted with EtOAc. The combined organic layers were washed with H2O (5×), 1 N HCl(aq), saturated NaHCO3 (aq) and brine before drying with Na2SO4, filtering and concentrating. The crude material was purified via chromatography (40% EtOAc/Hexanes) to give 0.188 g (70% yield) of TRV-1256. 1H NMR (500 MHz, CDCl3) δ=7.46-7.43 (m, 5H), 7.39-7.36 (m, 4H), 7.34-7.31 (m, 1H), 6.13 (d, J=1.0 Hz, 1H), 5.88 (s, 1H), 5.32 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H), 3.90 (br s, 2H), 3.58 (br s, 2H), 3.29 (br s, 2H), 3.15 (br s, 2H).
Reaction SMILES: [Br:1][C:2]1[C:22]([O:23][CH2:24][CH2:25][O:26][CH3:27])=[C:21]([S:28]([CH3:31])(=[O:30])=[O:29])[CH:20]=[CH:19][C:3]=1[C:4]([CH:6]([C:14]([CH:16]1[CH2:18][CH2:17]1)=[O:15])C(OC(C)(C)C)=O)=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:16]1([C:14](=[O:15])[CH2:6][C:4]([C:3]2[CH:19]=[CH:20][C:21]([S:28]([CH3:31])(=[O:30])=[O:29])=[C:22]([O:23][CH2:24][CH2:25][O:26][CH3:27])[C:2]=2[Br:1])=[O:5])[CH2:18][CH2:17]1
Reactant: COCCOc1c(S(C)(=O)=O)ccc(C(=O)C(C(=O)OC(C)(C)C)C(=O)C2CC2)c1Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCCOc1c(S(C)(=O)=O)ccc(C(=O)CC(=O)C2CC2)c1Br
Yield: 91.1 %

Procedure:
A mixture of crude t-butyl 2-[2-bromo-3-(2-methoxyethoxy)4-methylsulphonylbenzoyl]-3-cyclopropyl-3-oxopropanoate (10.2 g) and 4-toluenesulphonic acid (2 g) in dry toluene was stirred and heated at reflux for 2 hours. The cooled mixture was washed with water, dried (anhydrous magnesium sulphate) and filtered. The filtrate was evaporated to dryness to give 3-cyclopropyl-1-[2-bromo-3-(2-methoxyethoxy)-4-methylsulphonylphenyl]propan-1,3-dione (7.5 g) as a brown oil which was not purified further NMR(CDCl3) 0.9(4H,m), 1.5(1H,m), 3.1(3H,s), 3.3(3H,s), 3.6(2H, t), 4.2(2H, t), 5.7(1H, s), 7.15(1H, d), 7.8(1H, d).
Reaction SMILES: [H-].[Na+].[F:3][CH:4]([F:7])[CH2:5][OH:6].C(Cl)Cl.Cl[C:12]1[N:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>O.C1COCC1>[Cl:21][C:19]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[C:12]([O:6][CH2:5][CH:4]([F:7])[F:3])[N:20]=1
Reactant: OCC(F)F
Reactant: O=C(O)c1ccc(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)c1ccc(Cl)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH (55% dispersion in oil; 5.0 g, 114.6 mmol) is added portionwise at 10° C. to 2,2-difluoroethanol (6.25 mL, 99.0 mmol), DCM (200 mL) and THF (75 mL). After 10 min 2,6-dichloro-nicotinic acid (5.0 g, 24.7 mmol) is added to the reaction mixture and it is stirred at rt overnight. Then water is added and it is concentrated. The residue is diluted with water and extracted with Et2O. Formic acid is added to the aqueous layers the precipitate is filtered off, washed with water and dried to give the sub-title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:11]2[C:6]([CH3:19])([C:7]3[CH:15]=[CH:14][C:13]([C:16]([OH:18])=[O:17])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:33](O)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:19])([C:7]3[CH:15]=[CH:14][C:13]([C:16]([O:18][CH:33]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[O:17])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:20]
Reactant: OC(c1ccccc1)c1ccccc1
Reactant: CN1C(=O)CCC2(C)c3ccc(C(=O)O)cc3CCC12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(C(=O)OC(c4ccccc4)c4ccccc4)cc3CC[C@@H]12
Reaction time: 1 h
Yield: 87.7 %

Procedure:
Under an atmosphere of nitrogen, 100 mg of 4,10b-dimethyl-8-carboxy-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one and 66 mg of 1,1'-carbonyldiimidazole were dissolved in 5 mL of anhydrous dimethylformamide and stirred for 1 h. Then 74 mg of benzhydrol was added, and the reaction was stirred for 18 hours, still at ambient temperature. The volatiles were then removed under high vacuum, and the residue was dissolved in 50 mL of dichloromethane and washed with 40 mL of 1N hydrochloric acid, with two 40 mL portions of saturated aqueous sodium bicarbonate, and finally with 40 mL of brine. The organic layer was dried with sodium sulfate, filtered and evaporated under vacuum to give 141 mg of impure product, which was purified by chromatography on silica gel, eluting with ethyl acetate to obtain 91 mg (57%) of the desired product. An analytical sample was recrystallized from ethyl acetate/water. mp 130°-131°. FDMS: m/e=439.
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:10][CH2:9][CH2:8][C:4]=2[N:5]=[CH:6][N:7]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>C(O)C>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:2]2[C:3]3[CH2:10][CH2:9][CH2:8][C:4]=3[N:5]=[CH:6][N:7]=2)=[CH:14][CH:13]=1
Reactant: Clc1ncnc2c1CCC2
Reactant: Nc1ccc(Cl)cc1
Solvent: CCO
Product: Clc1ccc(Nc2ncnc3c2CCC3)cc1
Temperature: 130 °C

Procedure:
To 3.1 g (0.02 mole) of 4-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine were added 5.1 g (0.04 mole) of p-chloroaniline and about 10 ml of ethanol; the mixture was then heated at 130° C. for 5-10 minutes. The reaction mixture quickly became a solution and then produced crystals of the hydrochloride of the desired product on being allowed to cool.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH:8]=1)[NH2:7].C1C(=O)N([Br:19])C(=O)C1>CC(O)=O>[Br:19][C:3]1[C:2]([F:1])=[CH:8][C:6]([NH2:7])=[C:5]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: Nc1cc(F)ccc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: CC(=O)O
Product: Nc1cc(F)c(Br)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 70 %

Procedure:
A solution of 5-fluoro-2-nitroaniline (1.5 g, 9.61 mmol) and NBS (1.7 g, 9.55 mmol) in HOAc (75 mL) was heated at reflux for 90 min. The reaction mixture was then poured into ice water (300 mL) and stirred for 10 min. A bright yellow precipitate was collected by filtration and dried in vacuo overnight to afford 1.57 g (76%) of 4-bromo-5-fluoro-2-nitroaniline (96): MS (ESI) m/z=235 [M+1]+.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]([OH:28])[CH2:26][CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>O1CCOCC1.O=[Mn]=O>[C:1]([N:20]1[CH:24]=[C:23]([C:25](=[O:28])[CH2:26][CH3:27])[N:22]=[CH:21]1)([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: O=[Mn]=O
Solvent: C1COCCO1
Product: CCC(=O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 80 %

Procedure:
In a 50 ml three-necked flask fitted with a magnetic stirrer and a reflux condenser under inert atmosphere, 1-(1-trityl-1H-imidazol-4-yl)propan-1-ol x88 (1.21 g, 3.3 mmol) and MnO2 (2.85 g, 33 mmol) are dissolved in 20 ml of dioxane and the mixture is brought to reflux for 1 h. The mixture is filtered on Celite and the solvent is evaporated. Purification by chromatography on silicagel (CH2Cl2/MeOH/NH4OH: 90/9/1 (v/v/v)) affords 0.96 g of pure 1-(1-trityl-1H-imidazol-4-yl)propan-1-one x89.
Reaction SMILES: C([N:3]1[CH2:8][CH2:7][C:6]2([CH2:17][CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]2=[O:18])[CH2:5][CH2:4]1)C>C(O)C.[OH-].[K+]>[O:18]=[C:9]1[C:6]2([CH2:7][CH2:8][NH:3][CH2:4][CH2:5]2)[CH2:17][CH2:16][C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2
Reactant: CCN1CCC2(CCc3ccccc3C2=O)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1c2ccccc2CCC12CCNCC2
Yield: 77.7 %

Procedure:
A solution of 1.84 g (6.4 mmoles) ethyl 3,4-dihydro-1-oxospiro[naphthalene-2(1H),4'piperidine] in 32 ml ethanol and 16 ml of 50% potassium hydroxide solution was heated at reflux for 18 hours. The solution was concentrated in vacuo to remove ethanol and the aqueous residue was extracted with 3×40 ml ether. The combined organic extracts were extracted with 2×40 ml 3N hydrochloric acid. The combined aqueous extracts were made basic with 10N sodium hydroxide and extracted with 3×75 ml ether. The combined organic extracts were washed with 20 ml water and brine, dried, and the solvent was removed in vacuo to give 1.07 g (78%) product as an oil;
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[C:15](O)=[O:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.CC(O)=O.C([O-])(O)=O.[Na+]>C1COCC1.O>[CH2:1]([O:8][C:9]([N:11]1[CH2:14][CH2:13][C@H:12]1[CH2:15][OH:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)[C@@H]1CCN1C(=O)OCc1ccccc1
Agent: B
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=C(OCc1ccccc1)N1CC[C@H]1CO
Temperature: 0 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
To a solution of (S)-Azetidine-1,2-dicarboxylic acid 1-benzyl ester (Starting material I-34f, 94 mg, 0.4 mmol) in 0.3 ml dry THF cooled to 0° C. is added dropwise 450 μl of a 1 M solution of borane in THF. The resulting solution is allowed to stir for 1 h at 0° C. and warm up to rt overnight. AcOH (1 ml) and water (1 ml) are then added as well as some saturated NaHCO3 solution in water until pH=9 and no more gas evolution occurs. The resulting aqueous phase is extracted three times with AcOEt. The combined organic phase is washed once with some saturated NaHCO3 solution in water and once with water. The solvents are evaporated in vacuo and the crude oil dried under high vacuum overnight, yielding the title compound (79 mg) in 89% as a colourless oil: tR=0.84 min (LC-3), ESI-MS (pos.): m/z 222.08 [M+H]+; 1H-NMR (CDCl3): δ (ppm) 2.00 (m, 1H, CH2CH2N), 2.22 (m, 1H, CH2CH2N), 3.78-4.01 (m, 5H, CH2N and CH2OH), 4.52 (s, 2H, OCH2Ph), 7.35 (s, 5H, Harom.). Starting material I-35e of the following Table 63 is prepared using a procedure analogous to that described for Starting material I-34e, substituting Starting material I-35f for I-34f.