Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[Cl:13][C:14]1[CH:28]=[CH:27][C:17]2[O:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH2:21][NH:22][C:16]=2[CH:15]=1>CC(C)=O>[Cl:13][C:14]1[CH:28]=[CH:27][C:17]2[O:18][C:19]3[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=3[CH:21]=[N:22][C:16]=2[CH:15]=1
Reactant: Clc1ccc2c(c1)NCc1ccccc1O2
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CC(C)=O
Product: Clc1ccc2c(c1)N=Cc1ccccc1O2
Reaction time: 168 h

Procedure:
A culture of Hormodendrum cladosporioides NRRL 8132 is grown initially for 14 days on potato dextrose agar slants. The spores and mycelia from a single slant are used to inoculate a 500 ml. seed flask containing 100 ml. of cottonseed meal medium. After further incubation for 7 days at 23° - 25° C. on a rotary shaker at 190 rpm, 25 ml. of the growth is used to inoculate 100 ml. of cottonseed meal medium in a 500 ml. flask. This flask is then incubated at 23° - 25° C. for 24 - 48 hours on the shaker until good growth is evident. A solution of 0.025 part of 8-chloro-10,11-dihydrodibenz[b,f][1,4]oxazepine in 0.79 part acetone is added and incubation continued for an additional 48 hours. The culture broth is extracted three times with portions of methylene chloride. The methylene chloride extracts are combined, dried over anhydrous sodium sulfate, and stripped to dryness in vacuo. The residue is dissolved in ethyl acetate and chromatographed on silica gel using a 3:97 ethyl acetate-methylene chloride mixture as eluant. Recrystallization of the crude product affords 8-chlorodibenz[b,f][1,4]oxazepine melting at 73° - 73.5° C. and represented by the following structural formula. ##STR4##
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[N:9]=2)=[CH:6][CH:7]=1.Cl.[CH3:15][N:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2([CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:17]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>>[CH3:15][N:16]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]2([CH2:23][CH2:22][N:21]([C:2]3[N:3]=[N:4][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[N:9]=4)=[CH:6][CH:7]=3)[CH2:20][CH2:19]2)[C:17]1=[O:30]
Reactant: CN1C(=O)C2(CCNCC2)c2ccccc21
Reactant: Cc1noc(-c2ccc(Cl)nn2)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Cc1noc(-c2ccc(N3CCC4(CC3)C(=O)N(C)c3ccccc34)nn2)n1

Procedure:
The object product (40 mg, 53%) was obtained in the same manner as in Example 1 and using 3-chloro-6-(3-methyl-1,2,4-oxadiazol-5-yl)pyridazine (39 mg) obtained in Example 43(2), 1-methylspiro[indole-3,4′-piperidin]-2(1H)-one hydrochloride (51 mg) and potassium carbonate (55 mg).
Reaction SMILES: Br[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1.[Mg].[CH:16](=[O:18])[CH3:17].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:18][CH:16]([CH3:17])[CH2:2][CH:3]1[CH2:8][O:7][CH:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:5][CH2:4]1
Reactant: BrCC1COC(c2ccccc2)OC1
Reactant: CC=O
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(O)CC1COC(c2ccccc2)OC1
Temperature: -70 °C
Reaction time: 15 h

Procedure:
To a solution of 19.39 g (75.4 mM) of 5-bromomethyl-2-phenyl-1,3-dioxane m2 in 200 ml of tetrahydrofuran is added 1.923 g (79.17 mM) of magnesium and the mixture is allowed to react for 7 hours under ultrasonic bibration. The mixture is cooled to -70° C. and 21.27 ml (377 mM) of acetaldehyde is added and then the mixture is stirred at 0° C. for 15 hours. The mixture is poured into an ice-cooled saturated aqueous ammonium chloride solution and the product is isolated by ethyl acetate extraction. The ethyl acetate layer is washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated. By eliminating the polar impurity by passing short column of silica gel, 11.353 g of the crude titled compound m3 is obtained which is used to the next reaction without further purification.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][S:9][CH:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)=[CH:4][N:3]=1.[Cu][C:16]#[N:17].[NH4+].[OH-].CCCCCC.CCOC(C)=O>CN(C=O)C>[CH:10]1([S:9][CH2:8][C:5]2[CH:6]=[CH:7][C:2]([C:16]#[N:17])=[N:3][CH:4]=2)[CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Clc1ccc(CSC2CCCC2)cn1
Reactant: N#C[Cu]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: N#Cc1ccc(CSC2CCCC2)cn1
Temperature: 25 °C
Yield: 208.2 %

Procedure:
Set up reaction in 3 separate flasks. To flask number 1 slurry 2-chloro-5-cyclopentylthiomethyl-pyridine (1 g, 4.4 mmol) and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask number 2 slurry 2-chloro-5-cyclopentylthiolmethyl-pyridine (1 g, 4.4 mmol) and copper(I) cyanide (0.78 g, 8.7 mmol) in DMF (5 mL). To flask number 3 slurry 2-chloro-5-cyclopentyl-thiomethyl-pyridine (2 g, 8.8 mmol) and copper(I) cyanide (1.6 g, 17.6 mmol) in DMF (10 mL). Stir each reaction in a sealed flask at 170° C. for 16 h. Follow the reactions by GC/MS. Cool all reaction flasks to room temperature. Combine the flask contents and pour into a solution of NH4OH (120 mL) and hexane/EtOAc (1:1, 100 mL). Collect the organic phase and extract the aqueous phase twice with hexane/EtOAc (1:1, 100 mL). Concentrate in vacuo the combined organic extracts. Purify by chromatography on silica gel (90 g) eluting with hexane/EtOAc (49:1 to 4:1 gradient) to obtain the desired intermediate (2 g, 40%) that contains approximately 10% starting material. Use the material in the next step without additional purification. MS (APCI+) m/z: 218 (M)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:15]=[CH:14][C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=1.[OH-].[Li+]>O1CCCC1.CO.O>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([OH:12])=[O:11])=[CH:14][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ncco2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(-c2ncco2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of methyl 4-(1,3-oxazol-2-yl)benzoate (690 mg, 3.4 mmol) in a mixture of 2:1:1 tetrahydrofuran/methanol/water (20 mL) is added lithium hydroxide (430 mg, 3 mmol). The reaction mixture is stirred at room temperature for 2 h. The solvent is removed under reduced pressure and the residue is partitioned between diethyl ether and water. The aqueous layer is acidified to pH 1 with 1 N hydrochloric acid and a precipitate is observed. The solid is collected by filtration to afford the title compound. 1H NMR (300 MHz, CD3OD) δ 8.14 (s, 4H), 8.05 (s, 1H), 7.36 (s, 1H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[Br:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1F>C(#N)C>[Br:7][C:8]1[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[CH:11]=[CH:10][C:9]=1[N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(F)c(Br)c1
Reactant: C1COCCN1
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(N2CCOCC2)c(Br)c1
Yield: 98.7 %

Procedure:
Morpholine (7.92 mL, 90.9 mmol) was added to a solution of 2-bromo-1-fluoro-4-nitrobenzene (10 g, 45.5 mmol) in acetonitrile (100 mL) and the mixture was heated under reflux for 6 h. Volatile material was removed by evaporation and the residue was diluted with water (100 mL) then extracted with ethyl acetate (2×100 mL). The organic extracts were combined, dried and concentrated to give the title compound (12.9 g, 99%) as a solid; 1H NMR δ 8.40 (1H, s), 8.20 (1H, d), 7.10 (1H, d), 3.80-3.70 (4H, m), 3.20-3.10 (4H, m); MS m/e MH+ 287.
Reaction SMILES: [NH2:1][C:2]1[CH:13]=[CH:12][C:5]([C:6](NCCC)=[O:7])=[CH:4][CH:3]=1.[CH2:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][NH:15]1.Cl.C1C2C(=CC([C:33](OC)=[O:34])=CC=2)CN1>>[CH:6]([C:5]1[CH:12]=[CH:13][C:2]([NH:1][C:33]([N:15]2[CH2:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:14]2)=[O:34])=[CH:3][CH:4]=1)=[O:7]
Reactant: COC(=O)c1ccc2c(c1)CNC2
Reactant: c1ccc2c(c1)CNC2
Reactant: CCCNC(=O)c1ccc(N)cc1
Agent: Cl
Product: O=Cc1ccc(NC(=O)N2Cc3ccccc3C2)cc1

Procedure:
The title compound was prepared as described in Example 272B, substituting 4-aminobenzaldehyde for 4-amino-N-propylbenzamide and isoindoline for methyl isoindoline-5-carboxylate hydrochloride.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[N:19])[CH:13]=2)=[O:7])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[C:31]1([CH2:37][S:38](Cl)(=[O:40])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.C(OCC)(=O)C>CN(C)C=O>[C:18]([C:14]1[CH:13]=[C:12]([CH:17]=[CH:16][CH:15]=1)[O:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]1[CH:20]=[CH:21][C:2]([NH:1][S:38]([CH2:37][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:40])=[O:39])=[CH:3][CH:4]=1)#[N:19]
Reactant: N#Cc1cccc(OCCNC(=O)c2ccc(N)cc2)c1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(OCCNC(=O)c2ccc(NS(=O)(=O)Cc3ccccc3)cc2)c1
Reaction time: 13 h

Procedure:
670 mg (2.38 mmol) of 4-amino-N-[2-(3-cyanophenoxy)ethyl]benzamide was dissolved in 10 ml of dimethylformamide. 0.42 ml (2.38 mmol) of diisopropylethylamine and 454 mg (2.38 mmol) of α-toluenesulfonyl chloride were added to the solution at 0° C., and they were stirred for 13 hours. After the treatment with ethyl acetate as the extractant in an ordinary manner, the title compound was obtained.
Reaction SMILES: Cl[C:2]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][C:10]=1[Cl:11])=[N:3][OH:4].[CH2:12]([O:14][C:15](=[O:19])[C:16]#[C:17][CH3:18])[CH3:13].C(N(CC)CC)C>C(OCC)C>[CH2:12]([O:14][C:15]([C:16]1[C:2]([C:5]2[CH:6]=[N:7][CH:8]=[CH:9][C:10]=2[Cl:11])=[N:3][O:4][C:17]=1[CH3:18])=[O:19])[CH3:13]
Reactant: ON=C(Cl)c1cnccc1Cl
Reactant: CC#CC(=O)OCC
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CCOC(=O)c1c(-c2cnccc2Cl)noc1C
Yield: 27.4 %

Procedure:
Combine chloro(4-chloro(3-pyridyl))(hydroxyimino)methane (2.40 g, 0.013 mol) with ethyl-2-butynoate (3.66 mL, 0.031 mol) in diethyl ether (150 mL) under a nitrogen atmosphere. Add triethylamine (2.27 mL, 0.016 mol) in a dropwise manner and stir over a weekend at ambient temperature. Quench the mixture with water and extract with ethyl acetate. Concentrate the combined extracts and elute over silica gel with methanol/dichloromethane to give the desired isoxazole (0.95 g, 27%) as an oil. ES(EI): M+ 266.0, 267.0, 268.0 m/z.
Reaction SMILES: [F:1][CH:2]([F:23])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([OH:20])[C:5]=1[O:21][CH3:22].C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1([CH2:36][OH:37])[CH2:35][O:34][CH2:33]1>C(#N)C>[F:23][CH:2]([F:1])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[O:14][CH2:13]3)=[C:6]([O:20][CH2:31][C:32]2([CH2:36][OH:37])[CH2:35][O:34][CH2:33]2)[C:5]=1[O:21][CH3:22]
Reactant: OCC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(-c2ccc3c(c2)COC3=O)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 28.4 %

Procedure:
To a stirring solution of 5-(4-(difluoromethoxy)-2-hydroxy-3-methoxyphenyl)isobenzofuran-1(3H)-one (80 mg, 0.25 mmol) in acetonitrile (10 mL), was added potassium carbonate (103.5 mg, 0.75 mmol) and (3-bromomethyl-oxetan-3-yl)-methanol (135.7 mg, 0.75 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 0-30% ethyl acetate in pet ether) to afford title compound as a solid (30 mg, 28.8%).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:36])[N:27]3[C:30]([O:32][CH:33](Cl)[CH3:34])=[O:31])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1.[C:37]([OH:42])(=[O:41])[CH2:38][CH2:39][CH3:40].C(N(C(C)C)C(C)C)C>C(OCC)C>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:29]=[C:28]3[C:23]([CH2:24][CH2:25][C:26](=[O:36])[N:27]3[C:30]([O:32][CH:33]([O:41][C:37](=[O:42])[CH2:38][CH2:39][CH3:40])[CH3:34])=[O:31])=[CH:22][CH:21]=2)[CH2:13][CH2:14]1
Reactant: CCCC(=O)O
Reactant: CC(Cl)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CCCC(=O)OC(C)OC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21

Procedure:
1-chloroethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (2.0 g, 3.60 mmol) was stirred with butyric acid (1.0 mL, 10.81 mmol) and ethyldiisopropylamine (0.94 mL, 5.41 mmol) at 50° C. for 48 hours. The reaction was diluted with diethyl ether (20 mL) and quenched with aqueous saturated NaHCO3 (40 mL). The reaction was extracted with ethyl acetate (2×50 mL) and the combined organics were washed with water (50 mL), brine (50 mL) then dried (MgSO4). The crude product was purified by column chromatography on silica eluting with 0.5% Et3N/ethyl acetate to give 1-(butyryloxy)ethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate, Compound-90 (628 mg, 23% over 2 steps).
Reaction SMILES: [O-]S([O-])(=O)=O.[Mg+2].[CH3:7][C:8]([N:10](C)C)=O.[OH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[S:20]1[CH2:25][CH2:24]C(=O)[CH2:22][CH2:21]1.CC(C)(O)C#N>>[OH:13][CH:14]1[CH2:19][CH2:18][N:17]([C:7]2([C:8]#[N:10])[CH2:24][CH2:25][S:20][CH2:21][CH2:22]2)[CH2:16][CH2:15]1
Reactant: CC(=O)N(C)C
Reactant: OC1CCNCC1
Reactant: O=C1CCSCC1
Agent: CC(C)(O)C#N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: N#CC1(N2CCC(O)CC2)CCSCC1

Procedure:
It is prepared from MgSO4 (7.2 g, 60 mmoles), DMA (2.62 g, 30 mmoles), 4-hydroxy-piperidine (3.03 g, 20 mmoles), tetrahydro-4H-thiopyran-4-one (2.32 g, 20 mmoles) and acetone cyanhydrin (1.7 g, 20 mmoles). After treatment of the reaction, a white solid is obtained (4.7 g) which is crystallized from anhydrous ether. In this way, white crystals are obtained (3.6 g, 79%). M.p.=79-81° C.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C:7]([O:9][C@@H:10]4[O:16]3)=[O:8])[CH2:4][CH2:3]1.[BH4-].[Na+].F[C:24](F)(F)C(O)=O>CO>[CH3:1][C@H:2]1[C@@H:12]2[CH2:13][CH2:14][C@@:15]3([CH3:19])[O:17][O:18][C@:11]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([O:8][CH3:24])[O:9][C@@H:10]4[O:16]3)[CH2:4][CH2:3]1
Reactant: O=C(O)C(F)(F)F
Reactant: C[C@@H]1CC[C@H]2[C@@H](C)C(=O)O[C@@H]3O[C@]4(C)CC[C@@H]1[C@]32OO4
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CO[C@H]1O[C@@H]2O[C@@]3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Reaction time: 2 h

Procedure:
Artemisinin (100 g.) was dissolved in dry methanol (3 ml). Added sodium borohydride (30 mg.) at −5° C. The reaction mixture was stirred for 2 hours. After completion of the reaction, trifluroacetic acid (0.5 ml) was added and the reaction mixture was stirred for 5 hours. The methylation was incompleted and after workup the artemether was purified by prep TLC to yield 46 mg (46%) pure alpha, beta artemether.
Reaction SMILES: C(F)(F)=C(Cl)F.[Cl:7][C:8]1[CH:25]=[CH:24][C:11]2[C:12]([C:21](O)=[O:22])=[CH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH:9]=1>C(OCC)(=O)C.CCCCCC>[Cl:7][C:8]1[CH:25]=[CH:24][C:11]2[C:12]([CH2:21][OH:22])=[CH:13][C:14]3[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=3[O:16][C:10]=2[CH:9]=1
Reactant: O=C(O)C1=Cc2ccccc2Oc2cc(Cl)ccc21
Agent: FC(F)=C(F)Cl
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: OCC1=Cc2ccccc2Oc2cc(Cl)ccc21
Yield: 94 %

Procedure:
Preparation analogous to Example 12 f) aus 7-chloro-dibenz[b,f]oxepine-10-carboxylic acid. Yield: 94% in the form of an oil; TLC (silica gel; ethyl acetate/hexane=1:1; UV): Rf =0.38; 1H-NMR (CDCl3, 200 MHz): 1.72 (sbr, 1H); 4.67 (s, 2H); 6.91 (s, 1H); 7.10-7.40 (m, 7H) ; MS: 260/258 (M+), 217/215.
Reaction SMILES: [H][H].[CH2:3]([N:5]1[CH2:15][CH:14]2[O:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([N+:17]([O-])=O)=[CH:10][CH:9]=3)[CH2:6]1)[CH3:4]>[Pd].C(O)C.C(Cl)Cl>[CH2:3]([N:5]1[CH2:15][CH:14]2[O:16][CH:7]([C:8]3[C:13]2=[CH:12][C:11]([NH2:17])=[CH:10][CH:9]=3)[CH2:6]1)[CH3:4]
Reactant: [H][H]
Reactant: CCN1CC2OC(C1)c1cc([N+](=O)[O-])ccc12
Agent: [Pd]
Solvent: CCO
Solvent: ClCCl
Product: CCN1CC2OC(C1)c1cc(N)ccc12
Reaction time: 18 h
Yield: 87.4 %

Procedure:
Hydrogen was bubbled through a mixture of 10-ethyl-4-nitro-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-triene (115 mg, 0.56 mmol) and 10% palladium on carbon (53 mg, 0.050 mmol) in ethanol (3 mL) and CH2Cl2 (3 mL) for 5 min. The reaction was then stirred under a hydrogen atmosphere for 18 h. Filtration through Celite and concentration gave 10-Ethyl-12-oxa-10-aza-tricyclo[6.3.1.0*2,7*]dodeca-2,4,6-trien-4-ylamine as an off-white foam (100 mg, 100%). MS (m/e) 205 (M+1.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:7]([CH2:20][CH2:21]O)[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.CS(Cl)(=O)=O>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=4[Cl:19])[CH2:21][CH2:20][N:7]3[C:6]=2[C:5]([CH:23]([CH2:26][CH3:27])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(CC)c1ccc(Cl)c2nc(Nc3ccc(Cl)cc3Cl)n(CCO)c12
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)c1ccc(Cl)c2nc3n(c12)CCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 23.2 %

Procedure:
To a solution of 2-{4-chloro-2-[(2,4-dichlorophenyl)amino]-7-(1-ethylpropyl)-1H-benzimidazol-1-yl}ethanol (Reference Example 19; 66 mg, 0.155 mmol) in tetrahydrofuran (0.8 mL) were added diisopropylethylamine (0.053 ml, 0.310 mmol) and methanesulfonyl chloride (0.013 ml, 0.170 mmol) at 0° C., and the mixture was stirred at room temperature for 2 hr. Additional diisopropylethylamine (0.053 ml, 0.310 mmol) and methanesulfonyl chloride (0.013 mL, 0.170 mmol) were added at 0° C., followed by stirring at room temperature for 15 hr. The reaction mixture was diluted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-25% ethyl acetate/n-hexane gradient mixture. The desired fractions were concentrated in vacuo, and the resulting solid was washed with n-hexane to give the title compound (15 mg, 0.0360 mmol, 23%) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1([C:7]([NH2:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3]1.[CH:10](OC)(OC)OC.[ClH:17]>CC(C)=O>[ClH:17].[N:1]1[C:2]2([CH2:6][CH2:5][CH2:4][CH2:3]2)[C:7](=[O:8])[NH:9][CH:10]=1
Reactant: COC(OC)OC
Reactant: NC(=O)C1(N)CCCC1
Agent: Cl
Solvent: CC(C)=O
Product: O=C1NC=NC12CCCC2
Yield: 92.2 %

Procedure:
20 g (0.156 mol) of 1-aminocyclopentane-1-carboxamide and 28 g (0.19 mol) of trimethyl orthoformate are refluxed for 1 hour. The condenser is then changed to a "No hold up" condenser, and the temperature is elevated to 140° C. inner temperature. The residue is dissolved in 150 ml of acetone the pH is adjusted to 1-2 with concentrated hydrochloric acid and after cooling the resulting suspension the product is filtered of. 25 g of the title compound is obtained, yield 92.2%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH:16]=1.[O:17]1[CH2:19][C@H:18]1[CH2:20][O:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH:24]=[CH:25][NH:26]2>CS(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]1[CH2:12][CH2:13][N:14]([CH2:19][C@H:18]([OH:17])[CH2:20][O:21][C:22]2[CH:30]=[CH:29][CH:28]=[C:27]3[C:23]=2[CH:24]=[CH:25][NH:26]3)[CH2:15][CH:16]=1
Reactant: Fc1ccc2[nH]cc(C3=CCNCC3)c2c1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Solvent: CS(C)=O
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2c[nH]c3ccc(F)cc23)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 193 from 5-fluoro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole (1.00 g, 4.63 mmol) and (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.90 g, 4.8 mmol). The resulting free base was isolated as a white foam. Yield 1.04 g (55%). mp 95°-100° C. FDMS m/e=405 (M+ of free base). α[D]589 =5.91 (c=1.01, dimethylsulfoxide).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([Cl:12])[N:10]=2)[N:5]=[CH:4][C:3]=1[C:13](=[O:15])[CH3:14].[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]2[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]2)=[N:21][CH:22]=1>>[C:13]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:16][C:17]1[CH:18]=[CH:19][C:20]([N:23]3[CH2:28][CH2:27][CH2:26][CH:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:24]3)=[N:21][CH:22]=1)=[N:10][C:9]([Cl:12])=[CH:8][CH:7]=2)(=[O:15])[CH3:14]
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Cl
Reactant: CC(C)(C)OC(=O)NC1CCCN(c2ccc(N)cn2)C1
Product: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Yield: 33.8 %

Procedure:
Following general procedure I, 1-(4,6-dichloro-1,5-naphthyridin-3-yl)ethanone (610 mg, 2.5 mmol) was reacted with tert-butyl 1-(5-aminopyridin-2-yl)piperidin-3-ylcarbamate (590 mg, 3.0 mmol) to afford the desired product (420 mg, 35%) as an orange-red solid: 1H NMR (500 MHz, CDCl3) δ 11.47 (s, 1H), 9.01 (s, 1H), 8.09 (d, J=8.7 Hz, 1H), 8.01 (d, J=2.6 Hz, 1H), 7.45 (d, J=8.7 Hz, 1H), 7.34-7.28 (m, 1H), 6.72 (d, J=9.1 Hz, 1H), 4.95-4.90 (m, 1H), 3.85-3.67 (m, 3H), 3.47-3.27 (m, 2H), 2.69 (s, 3H), 1.97-1.88 (m, 1H), 1.86-1.75 (m, 1H), 1.73-1.59 (m, 2H), 1.45 (s, 9H); ESI MS m/z 497 [M+H]+
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][CH2:6][O:7][CH3:8].[F:9][C:10]([F:22])([F:21])[C:11]([NH:13][CH:14]([CH2:18][C:19]#[CH:20])[CH2:15][C:16]#[CH:17])=[O:12]>C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh].C(O)C>[F:9][C:10]([F:21])([F:22])[C:11]([NH:13][CH:14]1[CH2:15][C:16]2[C:19](=[CH:20][C:5]([CH2:6][O:7][CH3:8])=[C:4]([CH2:3][O:2][CH3:1])[CH:17]=2)[CH2:18]1)=[O:12]
Reactant: C#CCC(CC#C)NC(=O)C(F)(F)F
Reactant: COCC#CCOC
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCO
Product: COCc1cc2c(cc1COC)CC(NC(=O)C(F)(F)F)C2
Temperature: 80 °C

Procedure:
According to the procedure of Magnus et. al (Tetrahed. Lett., 34, 23-26 (1993)) a solution of commercially available 1,4-dimethoxy-2-butyne (1.32 g, 11.5 mmol) in nitrogen-degassed ethanol is heated to 80° C. with stirring under a nitrogen atmosphere. Tris(triphenylphosphine)rhodium chloride (64 mg, 0.07 mmol) and a solution of 2,2,2-trifluoro-N-[1-(2-propynyl)-3-butynyl]-acetamide (470 mg, 2.32 mmol; prepared from literature procedure; Romero, Arthur G.; Leiby, Jeffrey A PCT Int. Appl. WO 9623760) in nitrogen-degassed ethanol (2 ml) are added in portions over 2 hours. The mixture is stirred under nitrogen at 80° C. for a further 3 hours. The solvent is removed under vacuo and the residue is purified by flash chromatography on silica gel, elating with hexane/ethyl acetate (2:1)