Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N1C=CC=CC=1.[C:7]([C:10]1[CH:11]=[CH:12][C:13](Br)=[N:14][CH:15]=1)(=[O:9])[CH3:8].[C:17]1([CH3:26])[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C([O-])([O-])=O.[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O.C(#N)C>[C:17]1([CH3:26])[CH:22]=[CH:21][C:20]([C:13]2[N:14]=[CH:15][C:10]([C:7](=[O:9])[CH3:8])=[CH:11][CH:12]=2)=[CH:19][CH:18]=1
Reactant: CC(=O)c1ccc(Br)nc1
Reactant: Cc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)c1ccc(-c2ccc(C)cc2)nc1
Temperature: 80 °C
Yield: 91.5 %

Procedure:
According to the general Suzuki coupling of pyridine compounds, 5-acetyl-2-bromopyridine 38 (0.394 g, 1.97 mmol), 4-tolylboronic acid (0.535 g, 3.94 mmol), Na2CO3 (0.146 g, 1.38 mmol), Pd(PPh3)2Cl2 (0.042 g, 0.06 mmol, 3% Pd), acetonitrile (7.8 mL), water (7.8 mL) were heated at 80° C. for 14 h (overnight). Following the general workup and flash chromatography (SiO2, 20 g, 5% EtOAc/hexanes) coupled ketone was obtained as a white solid 41 (0.381 g, 92%); TLC Rf=0.4 (25% EtOAc/hexanes); mp 106-107.5° C.; 1H NMR (500 MHz, CDCl3) δ 9.19 (d, J=2.2 Hz, 1H), 8.24 (dd, J=8.3, 2.3 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.79 (d, J=8.4 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 2.63 (s, 3H), 2.40 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 196.6, 161.0, 150.2, 140.5, 136.4, 135.5, 130.5, 129.8, 127.4, 26.8, 21.5; IR (neat cm−1) 3024, 2911, 2853, 2042, 1671, 1589, 1555, 1371, 1279, 1141, 819, 762; HRMS (DART, M++H) m/z 212.1093 (calculated for C14H14NO, 212.1075).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][O:23]3)=[O:19])=[CH:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH3:28][N:29]1[CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH:31]=[N:30]1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH3:28][N:29]1[CH:33]=[C:32]([C:2]2[CH:7]=[CH:6][C:5]([S:8]([N:11]3[CH:15]=[CH:14][C:13](/[CH:16]=[CH:17]/[C:18]([NH:20][O:21][CH:22]4[CH2:27][CH2:26][CH2:25][CH2:24][O:23]4)=[O:19])=[CH:12]3)(=[O:10])=[O:9])=[CH:4][CH:3]=2)[CH:31]=[N:30]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: O=C(/C=C/c1ccn(S(=O)(=O)c2ccc(Br)cc2)c1)NOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: Cn1cc(-c2ccc(S(=O)(=O)n3ccc(/C=C/C(=O)NOC4CCCCO4)c3)cc2)cn1

Procedure:
(E)-3-[1-(4-Bromo-benzenesulfonyl)-1H-pyrrol-3-yl]-N-(tetrahydro-pyran-2-yloxy)-acrylamide (966 mg) and 1-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (662 mg) are dissolved in DME (35 mL) and (Ph3P)3PdCl2 (298 mg) and 2M Na2CO3-solution (3.2 mL) are added. The mixture is heated 16 h to reflux temperature. The mixture is filtered and evaporated and the crude product is purified by silica gel flash chromatography.
Reaction SMILES: [F:1][C:2]([C:8]1[CH:9]=[C:10]([N+:14]([O-])=O)[CH:11]=[CH:12][CH:13]=1)([Cl:7])[C:3]([F:6])([Cl:5])[Cl:4].Cl>C(O)C>[F:1][C:2]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[NH2:14])([Cl:7])[C:3]([F:6])([Cl:5])[Cl:4]
Reactant: O=[N+]([O-])c1cccc(C(F)(Cl)C(F)(Cl)Cl)c1
Agent: Cl
Solvent: CCO
Product: Nc1cccc(C(F)(Cl)C(F)(Cl)Cl)c1

Procedure:
104.4 G. of 3-(1,2-difluoro-1,2,2-trichloroethyl)-nitrobenzene is added over 10 min. to a solution of 325 g. of crystalline stannous chloride (SnCl2 . 2H2O) in 325 g. of concentrated HCl and 325 g. of ethanol with vigorous stirring, maintaining the temperature at 50° C. Stirring is continued for 3 additional hours. It is cooled in ice, and the precipitate collected by filtration. The solids are then suspended in 500 ml. water and 500 ml. of CH2Cl2, the mixture is cooled in ice and made basic by the addition of 50% aqueous NaOH until almost all solids are dissolved. The methylenechloride layer is separated, washed with water, dried with Na2SO4 and concentrated in vacuo to 75 g. of 3-(1,2-difluoro-1,2,2-trichloroethyl)-aniline as yellow oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:12]([CH2:14][CH:15]=[CH2:16])[CH3:13].C(N(CC)CC)C.C(#N)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.CCCCCC.C(OCC)(=O)C>[CH3:10][N:11]([C:17]([O:19][C:20]([CH3:21])([CH3:23])[CH3:22])=[O:18])[CH:12]([CH2:14]/[CH:15]=[CH:16]/[C:2]1[CH:7]=[N:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[CH3:13]
Reactant: C=CCC(C)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc(Br)cn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COc1ccc(/C=C/CC(C)N(C)C(=O)OC(C)(C)C)cn1
Temperature: 95 °C
Yield: 122.9 %

Procedure:
A 185 mL Ace-Glass pressure tube was charged with 5-bromo-2-methoxypyridine (2.80 g, 14.9 mmol), N-methyl-N-(tert-butoxycarbonyl)-4-penten-2-amine (2.97 g, 14.9 mmol), prepared as previously described, palladium(II) acetate (33.4 mg, 0.149 mmol), tri-o-tolylphosphine (181 mg, 0.596 mmol), triethylamine (5 mL) and acetonitrile (10 mL). The tube was flushed with nitrogen, sealed, and the mixture was stirred and heated at 95° C. (oil bath temperature) for 18 h. The tube contents were cooled; more palladium(II) acetate (33.4 mg, 0.149 mmol) and tri-o-tolylphosphine (181 mg, 0.596 mmol) were added. The mixture was further stirred and heated at 94° C. for 20 h. TLC analysis (hexane-ethyl acetate (2:1)) indicated the presence of 5-bromo-2-methoxypyridine. Therefore, more palladium(II) acetate (33.4 mg, 0.149 mmol) and tri-o-tolylphosphine (181 mg, 0.596 mmol) were added, and the mixture was heated at 95° C. for an additional 20 h. The mixture was cooled and concentrated via rotary evaporator. The residue was diluted with water (35 mL) and extracted with dichloromethane (50 mL, 2×35 mL). The combined dichloromethane extracts were dried (Na2SO4), filtered, and concentrated under vacuum to produce a light-brown, oily semisolid (5.61 g). The crude product was purified by column chromatography on silica gel (70-230 mesh) (200 g) eluting with a hexane-ethyl acetate gradient (64:1→6:1). Fractions containing the product (Rf 0.28 in hexane-ethyl acetate (6:1)) were combined and concentrated under vacuum to give 2.36 g of an oily, yellow semisolid. Impure fractions were combined and concentrated to give 1.48 g of a light-yellow oil. This material was re-chromatographed on the silica gel (70-230 mesh) (95 g) eluting with the previously described hexane-ethyl acetate gradient (64:1→6:1). All fractions containing the product were combined and concentrated under vacuum to give 0.85 g of a light-yellow oil, bringing the total yield to 2.915 (63.9%).
Reaction SMILES: [C:1]([Cl:6])(=O)[C:2]([Cl:4])=[O:3].ClC(=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:28])[F:27])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])C(O)=O>CN(C)C=O.C1(C)C=CC=CC=1>[Cl:6][C:1](=[CH:12][C:13]1[CH:18]=[C:17]([C:19]2[C:23]([Cl:24])=[C:22]([O:25][CH:26]([F:27])[F:28])[N:21]([CH3:29])[N:20]=2)[C:16]([Cl:30])=[CH:15][C:14]=1[Cl:31])[C:2]([Cl:4])=[O:3]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2Cl)c(Cl)c1OC(F)F
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)Cl)c(Cl)cc2Cl)c(Cl)c1OC(F)F

Procedure:
3 drops of dimethylformamide and then 11.1 g (87 mmol) of oxalyl chloride were added dropwise to a solution of 12.5 g (29 mmol) of 2-chloro-3-(2,4-dichloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)phenyl)propenoic acid in 300 ml of toluene. The reaction mixture was stirred at reflux temperature for 5 hours and then concentrated. Yield: quantitative.
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[CH:7][C:4]=1[CH:5]=[O:6].B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=2)=[CH:7][C:4]=1[CH:5]=[O:6]
Reactant: COc1ccc(-c2ccncc2)cc1C=O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(-c2ccncc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of aldehyde 192 (700 mg, 3.29 mmol) in DCM (8 mL) at −78° C. is treated with boron tribromide (0.93 mL, 9.85 mmol) dropwise over 5 minutes. After 1 h at −78° C., the reaction is warmed to RT and stirred 2 h. The reaction mixture is then cooled (0° C.), quenched with water (5 mL), basified with aqueous NaHCO3 (10 mL) and extracted into DCM (3×20 mL). The combined organic phases are dried over Na2SO4 and the solvent removed in vacuo to give the title compound.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1.[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH2:20]>O>[CH3:13][O:14][C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][C:23]=1[O:24][CH3:25])[CH2:18][CH2:19][NH:20][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[S:10][CH:11]=[CH:12][C:6]=2[CH2:5]1
Reactant: COc1ccc(CCN)cc1OC
Reactant: ClCCN1CCc2sccc2C1
Solvent: O
Product: COc1ccc(CCNCCN2CCc3sccc3C2)cc1OC
Temperature: 110 °C

Procedure:
Into a two liter reactor, fitted with an oil-bath and stirring means and under nitrogen circulation, were poured 201.5 g (1 mol) of 5-(2-chloroethyl)-4,5,6,7-tetrahydro-thieno-(3,2-c)-pyridine and slowly, under stirring, 181 g (1 mol) of 3,4-dimethoxyphenethylamine. The reacting mixture was warmed at 110° C. under stirring for two hours. The oily mixture obtained was cooled to about 70°-80° C. and then poured into icy water; after separation, washing, extraction with diethyl ether and drying, the residue was dissolved in a mixture of petroleum ether and isopropyl ether (50/50 by volume) and passed through a silica gel column. Elution was with acetone. The fraction containing the desired compound was evaporated to dryness, treated with diethyl ether and finally with acetone. Yield 163 g (47%) of a white crystalline powder soluble in water, melting at 260° C. (Tottoli) with decomposition, the analysis and NMR of which showed a good correspondence with the formula C19H26N2O2S.
Reaction SMILES: C(N(CC)CC)C.C(O[C:12](=[O:14])[CH3:13])(=O)C.Cl.[NH2:16][CH2:17][C:18]1[CH:34]=[CH:33][C:32]2[C:23]3[NH:24][C:25](=[O:31])[C:26]4[N:27]([CH:28]=[CH:29][N:30]=4)[C:22]=3[CH2:21][C:20]=2[CH:19]=1>CN(C)C=O>[O:31]=[C:25]1[NH:24][C:23]2[C:32]3[CH:33]=[CH:34][C:18]([CH2:17][NH:16][C:12](=[O:14])[CH3:13])=[CH:19][C:20]=3[CH2:21][C:22]=2[N:27]2[CH:28]=[CH:29][N:30]=[C:26]12
Reactant: NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccc2c(c1)Cc1c-2[nH]c(=O)c2nccn12
Reaction time: 18 h

Procedure:
1.1 ml of triethylamine and then 0.52 ml of acetic anhydride are added to a suspension of 0.8 g of 8-aminomethyl-5H,10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-4-one hydrochloride in 20 ml of dimethylformamide. After reacting for 18 hours at a temperature in the region of 20° C., the reaction mixture is filtered and the solid is washed successively with dimethylformamide, distilled water and acetone and then dried under reduced pressure (1 mbar) at 50° C. 0.81 g of N-[(4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]pyrazin-8-yl)methyl]acetamide is thus obtained in the form of a white solid melting above 260° C. (Analysis; % Calculated C: 65.30, H: 4.79, N: 19.04; % Found C: 65.3, H: 4.8, N: 18:7).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)=[O:9].[Li+].[OH-].C(Cl)(Cl)Cl>C1COCC1.O>[N:12]1[CH:13]=[CH:14][CH:15]=[C:10]([C:8]([NH:7][CH2:6][CH2:5][CH2:4][C:3]([OH:16])=[O:2])=[O:9])[CH:11]=1
Reactant: COC(=O)CCCNC(=O)c1cccnc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=C(O)CCCNC(=O)c1cccnc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.3 %

Procedure:
To a solution of 4[(pyridine-3-carbonyl)-amino]-butyric acid methyl ester (0.8 g, 3.5 mmol), in THF (14 mL) was added LiOH (0.75 g, 17.9 mmol), dissolved in water (6 mL). The mixture was allowed to stir at room temperature (25° C.) overnight. 50% starting material remains as such. Then reaction mixture heated at (45° C.). The reaction did not progress. The reaction mixture was worked up with chloroform to recover the starting material. The aqueous layer was diluted with water, acidified with 1.5N HCl till (pH=2-3), extracted with ethyl acetate (150 mL) and dried over sodium sulphate, concentrated to obtain yellow colour solid (0.6 g, 80%).
Reaction SMILES: N.C1[C@@H]2C3C(=O)OC(=O)C3[C@H]1C=C2.OC1C([O:22][S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])=C(I)C=CC=1>>[C:29]1([CH3:30])[CH:28]=[CH:27][C:26]([S:23]([OH:25])(=[O:22])=[O:24])=[CH:32][CH:31]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2c(O)cccc2I)cc1
Agent: N
Agent: O=C1OC(=O)C2C1[C@@H]1C=C[C@H]2C1
Product: Cc1ccc(S(=O)(=O)O)cc1

Procedure:
Scheme I describes the preferred enantioselective synthesis of azanoradamantane benzamide 11. Iodolactone 1 is treated with thionyl chloride to give the corresponding acid chloride which is converted to the primary amide 2 by treatment with ammonia. [Racemic 2 was previously prepared by a different route [JP 04013663 (1992); CA 116(25):255175s]from cis-5-norbornene-endo-2,3-dicarboxylic anhydride.]The primary amide 2 is then treated with HTIB [hydroxy(tosyloxy)iodobenzene] to afford the p-toluenesulfonic acid salt 3, followed by tosylation of the amine with toluenesulfonyl chloride in pyridine to afford the tosylamine 4. Treatment with zinc in acetic acid affords the norbornene carboxylic acid 5. Ozonolysis of 5, followed by treatment with sodium borohydride and an acidic workup yields the gamma-lactone 6. Ammonolysis of the gamma-lactone in methanol, affords the primary amide diol 7, which is reduced with borane to the primary amine and protected as the tert-butyl carbamate diol 8. Tosylation of the diol with toluenesulfonyl chloride in pyridine, deprotection of the tert-butyl carbamate with trifluoroacetic acid, and subsequent treatment with diisopropylethylamine in acetonitrile, affords the tosylaminoazanoradamantane 9. Deprotection of the tosylamine under Birch conditions, with alkali metals, and more preferably with calcium metal, affords the aminoazanoradamantane 10. The aminoazanoradamantane 10 is coupled directly, without resolution or purification, with 4-amino-5-chloro-2-methoxybenzoic acid in the presence of CDI to afford the desired azanoradamantane benzamide (+)-11 enantiomer, which is isolated directly by crystallization from the reaction mixture. The azanoradamantane benzamide 11 is then converted to the monohydrochloride salt.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][CH2:12][C:13]1[N:17]=[CH:16][NH:15][CH:14]=1.[F:18][C:19]1[C:20]([C:43](O)=[O:44])=[CH:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([C:33]4[C:34]([O:39][CH3:40])=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[CH:29][C:28]=3[OH:41])[NH:24][C:23]=2[CH:42]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1.CN(C=O)C>[F:18][C:19]1[C:20]([C:43]([NH:10][CH2:11][CH2:12][C:13]2[N:17]=[CH:16][NH:15][CH:14]=2)=[O:44])=[CH:21][C:22]2[N:26]=[C:25]([C:27]3[CH:32]=[C:31]([C:33]4[C:34]([O:39][CH3:40])=[N:35][CH:36]=[CH:37][CH:38]=4)[CH:30]=[CH:29][C:28]=3[OH:41])[NH:24][C:23]=2[CH:42]=1
Reactant: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)O)c(F)cc3[nH]2)c1
Reactant: NCCc1c[nH]cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ncccc1-c1ccc(O)c(-c2nc3cc(C(=O)NCCc4c[nH]cn4)c(F)cc3[nH]2)c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N,N-Diisopropylethylamine (4.6 mL, 26.4 mmol) and histamine.2HCl (1.16 g, 6.3 mmol) were successively added to a solution of acid 9a (2.3 g, 6 mmol) and HBTU (2.5 g, 6.6 mmol) in THF (70 mL) and DMF (35 mL). The reaction mixture was stirred at room temperature for 18 h and the solvent was evaporated in vacuo. Water (35 mL) was added to the residue and the fine precipitate was collected by filtration and suspended in methanol/water (1/1, 100 mL). The suspension was stirred at room temperature for 14 h and the solid was collected by filtration and dried in vacuo at 40° C. for 14 h to afford the desired 6-fluoro-N-[2-(1H-imidazol-4-yl)ethyl]-2-[2-hydroxy-5-(2-methoxypyridin-3-yl)phenyl] 1H-benzimidazole-5-carboxamide (10a) as a colorless solid. 1H NMR (DMSO-d6) δ 13.79-11.28 (br s, 2H), 8.45-8.16 (m, 3H), 7.94-7.91 (m, 2H), 7.69-7.51 (m, 3H), 7.17-7.11 (m, 2H), 6.88 (s, 1H), 3.92 (s, 3H), 3.59-3.48 (m, 2H), 2.79 (t, J=6.6 Hz, 2H). ES-MS MH+ 473.48. EA was in agreement with the formula C25H21FN6O3.0.75H2O.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([N:12]2[C@@H:20]3[C@@H:15]([C:16]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:17]=4[CH2:18][CH2:19]3)[CH2:14][C:13]2=O)[CH2:11][CH2:10][CH2:9][CH2:8]1.[NH4+].[Cl-]>C1COCC1>[CH:7]1([N:12]2[C@@H:20]3[C@@H:15]([C:16]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH3:26])[C:17]=4[CH2:18][CH2:19]3)[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: COc1cccc2c1CC[C@H]1[C@@H]2CC(=O)N1C1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1cccc2c1CC[C@H]1[C@@H]2CCN1C1CCCC1
Yield: 94.7 %

Procedure:
0.53 g (0.014 mol) of lithium aluminum hydride was suspended in 25 ml of THF under argon. A solution of 2.0 g (0.007 mol) of rac-cis-3-cyclopentyl-1,3,3a,4,5,9b-hexahydro-6-methoxy-2H-benzo[e]indol-2-one in 50 ml of THF was added dropwise thereto and the mixture was boiled under reflux for 1 hour. 10 ml of a saturated aqueous NH4Cl solution was cautiously added dropwise thereto and the mixture was filtered. The filtrate was extracted with ethyl acetate, the organic phase was washed with water, dried with MgSO4, filtered and the filtrate was concentrated. There were obtained 1.8 g (95%) of oily rac-cis-3-cyclopentyl-2,3,3a,4,5,9b-hexahydro-6-methoxy-1H-benzo[e]indole.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][CH2:23][CH:24]([CH3:26])[CH3:25])=[CH:18][C:17]=1[F:27])=[CH:5]/[O:6][CH3:7].[BH-](OC(C)=O)(OC(C)=O)O[C:31](C)=O.[Na+].C=O.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:28])/[C:4](/[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:31])=[CH:18][C:17]=1[F:27])=[CH:5]/[O:6][CH3:7]
Reactant: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc(NCC(C)C)cc1F
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CO/C=C(/C(=O)OC)c1ccccc1COc1ccc(N(C)CC(C)C)cc1F
Temperature: 25 °C
Reaction time: 22 h
Yield: 69.2 %

Procedure:
70 mg (0.18 mmol) of the compound obtained in Step 3 was dissolved in 1.5 ml of methylene chloride, and 57 mg (0.27 mmol) of NaBH(OAc)3 and 30 μl (0.40 mmol) of formaldehyde were added thereto. After stirring at room temperature for 22 hours, the reaction mixture was treated with a saturated sodium bicarbonate aqueous solution, and the water layer was separated and extracted twice with 10 ml of methylene chloride. The organic layers were combined, dried over anhydrous MgSO4, and concentrated under a reduced pressure. The residue was subjected to column chromatography using 20% ethyl acetate/hexane as an eluent to obtain 50 mg (yield 73%) of (E)-methyl-2-[2-((4-(N-isobutyl-N-methylamino)-2-fluorophenoxy)methyl)phenyl]-3-methoxyacrylate as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[OH:33][C@:29]([C:26]1[CH:25]=[C:24]([CH3:23])[O:28][N:27]=1)([CH3:30])[C:31]#[C:32][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([F:21])([F:20])[F:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1
Reactant: NC(=O)c1nc2n(c1C(F)(F)F)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3c(c2)-c2nc(C(N)=O)c(C(F)(F)F)n2CCO3)no1
Yield: 20 %

Procedure:
10-bromo-3-(trifluoromethyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (2R)-2-(5-methylisoxazol-3-yl)but-3-yn-2-ol via General Procedure E to afford 19 mg (20%) of 10-[(3R)-3-hydroxy-3-(5-methylisoxazol-3-yl)but-1-ynyl]-3-(trifluoromethyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: C([O:4][C@H:5]1[C@@H:9]([O:10]C(=O)C)[C@H:8]([N:14]2[CH:22]=[N:21][C:20]3[C:15]2=[N:16][C:17]([I:38])=[N:18][C:19]=3[NH:23][CH2:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:7][C@@H:6]1[CH2:39][O:40]C(=O)C)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>O.CO>[C:32]1([CH:25]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:24][NH:23][C:19]2[N:18]=[C:17]([I:38])[N:16]=[C:15]3[C:20]=2[N:21]=[CH:22][N:14]3[C@H:8]2[C@H:9]([OH:10])[C@H:5]([OH:4])[C@@H:6]([CH2:39][OH:40])[O:7]2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(I)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: OC[C@H]1O[C@@H](n2cnc3c(NCC(c4ccccc4)c4ccccc4)nc(I)nc32)[C@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 100.5 %

Procedure:
(2R,3R,4R,5R)-4-(Acetyloxy)-2-[(acetyloxy)methyl]-5-{6[(2,2-diphenylethyl)amino]-2-iodo-9H-purin-9-yl}tetrahydro-3-furanyl acetate (1.7 g, 2.43 mmol) (Preparation 1) was dissolved in 10:1, by volume, methanol water (88 ml). Solid sodium carbonate (1.5 g, 14.1 mmol) was added and the mixture stirred at room temperature for 90 minutes before removing the methanol by evaporation under reduced pressure. The residual aqueous solution was diluted with water (50 ml) and extracted with ethyl acetate (150 ml). The organic phase was washed sequentially with water and brine, dried over anhydrous sodium sulphate and the solvent removed under reduced pressure to yield the title compound as a white solid (1.4 g).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]([NH2:17])=O.CN(C)C=O.P(Cl)(Cl)(Cl)=O>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][C:15]#[N:17]
Reactant: Cc1oc(-c2ccccc2)nc1CCC(N)=O
Solvent: CN(C)C=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1oc(-c2ccccc2)nc1CCC#N
Temperature: 25 °C
Reaction time: 1 h
Yield: 89 %

Procedure:
To a mixture of 3-(5-methyl-2-phenyl-4-oxazolyl)propanamide (5.0 g) and N,N-dimethylformamide (100 ml) was added phosphoryl chloride (3.33 g) at room temperature and the mixture was stirred at room temperature for 1 hr. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give crystals (4.10 g, 89%) of 3-(5-methyl-2-phenyl-4-oxazolyl)propionitrile. Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 63-64° C.