Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]([CH3:22])[CH2:9][CH2:10][C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([C:20]#[N:21])[CH:18]=2)[NH:13][CH:12]=1>>[NH2:21][CH2:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2[CH2:10][CH2:9][N:8]([CH3:7])[CH3:22]
Reactant: CN(C)CCc1c[nH]c2ccc(C#N)cc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CN(C)CCc1c[nH]c2ccc(CN)cc12
Temperature: 25 °C

Procedure:
Lithium aluminium hydride (40.0 mg, 1.055 mmol, 1.5 equivalents) was placed in an argon purged oven dried flask fitted with a stirbar and condenser. Anhydrous diethylether (5 mL) was added and stirring begun. 3-(2-Dimethylamino-ethyl)-1H-indole-5-carbonitrile (57) (150.0 mg, 0.703 mmol, 1.0 equivalent) was dissolved in a separate dry flask in a mixture of anhydrous diethylether (5 mL) and anhydrous tetrahydrofuran (5 mL) and this solution added dropwise to the solution of lithium aluminium hydride and the resulting mixture heated to reflux. After 30 minutes the reaction was cooled to room temperature and quenched with distilled water (50 μL), aqueous 3N sodium hydroxide solution (75 μL) and distilled water (150 μL) sequentially. The solution was filtered and concentrated. The residue was purified via silica gel column chromatography (10-15-20% 2M NH3 in methanol/90-85-80% dichloromethane) to provide 245-(aminomethyl)-1H-indol-3-yl)-N,N-dimethylethanamine (58) as a pale yellow residue (73 mg, 47.8% yield). 1H NMR (DMSO) δ: 2.21 (s, 6H), 2.53 (m, 2 H), 2.78 (t, 2H), 3.79 (s, 2H), 7.02-7.05 (d, 1H), 7.09 (s, 1H), 7.24 (d, 1H), 7.44 (s, 1H), 10.66 (br s, 1H). MS: 218 (M+1), 201 (M+1-NH3).
Reaction SMILES: [CH:1]([N:4]=[C:5]=[O:6])([CH3:3])[CH3:2].Cl.Cl.[NH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][NH:17][C:18]2[N:19]([CH2:32][CH2:33][CH3:34])[N:20]=[C:21]3[C:30]=2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=[C:22]3[NH2:31])[CH2:11][CH2:10]1.C(N(CC)CC)C.CN(C)C=O>ClCCl>[NH2:31][C:22]1[C:21]2=[N:20][N:19]([CH2:32][CH2:33][CH3:34])[C:18]([NH:17][CH2:16][CH2:15][CH:12]3[CH2:13][CH2:14][N:9]([C:5]([NH:4][CH:1]([CH3:3])[CH3:2])=[O:6])[CH2:10][CH2:11]3)=[C:30]2[C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N:23]=1
Reactant: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCNCC1
Reactant: CC(C)N=C=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCCn1nc2c(N)nc3ccccc3c2c1NCCC1CCN(C(=O)NC(C)C)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10.7 %

Procedure:
Isopropyl isocyanate (0.29 g, 0.33 mL, 3.39 mmol) was added to a stirring suspension of N1-(2-piperidin-4-ylethyl)-2-propyl-2H-pyrazolo[3,4-c]quinoline-1,4-diamine dihydrochloride (1.2 g, 2.83 mmol) and triethylamine (2.9 g, 3.9 mL, 28.3 mmol) in dichloromethane (100 mL). After 10 minutes, N,N-dimethylformamide (15 mL) was added and the resulting suspension was stirred at ambient temperature 16 hours. The dichloromethane was removed under reduced pressure and water (100 mL) was added to the resulting oil. A solid formed which was removed by filtration and discarded. The filtrate was transferred to a separatory funnel and extracted with dichloromethane (50 mL). The aqueous layer was saturated with solid sodium bicarbonate and extracted with dichlioromethane (3×50 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting brown oil was purified by column chromatography using a HORIZON HPFC system (silica cartridge, eluting with 3-15% methanol in dichloromethane). The resulting oil was crystallized from acetonitrile and isolated by filtration to yield 132 mg of 4-{2-[(4-amino-2-propyl-2H-pyrazolo[3,4-c]quinolin-1-yl)amino]ethyl}-N-isopropylpiperidine-1-carboxamide as a white solid, mp 168-170° C. Anal. calcd for C24H35N7O: C, 65.88; H, 8.06; N, 22.41. Found: C, 65.89; H, 8.24; N, 22.67.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:15][C:16]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:17]=1[NH2:18].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:18][C:17]2[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:16]=2[CH3:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(C)c(N)c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: Cc1ccc(C)c(NC2CCN(C(=O)OC(C)(C)C)CC2)c1
Reaction time: 16 h
Yield: 98.2 %

Procedure:
A solution of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (1 g, 0.00502 mole) in dry 1,2-dichloroethane (10 mL) was stirred under an atmosphere of nitrogen for 10 minutes. 2,5-dimethylaniline (0.73 g, 0.00602 mole), acetic acid (0.301 g, 0.005 mole) and sodium triacetoxyborohydride (1.596 g, 0.00753 mole) were then added portionwise and stirring was continued at ambient temperature for 16 hours. The reaction mixture was basified with sodium bicarbonate solution and the product was extracted with dichloromethane. The dichloromethane layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The resulting transparent viscous liquid was purified by column chromatography using neutral aluminium oxide (1% ethyl acetate in hexane) to afford 1.5 g (82%) of 4-(2,5-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester. 1H NMR (CDCl3): δ 7.0 (t, 1H), 6.6 (d, 2H), 4.2 (dd, 2H), 3.5 (m, 1H), 2.9 (t, 2H), 2.3 (t, 3H), 2.15 (s, 3H), 2.05 (s, 3H), 1.5 (s, 9H), 1.3 (t, 2H). A solution of 4-(2,5-dimethyl-phenylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.5 g, 0.00492 mole) in ethyl acetate.HCl (7 mL) was stirred at ambient temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and the residue was washed with ether and dried to afford 1.1 g (80%) of (2,5-dimethyl-phenyl)-piperidin-4-yl-amine dihydrochloride. LCMS: 205.16 (M+1)+, 92.74%, 1H NMR (DMSO-d6): δ 9.4 (d, 1H), 9.0 (d, 1H), 7.2 (d, 2H), 7.1 (s, 1H), 3.7 (m, 1H), 3.6 (s, 1H), 3.4 (d, 2H), 3.2 (bs, 1H), 2.9 (m, 2H), 2.4 (s, 3H), 2.3 (s, 3H), 2.1 (m, 4H).
Reaction SMILES: Br[CH:2]([C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[C:6]#[N:7].[F:18][C:19]1[CH:20]=[C:21]([CH:26]([CH:31]2[CH2:34][NH:33][CH2:32]2)[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:22]=[C:23]([F:25])[CH:24]=1.C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([CH:2]([N:33]2[CH2:34][CH:31]([CH:26]([C:21]3[CH:20]=[C:19]([F:18])[CH:24]=[C:23]([F:25])[CH:22]=3)[C:27]([CH3:30])([CH3:28])[CH3:29])[CH2:32]2)[C:3]2[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=2)[C:6]#[N:7])=[CH:12][CH:13]=1
Reactant: N#Cc1cccc(C(Br)c2ccc(Cl)cc2)c1
Reactant: CC(C)(C)C(c1cc(F)cc(F)c1)C1CNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)C(c1cc(F)cc(F)c1)C1CN(C(c2ccc(Cl)cc2)c2cccc(C#N)c2)C1

Procedure:
A mixture of 263 mg (0.86 mmol) of 3-[bromo(4-chlorophenyl)methyl]benzonitrile, 213 mg (0.574 mmol) of 3-[1-(3,5-difluorophenyl)-2,2-dimethylpropyl]azetidine and 300 uL (1.72 mmol) of N,N-diisopropylethylamine in 6 mL of acetonitrile was heated to reflux for 3 h. Then the solution was concentrated and the residue was dissolved in 5 mL of hexane/ether. 1.5 mL of 1N HCl in ether was added to above solution to make salt. It was filtered and washed with hexane/ether. The residue was neutralized with base and was purified by silica gel chromatography with hexanes/ethyl acetate to afford one racemic diastereomer of the title compound; Mass Spectrum: m/e=465 (M+1 35Cl) and 467 (M+1 37Cl).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].IC.[C:19]([O-])([O-])=O.[K+].[K+].CN(C=O)C>[Cl-].[Na+].O>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH3:19])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1oc2cccc(OC)c2c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 76.1 %

Procedure:
4-Hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (200 mg) was mixed with iodomethane (0.5 mL), K2CO3 (200 mg) and 2 mL of DMF. The mixture was stirred at room temperature overnight. The mixture was mixed with brine and extracted with ethyl acetate, and the combined ethyl acetate layers were washed with brine. Removal of the solvent gave the crude product that was purified by column chromatographt to give 162 mg (76% yield) of 4-methoxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester as amber colored oil.
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)[C:2]#[CH:3].[Cl:12][C:13]1[N:18]=[C:17](Cl)[C:16]([F:20])=[CH:15][N:14]=1>CO.O.CCOC(C)=O>[Cl:12][C:13]1[N:18]=[C:17]([NH:9][C:8]2[CH:10]=[CH:11][C:5]([O:4][CH2:1][C:2]#[CH:3])=[CH:6][CH:7]=2)[C:16]([F:20])=[CH:15][N:14]=1
Reactant: C#CCOc1ccc(N)cc1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: C#CCOc1ccc(Nc2nc(Cl)ncc2F)cc1
Yield: 243.6 %

Procedure:
Crude 4-(prop-2-ynyloxy)aniline (0.750 g, 5.10 mmol) and 2,4-dichloro-5-fluoropyrimidine (1.27 g, 0.760 mmol) were stirred in MeOH/water (4:1, 35 mL) at room temperature for 18 h. The reaction mixture was diluted with EtOAc (200 mL) and washed with 1N HCl (50 mL) and brine (50 mL). The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by column chromatography (silica gel, hexanes ramped to EtOAc:hexanes (1:10)) to provide 2-chloro-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-4-pyrimidineamine as a light brown solid (0.514 g). 1H NMR (CDCl3): δ 8.03 (d, J=2.7 Hz, 1H), 7.53 (d, J=8.7 Hz, 2H), 7.02 (d, J=8.7 Hz, 2H), 6.86 (s, 1H), 4.71 (d, J=2.4 Hz, 2H), 2.55 (t, J=2.4 Hz, 1H); LCMS: purity: 99%; MS (m/e): 279 (MH+).
Reaction SMILES: C1N=CN([C:6]([N:8]2[CH:12]=N[CH:10]=[CH:9]2)=[O:7])C=1.[NH2:13][C@@H:14]([CH2:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1)[CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].CCN(C(C)C)C(C)C.[Cl:41][C:42]1[CH:43]=[C:44]([CH:48]([O:53][CH2:54][CH2:55][NH:56][C:57](=[O:60])[O:58][CH3:59])CCNC)[CH:45]=[CH:46][CH:47]=1>C(Cl)Cl>[CH3:59][O:58][C:57]([NH:56][CH2:55][CH2:54][O:53][CH:48]([C:44]1[CH:45]=[CH:46][CH:47]=[C:42]([Cl:41])[CH:43]=1)[CH2:10][CH2:9][N:8]([CH3:12])[C:6](=[O:7])[NH:13][C@@H:14]([CH2:25][CH:26]1[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1)[CH2:15][N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:22])[CH3:20])=[O:60]
Reactant: CN(C[C@@H](N)CC1CCCCC1)C(=O)OC(C)(C)C
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CNCCC(OCCNC(=O)OC)c1cccc(Cl)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)NCCOC(CCN(C)C(=O)N[C@@H](CC1CCCCC1)CN(C)C(=O)OC(C)(C)C)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 46.9 %

Procedure:
At 0° C., CDI (48.6 mg, 0.3 mmol) was added to a solution of (S)-tert-butyl 2-amino-3-cyclohexylpropyl(methyl)carbamate (81 mg, 0.3 mmol), prepared using procedures described in U.S. Prov. App No. 05/036,230 (PCT App No. 60/616,770), and DIEA (161 mg, 1.25 mmol) in anhydrous CH2Cl2 (8 mL) followed by stirring for 1 h. The solution was added to methyl 2-(1-(3-chlorophenyl)-3-(methylamino)propoxy)ethylcarbamate (75 mg, 0.25 mmol) in anhydrous CH2Cl2 (4 mL). The reaction mixture was allowed to warm to room temperature and stirred overnight. After the reaction was completed, the solvent was removed in vacuo. The product was purified with preparative TLC to afford tert-butyl (S)-2-(3-(3-(2-(methoxycarbonylamino)ethoxy)-3-(3-chlorophenyl)propyl)-3-methylureido)-3-cyclohexylpropyl(methyl)carbamate (70 mg, 50%).
Reaction SMILES: [CH3:1][C@H:2]1[C@:19]([OH:24])([C:20]([CH2:22][OH:23])=[O:21])[C@:18]2([CH3:25])[C@H:4]([C@H:5]3[C@:15](F)([C@@H:16]([OH:26])[CH2:17]2)[C@:14]2([CH3:28])[C:8](=[CH:9][C:10]([CH:12]=[CH:13]2)=[O:11])[CH2:7][CH2:6]3)[CH2:3]1.O[C@@]1([C@]2(C)[C@H]([C@H]3C(=CC2)[C@]2(C)C(=CC(=O)C=C2)CC3)CC1=C)C(=O)C>>[O:26]1[C@@H:16]2[C@:15]31[C@H:5]([C@H:4]1[C@:18]([CH3:25])([CH2:17]2)[C@@:19]([OH:24])([C:20](=[O:21])[CH2:22][OH:23])[C@H:2]([CH3:1])[CH2:3]1)[CH2:6][CH2:7][C:8]1[C@:14]3([CH3:28])[CH:13]=[CH:12][C:10](=[O:11])[CH:9]=1
Reactant: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]2(C)[C@@]1(O)C(=O)CO
Agent: C=C1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)C3=CC[C@]2(C)[C@]1(O)C(C)=O
Product: C[C@@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]34O[C@H]4C[C@]2(C)[C@@]1(O)C(=O)CO

Procedure:
Dexamethasone (9α-fluoro-11β,17α,21-trihydroxy-16α-methylpregna-1,4-diene-3,20-dione) can also be prepared from 17β-hydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione (VIIB, Example 18) by first transforming it to 17α,21-dihydroxy-16-methylenepregna-1,4,9(11)-triene-3,20-dione 21-acetate (IX) as described above and next transforming it to 17α,21-dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dione 21-acetate (XI) by the process of U.S. Pat. No. 3,130,209. 17α,21-Dihydroxy-16α-methylpregna-1,4,9(11)-triene-3,20-dioine 21-acetate (XI) is then epoxidized by means well known to those skilled in the art, see for example U.S. Pat. No. 3,980,778 Examples 2 and 7 to produce 9β,11β-epoxy-17α,21-dihydroxy-16α-methylpregna-1,4-diene-3,20-dione which is transformed to dexamethasone 21-acetate by the process of U.S. Pat. No. 3,007,923 Example 2.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[C:7](=[O:16])[C:5]=2[N:6]=1.[BH4-].[Na+]>C(O)C.ClCCl>[CH3:1][C:2]1[N:3]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[C:4]2[CH:11]=[CH:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH:7]([OH:16])[C:5]=2[N:6]=1
Reactant: COc1ccc(Cn2c(C)nc3c(=O)c4ccccc4ccc32)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc(Cn2c(C)nc3c2C=Cc2ccccc2C3O)cc1

Procedure:
To a stirred solution of the product from step (ii) (1 g) in ethanol (40 ml) and dichloromethane (20 ml) was added sodium borohydride (0.28 g). After 48 h the solvent was evaporated (without heat) under reduced pressure and the residue partitioned between dilute aqueous sodium hydroxide solution and dichloromethane. The organic phase was collected, dried, (MgSO4) and solvent evaporated under reduced pressure to leave a yellow foam.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH:10]1[C:22]2[NH:21][C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]=2[CH:13]=[C:12]([C:23]([OH:25])=O)[CH:11]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:48][CH2:49][C:50]([N:52]1[CH2:57][CH2:56][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:67])[F:66])[CH:60]=2)[CH2:54][CH2:53]1)=[O:51]>CN(C=O)C.O>[O:51]=[C:50]([N:52]1[CH2:53][CH2:54][CH:55]([O:58][C:59]2[CH:64]=[CH:63][CH:62]=[C:61]([C:65]([F:68])([F:66])[F:67])[CH:60]=2)[CH2:56][CH2:57]1)[CH2:49][NH:48][C:23]([C:12]1[CH:11]=[CH:10][C:22]2[NH:21][C:20]3[C:15]([C:14]=2[CH:13]=1)=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:25]
Reactant: NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1
Reactant: O=C(O)c1ccc2[nH]c3ccccc3c2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCC(Oc2cccc(C(F)(F)F)c2)CC1)c1ccc2[nH]c3ccccc3c2c1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 71.1 %

Procedure:
DIPEA (137 mg, 1.0 mmol) was added to a stirred solution of to a stirred solution of 9H-carbazole-3-carboxylic acid (50 mg, 0.23 mmol) in DMF (4 mL) followed by HOBt (35 mg, 0.26 mmol) and EDCI (116 mg, 0.59 mmol). After 2 minutes, 2-amino-1-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethanone hydrochloride (88 mg, 0.26 mmol) (prepared according to Step 1 and 5 of the General Scheme) was added and the resulting mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with cold water and the precipitate was filtered. The solid obtained was purified by recrystallisation from a mixture of 10% ethyl acetate in hexane and 50% MeOH in H2O to afford 81 mg (69.23% Yield) of 9H-carbazole-3-carboxylic acid {2-oxo-2-[4-(3-trifluoromethyl-phenoxy)-piperidin-1-yl]-ethyl}-amide. LC/MS [M+H]+: 496, 91.03%. 1H NMR (300 MHz, DMSO-d6): δ 11.6 (s, 1H), 8.8 (s, 1H), 8.6 (t, 1H), 8.1 (d, 1H), 8.0 (d, 1H), 7.6 (d, 2H), 7.46 (t, 1H), 7.36 (t, 2H), 7.24 (t, 1H), 4.9 (b, 1H), 4.3 (d, 3H), 4.0 (d, 2H), 3.5 (d, 2H), 2.1 (t, 2H), 1.7 (d, 2H).
Reaction SMILES: [CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[NH:7][C:8](=[O:14])[NH:9]2)[CH:2]=[CH2:3].C(N(CC)CC)C.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>CN(C=O)C.O>[CH2:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:15])[N:7]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[C:8](=[O:14])[NH:9]2)[CH:2]=[CH2:3]
Reactant: CCOC(=O)Cl
Reactant: C=CCc1cccc2[nH]c(=O)[nH]c(=O)c12
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: C=CCc1cccc2[nH]c(=O)n(C(=O)OCC)c(=O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of Step 4 intermediate (1.28 g, 6.33 mmol) in dry DMF (6.3 ml) was added triethylamine (4.38 ml, 31.35 mmol) and ethyl chloroformate (3.03 ml, 31.65 mmol). The reaction was stirred at room temperature for 24 h. The reaction was diluted with water, extracted with ethyl acetate, washed with brine and dried over Na2SO4. Purification of the crude product by silica gel column chromatography using 1% ethyl acetate in chloroform afforded 1.3 g of the title compound; 1H NMR (δ ppm, CDCl3, 300 MHz): 9.56 (br.s, 1H); 7.49 (t, J=7.8, 1H); 7.05 (d, J=7.2, 1H); 6.93 (d, J=8.4, 1H); 6.11-5.90 (m, 1H), 5.07-4.98 (m, 2H); 4.53 (q, J=7.2, 2H); 3.96 (d, J=6.3, 2H); 1.46 (t, J=7.2, 3H).
Reaction SMILES: [CH2:1](S(Cl)(=O)=O)C.NC1C2C=CC=CC=2OCCC1.C(N(CC)CC)C.[CH2:26]([S:28]([NH:31][CH:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH2:34][CH2:33]1)(=[O:30])=[O:29])[CH3:27].[H-].[Na+].CI>C1COCC1>[CH2:26]([S:28]([N:31]([CH:32]1[C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][C:37]=2[O:36][CH2:35][CH2:34][CH2:33]1)[CH3:1])(=[O:30])=[O:29])[CH3:27]
Reactant: CCS(=O)(=O)Cl
Reactant: CCS(=O)(=O)NC1CCCOc2ccccc21
Agent: NC1CCCOc2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)N(C)C1CCCOc2ccccc21
Reaction time: 8 h
Yield: 95.2 %

Procedure:
A solution of 10.0 g (62 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one (J. Chem. Soc., Perkin Trans. 1 (1991), 2763) and 4.63 g (68 mmol) of hydroxylamine hydrochloride in 45 ml of ethanol and 45 ml of pyridine was heated under reflux for 5 h. After distilling off the solvents on a rotary evaporator, the residue was treated with water, adjusted to pH 2 with dil hydrochloric acid and stirred for 3 h. After filtering off the precipitated product with suction and drying it, 10.2 g of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime were obtained, m.p. 96-98° C. b) A solution of 2.0 g (11.3 mmol) of 3,4-dihydro-1-benzoxepin-5(2H)-one oxime in 15 ml of 1,2-dimethoxyethane (DME) was added dropwise at 0° C. under argon to a mixture of 4.5 g (23.7 mmol) of titanium tetrachloride and 1.79 g (47.4 mmol) of sodium borohydride in 50 ml of DME over the course of 20 min. After stirring at RT for 2 days, 100 ml of water were added dropwise and the mixture was rendered alkaline using conc. ammonia solution. After filtering off the precipitate with suction, the filtrate was extracted three times with EA. After washing with sodium chloride solution, drying over magnesium sulfate and concentrating, 2.1 g of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine were obtained. c) 0.86 g (6.7 mmol) of ethanesulfonyl chloride was added dropwise with ice cooling to a solution of 1.0 g (6.1 mmol) of 5-amino-2,3,4,5-tetrahydro-1-benzoxepine and 2.5 g (24 mmol) of triethylamine in 20 ml of THF. The mixture was allowed to come to room temperature and was stirred overnight, and the solvent was distilled off in vacuo. After stirring the residue with water, the deposited product was filtered off with suction. 1.1 g of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-berzoxepine were obtained, m.p. 109-111° C. d) A solution of 1.0 g (3.9 mmol) of 5-ethylsulfonylamino-2,3,4,5-tetrahydro-1-benzoxepine in 15 ml of THF were added dropwise under nitrogen to a suspension of 0.16 g (5.4 mmol) of 80 percent sodium hydride in 10 ml of THF. After stirring at RT for 3 h, 1.6 g (11 mmol) of methyl iodide were added dropwise and the mixture was additionally stirred overnight at RT. After distilling off the solvent, the residue was treated with water and extracted with EA. The organic phase was concentrated in vacuo after drying over sodium sulfate. 1.0 g of 5-(N-ethylsulfonyl-N-methylamino)-2,3,4,5-tetrahydro-1-benzoxepine was obtained, m.p. 122-124° C.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[C:4]#[N:5].[CH3:11][NH2:12]>C(O)C>[NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:12][CH3:11])[C:3]=1[C:4]#[N:5]
Reactant: CN
Reactant: N#Cc1c(N)cccc1F
Solvent: CCO
Product: CNc1cccc(N)c1C#N

Procedure:
2-Amino-6-fluorobenzonitrile (200 mg) is heated in a sealed vessel in ethanol saturated with methylamine gas at 140° C. for 4 hrs. The solvent is evaporated, water is added and the product is extracted into methylene chloride. Evaporation of the solvent gives the title compound as an oil, (200 mg) which is converted to the crystalline hydrochloride with i-propanolic HCl-diethyl ether, m.p. 214°-216° C. (dec).
Reaction SMILES: C[C:2]1[N:3]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[O:5][C:6]=1[CH3:7].[CH:15]1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1>[Cu]>[CH3:15][O:14][C:11]1[CH:10]=[CH:9][C:8]([C:4]2[O:5][C:6]([CH3:7])=[CH:2][N:3]=2)=[CH:13][CH:12]=1
Reactant: Cc1nc(-c2ccc(O)cc2)oc1C
Reactant: c1ccc(-c2ccccc2)cc1
Agent: [Cu]
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(-c2ncc(C)o2)cc1
Yield: 35.5 %

Procedure:
2-(4-Methoxyphenyl)-5-methyloxazole was prepared in 35.5% yield by decarboxylation of the compound of part (c) with copper powder in Dowtherm at reflux temperature. The isolated product was distilled, b.p. 136°-140° C.(0.1 mm).
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]([OH:9])=O)[C:4](=[O:10])[N:3]1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[NH2:17][C:18]1[CH:39]=[CH:38][C:21]([O:22][C:23]2[CH:24]=[CH:25][C:26]3[N:27]([CH:29]=[C:30]([NH:32][C:33]([CH:35]4[CH2:37][CH2:36]4)=[O:34])[N:31]=3)[CH:28]=2)=[C:20]([F:40])[CH:19]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH:35]1([C:33]([NH:32][C:30]2[N:31]=[C:26]3[CH:25]=[CH:24][C:23]([O:22][C:21]4[CH:38]=[CH:39][C:18]([NH:17][C:7]([C:5]5[C:4](=[O:10])[N:3]([C:11]6[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=6)[N:2]([CH3:1])[CH:6]=5)=[O:9])=[CH:19][C:20]=4[F:40])=[CH:28][N:27]3[CH:29]=2)=[O:34])[CH2:36][CH2:37]1
Reactant: Nc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3c2)c(F)c1
Reactant: Cn1cc(C(=O)O)c(=O)n1-c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1cc(C(=O)Nc2ccc(Oc3ccc4nc(NC(=O)C5CC5)cn4c3)c(F)c2)c(=O)n1-c1ccccc1
Yield: 14.4 %

Procedure:
Using 1-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxylic acid (220 mg, 0.99 mmol), N-[6-(4-amino-2-fluorophenoxy)imidazo[1,2-a]pyridin-2-yl]cyclopropanecarboxamide (220 mg, 0.66 mmol), HATU (380 mg, 0.99 mmol), diisopropylethylamine (260 mg, 2.0 mmol) and N,N-dimethylformamide (6 mL) as starting materials and in the same manner as in Example 35, the title compound (50 mg, 15%) was obtained as a white solid.