Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:17][CH:16]2[C:13]([C:18]([OH:20])=[O:19])([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:21](N(CC)CC)C.C1(P(N=[N+]=[N-])([C:36]2[CH:41]=[CH:40]C=CC=2)=O)C=CC=CC=1.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C>[C:41]([O:19][C:18]([C:13]12[CH2:14][CH2:15][CH:16]1[CH2:17][N:11]([C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10])[CH2:12]2)=[O:20])([CH3:40])([CH3:36])[CH3:21]
Reactant: CCN(CC)CC
Reactant: O=C(OCc1ccccc1)N1CC2CCC2(C(=O)O)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)C12CCC1CN(C(=O)OCc1ccccc1)C2
Temperature: 70 °C
Reaction time: 9 h

Procedure:
To a solution of 3-benzyloxycarbonyl-3-azabicyclo[3.2.0]heptane-1-carboxylic acid (2.90mmol) in tertiary butanol (15 ml) were added 0.53 ml (3.8 mmol) of triethylamine and 0.819 ml (3.8 mmol) of diphenylphosphorylazide, followed by 9 hours of stirring at 70° C. After cooling to room temperature, the reaction solution was poured into saturated sodium bicarbonate and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over anhydrous sodium sulfate. After evaporation of the solvent, the resulting residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=4:1) to give 817.8 mg (2.27 mmol, 78.3% for 2 steps from Reference Example B-2) of the title compound.
Reaction SMILES: IC.[NH2:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[C:14](=[O:16])[CH3:15].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][O:10][C:8]1[C:7]([O:12][CH3:13])=[CH:6][C:5]([C:14](=[O:16])[CH3:15])=[C:4]([NH:3][CH3:17])[CH:9]=1
Reactant: COc1cc(N)c(C(C)=O)cc1OC
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNc1cc(OC)c(OC)cc1C(C)=O
Temperature: 25 °C
Reaction time: 40 h

Procedure:
Iodomethane (14 ml) was added to a stirred mixture of 2'-amino-4',5'-dimethoxyacetophenone (40 g), potassium carbonate (31.2 g) and dry dimethylformamide (200 ml) and the mixture stirred at ambient temperature for 40 hours. The solvent was evaporated under reduced pressure and the residue triturated with dichloromethane (250 ml). The mixture was filtered and the filter bed washed with dichloromethane (50 ml). The combined filtrate and washing were evaporated and the residue purified by flash chromatography on a silica gel column eluted with dichloromethane:industrial methylated spirit (99:1then 49:1) followed by trituration with diethyl ether (400 ml then 100 ml) to give the novel compound 4',5'-dimethoxy-2'-(methylamino)acetophenone, m.p. 121°-123.5°.
Reaction SMILES: [NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:17][CH2:18][C@H:19]1[O:23][C@@H:22](N2C=CC(=O)NC2=O)[C@H:21]([OH:32])[C@@H:20]1[OH:33]>>[NH:1]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[N:14]([C@@H:22]3[O:23][C@H:19]([CH2:18][Cl:17])[C@@H:20]([OH:33])[C@H:21]3[OH:32])[CH:15]=[N:16][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(Nc2ccnc3[nH]cnc23)cc1
Reactant: O=c1ccn([C@@H]2O[C@H](CCl)[C@@H](O)[C@H]2O)c(=O)[nH]1
Product: O[C@@H]1[C@H](O)[C@@H](CCl)O[C@H]1n1cnc2c(Nc3ccccc3)ccnc21
Temperature: 35 °C

Procedure:
7-Anilino-3H-imidazo[4,5-b]pyridine (0.8 g, 3.7 mmol) and 5'-chloro-5'-deoxyuridine (15 g, 5.7 mmol) were combined in 10 mL of 10 mM KxHxPO4, pH 7.4. Uridine phosphorylase (315 units) and purine nucleoside phosphorylase (1800 units) previously purified from E. coli, were added and the reaction stirred at 35° C. After 4 days an additional 84 units of uridine phosphorylase and 100 mL phosphate buffer were added. Twenty-one days later the particulates were collected by filtration and recrystallized from boiling ethanol yielding 0.982 g of 72% of 7-anilino-3-(5-chloro-5-deoxy-β-D-ribofuranosyl)-3H-imidazo[4,5-b]pyridine, m.p. 195° C. (dec.):
Reaction SMILES: C([CH2:4][C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])[C:8]([S:18][CH2:19][CH2:20][CH3:21])=[N:7][CH:6]=1)(O)=O.[H-].C([Al+]CC(C)C)C(C)C.[O:32]1CCCC1>C1(C)C=CC=CC=1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:9]1[C:5]([CH2:4][OH:32])=[CH:6][N:7]=[C:8]1[S:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCSc1ncc(CC(=O)O)n1Cc1ccccc1Cl
Reactant: C1CCOC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Product: CCCSc1ncc(CO)n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
A solution of 5-carboxymethyl-1-1-(2-chloro-phenyl)methyl-2-propylthio-1H-imidazole (3.74 g, 11.5 mmol) in dry tetrahydrofuran (50 mL) was cooled to -78° C. under argon, and a solution of diisobutyl aluminum hydride in toluene (30 mL of 1 M) was added dropwise. The mixture was stirred at -78° C. for 1.5 hours, then allowed to slowly warm to room temperature. The reaction was quenched by pouring onto iced dilute acetic acid, the product was extracted into methylene chloride and the organic extracts were washed with water, 5% sodium carbonate solution and brine. The dried, concentrated product was a light tan solid (3.32 g). Crystallization from ethanol/water gave 1-(2-chlorophenyl)methyl-5-hydroxymethyl-2-propylthio-1H-imidazole; m.p. 98-101° C.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].N1C=CC=CC=1.[Cl:14][C:15]1C=C(O)[CH:18]=[CH:19][C:20]=1[CH3:21]>CCOCC>[C:5]([O:4][C:1]1[CH:18]=[CH:19][C:20]([CH3:21])=[C:15]([Cl:14])[CH:2]=1)(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1ccc(O)cc1Cl
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(=O)Oc1ccc(C)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
Acetic anhydride (430 mg) and pyridine (416 mg) were added to a solution of 3-chloro-4-methylphenol (500 mg) in ether (5.0 ml), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was washed once with 1N hydrochloric acid and twice with saturated brine, dried over magnesium sulfate, and concentrated to dryness under reduced pressure to give 4-acetoxy-2-chlorotoluene as a pale-yellow oil (645 mg).
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:17][CH2:16][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][NH:25][CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:14][CH2:13]1.C([O-])([O-])=O.[K+].[K+].BrCCF>CC(C)=O>[F:8][C:9]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:10]=1[O:11][CH:12]1[CH2:13][CH2:14][N:15]([C:18]2[N:23]=[C:22]3[CH2:24][N:25]([CH2:2][CH2:4][F:5])[CH2:26][CH2:27][C:21]3=[N:20][C:19]=2[NH:28][CH:29]([CH3:31])[CH3:30])[CH2:16][CH2:17]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CNCC2
Agent: FCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)=O
Product: CC(C)Nc1nc2c(nc1N1CCC(Oc3ccc(F)cc3F)CC1)CN(CCF)CC2
Temperature: 23 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-(4-(2,4-difluorophenoxyl)piperidin-1-yl)-N-isopropyl-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-2-amine TFA salt (50 mg, 0.080 mmol) and K2CO3 (44.4 mg, 0.322 mmol) in acetone (2.0 mL) was added 1-bromo-2-fluoroethane (5.4 μL, 0.072 mmol) at 23° C. The reaction mixture was stirred at 23° C. for 1 h and then at 50° C. for 3 days. The reaction mixture was cooled to 23° C., an additional portion of 1-bromo-2-fluoroethane (2.7 μL, 0.036 mmol) was added, and the reaction mixture was heated for an additional 1.5 hr at 50° C., cooled to 23° C., and concentrated via rotary evaporation. The resulting crude material was reconstituted in DMSO, filtered, rinsed with DMSO, and purified by HPLC Method B using a 30% to 70% ACN gradient to give the title compound as a TFA salt (10.7 mg, 23.6%) as a yellow film. 1H NMR (500 MHz, DMSO-d6, mixture of rotamers) δ ppm 1.19 (d, J=6.8 Hz, 6H), 1.83-1.92 (m, 2H), 2.02-2.13 (m, 2H), 2.79-2.96 (m, 3H), 2.96-3.11 (m, 0.9H), 3.24-3.36 (m, 2H), 3.38-3.55 (m, 1.1H) 3.65 (br s, 1.1H), 3.71 (m, 0.9H), 3.73-3.84 (m, 1H), 4.12-4.19 (m, 1H), 4.28 (br s, 0.9H), 4.30 (br s, 1.1H), 4.54 (ddd, J=11.7, 7.8, 3.9 Hz, 1H), 4.87 (t, J=4.4 Hz, 0.9H), 4.88-4.95 (m, 1H), 4.97 (t, J=4.4 Hz, 1.1H), 5.86 (d, J=8.3 Hz, 1H), 6.97-7.08 (m, 1H), 7.25-7.37 (m, 2H); ESI-MS m/z [M+H]+ 450.5.
Reaction SMILES: [S:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[NH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:22]([CH3:25])([CH3:24])[CH3:23])=[C:19]([OH:21])[CH:20]=1.N1C=CC=CC=1>ClCCl>[C:22]([C:18]1[CH:17]=[CH:16][C:15]([NH:14][C:11]([CH:2]2[CH2:3][NH:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[S:1]2)=[O:13])=[CH:20][C:19]=1[OH:21])([CH3:25])([CH3:23])[CH3:24]
Reactant: O=C(O)C1CNc2ccccc2S1
Reactant: CC(C)(C)c1ccc(N)cc1O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)c1ccc(NC(=O)C2CNc3ccccc3S2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.3 %

Procedure:
A solution of 3,4-dihydro-2H-1,4-benzothiazine-2-carboxylic acid (80 mg, 0.41 mmol) and 5-amino-2-tert-butyl-phenol (67 mg, 0.41 mmol) in dichloromethane (3 mL) was treated with propane phosphonic acid anhydride (610 μl, of 50% w/w in ethyl acetate, 1.02 mmol) and pyridine (99 μL, 1.2 mmol) and stirred for 30 min at room temperature. The reaction was washed with water, dried over Na2SO4, and concentrated in vacuo. HPLC purification (20-99% CH3CN/0.05% TFA) provided N-(4-tert-butyl-3-hydroxy-phenyl)-3,4-dihydro-2H-1,4-benzothiazine-2-carboxamide (51 mg, 36% yield). LC/MS m/z 343.2 [M+H]+. 1H NMR (400.0 MHz, DMSO-d6) δ 10.07 (s, 1H), 9.38 (s, 1H), 7.20 (d, J=2.0 Hz, 1H), 7.03 (d, J=8.4 Hz, 1H), 6.93 (dd, J=1.1, 7.7 Hz, 1H), 6.88-6.83 (m, 2H), 6.58 (d, J=7.5 Hz, 1H), 6.51-6.47 (t, J=7.5, 1H), 3.92 (dd, J=3.0, 8.0 Hz, 1H), 3.72 (dd, J=3.0, 12.3 Hz, 1H), 3.53 (dd, J=8.1, 12.3 Hz, 1H), 1.31 (s, 9H).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH:12]=O)=[N:2]1.[ClH:18].[CH3:19][NH:20][CH3:21].[BH4-].[Na+]>CO.C(OCC)(=O)C>[ClH:18].[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([C:10]2[CH:17]=[CH:16][CH:15]=[CH:14][C:11]=2[CH2:12][N:20]([CH3:21])[CH3:19])=[N:2]1
Reactant: CNC
Reactant: O=Cc1ccccc1-c1noc2ccccc12
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN(C)Cc1ccccc1-c1noc2ccccc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.9 %

Procedure:
In one portion, a total of 2.0 g of 2-(1,2-benzisoxazol-3-yl)-benzaldehyde was added to a solution of 8.0 g of dimethylamine hydrochloride in 70 ml of methanol. The reaction mixture was stirred at room temperature for 16 h, after which 2.0 g of sodium borohydride were added. After stirring at room temperature for another 24 h, the solids were filtered off, and the residue was washed with dichloromethane. The combined filtrate was dried over magnesium sulphate and evaporated to dryness under reduced pressure. The resulting solid was purified by chromatography on silica gel, eluting with ethyl acetate, affording 0.89 g. This solid was dissolved in ethyl acetate, and triturated with a solution of hydrogen chloride in methanol. This solution was evaporated to dryness under reduced pressure and the residue was crystallised from ethanol/diethyl ether/hexane, yielding 0.54 g of pure 2-(1,2-benzisoxazol-3-yl)-N, N-dimethyl-benzenemethanamine hydrochloride, melting at 190° C.
Reaction SMILES: C[Si](C)(C)CC[S:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].Cl>CN(C=O)C.C1COCC1.O>[SH:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:17]3[CH:21]=[CH:20][O:19][CH:18]=3)=[CH:11][C:12](=[O:16])[O:13]2)=[CH:8][CH:7]=1
Reactant: C[Si](C)(C)CCSc1ccc2c(-c3ccoc3)cc(=O)oc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=c1cc(-c2ccoc2)c2ccc(S)cc2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
The coumarin from Step 1 (963 mg) was dissolved in DMF (25 mL) and to this solution there was added n-Bu4NF (1M) in THF (8.4 mL). The mixture was stirred at r.t. for 2 h, poured onto 1N aqueous HCl (50 mL), diluted with H2O (50mL) and filtered to afford the title compound (620 mg) as a tan. solid. m.p.: 167°-170° C.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[Cl:6][C:7]1[CH:25]=[CH:24][C:10]([CH:11]([N:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:9][CH:8]=1>C(O)C>[OH2:5].[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:25][CH:24]=2)[CH2:23][CH2:22]1.[Cl:2][CH2:1][CH:3]([OH:5])[CH2:4][N:21]1[CH2:20][CH2:19][N:18]([CH:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:10]2[CH:9]=[CH:8][C:7]([Cl:6])=[CH:25][CH:24]=2)[CH2:23][CH2:22]1
Reactant: ClCC1CO1
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Solvent: CCO
Product: O
Product: OC(CCl)CN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Reaction time: 20 h
Yield: 26.3 %

Procedure:
To a mixture of epichlorohydrin (3.92 mL, 50 mmol) in ethanol (25 mL) and NAHCO3 (4.2 g, 50 mmol) 4-chlorobenzhydryl piperazine (14.34 g, 50 mmol) in EtOH (150 mL) was added dropwise over 45 min at 0° C. under nitrogen. After 20 h, the EtOH was removed in vacuo and the residue was eluted through silica gel using 50% MeOH:CH2Cl2 to give the pure product (3.40 g, 18.3%) as a white solid, mp 72°-74° C. DCI/MS (M+1) 379; 400 MHz 1H NMR (CDCl3) δ: 7.5-7.35 (m, 9H), 4.2 (s, 1H), 3.65 (m, 2H), 2.9 (m, 2H), 2.7-2.6 (m, 8H).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][C@@H:12]1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N([CH:35]([CH3:37])C)CC)(C)C.ClCCl.C(=O)([O-])[O-:42].[K+].[K+]>O1CCOCC1>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([N:21]([C:35](=[O:42])[CH3:37])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][C@@H:12]1[CH3:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: CCN(C(C)C)C(C)C
Reactant: C[C@H]1C[C@@H](Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)N(c1ccccc1)[C@@H]1C[C@H](C)N(C(=O)OCc2ccccc2)c2ccccc21
Yield: 64 %

Procedure:
To a solution of cis-2-methyl-4-phenylamino-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (5.3 g), diisopropyl ethyl amine (2.73 g) in dioxane (31 ml), anhydride acetic (7.26 g) was added under stirring. The mixture was heated under reflux over night. After cooling, dichloromethane and an aqueous solution of potassium carbonate were added. The organic layer was separated, and then dried over sodium sulfate. Organic solvent was removed under reduce pressure to give the crude compound (18 g). The desired compound (3.8 g, 64% yield) was obtained after purification by flash chromatography on silica gel with cyclohexane/ethyl acetate (80/20) as eluent and then cyclohexane/ethyl acetate (50/50).
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[N:19]1([C:25]2[C:26]([C:31](O)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.N1C2C(=NC=CC=2)N(O)N=1.C(Cl)CCl.C(N(CC)CC)C>C(Cl)Cl>[N:19]1([C:25]2[C:26]([C:31]([NH:16][C@H:12]3[CH2:13][CH2:14][CH2:15][C@@H:11]3[NH:10][C:7]3[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=3)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=2)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ncccc1N1CCCCC1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ncccc1N1CCCCC1

Procedure:
A solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 75 mg, 0.27 mmol), 3-(piperidin-1-yl)pyridine-2-carboxylic acid (CAS number 898289-01-5; 66 mg, 0.32 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (54 mg, 0.40 mmol), EDC (76 mg, 0.40 mmol) and triethylamine (0.111 ml, 0.80 mmol) in DCM (1 ml) was stirred at room temperature overnight. The reaction was partitioned between DCM and a saturated solution of sodium bicarbonate, filtered through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 40-100% ethyl acetate/petrol) and then further purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([CH:10]([CH3:12])[CH3:11])=[C:5]([C:7]([O-:9])=[O:8])[N:6]=1.[F:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][N:21]=[C:22]=[O:23])[CH:15]=1.[CH2:24]1COCC1>>[F:13][C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][NH:21][C:22](=[O:23])[NH:1][C:2]1[S:3][C:4]([CH:10]([CH3:12])[CH3:11])=[C:5]([C:7]([O:9][CH3:24])=[O:8])[N:6]=1
Reactant: CC(C)c1sc(N)nc1C(=O)[O-]
Reactant: O=C=NCc1cccc(F)c1
Reactant: C1CCOC1
Product: COC(=O)c1nc(NC(=O)NCc2cccc(F)c2)sc1C(C)C

Procedure:
A THF (5 mL) solution of methy; 2-amino-5-isopropylthiazole-4-carboxylate (commercially available, 200 mg, 1 mmol) and 1-fluoro-3-(isocyanatomethyl)benzene (140 μL, 1.1 mmol) was microwave irradiated at 160 C for 35 minutes. Usual work-up concluded with recrystallization from MeOH afforded methyl 2-(3-(3-fluorobenzyl)ureido)-5-isopropylthiazole-4-carboxylate. 1H NMR (400 MHz, DMSO-d6): δ7.35 (m, 1H), 7.08 (m, 3H), 4.34 (d, 2H), 3.94 (m, 1H), 3.76 (s, 3H), 1.24 (d, 6H). MS (ES+): M/Z 452 (M+H)+.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[N:5]=[C:4]([CH3:8])[C:3]=1[O:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[Cl:17].[F:18][C:19]1[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:11]1[CH:12]=[C:13]([F:16])[CH:14]=[CH:15][C:10]=1[O:9][C:3]1[C:4]([CH3:8])=[N:5][N:6]([CH3:7])[C:2]=1[C:22]1[CH:21]=[CH:20][C:19]([F:18])=[CH:24][C:23]=1[F:25]
Reactant: Cc1nn(C)c(Br)c1Oc1ccc(F)cc1Cl
Reactant: OB(O)c1ccc(F)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: Cc1nn(C)c(-c2ccc(F)cc2F)c1Oc1ccc(F)cc1Cl
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-4-(2-chloro-4-fluorophenoxy)-1,3-dimethyl-1H-pyrazole (i.e. the product of Step C) (250 mg, 0.78 mmol) in 1,2-dimethoxyethane/water (5 mL, 2:1) was sparged with a subsurface stream of argon for 30 minutes, and then 2,4-difluorophenylboronic acid (371 mg, 2.34 mmol), potassium carbonate (1.08 g, 7.82 mmol) and tetrakis(triphenylphosphine)palladium (90 mg, 0.078 mmol) were added. The reaction mixture was heated to 80° C. for 15 h, and then cooled and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting material was purified by silica gel column chromatography (5 to 30% gradient of ethyl acetate in hexanes as eluant) to provide the title compound, a compound of the present invention, as a pale yellow solid (150 mg) melting at 70-72° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=C(C#N)[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]([CH3:15])[CH3:14].[OH-:16].[Na+].[CH3:18][CH2:19][OH:20]>O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:18]([C:19]([OH:16])=[O:20])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:13]([CH3:15])[CH3:14]
Reactant: CCO
Reactant: [OH-]
Reactant: CC(C)c1c[nH]c2c(C#N)cc(Br)cc12
Agent: [Na+]
Solvent: O
Product: CC(C)c1c[nH]c2c(C(=O)O)cc(Br)cc12
Temperature: 100 °C
Reaction time: 24 h
Yield: 129 %

Procedure:
To a stirred solution of 5-bromo-3-(1-methylethyl)-1H-indole-7-carbonitrile (1.66 g, 6.31 mmol) in EtOH (45 mL) and water (15 mL) was added 6 N NaOH (10 mL, 60.0 mmol). The reaction was heated at reflux (100° C. oil bath) under N2 for 72 h. LCMS showed that the reaction was complete after 24 h. The reaction was cooled to RT, evaporated to near dryness, diluted with water (˜100 mL), and acidified with 6 N HCl (10 mL). The suspension was triturated, filtered, washed with water and dried under vacuum to give the product 5-bromo-3-(1-methylethyl)-1H-indole-7-carboxylic acid (2.29 g, 8.12 mmol, 129% yield) as an off-white solid. MS (ES)+ m/e 282.4 [M+H]+.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[NH:9][C:8]=2[CH:18]=1.CS(O[C@H:24]1[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([N:37]3[CH2:41][CH2:40][CH2:39][CH2:38]3)[CH:32]=2)[CH2:25]1)(=O)=O.[Cl-].[Na+]>CCCCCC.CS(C)=O.C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[CH2:13][O:12][C:11]3[CH:14]=[CH:15][CH:16]=[CH:17][C:10]=3[N:9]([C@@H:28]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([N:37]5[CH2:41][CH2:40][CH2:39][CH2:38]5)[CH:32]=4)[CH2:27]3)[C:8]=2[CH:18]=1
Reactant: CS(=O)(=O)O[C@H]1CCN(CCc2cccc(N3CCCC3)c2)C1
Reactant: Fc1ccc2c(c1)Nc1ccccc1OC2
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Fc1ccc2c(c1)N([C@@H]1CCN(CCc3cccc(N4CCCC4)c3)C1)c1ccccc1OC2
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
60% sodium hydride (88 mg, 2.2 mmol) was washed with hexane in argon gas stream and then suspended in dimethyl sulfoxide (10 ml). The obtained suspension was stirred at room temperature for 30 minutes. 3-Fluoro-5,11-dihydrodibenzo[b,e][1,4]oxazepine (0.43 g, 2.0 mmol) was added to the suspension, and they were stirred at room temperature for 30 minutes. After stirring at 50° C. for 30 minutes, a solution of (S)-3-methanesulfonyloxy-1-(3-pyrrolidinophenethyl)pyrrolidine (0.34 g, 1.0 mmol) in dimethyl sulfoxide (4 ml) was added dropwise to the obtained solution, and they were stirred at 70° C. for 2 hours. The reaction mixture was distributed into saturated aqueous sodium chloride solution and ethyl acetate. The organic layer was dried and the solvent was evaporated under reduced pressure. The residue was subjected to the silica gel column chromatography. After the elution with hexane and ethyl acetate (1:1) as the eluent, suitable fractions were collected and the solvent was evaporated under reduced pressure to obtain (R)-3-fluoro-5,11-dihydro-5-[1-(3-pyrrolidinophenethyl)pyrrolidin-3-yl]dibenzo[b,e]-[1,4]oxazepine in the form of a light yellow oily substance (0.19 g, 42%).
Reaction SMILES: NC1C=CC(C2C=C(C)C=CC=2S(C2C=CC(C)=CC=2C2C=CC(N)=C([N+]([O-])=O)C=2)=O)=CC=1[N+]([O-])=O.[Cl:37][C:38]1[CH:43]=[CH:42][C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])=[CH:40][C:39]=1[N+:58]([O-])=O>>[NH2:58][C:39]1[CH:40]=[C:41]([S:44]([C:46]2[CH:51]=[CH:50][C:49]([C:52]3[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=3)=[CH:48][CH:47]=2)=[O:45])[CH:42]=[CH:43][C:38]=1[Cl:37]
Reactant: O=[N+]([O-])c1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Agent: Cc1ccc(S(=O)c2ccc(C)cc2-c2ccc(N)c([N+](=O)[O-])c2)c(-c2ccc(N)c([N+](=O)[O-])c2)c1
Product: Nc1cc(S(=O)c2ccc(-c3ccccc3)cc2)ccc1Cl
Yield: 85 %

Procedure:
Following the procedure described in Example 40 but using as a starting material instead of (4-amino-3-nitrophenyl)-4-methylphenyl sulfoxide a corresponding amount of 4-(4-chloro-3-nitrophenylsulfinyl)-biphenyl, the title compound is obtained.