Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:10]=[C:9]([O:11]C)[CH:8]=[CH:7][C:4]=1[CH:5]=[O:6].[C:13](Cl)(=[O:15])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)Cl>[C:13]([C:8]1[C:9]([OH:11])=[CH:10][C:3]([OH:2])=[C:4]([CH:7]=1)[CH:5]=[O:6])(=[O:15])[CH3:14]
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: CC(=O)Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1cc(C=O)c(O)cc1O
Temperature: 0 °C

Procedure:
To a mixture of 49.8 g of 2,4-dimethoxybenzaldehyde, 23.6 ml of acetyl chloride, and 1000 ml of methylene chloride cooled to approximately 0° C. were added 119.7 g of aluminum chloride with stirring under a nitrogen atmosphere. The reaction was allowed to warm to room temperature while stirring overnight. The mixture was added to a slurry of ice and concentrated hydrochloric acid. The organic layer was separated and washed with a saturated sodium chloride solution, dried over sodium sulfate, and concentrated in vacuo. The 15 residue was purified by high pressure liquid chromatography over silica gel eluting with a 0-40% ethyl acetate in hexane gradient. The appropriate fractions were pooled and concentrated to provide 5.85 g of the desired title intermediate, m.p. =142°-143° C.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.CCN(C(C)C)C(C)C.[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH:42][C:43](N1C=CN=C1)=[O:44]>CN(C=O)C.[Cl-].[Na+].O>[NH:37]1[CH:41]=[CH:40][N:39]=[C:38]1[NH:42][C:43]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:44]
Reactant: O=C(Nc1ncc[nH]1)n1ccnc1
Reactant: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCNCC2)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cnc(CN(Cc2nccc3ccccc23)C2CCN(C(=O)Nc3ncc[nH]3)CC2)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 75 %

Procedure:
To a warm (70° C.), stirred, solution of (3,5-Dimethyl-pyridin-2-ylmethyl)-isoquinolin-1-ylmethyl-piperidin-4-yl-amine (0.101 g, 0.28 mmol) and DIPEA (0.29 mL, 1.67 mmol) in DMF (3 mL) was added freshly prepared imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide (2 equivs). After 1 hour, the mixture was cooled to room temperature, diluted with brine (5 mL) and extracted with CH2Cl2 (4×10 mL). The combined organic extracts were washed with water (5×10 mL), dried (Na2SO4) and concentrated. Purification of the crude material by column chromatography on silica gel (20:1:1 CH2Cl2-MeOH—NH4OH) provided 102 mg (75%) of COMPOUND 274 as a white solid. 1H NMR (CDCl3) δ 1.60-1.79 (m, 2H), 1.96-2.03 (m, 5H), 2.27 (s, 3H), 2.66-2.75 (m, 3H), 3.85 (s, 2H), 4.26-4.30 (m, 4H), 6.69 (s, 2H), 7.22-7.26 (m, 2H), 7.32-7.37 (m, 1H), 7.53-7.62 (m, 2H), 7.75 (d, 1H, J=8.1 Hz), 7.87 (d, 1H, J=8.7 Hz), 8.18 (s, 1H), 8.40 (d, 1H, J=6.0 Hz); 13C NMR (CDCl3) δ 18.32, 18.49, 27.57, 44.75, 54.92, 55.42, 58.07, 120.85, 126.62, 126.77, 127.23, 128.09, 130.13, 132.31, 133.26, 136.67, 139.17, 141.76, 145.51, 146.85, 154.35, 155.80, 159.42; ES-MS m/z 470 (M+H). Anal. Calcd. For C27H31N7O.1.0H2O: C, 66.51; H, 6.82; N, 20.11. Found: C, 66.34; H, 6.68; N, 19.74.
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([NH:9][CH2:10][C@@H:11]([OH:21])[CH2:12][O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:4]([C:22]#[C:23][C:24]([CH3:35])([CH3:34])[CH2:25][O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1>C(#N)C.[Cu]I>[NH2:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:6][C:7]=1[F:8])[N:9]([CH2:10][C@@H:11]([OH:21])[CH2:12][O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:23]([C:24]([CH3:35])([CH3:34])[CH2:25][O:26][CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[CH:22]2
Reactant: CC(C)(C#Cc1cc(N)c(F)cc1NC[C@@H](O)COCc1ccccc1)COCc1ccccc1
Agent: [Cu]I
Solvent: CC#N
Product: CC(C)(COCc1ccccc1)c1cc2cc(N)c(F)cc2n1C[C@@H](O)COCc1ccccc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 27 %

Procedure:
Bis-acetonitriledichloropalladium (0.1 eq) and CuI (0.1 eq) are charged to the reactor and then suspended in a solution of (R)-1-((4-amino-2-(4-(benzyloxy)-3,3-dimethylbut-1-yn-1-yl)-5-fluorophenyl)amino)-3-(benzyloxy)propan-2-ol obtained above (1 eq) in acetonitrile (9.5 vol total). The mixture is sparged with nitrogen gas for 1 h and then is heated to 80° C. The reaction progress is monitored by HPLC and the reaction is typically complete within 1-3 h. The mixture is filtered through Celite and the cake is washed with acetonitrile. A solvent swap into ethyl acetate (7.5 vol) is performed. The ethyl acetate solution is washed with aqueous NH3—NH4Cl solution (2×2.5 vol) followed by 10% brine (2.5 vol). The ethyl acetate solution is then stirred with silica gel (1.8 wt eq) and Si-TMT (0.1 wt eq) for 6 h. After filtration, the resulting solution is concentrated down. The residual oil is dissolved in DCM/heptane (4 vol) and then purified by column chromatography. The oil thus obtained is then crystallized from 25% EtOAc/heptane (4 vol). Crystalline (R)-1-(5-amino-2-(1-(benzyloxy)-2-methylpropan-2-yl)-6-fluoro-1H-indol-1-yl)-3-(benzyloxy)propan-2-ol is typically obtained in 27-38% yield. 1H NMR (400 MHz, DMSO) δ 7.38-7.34 (m, 4 H), 7.32-7.23 (m, 6 H), 7.21 (d, 1 H, J=12.8 Hz), 6.77 (d, 1H, J=9.0 Hz), 6.06 (s, 1 H), 5.13 (d, 1H, J=4.9 Hz), 4.54 (s, 2 H), 4.46 (br. s, 2 H), 4.45 (s, 2 H), 4.33 (d, 1 H, J=12.4 Hz), 4.09-4.04 (m, 2 H), 3.63 (d, 1H, J=9.2 Hz), 3.56 (d, 1H, J=9.2 Hz), 3.49 (dd, 1H, J=9.8, 4.4 Hz), 3.43 (dd, 1H, J=9.8, 5.7 Hz), 1.40 (s, 6 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([NH:19][C:20](=[O:23])[CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH3:14].[H-].[Na+].I[CH2:27][CH2:28][CH3:29]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]2[N:17]=[C:16]([CH3:18])[C:15]([N:19]([CH2:27][CH2:28][CH3:29])[C:20](=[O:23])[CH2:21][CH3:22])=[C:11]2[O:12][C:13]=1[CH3:14]
Reactant: CCC(=O)Nc1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Reactant: CCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCN(C(=O)CC)c1c(C)nn2c(-c3ccc(Cl)cc3Cl)c(C)oc12
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
N-(3-(2,4-Dichlorophenyl)-2,6-dimethylpyrazolo[5,1-b]oxazol-7-yl) propionamide (634 mg, 1.800 mmol) is suspended in dry DMF (20 ml) and treated with NaH (60% in oil) (86 mg, 2.160 mmol) under N2 at RT. The mixture is stirred at RT for 10 minutes before cooling to 0° C. in an ice bath. 1-Iodopropane (0.263 ml, 2.70 mmol) is added dropwise and the reaction mixture is stirred at 0° C. for 1 hr. The solvent is removed in vacuo and the resulting residue is dissolved in EtOAc and washed with 1M NaOH, 1M HCl, H2O, brine, dried (MgSO4) and evaporated down to give a brown oil. Purification by chromatography on silica eluting with 0% to 50% EtOAc/iso-hexane affords the title compound as a clear oil; MS: m/z 394.1 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][OH:14])[C:5]([O:15]C)=[C:4]([Cl:17])[N:3]=1.[Cl-].[Li+]>CN(C=O)C>[Cl:1][C:2]1[N:3]=[C:4]([Cl:17])[C:5]([OH:15])=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[CH2:13][OH:14])[N:7]=1
Reactant: COc1c(Cl)nc(Cl)nc1N1CCC[C@H]1CO
Agent: [Cl-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: OC[C@@H]1CCCN1c1nc(Cl)nc(Cl)c1O
Temperature: 160 °C

Procedure:
A mixture of [(S)-1-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-pyrrolidin-2-yl]-methanol (900 mg, 3.24 mmol) and lithium chloride (360 mg, 8.48 mmol) in anhydrous DMF (10 mL) was heated at 160° C. for 10 mins in a microwave reactor, then concentrated in vacuo to give 2,4-dichloro-6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyrimidin-5-ol. DIAD (700 μL, 3.56 mmol) was added to a solution of 2,4-dichloro-6-((S)-2-hydroxymethyl-pyrrolidin-1-yl)-pyrimidin-5-ol (3 mmol) and triphenyl phosphine (900 mg, 3.43 mmol) in 1,4-dioxane (10 mL) and the mixture stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 20% ethyl acetate in cyclohexane) affording (S)-6,8-dichloro-2,3,3a,4-tetrahydro-1H-5-oxa-7,9,9b-triaza-cyclopenta[a]naphthalene. LCMS (method A): RT=2.98 min, [M+H]−=246/248.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13].[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20](Cl)=[O:21])([O-:16])=[O:15].N1C=CC=CC=1>CN(C)C1C=CN=CC=1.ClCCl>[N+:14]([C:17]1[CH:18]=[C:19]([CH:23]=[C:24]([N+:26]([O-:28])=[O:27])[CH:25]=1)[C:20]([O:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])=[O:21])([O-:16])=[O:15]
Reactant: O=C(Cl)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: OCCCCCCCCCCCBr
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 0 °C
Yield: 89.5 %

Procedure:
11.4 g (45.4 mmol) 11-bromo-1-undecanol, 11.0 g (47.7 mmol) 3,5-dinitrobenzoyl chloride, 54 mg 4-dimethylaminopyridine were dissolved in 94 ml dichloromethane. The solution was subsequently cooled to 0° C. and then 18.3 ml (227 mmol) pyridine was added dropwise, in the course of 25 minutes. After 4.5 hours at 0° C. the reaction mixture was partitioned between dichloromethane and water; the organic phase was washed repeatedly with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using Toluene yielded 18.1 g (90%) 11-bromoundecyl 3,5-dinitrobenzoate as yellow powder.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:17]#[N:18])[C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=1.[F-:19].[K+].C(OCC)(=O)C.O>CS(C)=O>[C:17]([C:4]1[C:5]([NH:8][C:9](=[O:16])[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N:6][CH:7]=[C:2]([F:19])[N:3]=1)#[N:18]
Reactant: N#Cc1nc(Br)cnc1NC(=O)c1ccccc1
Reactant: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1nc(F)cnc1NC(=O)c1ccccc1
Temperature: 112.5 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
In 86 mL of dimethyl sulfoxide was dissolved 4.3 g of N-(5-bromo-3-cyano-2-pyrazinyl)benzamide. After adding 8.3 g of potassium fluoride, the mixture thus obtained was stirred at 110-115° C. for one hour. The reaction mixture was returned to room temperature, a mixture of 100 mL of ethyl acetate and 200 mL of water was added, and the organic layer was separated. The organic layer thus obtained was washed successively with water and saturated aqueous solution of sodium chloride, treated with active charcoal and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent: toluene:ethyl acetate=5:1] to obtain 0.47 g of N-(3-cyano-5-fluoro-2-pyrazinyl)benzamide as a white-colored solid product.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([O:10]C)[C:5]([O:8]C)=[CH:6][CH:7]=1.[Br:12]B(Br)Br>ClCCl>[Br:12][C:7]1[CH:6]=[C:5]([OH:8])[C:4]([OH:10])=[CH:3][C:2]=1[F:1]
Reactant: BrB(Br)Br
Reactant: COc1ccc(F)cc1OC
Solvent: ClCCl
Product: Oc1cc(F)c(Br)cc1O
Temperature: 20 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
To a cooled (−78° C.) solution of 4-fluoroveratrole (5.0 g, 32 mmol) in dichloromethane (106 mL) was slowly added a solution of tribromoborane in dichloromethane (1M, 96 mL, 96 mmol, 3.0 eq.). The reaction mixture was warmed to 20° C. and stirred overnight. The reaction mixture was poured into ice water, extracted with ethyl acetate (3 times). The combined organic layer was washed with an aqueous solution of sodium bicarbonate, dried over sodium sulfate and filtered. The volatiles were removed in vacuo. The brown solid was diluted with chloroform (50 mL) and dichloromethane (10 mL). A solution of bromine in carbon tetrachloride (5 ml) was slowly added. After 3 hours, the volatiles were removed in vacuo. Purification by flash chromatography afforded the title compound (6.51 g, 98%) as a brown solid
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[CH:4][C:3]=1[S:10]([CH3:13])(=[O:12])=[O:11].C1(P([N:28]=[N+:29]=[N-:30])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:28]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([CH3:1])=[C:3]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:4]=1)=[N+:29]=[N-:30]
Reactant: Cc1ccc(CO)cc1S(C)(=O)=O
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(CN=[N+]=[N-])cc1S(C)(=O)=O
Temperature: 25 °C
Yield: 58.9 %

Procedure:
A round bottom flask was charged with (4-methyl-3-(methylsulfonyl)phenyl)methanol (6.0 g, 30.14 mmol), toluene (70 mL). Diphenyl phosphoryl azide (7.8 mL, 36.1 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.3 mL, 36.1 mmol) were added at 0° C. and the reaction mixture was stirred over night at room temperature. The solvent was removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic phases were concentrated under reduced pressure and the residue was purified by column chromatography to get the title compound (4 g, 62% yield).
Reaction SMILES: C(O[CH:4]([O:8]CC)[C:5]([NH2:7])=[S:6])C.Br[CH2:12][C:13]([C:15]1[O:19][N:18]=[C:17]([CH3:20])[CH:16]=1)=O>C(O)C>[CH3:20][C:17]1[CH:16]=[C:15]([C:13]2[N:7]=[C:5]([CH:4]=[O:8])[S:6][CH:12]=2)[O:19][N:18]=1
Reactant: CCOC(OCC)C(N)=S
Reactant: Cc1cc(C(=O)CBr)on1
Solvent: CCO
Product: Cc1cc(-c2csc(C=O)n2)on1
Reaction time: 8 h

Procedure:
A solution of diethoxythioacetamide (6.65 g; 0.04077 mol) and 2-bromo-1-(3-methylisoxazol-5-yl)ethanone (10 g; 0.04077 mol), prepared as described in the above step, in absolute ethanol (31.3 ml) was kept overnight at room temperature and then refluxed for 30 minutes.
Reaction SMILES: [H-].[Na+].[CH2:3](Br)[CH:4]=[CH2:5].C([O:11][CH:12](OCCCC)[C:13]1[N:14]=[CH:15][CH:16]=[C:17]2[C:21]([CH3:22])=[C:20]([CH3:23])[NH:19][C:18]=12)CCC.Cl>O1CCCC1.O>[CH2:3]([N:19]1[C:18]2=[C:13]([CH:12]=[O:11])[N:14]=[CH:15][CH:16]=[C:17]2[C:21]([CH3:22])=[C:20]1[CH3:23])[CH:4]=[CH2:5]
Reactant: C=CCBr
Reactant: CCCCOC(OCCCC)c1nccc2c(C)c(C)[nH]c12
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C=CCn1c(C)c(C)c2ccnc(C=O)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
Sodium hydride (60%, 23 mg, 0.562 mmol) and allyl bromide (36 μl, 0.413 mmol) were added at 0° C. to a solution of 7-dibutoxymethyl-2,3-dimethyl-1H-pyrrolo[2,3-c]pyridine (0.109 g, 0.375 mmol) prepared in Step 3 in anhydrous tetrahydrofuran (3 ml). The reaction mixture was stirred for 1 hour at room temperature and water (1 ml) was added thereto. The reaction mixture was extracted with ethyl acetate (10 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. Tetrahydrofuran (10 ml) was added to the resulting residue. 0.5N hydrochloric acid (3 ml, 1.5 mmol) was added to the reaction mixture, which was then refluxed overnight. The reaction mixture was cooled to room temperature, concentrated under reduced pressure, basified with a saturated sodium bicarbonate solution, extracted with ethyl acetate (20 ml), dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography (ethyl acetate/n-hexane=1/5, v/v) to give 50 mg of the titled compound as yellow oil.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:15])[F:14])[CH:11]=2)[NH:6][CH:5]=1.C[N:18](C=O)C>>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([F:16])([F:14])[F:15])[CH:11]=2)[N:6]([NH2:18])[CH:5]=1
Reactant: Cc1c[nH]c2ccc(C(F)(F)F)cc12
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1cn(N)c2ccc(C(F)(F)F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 52 %

Procedure:
60% NaH (1.21 g, 30.2 mmol) is added to a stirred solution of 3-methyl-5-trifluoromethyl-1H-indole (400 mg, 2.01 mmol) in DMF (6 mL) at 0° C. in portions. The mixture is stirred at 0° C. for 1 h. HOSA (1.14 g, 10.0 mmol) is added in portions at 0° C. and the mixture is allowed to warm to rt over 2 h. The reaction is quenched with aqueous saturated ammonium chloride, extracted with extracted three times with DCM. The combined organic layer is dried (Na2SO4), filtered and concentrated. The residue is chromatographed through silica gel eluting with 0-40% EtOAc in heptane to afford 3-methyl-5-trifluoromethyl-indol-1-ylamine (223 mg, 52%). MS: 215 (M+H); 1H NMR (300 MHz, CDCl3): δ=7.84 (s, 1H), 7.48 (s, 2H), 7.04 (s, 1H), 4.77 (s, 2H), 2.34 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([O:22]C)=O)[O:17][C:16]2=[O:24])[CH:3]=1.[NH3:25]>CO>[F:1][C:2]1[C:7]2[N:8]([CH:12]([CH3:14])[CH3:13])[C:9](=[O:11])[O:10][C:6]=2[CH:5]=[C:4]([N:15]2[CH2:19][C@H:18]([C:20]([NH2:25])=[O:22])[O:17][C:16]2=[O:24])[CH:3]=1
Reactant: COC(=O)[C@H]1CN(c2cc(F)c3c(c2)oc(=O)n3C(C)C)C(=O)O1
Reactant: N
Solvent: CO
Product: CC(C)n1c(=O)oc2cc(N3C[C@H](C(N)=O)OC3=O)cc(F)c21

Procedure:
Prepared from methyl(5R)-3-(4-fluoro-3-isopropyl-2-oxo-2,3-dihydro-6-benzoxazolyl)-2-oxo-5-oxazolidinecarboxylate (Step 4, 0.250 g, 7.39 mmol) and ammonia in methanol (5 ml) according to the method of EXAMPLE 86, Step 10 (0.14 g, 59%); MS for C14H14FN3O5 m/z 324 (M+H)+; 1H NMR (DMSO-d6, 300 Mhz) δ 7.88 (br s, 1H), 7.63 (br s, 1H), 7.53 (d, 1H), 7.44 (dd, 1H), 5.04 (dd, 1H), 4.55 (m, 1H), 4.26 (t, 1H), 4.02 (dd, 1H), 1.41 (dd, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]([CH3:13])[CH3:12])=[CH:7][CH2:8]2)=[CH:4][CH:3]=1.B.[OH-].[Na+].OO.C(=O)([O-])[O-:20].[K+].[K+]>O1CCCC1.O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5](=[CH:4][CH:3]=1)[C@@H:6]([CH:11]([CH3:13])[CH3:12])[C@H:7]([OH:20])[CH2:8]2
Reactant: O=C([O-])[O-]
Reactant: CC(C)C1=CCc2cc(Cl)ccc21
Agent: B
Agent: OO
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H]1c2ccc(Cl)cc2C[C@H]1O
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
A solution of 6-chloro-3-isopropyl-1H-indene (6.45 g) in anhydrous tetrahydrofuran (15 ml) was added to a solution of borane:tetrahydrofuran complex (84.3 ml of 1.0M solution) at 0° C. under nitrogen atmosphere. The temperature of the reaction solution was kept below 5° C. during the addition. After the addition, the solution was further stirred at 0° C. for 0.5 hr and at room temperature for 2 hr. The solution was cooled to 0° C. and water (100 ml) was added, followed by 6N NaOH solution (100 ml) and hydrogen peroxide (100 ml, 30% aqueous solution). The mixture was stirred for one hour, then potassium carbonate (100 g) was added, ad the whole mixture was extracted with diethyl ether (3×150 ml). The combined ether extracts was washed with water, dried (MgSO4) and condensed to give an oil. This oil was purified by flash chromatography to give trans-5-chloro-1-isopropyl-2-indanol (6.67 g).
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COCCOC[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[C:24]3[C:25](=[O:33])[C:26]4[C:31]([C:18]([C:19]=23)=[N:17]1)=[CH:30][CH:29]=[CH:28][C:27]=4[NH2:32].C(N(CC)CC)C.Cl>C(Cl)Cl>[C:1]([NH:32][C:27]1[CH:28]=[CH:29][CH:30]=[C:31]2[C:26]=1[C:25](=[O:33])[C:24]1[C:19]3[C:18]2=[N:17][NH:16][C:20]=3[CH:21]=[CH:22][CH:23]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCOCn1nc2c3c(cccc31)C(=O)c1c(N)cccc1-2
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2c1C(=O)c1cccc3[nH]nc-2c13)c1ccccc1
Temperature: 80 °C
Reaction time: 16 h

Procedure:
Benzoyl chloride is added to a solution of 2-(methoxyethoxymethyl)-7-aminoanthra[1,9cd]pyrazol-6-(2H)one and triethylamine in methylene chloride at 0° C. The mixture is stirred for 16 hours, quenched with water, and extracted with ethyl acetate (×2). The combined organic layer is washed with sodium bicarbonate solution, and brine, dried and evaporated. The crude reaction mixture is then taken in aqueous 6N hydrochloric acid, and heated at 80° C. for 4 hours. After cooling, the mixture is extracted with ethyl acetate (×2), washed with brine, dried, and evaporated. The residue is chromatographed on silica gel to furnish the desired amide as a yellow solid.
Reaction SMILES: [CH:1]([Si:4]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[O:5][CH2:6][CH2:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O)([CH3:3])[CH3:2].[CH2:22]1[C:27](=[O:28])[CH2:26][C:24](=[O:25])[CH2:23]1.N1CCC[C@H]1C(O)=O.CC1NC(C)=C(C(OCC)=O)CC=1C(OCC)=O>ClCCl>[OH:25][C:24]1[CH2:23][CH2:22][C:27](=[O:28])[C:26]=1[CH2:11][C:10]1[CH:13]=[CH:14][CH:15]=[C:8]([CH2:7][CH2:6][O:5][Si:4]([CH:19]([CH3:21])[CH3:20])([CH:1]([CH3:3])[CH3:2])[CH:16]([CH3:18])[CH3:17])[CH:9]=1
Reactant: CC(C)[Si](OCCc1cccc(C=O)c1)(C(C)C)C(C)C
Reactant: O=C1CCC(=O)C1
Agent: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: ClCCl
Product: CC(C)[Si](OCCc1cccc(CC2=C(O)CCC2=O)c1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 76 %

Procedure:
To a solution of 14 (0.920 g, 3.0 mmol), 1,3-cyclopentadione (0.098 g, 1.0 mmol), and L-proline (0.005 mg) in dichloromethane (5 mL), diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (0.253 g, 1.0 mmol) was added, and the resulting mixture was allowed to stir at rt for 12 h. The reaction mixture was directly purified by silica gel column chromatography using a gradient of ethyl acetate in hexanes as eluent, obtaining the title compound. Yield: 76%.
Reaction SMILES: [NH2:1][C@H:2]1[C@H:8]([OH:9])[C:7]2[CH:10]=[CH:11][CH:12]=[C:13]3[NH:14][C:15](=[O:16])[N:5]([C:6]=23)[CH2:4][CH2:3]1.[CH3:17][N:18]1[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]1.C([BH3-])#N.[Na+].Cl.[OH-].[Na+]>CO>[CH3:17][N:18]1[CH2:23][CH2:22][CH:21]([NH:1][C@H:2]2[C@H:8]([OH:9])[C:7]3[CH:10]=[CH:11][CH:12]=[C:13]4[NH:14][C:15](=[O:16])[N:5]([C:6]=34)[CH2:4][CH2:3]2)[CH2:20][CH2:19]1
Reactant: N[C@@H]1CCn2c(=O)[nH]c3cccc(c32)[C@H]1O
Reactant: CN1CCC(=O)CC1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CN1CCC(N[C@@H]2CCn3c(=O)[nH]c4cccc(c43)[C@H]2O)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 7.6 g of (6RS,trans) 6-amino-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][1]-benzazepin-2(1H)-one, 7.6 ml of N-methyl-4-piperidone, 380 ml of methanol and 7.6 g of sodium cyanoborohydride was stirred at room temperature for 24 hours and after cooling to less than 0° C., 5 ml of concentrated hydrochloric acid were added thereto dropwise. The mixture was stirred at room temperature for 10 minutes and was cooled to 0° C. and adjusted to a pH of 8 by addition of sodium hydroxide. The methanol was evaporated and the residue was taken up in methylene chloride containing 10% methanol. The mixture was filtered and the filtrate was evaporated to dryness. The residue was chromatographed over silica gel and was eluted with an 80-15-5 ethyl acetate-methanol-ammonium hydroxide mixture to obtain 7.3 g of (6RS,trans) 6-(1-methyl-4-piperidinylamino)-7-hydroxy-4,5,6,7-tetrahydro-imidazo[4,5,l-j-k][1]-benzazepin-2(1H)-one. The said base was dissolved in 40 ml of ethanol and 20 ml of ethanolic hydrogen chloride were added thereto. The mixture was vacuum filtered to obtain 7 g of the dihydrochloride melting at ≃260° C.